Prenatal tobacco exposure: developmental outcomes in the neonatal period.
Smoking during pregnancy is a persistent public health problem that has been linked to later adverse outcomes. The neonatal period--the first month of life--carries substantial developmental change in regulatory skills and is the period when tobacco metabolites are cleared physiologically. Studies to date mostly have used cross-sectional designs that limit characterizing potential impacts of prenatal tobacco exposure on the development of key self-regulatory processes and cannot disentangle short-term withdrawal effects from residual exposure-related impacts. In this study, pregnant participants (N = 304) were recruited prospectively during pregnancy, and smoking was measured at multiple time points, with both self-report and biochemical measures. Neonatal attention, irritable reactivity, and stress dysregulation were examined longitudinally at three time points during the first month of life, and physical growth indices were measured at birth. Tobacco-exposed infants showed significantly poorer attention skills after birth, and the magnitude of the difference between exposed and nonexposed groups attenuated across the neonatal period. In contrast, exposure-related differences in irritable reactivity largely were not evident across the 1st month of life, differing marginally at 4 weeks of age only. Third-trimester smoking was associated with pervasive, deleterious, dose–response impacts on physical growth measured at birth, whereas nearly all smoking indicators throughout pregnancy predicted level and growth rates of early attention. The observed neonatal pattern is consistent with the neurobiology of tobacco on the developing nervous system and fits with developmental vulnerabilities observed later in life.


[Comparative study of end-to-end cervical esophagogastric anastomosis with or without invagination after esophagectomy for cancer].
To assess the incidence of fistula and stenosis of cervical esophagogastric anastomosis with invagination of the esophageal stump into the gastric tube in esophagectomy for esophagus cancer. Two groups of patients with thoracic and abdominal esophagus cancer undergoing esophagectomy and esophagogastroplasty were studied. Group I comprised 29 patients who underwent cervical esophagogastric anastomosis with invagination of the proximal esophageal stump segment within the stomach, in the period of 1998 to 2007 while Group II was composed of 36 patients submitted to end-to-end cervical esophago-gastric anastomosis without invagination during the period of 1989 to 1997. In Group I, esophagogastric anastomosis by invagination presented fistula with mild clinical implications in 3 (10.3%) patients, whereas in Group II, fistulas with heavy saliva leaks were observed in 11 (30.5%) patients. The frequency of fistulas was significantly lower in Group I patients (p=0.04) than in Group II. In Group I, fibrotic stenosis of anastomoses occurred in 7 (24.1%) subjects, and 10 patients (27.7%) in Group II evolved with stenosis, while no significant difference (p=0.72) was found between the two groups. In esophagectomy for esophagus cancer, cervical esophagogastric anastomosis with invagination presented a lower rate of esophagogastric fistula versus anastomosis without invagination. Stenosis rates in esophagogastric anastomosis proved similar in both approach with or without invagination.


Additive genetic variance, heritability, and inbreeding depression in male extra-pair reproductive success.
The hypothesis that female extra-pair reproduction in socially monogamous animals reflects indirect genetic benefits requires that there be additive and/or nonadditive genetic variance in fitness. However, the specific hypotheses that male extra-pair reproductive success (EPRS) shows additive genetic variance (V(A)), heritability (h2), or inbreeding depression, and hence that females could acquire indirect genetic benefits through increased EPRS of sons, have not been explicitly tested. We used comprehensive genetic pedigree data from song sparrows (Melospiza melodia) to estimate V(A), h2, and inbreeding depression in the number of extra-pair offspring a male sired per year and the probability that a male would sire any extra-pair offspring per year. Inbreeding depression was substantial: more inbred males sired fewer extra-pair offspring and were less likely to sire any extra-pair offspring. In contrast, estimates of V(A) and h2 were close to 0, although 95% credible intervals were relatively wide. These data suggest that females could accrue indirect genetic benefits, in terms of increased EPRS of outbred sons, by mating with unrelated social or extra-pair mates. In contrast, any indirect benefit of extra-pair reproduction in terms of producing sons with high additive genetic value for EPRS is most likely to be small.


S, N-Co-Doped Graphene-Nickel Cobalt Sulfide Aerogel: Improved Energy Storage and Electrocatalytic Performance.
Metal sulfides are commonly used in energy storage and electrocatalysts due to their redox centers and active sites. Most literature reports show that their performance decreases significantly caused by oxidation in alkaline electrolyte during electrochemical testing. Herein, S and N co-doped graphene-based nickel cobalt sulfide aerogels are synthesized for use as rechargeable alkaline battery electrodes and oxygen reduction reaction (ORR) catalysts. Notably, this system shows improved cyclability due to the stabilization effect of the S and N co-doped graphene aerogel (SNGA). This reduces the rate of oxidation and the decay of electronic conductivity of the metal sulfides materials in alkaline electrolyte, i.e., the capacity decrease of CoNi2S4/SNGA is 4.2% for 10 000 cycles in a three-electrode test; the current retention of 88.6% for Co-S/SNGA after 12 000 s current-time chronoamperometric response in the ORR test is higher than corresponding Co-S nanoparticles and Co-S/non-doped graphene aerogels. Importantly, the results here confirm that the Ni-Co-S ternary materials behave as an electrode for rechargeable alkaline batteries rather than supercapacitors electrodes in three-electrode test as commonly described and accepted in the literature. Furthermore, formulas to evaluate the performance of hybrid battery devices are specified.


Early and Partial Reduction in CD4+Foxp3+ Regulatory T Cells during Colitis-Associated Colon Cancer Induces CD4+ and CD8+ T Cell Activation Inhibiting Tumorigenesis.
Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CRC is associated with inflammatory responses in which intestinal pathology is caused by different cell populations including a T cell dysregulation that concludes in an imbalance between activated T (Tact) and regulatory T (Treg) cells. Treg cells are CD4+Foxp3+ cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis. A tumor-promoting function for Treg cells has been suggested in CRC, but the kinetics of Treg cells during CRC development are poorly known. Therefore, using a mouse model of colitis-associated colon cancer (CAC) induced by azoxymethane and dextran sodium sulfate, we observed the dynamic and differential kinetics of Treg cells in blood, spleen and mesenteric lymph nodes (MLNs) as CAC progresses, highlighting a significant reduction in Treg cells in blood and spleen during early CAC development, whereas increasing percentages of Treg cells were detected in late stages in MLNs. Interestingly, when Treg cells were decreased, Tact cells were increased and vice versa. Treg cells from late stages of CAC displayed an activated phenotype by expressing PD1, CD127 and Tim-3, suggesting an increased suppressive capacity. Suppression assays showed that T-CD4+ and T-CD8+ cells were suppressed more efficiently by MLN Treg cells from CAC animals. Finally, an antibody-mediated reduction in Treg cells during early CAC development resulted in a better prognostic value, because animals showed a reduction in tumor progression associated with an increased percentage of activated CD4+CD25+Foxp3- and CD8+CD25+ T cells in MLNs, suggesting that Treg cells suppress T cell activation at early steps during CAC development.


Dual blockade of the renin-angiotensin-aldosterone system in cardiac and renal disease.
Renin-angiotensin-aldosterone system (RAAS) blockade improves outcome in cardiovascular disease (CVD) and chronic kidney disease (CKD), but the residual risk during monotherapy RAAS blockade remains very high. This review discusses the place of dual RAAS blockade in improving these outcomes. The combination of angiotensin-converting enzyme inhibitor (ACEI) with angiotensin II type 1 receptor blocker (ARB) generally had a better antihypertensive and antiproteinuric effect than monotherapy in many studies, but is also associated with more adverse effects. Unfortunately, the effect on hard renal and cardiovascular endpoints is not unequivocal. The combination of ACEI (or ARB) with aldosterone blockade has long-term benefits in heart failure, and an added effect on proteinuria in CKD, but data on hard renal endpoints are lacking. Dual blockade including renin inhibition has added antiproteinuric effects, but studies to gather long-term data are still under way. Available strategies to optimize the effect of monotherapy RAAS blockade include dose titration and correction of volume excess. Whether dual blockade has better efficacy and/or fewer adverse effects than optimized monotherapy has not been investigated. Several options are available to increase the effect of monotherapy RAAS blockade. For proteinuric CKD, these can be combined in a stepwise approach aimed at maximal proteinuria reduction; this includes dual blockade for patients with persistent proteinuria during optimized monotherapy RAAS blockade. Long-term randomized studies, however, are needed to support the benefits of dual blockade for long-term renal and cardiovascular outcome in CKD.


Prospective study of physical activity and the risk of symptomatic diverticular disease in men.
The relationship between physical activity and risk of symptomatic diverticular disease has not been investigated directly. This association was examined in a prospective cohort of 47,678 American men, 40 to 75 years of age, and free of diagnosed diverticular disease, colon or rectal polyp, ulcerative colitis, and cancer before 1988. During four years of follow up, 382 newly diagnosed cases of symptomatic diverticular disease were documented. After adjustment for age, energy adjusted dietary fibre, and energy adjusted total fat, overall physical activity was inversely associated with the risk of symptomatic diverticular disease (for highest versus lowest extremes, relative risk (RR) = 0.63 (95% confidence interval (CI) 0.45, 0.88). Most of the inverse association was attributable to vigorous activity, for extreme categories RR = 0.60 (95% CI 0.41, 0.87). For activity that was not vigorous the RR was 0.93 (95% CI 0.67, 1.69). Several specific activities were inversely associated with the risk of diverticular disease, but jogging and running combined was the only individual activity that was statistically significant (p for trend = 0.03). For men in the lowest quintile for dietary fibre intake and total physical activity (compared with those in the opposite extreme), the RR was 2.56 (95% CI 1.36, 4.82). Physical activity, along with a high fibre diet, may be an important factor in the prevention of symptomatic diverticular disease.


De qi, a threshold of the stimulus intensity, elicits the specific response of acupoints and intrinsic change of human brain to acupuncture.
Objectives. De qi is the subjective constellation of sensations perceived by the acupuncturists and patients as described in several literatures, but the absence of quantitative evaluation methods in de qi restricts the use of acupuncture treatment widely in the world. In the present study, we tried to investigate the intrinsic property of de qi is and how evaluate it quantitatively. Methods. 30 healthy adult volunteers were determined to investigate intrinsic changes in the human body after acupuncture with de qi. Results. Acupuncture treatment with de qi apparently increased acupoint blood flow, tissue displacement, and the amplitude of myoelectricity after de qi on acupoints. Furthermore, acupuncture treatment induced fMRI signal increase/decrease in different brain regions although no significant change in electroencephalography. Interpretation. The intrinsic change of the subjects representing the specific response of acupoints and human brain to acupuncture indicated that de qi might be evaluated quantitatively by those above aspects, which facilitated the confirmation in validity and propagation of this treatment modality widely in the world.


Relationship between self-reported and objectively measured physical activity and subjective memory impairment in breast cancer survivors: role of self-efficacy, fatigue and distress.
Many breast cancer survivors report cancer and cancer treatment-associated cognitive change. However, very little is known about the relationship between physical activity and subjective memory impairment (SMI) in this population. The purpose of this study is to examine the relationship between physical activity and SMI and longitudinally test a model examining the role of self-efficacy, fatigue and distress as potential mediators. Post-treatment breast cancer survivors (N = 1477) completed measures of physical activity, self-efficacy, distress (depression, concerns about recurrence, perceived stress, anxiety), fatigue and SMI at baseline and 6-month follow-up. A subsample (n = 362) was randomly selected to wear an accelerometer. It was hypothesized that physical activity indirectly influences SMI via exercise self-efficacy, distress and fatigue. Relationships were examined using panel analysis within a covariance modeling framework. The hypothesized model provided a good fit in the full sample (χ2 = 1462.5, df = 469, p = <0.001; CFI = 0.96; SRMR = 0.04) and the accelerometer subsample (χ2 = 961.8, df = 535, p = <0.001, CFI = 0.94, SRMR = 0.05) indicating increased physical activity is indirectly associated with reduction in SMI across time, via increased exercise self-efficacy and reduced distress and fatigue. Higher levels of physical activity, lower levels of fatigue and distress and higher exercise self-efficacy may play an important role in understanding SMI in breast cancer survivors across time. Future research is warranted to replicate and explore these relationships further. Copyright © 2016 John Wiley & Sons, Ltd.


Vasopressin and arterial pressure regulation. Special lecture.
Data from conscious rats, dogs, and humans show that plasma arginine vasopressin (AVP) begins to exert vasoconstrictor activity at concentrations in the same range as those associated with maximum antidiuretic activity. Minimum pressor responses are observed with elevated plasma AVP, due in part to decreases of cardiac output and in part to withdrawal of sympathetic neural tone to various regions of the systemic circulation. These responses appear to some extent to be species-dependent. In conscious dogs, but not in rats, the fall of cardiac output is mediated by AVP stimulation of baroreceptor reflex pathways. Studies in rats indicate that AVP inhibits the sympathetic nervous system by direct action on the central nervous system. No evidence was found for inhibition at peripheral sites such as autonomic ganglia or vascular smooth muscle receptors. Also, AVP plays an important role in the regulation of arterial pressure with blood loss by direct vasoconstriction and by AVP enhancement of the strength of the baroreceptor reflex responses. The role of AVP in the long-term control of arterial pressure and in hypertension remains controversial, but plasma AVP is elevated in many experimental and human forms of hypertension. The link between plasma AVP and hypertension remains unclear because long-term elevation of AVP alone cannot sustain volume expansion or hypertension, and excess AVP does not enhance hypertension produced by sodium-retaining hormones or other vasoconstrictor agents. It appears that AVP plays mainly a permissive role by its fluid-retaining effects in most forms of hypertension. It is also possible that it acts as a central nervous system neural transmitter and modifies autonomic pathways in some forms of hypertension.


Interaction of NDPK-D with cardiolipin-containing membranes: Structural basis and implications for mitochondrial physiology.
Nucleoside diphosphate kinases (NDPKs/Nm23), responsible for intracellular di- and tri-phosphonucleoside homeostasis, play multi-faceted roles in cellular energetic, signaling, proliferation, differentiation and tumor invasion. The mitochondrial NDPK-D, the NME4 gene product, is a peripheral protein of the inner membrane. Several new aspects of the interaction of NDPK-D with the inner mitochondrial membrane have been recently characterized. Surface plasmon resonance analysis using recombinant NDPK-D and different phospholipid liposomes showed that NDPK-D interacts electrostatically with anionic phospholipids, with highest affinity observed for cardiolipin, a phospholipid located mostly in the mitochondrial inner membrane. Mutation of the central arginine (R90) in a surface exposed cationic RRK motif unique to NDPK-D strongly reduced phospholipid interaction in vitro and in vivo. Stable expression of NDPK-D proteins in HeLa cells naturally almost devoid of this isoform revealed a tight functional coupling of NDPK-D with oxidative phosphorylation that depends on the membrane-bound state of the enzyme. Owing to its symmetrical hexameric structure exposing membrane binding motifs on two opposite sides, NDPK-D could bridge liposomes containing anionic phospholipids and promote lipid transfer between them. In vivo, NDPK-D could induce intermembrane contacts and facilitate lipid movements between mitochondrial membranes. Most of these properties are reminiscent to those of the mitochondrial creatine kinase. We review here the common properties of both kinases and we discuss their potential roles in mitochondrial functions such as energy production, apoptosis and mitochondrial dynamics.


The physiologic state of Escherichia coli O157:H7 does not affect its detection in two commercial real-time PCR-based tests.
Multiplex real-time PCR detection of Escherichia coli O157:H7 is an efficient molecular tool with high sensitivity and specificity for meat safety assurance. The Biocontrol GDS(®) and DuPont Qualicon BAX(®)-RT rapid detection systems are two commercial tests based on real-time PCR amplification with potential applications for quantification of specific E. coli O157:H7 gene targets in enriched meat samples. However, there are arguments surrounding the use of these tests to predict pre-enrichment concentrations of E. coli O157:H7, as well as arguments pertaining to the influence of non-viable cells causing false positive results. The present study attempts to illustrate the effects of different bacterial physiologic states and the presence of non-viable cells on the ability of these systems to accurately measure contamination levels of E. coli O157:H7 in ground beef. While the PCR threshold cycle (C(T)) values of these assays showed a direct correlation with the number of bacteria present in pure cultures, this was not the case for ground beef samples spiked with various levels of injured or healthy cells. Furthermore, comparison of post-enrichment cell densities of bacteria did not correlate with injured or healthy cell numbers inoculated before enrichment process. Ground beef samples spiked with injured or healthy cells at different doses could not be distinguished by C(T) values from either assay. In addition, the contribution of nonviable cells in generating positive real-time PCR signals was investigated using both assays on pre-enriched and post-enriched beef samples, but only if inoculated at levels of 10(6) cells/sample or higher, which are levels not typically seen in ground beef.


Consensus statement: a framework for safe and effective intubation by paramedics.
This consensus statement provides profession-specific guidance in relation to tracheal intubation by paramedics - a procedure that the College of Paramedics supports. Tracheal intubation by paramedics has been the subject of professional and legal debate as well as crown investigation. It is therefore timely that the College of Paramedics, through this consensus group, reviews the available evidence and expert opinion in order to prevent patient harm and promote patient safety, clinical effectiveness and professional standards. It is not the purpose of this consensus statement to remove the skill of tracheal intubation from paramedics. Neither is it intended to debate the efficacy of intubation or the effect on mortality or morbidity, as other formal research studies will answer those questions. The consensus of this group is that paramedics can perform tracheal intubation safely and effectively. However, a safe, well-governed system of continual training, education and competency must be in place to serve both patients and the paramedics delivering their care.


Yersinia enterocolitica strains associated with human infections in Switzerland 2001-2010.
Yersinia enterocolitica infections are common in humans. However, very scarce data are available on the different biotypes and virulence factors of human strains, which has proved to be problematic to assess the clinical significance of the isolated strains. In this study, the presence of the ail gene and distribution of different bio- and serotypes among human Y. enterocolitica strains and their possible relation to the genotype and antimicrobial resistance were studied. In total, 128 Y. enterocolitica strains isolated from human clinical samples in Switzerland during 2001-2010 were characterised. Most (75 out of 128) of the Y. enterocolitica strains belonged to biotypes 2, 3 or 4 and carried the ail gene. One of the 51 strains that belonged to biotype 1A was also ail positive. Most of the ail-positive strains belonged to bioserotype 4/O:3 (47 out of 76) followed by 2/O:9 (22 out of 76). Strains of bioserotype 4/O:3 were dominant among patients between 20 and 40 years old and strains of biotype 1A dominate in patients over 40 years. Strains belonging to biotypes 2, 3 and 4, which all carried the ail gene, exhibited a high homogeneity with PFGE typing. Y. enterocolitica 2/O:5,27 and 2/O:9 strains showed resistance to amoxicillin/clavulanic acid and cefoxitin, but Y. enterocolitica 4/O:3 strains did not.


The effects of reflexology on chronic low back pain intensity in nurses employed in hospitals affiliated with Isfahan University of Medical Sciences.
Humans have been involved with the phenomena of pain and pain relief from the ancient times. Back pain is the most common pain. In fact, eight out of ten people experience it in their lifetime. However, individuals with specific jobs, including nurses, are faced with this problem more. Nursing is in the top ten careers suffering from the most severe musculoskeletal injuries. There are non-pharmacologic and pharmacologic treatments to relieve back pain. One of the non-medical treatments of pain is called reflexology which is a branch of complementary and alternative therapies. This research has been conducted to investigate the effect of reflexology on chronic low back pain intensity. This study was a double-blind clinical trial. The study population consisted of 50 female and male nurses suffering from chronic low back pain working in hospitals affiliated with Isfahan University of Medical Sciences. The participants were divided into two groups of reflexology and non-specific massage. A questionnaire was completed through interviews and a 40 minute sessions of interventions were performed three times a week for two weeks. Pain intensity was measured by Numerical Analogue Scale for pain before and after the intervention. Descriptive and inferential statistics, including independent t-test and chi-square test, were used to analyze the data. The results showed a significantly higher reduction in pain intensity scores in the reflexology group after the intervention as compared with the non-specific massage group. However, the non-specific massage was also significantly effective in reducing pain. Reflexology can be effective in reducing the severity of chronic back pain, i.e. it is able to reduce pain from moderate to mild. Thus, this technique is recommended to be performed by nurses as a complementary therapy in patient care.


The effect of dissolved nickel and copper on the adult coral Acropora muricata and its microbiome.
The potential impacts of mining activities on tropical coastal ecosystems are poorly understood. In particular, limited information is available on the effects of metals on scleractinian corals which are foundation species that form vital structural habitats supporting other biota. This study investigated the effects of dissolved nickel and copper on the coral Acropora muricata and its associated microbiota. Corals collected from the Great Barrier Reef were exposed to dissolved nickel (45, 90, 470, 900 and 9050 μg Ni/L) or copper (4, 11, 32 and 65 μg Cu/L) in flow through chambers at the National Sea Simulator, Townsville, Qld, Australia. After a 96-h exposure DNA metabarcoding (16S rDNA and 18S rDNA) was undertaken on all samples to detect changes in the structure of the coral microbiome. The controls remained healthy throughout the study period. After 36 h, bleaching was only observed in corals exposed to 32 and 65 μg Cu/L and very high nickel concentrations (9050 μg Ni/L). At 96 h, significant discolouration of corals was only observed in 470 and 900 μg Ni/L treatments, the highest concentrations tested. While high concentrations of nickel caused bleaching, no changes in the composition of their microbiome communities were observed. In contrast, exposure to copper not only resulted in bleaching, but altered the composition of both the eukaryote and bacterial communities of the coral's microbiomes. Our findings showed that these effects were only evident at relatively high concentrations of nickel and copper, reflecting concentrations observed only in extremely polluted environments. Elevated metal concentrations have the capacity to alter the microbiomes which are inherently linked to coral health.


Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks.
To understand the possible effect that length of time has on disease severity with sequential dengue infections. Death and hospitalization rates for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) per 10,000 secondary dengue-2 infections were compared in the same age group for two dengue-2 (DEN-2) epidemics in Cuba. The first DEN-2 epidemic affected all of Cuba in 1981; the second one, in 1997, impacted only the city of Santiago de Cuba. The sensitizing infection for DHF/DSS for each of the DEN-2 epidemics was dengue-1 (DEN-1) serotype virus, which was transmitted in 1977-1979, that is, 4 years and 20 years before the two DEN-2 epidemics. Using published seroepidemiological data from the cities of Havana and Santiago de Cuba, we estimated the rates at which persons aged 15-39 years old and those 40 years and older were hospitalized or died of DHF/DSS in Havana and in all of Cuba in 1981 and in just Santiago de Cuba in 1997. Among adults 15-39 years old the death rate per 10,000 secondary DEN-2 infections was 38.5 times as high in Santiago de Cuba in 1997 as in Havana in 1981. As a further indication of the increased severity coming with a longer period between the initial DEN-1 infection and the secondary DEN-2 infection, the case fatality rate for that same age group was 4.7 times as high in Santiago in 1997 as it was in Havana in 1981. We found a marked increase in severity with the longer of the two intervals (20 years) between an initial DEN-1 infection and a secondary DEN-2 infection. Such a difference may be due to subtle shifts in causative dengue strains or to changes with the passage of time in the circulating population of human dengue antibodies. These observations have important implications for dengue control, pathogenic mechanisms, and vaccine development.


Current concepts of children's perceptions of control.
Beliefs about control have been identified as an important aspect of the occupational therapy evaluation process because of their potential influence over the course of action chosen. This paper reviews the current status of research and theory in this area as it relates to children. Issues addressed include the drawbacks of the downward extension of adult theoretical models and tests to children, the multidimensionality of perceived control, and the relation between cognitive development and changes in beliefs. Recent revisions in theoretical models and new measures that provide more differentiated information on children's beliefs about causality and personal efficacy are reviewed. The implications for the selection of instruments and interpretation of results for the assessment of children's perceived control in clinical practice are discussed.


Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study.
Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing. A total of 27,349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined. The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001). The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.


Hemodynamic effects of methylprednisolone acetate administration in cats.
To investigate the mechanisms by which corticosteroid administration may predispose cats to congestive heart failure (CHF). 12 cats receiving methylprednisolone acetate (MPA) for the treatment of dermatologic disorders. The study was conducted as a repeated-measures design. Various baseline variables were measured, after which MPA (5 mg/kg, IM) was administered. The same variables were then measured at 3 to 6 days and at 16 to 24 days after MPA administration. Evaluations included physical examination, systolic blood pressure measurement, hematologic analysis, serum biochemical analysis, thoracic radiography, echocardiography, and total body water and plasma volume determination. MPA resulted in a substantial increase in serum glucose concentration at 3 to 6 days after administration. Concurrently, RBC count, Hct, and hemoglobin concentration as well as serum concentrations of the major extracellular electrolytes, sodium and chloride, decreased. Plasma volume increased by 13.4% (> 40% in 3 cats), whereas total body water and body weight slightly decreased. All variables returned to baseline by 16 to 24 days after MPA administration. These data suggest that MPA administration in cats causes plasma volume expansion as a result of an intra to extracellular fluid shift secondary to glucocorticoid-mediated extracellular hyperglycemia. This mechanism is analogous to the plasma volume expansion that accompanies uncontrolled diabetes mellitus in humans. Any cardiovascular disorders that impair the normal compensatory mechanisms for increased plasma volume may predispose cats to CHF following MPA administration.


Impact of the steepness of the slope on the biomechanics of World Cup slalom skiers.
Numerous environmental factors can affect alpine-ski-racing performance, including the steepness of the slope. However, little research has focused on this factor. Accordingly, the authors' aim was to determine the impact of the steepness of the slope on the biomechanics of World Cup slalom ski racers. The authors collected 3-dimensional kinematic data during a World Cup race from 10 male slalom skiers throughout turns performed on a relatively flat (19.8°) and steep (25.2°) slope under otherwise similar course conditions. Kinematic data revealed differences between the 2 slopes regarding the turn radii of the skis and center of gravity, velocity, acceleration, and differential specific mechanical energy (all P < .001). Ground-reaction forces (GRFs) also tended toward differences (P = .06). Examining the time-course behaviors of variables during turn cycles indicated that steeper slopes were associated with slower velocities but greater accelerations during turn initiation, narrower turns with peak GRFs concentrated at the midpoint of steering, more pronounced lateral angulations of the knees and hips at the start of steering that later became less pronounced, and overall slower turns that involved deceleration at completion. Consequently, distinct energy-dissipation-patterns were apparent on the 2 slope inclines, with greater pregate and lesser postgate dissipation on the steeper slope. The steepness of the slope also affected the relationships between mechanical skiing variables. The findings suggest that specific considerations during training and preparation would benefit the race performance of slalom skiers on courses involving sections of varying steepness.


Tumor board formats: "fascinating case" versus "working conference".
To test the hypothesis that a "working conference" (WC; tumor board format in which any case requiring multispecialty input is presented for discussion) was preferable to a "fascinating case" (FC; only "interesting" or "unusual" cases presented) format, tumor board format at the Portland Veterans Affairs Medical Center was changed from FC to WC. The number of cases presented in tumor board reflected this change. For example, for the period from 1990 to 1991 (prior to the change), 63 of 557 registered cases (11%) were presented in tumor board. By 1992-1993, 206 of 547 registered cases (38%) were presented. This increase was highly significant (p < 0.001). Three years after the format change, the authors surveyed 22 regular participants of the tumor board, many of whom had been participants prior to the change. Of those surveyed, 77% preferred the WC to the FC format, and 18% preferred a combined format. Most of those surveyed felt that the WC format was more helpful to the provider and to patient care (86% and 100%, respectively). Eighty percent felt that the WC format facilitated protocol enrollment, and 100% of the respondents were satisfied with the quality of case discussion that resulted from the WC format. The change to a "working case" format increased provider satisfaction with tumor board quality compared with the previous "fascinating case" format.


Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease with GBA1 Pathogenic Variants.
Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Adequacy of vitamin D replacement in severe deficiency is dependent on body mass index.
Obesity is associated with hypovitaminosis D. Whether body mass index (BMI) determines the replacement dose of vitamin D to achieve sufficiency is unclear. To determine the relationship between BMI and serum 25-OH vitamin D concentrations and whether the increase in serum 25-OH vitamin D concentrations with vitamin D replacement is dependent on BMI. Retrospective review of anthropometric data and serum 25-OH vitamin D concentrations in 95 patients attending an outpatient clinic in a tertiary hospital. In a second component of the study, 17 hospital inpatients with severe vitamin D deficiency (serum 25-OH D concentrations<6 ng/mL [15 nmol/L]) were supplemented with 10,000 units vitamin D(3)/day orally for 1 week. Biochemistry and anthropometric measurements were compared before and after vitamin D replacement. Serum 25-OH vitamin D concentrations correlated negatively with BMI in the 95 outpatients (r(2) = 0.11, P <.01). In the longitudinal study, BMI correlated positively with serum intact parathyroid hormone (r(2) = 0.84, P <.01) and negatively with 1.25-(OH)(2) vitamin D (r(2) = 0.19, P=.06) at baseline. Serum 25-OH D concentrations achieved following 1 week of vitamin D(3) replacement correlated negatively with BMI (r(2) = 0.63, P <.01). Efficacy of vitamin D supplementation is dependent on BMI. Overweight and obese patients with hypovitaminosis D might require higher doses of vitamin D to achieve vitamin D repletion compared with individuals with normal body weight.


Estimating the population local wavelet spectrum with application to non-stationary functional magnetic resonance imaging time series.
Functional magnetic resonance imaging (fMRI) is a dynamic four-dimensional imaging modality. However, in almost all fMRI analyses, the time series elements of this data are assumed to be second-order stationary. In this paper, we examine, using time series spectral methods, whether such stationary assumptions can be made and whether estimates of non-stationarity can be used to gain understanding into fMRI experiments. A non-stationary version of replicated stationary time series analysis is proposed that takes into account the replicated time series that are available from nearby voxels in a region of interest (ROI). These are used to investigate non-stationarities in both the ROI itself and the variations within the ROI. The proposed techniques are applied to simulated data and to an anxiety-inducing fMRI experiment.


Shared decision making in medicine: the influence of situational treatment factors.
Although shared decision making (SDM) has become increasingly important in bioethical discussions and clinical practice, it is not clear in which treatment situations SDM is suitable. We address this question by investigating social norms on the appropriateness of SDM in different situations. We conducted qualitative expert interviews with patients, general practitioners, and health administration and research professionals. SDM was considered to be most important in severe illness and chronic condition. Furthermore, SDM was indicated to be required if there is more than one therapeutic option, especially if it is not clear which option is best. Interviewees classified end-of-life decisions and decisions about prevention as those that primarily should be made by informed patients. On the other hand a paternalistic decision was considered most appropriate in emergency situations and when the patient does not want to participate in decision making. This study demonstrates that multiple situational factors and their interactions must be considered regarding the scope of SDM in medical consultation. Research addressing this question will help physicians adjust their consultation style and allow implementations of SDM and decision aids to be tailored more appropriately to complex treatment situations.


Pancratistatin Inhibits the Growth of Colorectal Cancer Cells by Inducing Apoptosis, Autophagy, and G2/M Cell Cycle Arrest.
BACKGROUND Worldwide, colorectal cancer is ranked as the third most prevalent cancer. The natural compound, pancratistatin, extracted from the spider lily, has previously been shown to target apoptosis in cancer cells lines. This study aimed to investigate the effects of pancratistatin in human colorectal cancer cells in vitro. MATERIAL AND METHODS Human colorectal cancer cell lines, including HTC-15 cells, were compared with a normal human colonic fibroblast cell line, CDD-18Co. Cells were treated with increasing doses of pancratistatin. The MTT assay was used to assess cell viability. Fluorescence microscopy using DAPI and Annexin-V/propidium iodide (PI) was used to detect cell apoptosis. Cell autophagy was detected by electron microscopy. Cell migration was evaluated using a wound healing assay, and Western blot determined the expression levels of cell cycle proteins. RESULTS Pancratistatin inhibited the growth of the colorectal cancer cells with an IC₅₀ ranging from 15-25 µM, but had a limited effect in normal CCD-18Co cells, with an IC₅₀ of >100 µM. Pancratistatin reduced HCT-15 cell migration. Growth inhibition due to pancratistatin was associated with morphological changes of HCT-15 cells and included autophagy and apoptosis, and increased expression the autophagic proteins, LC3II, beclin-1, and Bax. Pancratistatin induced arrest of HCT-15 cells at G2/M of the cell cycle and inhibited phosphorylation of cdc2/cyclin-dependent kinase 1 (CDK1) and Cdc25c and the expression of cyclin B1. CONCLUSIONS Pancratistatin inhibited the growth of colorectal cancer cells in vitro by inducing apoptosis, autophagy, and G2/M cell cycle arrest.


Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain.
The SHC proteins have been implicated in insulin receptor (IR) signaling. In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR. The interaction is mediated by SHC amino acids 1 to 238 and is therefore independent of the Src homology 2 domain. The interaction is dependent upon IR autophosphorylation, since the interaction is eliminated by mutation of the IR ATP-binding site. In addition, mutational analysis of the Asn-Pro-Glu-Tyr (NPEY) motif within the juxtamembrane domain of the IR showed the importance of the Asn, Pro, and Tyr residues to both SHC and IR substrate 1 (IRS-1) binding. We conclude that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction. This interaction is highly reminiscent of that of IRS-1 with the IR, and we show that the SHC IR-binding domain can substitute for that of IRS-1 in yeast and COS cells. We identify a homologous region within the IR-binding domains of SHC and IRS-1, which we term the SAIN (SHC and IRS-1 NPXY-binding) domain, which may explain the basis of these interactions. The SAIN domain appears to represent a novel motif which is able to interact with autophosphorylated receptors such as the IR.


Formation of multinucleated cells that respond to osteotropic hormones in long term human bone marrow cultures.
Studies of osteoclasts and their precursors in normal and pathological states have been severely hampered by the lack of an in vitro system for forming osteoclasts. We developed a human marrow culture system in which multinucleated cells with several characteristics of osteoclasts form. Multinucleated cells began to form during the first week of culture, with maximum numbers formed after 3 weeks. PTH (25-50 ng/ml) and 1,25-dihydroxyvitamin D3 (10(-10)-10(-8) M) increased formation of these cells, and these effects were inhibited by calcitonin. These multinucleated cells contained nonspecific esterase and tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts, and had several ultrastructural features of osteoclasts. We used this marrow cell culture technique to study a patient with hyperparathyroidism and markedly increased osteoclasts on bone marrow biopsy. The marrow from this patient formed increased numbers of multinucleated cells in vitro. After parathyroidectomy both multinucleated cell formation in vitro and osteoclast numbers on bone biopsy decreased significantly. This long term marrow culture system represents the first demonstration of human osteoclast-like cell formation in vitro. This system should permit studies to evaluate factors controlling formation of cells with certain osteoclast characteristics in vitro and their precursors as well as to evaluate abnormalities in osteoclast formation in patients with metabolic bone disease.


Relative Visual Oscillation Can Facilitate Visually Induced Self-Motion Perception.
Adding simulated viewpoint jitter or oscillation to displays enhances visually induced illusions of self-motion (vection). The cause of this enhancement is yet to be fully understood. Here, we conducted psychophysical experiments to investigate the effects of different types of simulated oscillation on vertical vection. Observers viewed horizontally oscillating and nonoscillating optic flow fields simulating downward self-motion through an aperture. The aperture was visually simulated to be nearer to the observer and was stationary or oscillating in-phase or counter-phase to the direction of background horizontal oscillations of optic flow. Results showed that vection strength was modulated by the oscillation of the aperture relative to the background optic flow. Vertical vection strength increased as the relative oscillatory horizontal motion between the flow and the aperture increased. However, such increases in vection were only generated when the added oscillations were orthogonal to the principal direction of the optic flow pattern, and not when they occurred in the same direction. The oscillation effects observed in this investigation could not be explained by motion adaptation or different (motion parallax based) effects on depth perception. Instead, these results suggest that the oscillation advantage for vection depends on relative visual motion.


Large Scale Profiling of Protein Isoforms Using Label-Free Quantitative Proteomics Revealed the Regulation of Nonsense-Mediated Decay in Moso Bamboo (Phyllostachys edulis).
Moso bamboo is an important forest species with a variety of ecological, economic, and cultural values. However, the gene annotation information of moso bamboo is only based on the transcriptome sequencing, lacking the evidence of proteome. The lignification and fiber in moso bamboo leads to a difficulty in the extraction of protein using conventional methods, which seriously hinders research on the proteomics of moso bamboo. The purpose of this study is to establish efficient methods for extracting the total proteins from moso bamboo for following mass spectrometry-based quantitative proteome identification. Here, we have successfully established a set of efficient methods for extracting total proteins of moso bamboo followed by mass spectrometry-based label-free quantitative proteome identification, which further improved the protein annotation of moso bamboo genes. In this study, 10,376 predicted coding genes were confirmed by quantitative proteomics, accounting for 35.8% of all annotated protein-coding genes. Proteome analysis also revealed the protein-coding potential of 1015 predicted long noncoding RNA (lncRNA), accounting for 51.03% of annotated lncRNAs. Thus, mass spectrometry-based proteomics provides a reliable method for gene annotation. Especially, quantitative proteomics revealed the translation patterns of proteins in moso bamboo. In addition, the 3284 transcript isoforms from 2663 genes identified by Pacific BioSciences (PacBio) single-molecule real-time long-read isoform sequencing (Iso-Seq) was confirmed on the protein level by mass spectrometry. Furthermore, domain analysis of mass spectrometry-identified proteins encoded in the same genomic locus revealed variations in domain composition pointing towards a functional diversification of protein isoform. Finally, we found that part transcripts targeted by nonsense-mediated mRNA decay (NMD) could also be translated into proteins. In summary, proteomic analysis in this study improves the proteomics-assisted genome annotation of moso bamboo and is valuable to the large-scale research of functional genomics in moso bamboo. In summary, this study provided a theoretical basis and technical support for directional gene function analysis at the proteomics level in moso bamboo.


Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations.
The prevalence of mild and severe radiological osteoarthritis was investigated in a random sample of 6585 inhabitants of a Dutch village. Radiographs were graded 0-4 according to the criteria described by Kellgren and Lawrence. The prevalence of radiological osteoarthritis increased strongly with age and was highest for cervical spine (peak: men 84.8%, women 84.3%), lumbar spine (peak: 71.9%, women 67.3%), and distal interphalangeal joints of the hands (peak: men 64.4%, women 76%). Prevalence did not exceed 10% in sacroiliac joints, lateral carpometacarpal joints, and tarsometatarsal joints. Severe radiological osteoarthritis (grade 3 or grade 4) was uncommon under age 45; in elderly persons the prevalence of severe radiological osteoarthritis did not exceed 20% except for the cervical and lumbar spine, distal interphalangeal joints of the hands and, in women only, metacarpophalangeal joints, first carpometacarpal joints, first metatarsophalangeal joints, and knees. Overall, differences between men and women were small except for hips and knees; however, severe radiological osteoarthritis was found in a higher proportion in most of the joints in women. Our data were compared with data from similar population surveys. The slope between joint involvement and age was strikingly constant for most of the joints. Differences between populations were mainly differences in level. These differences of prevalence of radiological osteoarthritis may be attributed to interobserver differences--that is, different criteria used to establish radiological osteoarthritis, in addition to genetic or environmental factors, or both.


One of these things is not like the others: the idea of precedence in health technology assessment and coverage decisions.
Health plans often deliberate covering technologies with challenging purposes, effects, or costs. They must integrate quantitative evidence (e.g., how well a technology works) with qualitative, normative assessments (e.g., whether it works well enough for a worthwhile purpose). Arguments from analogy and precedent help integrate these criteria and establish standards for their policy application. Examples of arguments are described for three technologies (ICSI, genetic tests, and Viagra). Drawing lessons from law, ethics, philosophy, and the social sciences, a framework is developed for case-based evaluation of new technologies. The decision-making cycle includes (1) taking stock of past decisions and formulating precedents, (2) deciding new cases, and (3) assimilating decisions into the case history and evaluation framework. Each stage requires distinctive decision maker roles, information, and methods.


Light-Gap disturbances, recruitment limitation, and tree diversity in a neotropical forest
Light gap disturbances have been postulated to play a major role in maintaining tree diversity in species-rich tropical forests. This hypothesis was tested in more than 1200 gaps in a tropical forest in Panama over a 13-year period. Gaps increased seedling establishment and sapling densities, but this effect was nonspecific and broad-spectrum, and species richness per stem was identical in gaps and in nongap control sites. Spatial and temporal variation in the gap disturbance regime did not explain variation in species richness. The species composition of gaps was unpredictable even for pioneer tree species. Strong recruitment limitation appears to decouple the gap disturbance regime from control of tree diversity in this tropical forest.


Measurement of the forward-backward asymmetry in the B→K*μ(+)μ(-) decay and first observation of the B(s)0→ϕμ(+)μ(-) decay.
We reconstruct the rare decays B(+)→K(+)μ(+0μ(-0, B90)→K*(892)(0)μ(+)μ(-), and B(s)(0)→ϕ(1020)μ(+)μ(-) in a data sample corresponding to 4.4 fb(-1) collected in pp collisions at √[s]=1.96 TeV by the CDF II detector at the Tevatron Collider. Using 121±16 B(+)→K(+)μ(+)μ(-) and 101±12 B(0)→K(*0)μ(+)μ(-) decays we report the branching ratios. In addition, we report the differential branching ratio and the muon forward-backward asymmetry in the B(+) and B(0) decay modes, and the K(*0) longitudinal polarization fraction in the B(0) decay mode with respect to the squared dimuon mass. These are consistent with the predictions, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the B(s)(0)→ϕμ(+)μ(-) decay and measure its branching ratio BR(B(s)(0)→ϕμ(+)μ(-))=[1.44±0.33±0.46]×10(-6) using 27±6 signal events. This is currently the most rare B(s)(0) decay observed.


Enterovirus-71 virus-like particles induce the activation and maturation of human monocyte-derived dendritic cells through TLR4 signaling.
Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation.


The relation of menarcheal age to obesity in childhood and adulthood: the Bogalusa heart study.
Several studies have shown that girls who undergo menarche at a relatively young age tend to be more obese as adults. However, because childhood (pre-menarcheal) levels of weight and height are associated with an earlier menarche, the increased prevalence of adult obesity among early maturers may largely reflect the persistence of childhood obesity into adulthood. We examined these interrelationships among 1179 girls (65% white, 35% black) who were examined as children (mean age, 9 y), adolescents, and adults (mean age, 26 y) in the Bogalusa Heart Study. Both white and black women who reported that they underwent menarche before age 12 y had, on average, higher adult levels of weight (+10 kg), body mass index (BMI, +4 kg/m2) and skinfold thicknesses (+6 mm) than did women who underwent menarche after age 13.5 y. However, relatively fat children tended to undergo menarche earlier than did thinner children, with each standard deviation increase in pre-menarcheal BMI increasing the odds of early menarche (<12 y) by approximately 2-fold. Stratified and regression analyses indicated that (1) adult obesity was more strongly associated with childhood obesity than with menarcheal age, and (2) about 60% to 75% of the apparent effect of menarcheal age was due to the influence of childhood obesity on both menarcheal age and adult obesity. Although additional longitudinal studies are needed, it is likely that the importance of early menarche in adult obesity has been overestimated. Most of apparent influence of menarcheal age on adult obesity is attributable to the association of childhood obesity with both menarcheal age and adult obesity.


Sex and genotype effects on nutrient-dependent fitness landscapes in Drosophila melanogaster.
The sexes perform different reproductive roles and have evolved sometimes strikingly different phenotypes. One focal point of adaptive divergence occurs in the context of diet and metabolism, and males and females of a range of species have been shown to require different nutrients to maximize their fitness. Biochemical analyses in Drosophila melanogaster have confirmed that dimorphism in dietary requirements is associated with molecular sex differences in metabolite titres. In addition, they also showed significant within-sex genetic variation in the metabolome. To date however, it is unknown whether this metabolic variation translates into differences in reproductive fitness. The answer to this question is crucial to establish whether genetic variation is selectively neutral or indicative of constraints on sex-specific physiological adaptation and optimization. Here we assay genetic variation in consumption and metabolic fitness effects by screening male and female fitness of thirty D. melanogaster genotypes across four protein-to-carbohydrate ratios. In addition to confirming sexual dimorphism in consumption and fitness, we find significant genetic variation in male and female dietary requirements. Importantly, these differences are not explained by feeding responses and probably reflect metabolic variation that, in turn, suggests the presence of genetic constraints on metabolic dimorphism.


Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae.
The TOR (target of rapamycin) signal transduction pathway is an important mechanism by which cell growth is controlled in all eucaryotic cells. Specifically, TOR signaling adjusts the protein biosynthetic capacity of cells according to nutrient availability. In mammalian cells, one branch of this pathway controls general translational initiation, whereas a separate branch specifically regulates the translation of ribosomal protein (r-protein) mRNAs. In Saccharomyces cerevisiae, the TOR pathway similarly regulates general translational initiation, but its specific role in the synthesis of ribosomal components is not well understood. Here we demonstrate that in yeast control of ribosome biosynthesis by the TOR pathway is surprisingly complex. In addition to general effects on translational initiation, TOR exerts drastic control over r-protein gene transcription as well as the synthesis and subsequent processing of 35S precursor rRNA. We also find that TOR signaling is a prerequisite for the induction of r-protein gene transcription that occurs in response to improved nutrient conditions. This induction has been shown previously to involve both the Ras-adenylate cyclase as well as the fermentable growth medium-induced pathways, and our results therefore suggest that these three pathways may be intimately linked.


A break in the nitrogen cycle in aridlands? Evidence from δp15N of soils.
We examined the content and isotopic composition of nitrogen within soils of a juniper woodland and found that a cryptobiotic crust composed of cyanobacteria, lichens, and mosses was the predominant source of nitrogen for this ecosystem. Disturbance of the crust has resulted in considerable spatial variability in soil nitrogen content and isotopic composition; intercanopy soils were significantly depleted in nitrogen and had greater abundance of 15N compared to intra-canopy soils. Variations in the 15N/14N ratio for inter- and intra-canopy locations followed similar Rayleigh distillation curves, indicating that the greater 15N/14N ratios for inter-canopy soils were due to relatively greater net nitrogen loss. Coverage of cryptobiotic crusts has been reduced by anthropogenic activities during the past century, and our results suggest that destruction of the cryptobiotic crust may ultimately result in ecosystem degradation through elimination of the predominant source of nitrogen input.


Cordycepin-hypersensitive growth links elevated polyphosphate levels to inhibition of poly(A) polymerase in Saccharomyces cerevisiae.
To identify genes involved in poly(A) metabolism, we screened the yeast gene deletion collection for growth defects in the presence of cordycepin (3'-deoxyadenosine), a precursor to the RNA chain terminating ATP analog cordycepin triphosphate. Deltapho80 and Deltapho85 strains, which have a constitutively active phosphate-response pathway, were identified as cordycepin hypersensitive. We show that inorganic polyphosphate (poly P) accumulated in these strains and that poly P is a potent inhibitor of poly(A) polymerase activity in vitro. Binding analyses of poly P and yeast Pap1p revealed an interaction with a k(D) in the low nanomolar range. Poly P also bound mammalian poly(A) polymerase, however, with a 10-fold higher k(D) compared to yeast Pap1p. Genetic tests with double mutants of Deltapho80 and other genes involved in phosphate homeostasis and poly P accumulation suggest that poly P contributed to cordycepin hypersensitivity. Synergistic inhibition of mRNA synthesis through poly P-mediated inhibition of Pap1p and through cordycepin-mediated RNA chain termination may thus account for hypersensitive growth of Deltapho80 and Deltapho85 strains in the presence of the chain terminator. Consistent with this, a mutation in the 3'-end formation component rna14 was synthetic lethal in combination with Deltapho80. Based on these observations, we suggest that binding of poly P to poly(A) polymerase negatively regulates its activity.


Displacement of the underserved: medical needs of Hurricane Katrina evacuees in West Virginia.
On August 29, 2005 Hurricane Katrina struck Louisiana, Mississippi, and Alabama. During the aftermath of the storm, hurricane victims were evacuated to over 1,000 evacuation centers in 27 states. Three-hundred and twenty-three evacuees from 220 households were provided housing, food, and medical care at an evacuation center in West Virginia. A needs assessment followed to identify current needs of the evacuees. One-hundred and sixty-four evacuees were interviewed. Twenty-five percent reported an acute illness, while 46% reported having at least one chronic medical condition. The greatest need reported was for dental care (57%), followed by eyeglasses (34%), dentures (28%), and medical services (25%). Two weeks after the hurricane, the basic needs of food, shelter, and hygiene were met. The assessment identified and led to a successful response regarding the ongoing need for durable medical equipment (dentures and eyeglasses), as well as dental care.


The First Bromeligenous Species of Dendropsophus (Anura: Hylidae) from Brazil's Atlantic Forest.
We describe a new treefrog species of Dendropsophus collected on rocky outcrops in the Brazilian Atlantic Forest. Ecologically, the new species can be distinguished from all known congeners by having a larval phase associated with rainwater accumulated in bromeliad phytotelms instead of temporary or lentic water bodies. Phylogenetic analysis based on molecular data confirms that the new species is a member of Dendropsophus; our analysis does not assign it to any recognized species group in the genus. Morphologically, based on comparison with the 96 known congeners, the new species is diagnosed by its small size, framed dorsal color pattern, and short webbing between toes IV-V. The advertisement call is composed of a moderate-pitched two-note call (~5 kHz). The territorial call contains more notes and pulses than the advertisement call. Field observations suggest that this new bromeligenous species uses a variety of bromeliad species to breed in, and may be both territorial and exhibit male parental care.


Malaria epidemiology and anti-malarial drug efficacy in Guinea: a review of clinical and molecular studies.
Malaria is one of the leading causes of mortality and morbidity in Guinea. The entire country is considered at risk of the disease. Transmission occurs all year round with peaks occurring from July through October with Plasmodium falciparum as the primary parasite species. Chloroquine (CQ) was the first-line drug against uncomplicated P. falciparum in Guinea until 2005, prior to the adoption of artemisinin-based combination therapy (ACT). In this review, data on therapeutic efficacy of CQ and artemisinin-based combinations reported in published literature is summarized. Against CQ, a failure rate of 27% (12/44) was reported in a study in 1992; a median failure rate of 15.6% [range: 7.7-28.3; 8 studies] was observed during 1996-2001, and 81% (17/21) of the patients failed to clear parasitaemia in a study conducted in 2007. For artemisinin-based combinations, three published studies were identified (1495 patients; 2004-2016); all three studies demonstrated day 28 polymerase chain reaction corrected efficacy > 95%. One study characterized kelch-13 mutations (389 tested; samples collected in 2016) with no evidence of mutations currently known to be associated with artemisinin resistance. The impact of the ongoing COVID-19 pandemic and widespread usage of counterfeit medicines are immediate challenges to malaria control activities in Guinea.


The role of material deprivation and consumerism in the decisions to engage in transactional sex among young people in the urban slums of Blantyre, Malawi.
Transactional sex has been associated with a high risk of HIV acquisition and unintended pregnancy among young women in urban slums in sub-Saharan Africa. However, few studies have explored the structural drivers of transactional sex from the perspective of both genders in these settings. This paper explores how young men and women understand the factors that lead to transactional sex among their peers, and how deprivation of material resources (housing, food and health care access) and consumerism (a desire for fashionable goods) may instigate transactional sex in the urban slums of Blantyre, Malawi. Data from 5 focus group discussions and 12 in-depth interviews undertaken with a total of 60 young men and women aged 18-23 years old, conducted between December 2012 and May 2013, were analysed using anticipated and grounded codes. Housing and food deprivation influenced decisions to engage in transactional sex for both young men and women. Poor health care access and a desire for fashionable goods (such as the latest hair or clothing styles and cellular phones) influenced the decisions of young women that led to transactional sex. Interventions that engage with deprivations and consumerism are essential to reducing sexual and reproductive health risks in urban slums.


Coping with cognitive impairment and family caregiving: Introduction to the special section.
Consistent with the long history within Psychology and Aging of publishing high impact articles on family caregiving, the current Special Section includes 5 articles that provide important advances, in knowledge and in methodological sophistication, to the study of cognitive difficulty, impairment and family caregiving. One study used daily diary data over 14 days to conduct microlongitudinal analyses of the prospective impact of everyday memory failures on negative affect and marital interactions in older couples. Also relying on dyadic data, 2 other articles addressed the impact of caregiving on family members, including a study of the effects of transitioning to family caregiving over time on well-being in older husbands and wives, and a comparison of primary and secondary caregivers. Together, these articles represent important methodological advances in terms of the use of longitudinal data to study the effects of transition to cognitive impairment and spousal caregiving within the couple, and the inclusion of multiple caregivers to illustrate the impacts of caregiving in the broader family. In addition, two articles examined issues in clinical intervention for caregivers. Both articles offer new insights about the effectiveness of caregiver interventions, with the former focusing on the relative merits of offering intervention components in a flexible way over the manualized approach, and the latter a comprehensive systematic review and meta-analysis to tease out the relative utility of different intervention characteristics and approaches, with a new lens to look at psychoeducational programs. The implications of these articles for family caregiving and further research advances are discussed. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Sociodemographic Information, Aversive and Traumatic Events, Offence-Related Characteristics, and Mental Health of Delinquent Women in Forensic-Psychiatric Care in Switzerland.
The present study describes a much understudied group-namely, female prisoners under forensic-psychiatric care in the German-speaking part of Switzerland-to improve understanding of their risks and their needs. Data were derived from internal databases of a Forensic-Psychiatric Service. Data were collected in the form of their sociodemographic characteristics, prevalence of aversive and traumatic events, type of offence committed, and mental health conditions. Based on a full-sample approach, a total of 1,571 files were analysed. Results reveal that two thirds of the participants were not in a stable relationship, more than half did not complete a school degree, and three quarters were without stable employment prior to their incarceration. Two thirds were mothers and about one third did not grow up with their parents. Almost half grew up with an alcohol abusing parent, about half experienced violence and/or neglect in childhood, and about a quarter of the cases sexual abuse. About 95% had a mental health diagnosis according to International Classification of Diseases-Version 10 (ICD-10), and the most prevalent mental and behavioural disorder was due to psychoactive substance abuse. The most frequent offence type was drug-related crimes. Women convicted for drug-related crimes were more likely to have an ICD-10 F1 disorder compared with those convicted for other crimes. Conversely, women with violent offences were less likely to suffer from ICD-10 F1 disorder than those who had committed nonviolent offences. Findings have implications for practitioners and policy makers, and contribute to the cycle of violence theory discussion. In conclusion, future research areas are suggested.


A primer on extramammary Paget's disease for the urologist.
Extramammary Paget's disease (EMPD) is a rare and lethal intraepithelial malignancy that remains poorly understood. No standardized guidelines or consensus statements exist with regards to the diagnostic evaluation, therapeutic approaches and follow-up management. Complete surgical excision with negative margins has been accepted as the mainstay of treatment for EMPD to decrease the risk of local recurrence and to maximize durable cure. Non-invasive therapies, such as laser therapy, photodynamic therapy, radiotherapy and topical chemotherapy have been utilized, but are best reserved for non-surgical candidates. While the debate on the surgical approach between wide local excision (WLE) and Mohs micrographic surgery (MMS) continues, several studies have demonstrated the ability of WLE to be performed safely and effectively and to yield equally satisfactory outcomes with similar rates of recurrence to MMS. Patients undergoing surgical excision often require complex closures with skin grafting or local flaps to close genital defects. We aim to provide an up-to-date review of the current knowledge of EMPD. In addition to discussing the clinical presentation and prognostic outcomes, we focus and elaborate on the diagnostic approaches and treatment alternatives available. This information may serve as a primer for the urologist who may be called upon to treat this malignancy primarily or to provide wound coverage secondarily.


Vortex wake, downwash distribution, aerodynamic performance and wingbeat kinematics in slow-flying pied flycatchers.
Many small passerines regularly fly slowly when catching prey, flying in cluttered environments or landing on a perch or nest. While flying slowly, passerines generate most of the flight forces during the downstroke, and have a 'feathered upstroke' during which they make their wing inactive by retracting it close to the body and by spreading the primary wing feathers. How this flight mode relates aerodynamically to the cruising flight and so-called 'normal hovering' as used in hummingbirds is not yet known. Here, we present time-resolved fluid dynamics data in combination with wingbeat kinematics data for three pied flycatchers flying across a range of speeds from near hovering to their calculated minimum power speed. Flycatchers are adapted to low speed flight, which they habitually use when catching insects on the wing. From the wake dynamics data, we constructed average wingbeat wakes and determined the time-resolved flight forces, the time-resolved downwash distributions and the resulting lift-to-drag ratios, span efficiencies and flap efficiencies. During the downstroke, slow-flying flycatchers generate a single-vortex loop wake, which is much more similar to that generated by birds at cruising flight speeds than it is to the double loop vortex wake in hovering hummingbirds. This wake structure results in a relatively high downwash behind the body, which can be explained by the relatively active tail in flycatchers. As a result of this, slow-flying flycatchers have a span efficiency which is similar to that of the birds in cruising flight and which can be assumed to be higher than in hovering hummingbirds. During the upstroke, the wings of slowly flying flycatchers generated no significant forces, but the body-tail configuration added 23 per cent to weight support. This is strikingly similar to the 25 per cent weight support generated by the wing upstroke in hovering hummingbirds. Thus, for slow-flying passerines, the upstroke cannot be regarded as inactive, and the tail may be of importance for flight efficiency and possibly manoeuvrability.


TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii.
Alpha-defensins (or Cryptdins [Crps]) are a group of antimicrobial peptides produced as a component of Paneth cell (PC) secretory granules in the small intestine. In vivo ligation of TLR9 by synthetic agonists leads to PC degranulation, although the mechanism by which this occurs remains uncertain. In this report, we investigated TLR9-dependent mechanisms, triggered by the parasite Toxoplasma gondii, inducing Crp release in the lumen. Oral challenge of C57BL/6J (B6) wild-type (WT) mice with T. gondii induced TLR9 mRNA upregulation associated with a marked increase of type I IFN mRNA expression. PC secretory granules were released, and Crp-3/-5 mRNA expression by purified epithelial cells was increased following oral challenge of B6 WT mice. Although PCs failed to degranulate in infected B6 TLR9-/- mice, i.p. injection of mouse IFN-beta alone led to Crp-3/-5 mRNA upregulation in B6 WT and TLR9-/- mice. In addition, modulation of Crp mRNA expression in response to T. gondii infection was abrogated in B6 IFNAR-/- mice, which lack a functional type I IFN receptor. Taken together, these data demonstrate that T. gondii induces Crp-3/-5 production and release by PCs via a TLR9-dependent production of type I IFNs. Crps have a limited direct effect against T. gondii but may indirectly affect the early control of T. gondii invasiveness by promoting the initiation of a protective Th1 response against the parasite.


The association of statin use after cancer diagnosis with survival in pancreatic cancer patients: a SEER-medicare analysis.
Pancreatic cancer has poor prognosis and existing interventions provide a modest benefit. Statin has anti-cancer properties that might enhance survival in pancreatic cancer patients. We sought to determine whether statin treatment after cancer diagnosis is associated with longer survival in those with pancreatic ductal adenocarcinoma (PDAC). We analyzed data on 7813 elderly patients with PDAC using the linked Surveillance, Epidemiology, and End Results (SEER) - Medicare claims files. Information on the type, intensity and duration of statin use after cancer diagnosis was extracted from Medicare Part D. We treated statin as a time-dependent variable in a Cox regression model to determine the association with overall survival adjusting for follow-up, age, sex, race, neighborhood income, stage, grade, tumor size, pancreatectomy, chemotherapy, radiation, obesity, dyslipidemia, diabetes, chronic pancreatitis and chronic obstructive pulmonary disease (COPD). Overall, statin use after cancer diagnosis was not significantly associated with survival when all PDAC patients were considered (HR = 0.94, 95%CI 0.89, 1.01). However, statin use after cancer diagnosis was associated with a 21% reduced hazard of death (Hazard ratio = 0.79, 95% confidence interval (CI) 0.67, 0.93) in those with grade I or II PDAC and to a similar extent in those who had undergone a pancreatectomy, in those with chronic pancreatitis and in those who had not been treated with statin prior to cancer diagnosis. We found that statin treatment after cancer diagnosis is associated with enhanced survival in patients with low-grade, resectable PDAC.


Identification methods of key contributing factors in crashes with high numbers of fatalities and injuries in China.
In China, serious road traffic crashes (SRTCs) are those in which there are 10-30 fatalities, 50-100 serious injuries, or a total cost of 50-100 million RMB (U.S.$8-16 M), and particularly serious road traffic crashes (PSRTCs) are those that are more severe or costly. Due to the large number of fatalities and injuries as well as the negative public reaction they elicit, SRTCs and PSRTCs have become of great concern to China during recent years. The aim of this study is to identify the main factors contributing to these road traffic crashes and to propose preventive measures to reduce their number. 49 contributing factors of the SRTCs and PSRTCs that occurred from 2007 to 2013 were collected from the database "In-depth investigation and analysis system for major road traffic crashes" (IIASMRTC) and were analyzed through the integrated use of principal component analysis and hierarchical clustering to determine the primary and secondary groups of contributing factors. Speeding and overloading of passengers were the primary contributing factors, featuring in up to 66.3 and 32.6% of accidents, respectively. Two secondary contributing factors were road related: lack of or nonstandard roadside safety infrastructure and slippery roads due to rain, snow, or ice. The current approach to SRTCs and PSRTCs is focused on the attribution of responsibility and the enforcement of regulations considered relevant to particular SRTCs and PSRTCs. It would be more effective to investigate contributing factors and characteristics of SRTCs and PSRTCs as a whole to provide adequate information for safety interventions in regions where SRTCs and PSRTCs are more common. In addition to mandating a driver training program and publicization of the hazards associated with traffic violations, implementation of speed cameras, speed signs, markings, and vehicle-mounted Global Positioning Systems (GPS) are suggested to reduce speeding of passenger vehicles, while increasing regular checks by traffic police and passenger station staff and improving transportation management to increase income of contractors and drivers are feasible measures to prevent overloading of people. Other promising measures include regular inspection of roadside safety infrastructure and improving skid resistance on dangerous road sections in mountainous areas.


Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration.
Evidence from animal models and observational studies in humans has suggested that there is an inverse relationship between dietary intake of omega 3 long-chain polyunsaturated fatty acids (LCPUFA) and risk of developing age-related macular degeneration (AMD) or progression to advanced AMD. To review the evidence that increasing the levels of omega 3 LCPUFA in the diet (either by eating more foods rich in omega 3 or by taking nutritional supplements) prevents AMD or slows the progression of AMD. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2015), EMBASE (January 1980 to February 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to February 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 February 2015. We included randomised controlled trials (RCTs) where increased dietary intake of omega 3 LCPUFA was compared to placebo or no intervention with the aim of preventing the development of AMD, or slowing its progression. Both authors independently selected studies, assessed them for risk of bias and extracted data. One author entered data into RevMan 5 and the other author checked the data entry. We conducted a meta-analysis for one primary outcome, progression of AMD, using a fixed-effect inverse variance model. We included two RCTs in this review, in which 2343 participants with AMD were randomised to receive either omega 3 fatty acid supplements or a placebo. The trials, which had a low risk of bias, were conducted in the USA and France. Overall, there was no evidence that people who took omega 3 fatty acid supplements were at decreased (or increased risk) of progression to advanced AMD (pooled hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.84 to 1.10, high quality evidence). Similarly, people taking these supplements were no more (or less) likely to lose 15 or more letters of visual acuity (USA study HR 0.96, 95% CI 0.84 to 1.10; French study at 36 months risk ratio (RR) 1.25, 95% CI 0.69 to 2.26, participants = 230). The number of adverse events was similar in the intervention and placebo groups (USA study participants with one or more serious adverse event RR 1.00, 95% CI 0.91 to 1.09, participants = 2080; French study total adverse events RR 1.05, 95% CI 0.97 to 1.13, participants = 263). This review found that omega 3 LCPUFA supplementation in people with AMD for periods up to five years does not reduce the risk of progression to advanced AMD or the development of moderate to severe visual loss. No published randomised trials were identified on dietary omega 3 fatty acids for primary prevention of AMD. Currently available evidence does not support increasing dietary intake of omega 3 LCPUFA for the explicit purpose of preventing or slowing the progression of AMD.


Song presentation induces gene expression in the songbird forebrain.
We investigated the participation of genomic regulatory events in the response of the songbird brain to a natural auditory stimulus of known physiological and behavioral relevance, birdsong. Using in situ hybridization, we detected a rapid increase in forebrain mRNA levels of an immediate-early gene encoding a transcriptional regulator (ZENK; also known as zif-268, egr-1, NGFI-A, or Krox-24) following presentation of tape-recorded songs to canaries (Serinus canaria) and zebra finches (Taeniopygia guttata). ZENK induction is most marked in a forebrain region believed to participate in auditory processing and is greatest when birds hear the song of their own species. A significantly lower level of induction occurs when birds hear the song of a different species and no induction is seen after exposure to tone bursts. Cellular analysis indicates that the level of induction reflects the proportion of neurons recruited to express the gene. These results suggest a role for genomic responses in neural processes linked to song pattern recognition, discrimination, or the formation of auditory associations.


Pierre Robin sequence and Treacher Collins hypoplastic mandible comparison using three-dimensional morphometric analysis.
Pierre Robin sequence and Treacher Collins syndrome are both associated with mandibular hypoplasia. It has been hypothesized, however, that the mandible may be differentially affected. The purpose of this study was to therefore compare mandibular morphology in children with Pierre Robin sequence with children with Treacher Collins syndrome using three-dimensional analysis of computed tomographic scans. A retrospective analysis was performed identifying children with Pierre Robin sequence and Treacher Collins syndrome undergoing computed tomography. Three-dimensional reconstruction was performed, and ramus height, mandibular body length, and gonial angle were measured. These were then compared with those in control children with normal mandibles and with the clinical norms corrected for age and sex based on previously published measurements. Mandibular body length was found to be significantly shorter for children with Pierre Robin sequence, whereas ramus height was significantly shorter for children with Treacher Collins syndrome. This resulted in distinctly different ramus height-mandibular body length ratios. In addition, the gonial angle was more obtuse in both the Pierre Robin sequence and Treacher Collins syndrome groups compared with the controls. Three-dimensional mandibular morphometric analysis in patients with Pierre Robin sequence and Treacher Collins syndrome thus revealed distinctly different patterns of mandibular hypoplasia relative to normal controls. These findings underscore distinct considerations that must be made in surgical planning for reconstruction.


Immunodominant HIV-specific CD8+ T-cell responses are common to blood and gastrointestinal mucosa, and Gag-specific responses dominate in rectal mucosa of HIV controllers.
Previous studies have suggested that polyfunctional mucosal CD8(+) T-cell responses may be a correlate of protection in HIV controllers. Mucosal T-cell breadth and/or specificity may also contribute to defining protective responses. In this study, rectal CD8(+) T-cell responses to HIV Gag, Env, and Nef were mapped at the peptide level in four subject groups: elite controllers (n = 16; viral load [VL], <75 copies/ml), viremic controllers (n = 14; VL, 75 to 2,000 copies/ml), noncontrollers (n = 14; VL, >10,000 copies/ml), and antiretroviral-drug-treated subjects (n = 8; VL, <75 copies/ml). In all subject groups, immunodominant CD8(+) T-cell responses were generally shared by blood and mucosa, although there were exceptions. In HIV controllers, responses to HLA-B27- and HLA-B57-restricted epitopes were common to both tissues, and their magnitude (in spot-forming cells [SFC] per million) was significantly greater than those of responses restricted by other alleles. Furthermore, peptides recognized by T cells in both blood and rectal mucosa, termed "concordant," elicited higher median numbers of SFC than discordant responses. In magnitude as well as breadth, HIV Gag-specific responses, particularly those targeting p24 and p7, dominated in controllers. Responses in noncontrollers were more evenly distributed among epitopes in Gag, Env, and Nef. Viremic controllers showed significantly broader mucosal Gag-specific responses than other groups. Taken together, these findings demonstrate that (i) Gag-specific responses dominate in mucosal tissues of HIV controllers; (ii) there is extensive overlap between CD8(+) T cells in blood and mucosal tissues, with responses to immunodominant epitopes generally shared by both sites; and (iii) mucosal T-cell response breadth alone cannot account for immune control.


Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.
Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.


Breeding state and season affect interspecific interaction types: indirect resource competition and direct interference.
Indirect resource competition and interference are widely occurring mechanisms of interspecific interactions. We have studied the seasonal expression of these two interaction types within a two-species, boreal small mammal system. Seasons differ by resource availability, individual breeding state and intraspecific social system. Live-trapping methods were used to monitor space use and reproduction in 14 experimental populations of bank voles Myodes glareolus in large outdoor enclosures with and without a dominant competitor, the field vole Microtus agrestis. We further compared vole behaviour using staged dyadic encounters in neutral arenas in both seasons. Survival of the non-breeding overwintering bank voles was not affected by competition. In the spring, the numbers of male bank voles, but not of females, were reduced significantly in the competition populations. Bank vole home ranges expanded with vole density in the presence of competitors, indicating food limitation. A comparison of behaviour between seasons based on an analysis of similarity revealed an avoidance of costly aggression against opponents, independent of species. Interactions were more aggressive during the summer than during the winter, and heterospecific encounters were more aggressive than conspecific encounters. Based on these results, we suggest that interaction types and their respective mechanisms are not either-or categories and may change over the seasons. During the winter, energy constraints and thermoregulatory needs decrease direct aggression, but food constraints increase indirect resource competition. Direct interference appears in the summer, probably triggered by each individual's reproductive and hormonal state and the defence of offspring against conspecific and heterospecific intruders. Both interaction forms overlap in the spring, possibly contributing to spring declines in the numbers of subordinate species.


Can trained volunteers make a difference at mealtimes for older people in hospital? A qualitative study of the views and experience of nurses, patients, relatives and volunteers in the Southampton Mealtime Assistance Study.
Malnutrition is common amongst hospitalised older patients and associated with increased morbidity and mortality. Poor dietary intake results from factors including acute illness and cognitive impairment but additionally patients may have difficulty managing at mealtimes. Use of volunteers to help at mealtimes is rarely evaluated. To obtain multiple perspectives on nutritional care of older inpatients, acceptability of trained volunteers and identify important elements of their assistance. A qualitative study 1 year before and after introduction of volunteer mealtime assistants on one ward and parallel comparison with a control ward in a Medicine for Older People department at a UK university hospital. Semi-structured interviews and focus groups, in baseline and intervention years, with purposively sampled nursing staff at different levels of seniority; patients or close relatives; and volunteers. At baseline staff felt under pressure with insufficient people assisting at mealtimes. Introducing trained volunteers was perceived by staff and patients to improve quality of mealtime care by preparing patients for mealtimes, assisting patients who needed help, and releasing nursing time to assist dysphagic or drowsy patients. There was synergy with other initiatives, notably protected mealtimes. Interviews highlighted the perceived contribution of chronic poor appetite and changes in eating patterns to risk of malnutrition. Improved quality of mealtime care attributed to volunteers' input has potential to enhance staff morale and patients'/relatives' confidence. A volunteer mealtime assistance scheme may work best when introduced in context of other changes reflecting commitment to improving nutrition. (i) A mealtime assistance scheme should incorporate training, supervision and support for volunteers; (ii) Good relationships and a sense of teamwork can develop between wards staff and volunteers; (iii) Impact may be maximised in the context of 'protected mealtimes'.


Intensive meditation training improves perceptual discrimination and sustained attention.
The ability to focus one's attention underlies success in many everyday tasks, but voluntary attention cannot be sustained for extended periods of time. In the laboratory, sustained-attention failure is manifest as a decline in perceptual sensitivity with increasing time on task, known as the vigilance decrement. We investigated improvements in sustained attention with training (approximately 5 hr/day for 3 months), which consisted of meditation practice that involved sustained selective attention on a chosen stimulus (e.g., the participant's breath). Participants were randomly assigned either to receive training first (n = 30) or to serve as waiting-list controls and receive training second (n = 30). Training produced improvements in visual discrimination that were linked to increases in perceptual sensitivity and improved vigilance during sustained visual attention. Consistent with the resource model of vigilance, these results suggest that perceptual improvements can reduce the resource demand imposed by target discrimination and thus make it easier to sustain voluntary attention.