Relationship between cold-induced thermoregulation and spontaneous rapid body weight loss of aging F344 rats.
We previously showed that, although cold-induced thermoregulation is attenuated in 26-mo-old male Fischer 344 (F344) rats, not all rats this age exhibit the same degree of cold-exposed hypothermia or diminished brown adipose tissue nonshivering thermogenic capacity. Examination of this heterogeneity suggested the hypothesis that it was associated with a difference in the physiological state between aged rats that were maintaining stable body weight versus those showing the rapid weight loss often occurring near the end of the rat's natural life span. To test this, we acutely exposed male F344 rats to cold (4 h at 6 degrees C) beginning at 24 mo of age. This exposure was weekly for the first 2 wk and then on alternate weeks as long as the rat's body weight was stable. If body weight progressively declined for 3-5 consecutive days, the rat's response to the acute cold exposure was again measured, as was that of two additional rats not displaying this rapid loss in body weight. If body temperature decreased during the cold exposure to intraperitoneal temperatures < or = 32.5 degrees C, the rat was killed with pentobarbital sodium and interscapular brown adipose tissue was removed. One of the age-matched controls was also killed at this time. The age at which body weight showed a spontaneous rapid decline ranged from 24.5 to 29 mos. All eight rats displaying spontaneous rapid weight loss had significant hypothermia during the acute cold exposure, whereas none of the eight weight-stable rats did. The development of hypothermia in the spontaneous rapid weight loss group was not, in general, observed before their weight loss. The weight loss and hypothermia were associated with lower levels of brown fat uncoupling protein and significant changes in body fat and protein. These data suggest that the development of senescence-related hypothermia occurs rapidly and is not a simple function of chronological age or the median life span of the animals. Furthermore, these data imply that the rate of aging in terms of maintenance of thermoregulatory homeostasis has both a gradual and rapid component, the latter being associated with a different physiological state than the former.


Clinical profile of patients with rare inherited coagulation disorders: a retrospective analysis of 67 patients from northern India.
Inherited bleeding disorders are characterized by the absence or reduced level of clotting factors, and the clinical manifestations vary according to the type and magnitude of the deficient factor. To study the clinical presentation of the rare inherited coagulation factor disorders in a tertiary care hospital and to compare the data from those reported in other populations. Sixty-seven patients, who presented to the Department of Hematology, All India Institute of Medical Sciences, New Delhi, were evaluated retrospectively from 2005 to 2011. The tests performed included platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), factors assay and clot solubility test in 5 M urea. Factor XI assays were aPTT based while factors V, VII and X assays were PT based. Male to female ratio was 2:1. The median age of onset of the first episode of bleeding was at 6 months (range, from birth to 20 years) whereas the median age of presentation to our hospital was 9 years (range, 2 months to 54 years). The most common deficient factor was factor X (43%), followed by factor XIII (27%) and factor VII (10%). There is a wide gap between the initial manifestation of the bleeding disorders and first presentation to the tertiary care hospital for assessment and treatment. Factor X deficiency is the most common among these rare coagulation disorders in our population, whereas factor VII deficiency is more common in Iranian and North American population.


Surface plasmon resonance-based highly sensitive optical touch sensor with a hybrid noise rejection scheme.
A surface plasmon resonance (SPR)-based optical touch sensor structure is proposed that provides high switch sensitivity and requires a weak activating force. Our proposed SPR-based optical touch sensor is arranged in a compact Kretschmann-Raether configuration in which the prism acting as our sensor head is coated with a metal nanofilm. Our optical-based noise rejection scheme relies on wavelength filtering, spatial filtering, and high reflectivity of the metal nanofilm, whereas our electrical-based noise reduction is obtained by means of an electrical signal filtering process. In our experimental proof of concept, a visible laser diode at a 655 nm centered wavelength and a prism made from BK7 with a 50 nm thick gold layer on the touching surface are used, showing a 7.85 dB optical contrast ratio for the first touch. An estimated weak mechanical force of <0.1 N is also observed that sufficiently activates the desired electrical load. It is tested for 51 operations without sensor malfunction under typical and very high illumination of 342 and 3000 lx, respectively. In this case, a measured average optical contrast of 0.80 dB is obtained with a +/-0.47 dB fluctuation, implying that the refractive index change in a small 3.2% of the overall active area is enough for our SPR-based optical touch sensor to function properly. Increasing optical contrast in our SPR-based optical touch sensor can be accomplished by using a higher polarization-extinction ratio and a narrower-bandwidth optical beam. A controlled environment and gold-coated surface using the thin-film sputtering technique can help improve the reliability and the durability of our SPR-based optical touch sensor. Other key features include ease of implementation, prevention of a light beam becoming incident on the user, and the ability to accept both strong and weak activating forces.


The initial effects of a sustained glenohumeral postero-lateral glide during elevation on shoulder muscle activity: A repeated measures study on asymptomatic shoulders.
Manual therapy enhances pain-free range of motion and reduces pain levels, but its effect on shoulder muscle activity is unclear. This study aimed to assess the effects of a sustained glenohumeral postero-lateral glide during elevation on shoulder muscle activity. Thirty asymptomatic individuals participated in a repeated measures study of the electromyographic activity of the supraspinatus, infraspinatus, posterior deltoid, and middle deltoid. Participants performed four sets of 10 repetitions of shoulder scaption and abduction with and without a glide of the glenohumeral joint. Repeated-measures multivariate analysis of variance (MANOVA) was used to assess the effects of movement direction (scaption and abduction), and condition (with and without glide) (within-subject factors) on activity level of each muscle (dependent variables). Significant MANOVAs were followed-up with repeated-measures one-way analysis of variance. During shoulder scaption with glide, the supraspinatus showed a reduction of 4.1% maximal isometric voluntary contraction (MVIC) (95% CI 2.4, 5.8); and infraspinatus 1.3% MVIC (95% CI 0.5, 2.1). During shoulder abduction with a glide, supraspinatus presented a reduction of 2.5% MVIC (95% CI 1.1, 4.0), infraspinatus 2.1% MVIC (95% CI 1.0, 3.2), middle deltoid 2.2% MVIC (95% CI = 0.4, 4.1), posterior deltoid 2.1% MVIC (95% CI 1.3, 2.8). In asymptomatic individuals, sustained glide reduced shoulder muscle activity compared to control conditions. This might be useful in enhancing shoulder movement in clinical populations. Reductions in muscle activity might result from altered joint mechanics, including simply helping to lift the arm, and/or through changing afferent sensory input about the shoulder.


Fusing visual and behavioral cues for modeling user experience in games.
Estimating affective and cognitive states in conditions of rich human-computer interaction, such as in games, is a field of growing academic and commercial interest. Entertainment and serious games can benefit from recent advances in the field as, having access to predictors of the current state of the player (or learner) can provide useful information for feeding adaptation mechanisms that aim to maximize engagement or learning effects. In this paper, we introduce a large data corpus derived from 58 participants that play the popular Super Mario Bros platform game and attempt to create accurate models of player experience for this game genre. Within the view of the current research, features extracted both from player gameplay behavior and game levels, and player visual characteristics have been used as potential indicators of reported affect expressed as pairwise preferences between different game sessions. Using neuroevolutionary preference learning and automatic feature selection, highly accurate models of reported engagement, frustration, and challenge are constructed (model accuracies reach 91%, 92%, and 88% for engagement, frustration, and challenge, respectively). As a step further, the derived player experience models can be used to personalize the game level to desired levels of engagement, frustration, and challenge as game content is mapped to player experience through the behavioral and expressivity patterns of each player.


Labor market outcomes and the transition to adulthood.
According to Sheldon Danziger and David Ratner, changes in the labor market over the past thirty-five years, such as labor-saving technological changes, increased globalization, declining unionization, and the failure of the minimum wage to keep up with inflation, have made it more difficult for young adults to attain the economic stability and self-sufficiency that are important markers of the transition to adulthood. Young men with no more than a high school degree have difficulty earning enough to support a family. Even though young women have achieved gains in earnings, employment, and schooling relative to men in recent decades, those without a college degree also struggle to achieve economic stability and self-sufficiency. The authors begin by describing trends in labor market outcomes for young adults-median annual earnings, the extent of low-wage work, employment rates, job instability, and the returns to education. Then they examine how these outcomes may contribute to delays in other markers of the transition to adulthood-completing an education, establishing independent living arrangements, and marrying and having children. They conclude that adverse changes in labor market outcomes are related to those delays but have not been shown to be the primary cause. Danziger and Ratner next consider several public policy reforms that might improve the economic outlook for young adults. They recommend policies that would increase the returns to work, especially for less-educated workers. They propose raising the federal minimum wage and adjusting it annually to maintain its value relative to the median wage. Expanding the Earned Income Tax Credit for childless low-wage workers, the authors say, could also raise the take-home pay of many young adult workers, with minimal adverse employment effects. New policies should also provide work opportunities for young adults who cannot find steady employment either because of poor economic conditions or because of physical and mental disabilities or criminal records that make it hard for them to work steadily even when the economy is strong. Finally, the authors recommend increasing federal Pell grants for college and improving access to credit for would-be college students to raise the educational attainment of young adults from low-income families.


Efficiency of four currently used decontamination conditionings in Romania against Aspergillus and Candida strains.
Efficacy of four commercial biocidal products (noted A to D), using manufacturers' recommendations, and a contact time of 30minutes, were evaluated in the purpose of standard SR EN1657: 2006 adapted. Were used four strains, two as reference: Aspergillus brasiliensis (niger) (ATCC 16404) and Candida albicans (ATCC 10231), and two isolates: Aspergillus flavus and respectively Aspergillus fumigatus. The inoculum plates containing Malt Extract Agar (MEA) were incubated 48h for C. albicans and 72hours for Aspergillus spp. The standard SR EN1657: 2006 adapted was conducted in two phases: the test cultures preparation and the method validation. Method validation included: the control of experimental conditions and of neutralizant solution, and the method verification. Results revealed that three from the four tested products (A, B and D) had exerted biocidal effect on the studied strains at the recommended concentrations, the registered CFU values being reduced by more than 4 log10, conversely in the case of the product (C), applied against A. fumigatus at the recommended concentration of 2%, the biocidal effect was not detected, fact confirmed also by the CFU's value (3.59 log10). The biocide retested at a greater concentration (of 5%), showed a biocidal effect against A. fumigatus after 30minutes, the CFU value being reduced, by more than 5.29 log10, evidencing the resistance emergence of A. fumigatus under the repeated pressure of biocides. It is re-confirming that merely the "chemical" defense measures to defuse the fungi's strategies become unproductive.


Age-related changes of movement patterns in discrete Fitts' task.
Inspired by the framework of dynamical system theory, we aimed at exploring how the behavioural repertoire of the sensorimotor system can be reshaped with aging. Our reasoning was founded on the assumption that, with age, some of the existing patterns can be destabilized or even lost. In the present paper, this issue was investigated through the study of age-related changes in the movement patterns that are used to perform a discrete Fitts' task. We analysed the performance of two groups of participants (young and older adults) across nine task difficulty levels, obtained via manipulation of target width. Two movement patterns were revealed by the fact that increase in the index of the difficulty (ID) was accommodated through either the lengthening of both acceleration (AT) and deceleration (DT) times (co-variation pattern), or only DT (dissociation pattern). Analysis of the discontinuity in ID-AT relation showed that young participants switched from the co-variation to the dissociation pattern as ID increased. Pattern switching was accompanied by concomitant changes in the variability of AT/DT ratio. Older adults, on the other hand, used the dissociation pattern regardless of the ID. Consequently, they showed neither an abrupt discontinuity in ID-AT relation nor significant changes in the variability of AT/DT ratio across difficulty levels. Though the dissociation pattern was adaptive in young adults for high accuracy constraints, in older adults, it compromised task performance for lower difficulty levels. These findings support the view that aging may result in a compression of the neuro-behavioural repertoire. In sensorimotor tasks, it can lead to a loss of multi-stability in terms of available movement patterns, thereby compromising the ability of the neuro-musculo-skeletal system to adapt and face task constraints.


Prevalence and coexistence of cardiovascular comorbidities among the US dyslipidemic population aged ≥ 65 years by lipid-lowering medication use status.
Using data from the 2001-2002, 2003-2004, and 2005-2006 National Health and Nutrition Examination Surveys, we generated current estimates of the prevalence and overlap of cardiovascular comorbidities among older US adults (aged ≥ 65 years) with dyslipidemia, stratified by lipid-lowering medication use. We estimated that among the 32.5 million older US adults, 67% (21.8 million) are dyslipidemic. Among these subjects, the prevalence of congestive heart failure (CHF) is 9.9% (2.2 million); coronary heart disease (CHD): 27.0% (5.9 million); history of stroke: 10.4% (2.3 million); diabetes: 26.5% (5.8 million); and ≥ 1 of these comorbidities: 51.2% (11.1 million). Among dyslipidemic subjects who are receiving lipid-lowering medication (10.4 million), these figures are CHF: 10.1% (1.0 million); CHD: 29.6% (3.1 million); history of stroke: 12.3% (1.3 million); diabetes: 31.5% (3.3 million); and ≥ 1 of these comorbidities: 55.3% (5.7 million); compared with those who are not receiving lipid-lowering medication (11.4 million), CHF: 9.8% (1.1 million); CHD: 24.7% (2.8 million); history of stroke: 8.6% (1 million); diabetes: 21.9% (2.5 million); and ≥ 1 of these comorbidities: 47.5% (5.4 million). Among older US adults with dyslipidemia, 51.2% have ≥ 1 of the cardiovascular conditions studied. Among those who are receiving lipid-lowering medication, 55.3% report having comorbidities that put them at high risk for new or recurring cardiovascular events. Even more noteworthy is that 47.5% of dyslipidemic older adults who are not taking statins also have significant comorbidities. This highlights a critical unmet medical need for this growing population, which, solely based on age, is more likely to be at risk for cardiovascular events.


General Bayesian estimation for speckle noise reduction in optical coherence tomography retinal imagery.
An important image post-processing step for optical coherence tomography (OCT) images is speckle noise reduction. Noise in OCT images is multiplicative in nature and is difficult to suppress due to the fact that in addition the noise component, OCT speckle also carries structural information about the imaged object. To address this issue, a novel speckle noise reduction algorithm was developed. The algorithm projects the imaging data into the logarithmic space and a general Bayesian least squares estimate of the noise-free data is found using a conditional posterior sampling approach. The proposed algorithm was tested on a number of rodent (rat) retina images acquired in-vivo with an ultrahigh resolution OCT system. The performance of the algorithm was compared to that of the state-of-the-art algorithms currently available for speckle denoising, such as the adaptive median, maximum a posteriori (MAP) estimation, linear least squares estimation, anisotropic diffusion and wavelet-domain filtering methods. Experimental results show that the proposed approach is capable of achieving state-of-the-art performance when compared to the other tested methods in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), edge preservation, and equivalent number of looks (ENL) measures. Visual comparisons also show that the proposed approach provides effective speckle noise suppression while preserving the sharpness and improving the visibility of morphological details, such as tiny capillaries and thin layers in the rat retina OCT images.


Multiple-relaxation-time lattice Boltzmann simulation for flow, mass transfer, and adsorption in porous media.
In this paper, to predict the dynamics behaviors of flow and mass transfer with adsorption phenomena in porous media at the representative elementary volume (REV) scale, a multiple-relaxation-time (MRT) lattice Boltzmann (LB) model for the convection-diffusion equation is developed to solve the transfer problem with an unsteady source term in porous media. Utilizing the Chapman-Enskog analysis, the modified MRT-LB model can recover the macroscopic governing equations at the REV scale. The coupled MRT-LB model for momentum and mass transfer is validated by comparing with the finite-difference method and the analytical solution. Moreover, using the MRT-LB method coupled with the linear driving force model, the fluid transfer and adsorption behaviors of the carbon dioxide in a porous fixed bed are explored. The breakthrough curve of adsorption from MRT-LB simulation is compared with the experimental data and the finite-element solution, and the transient concentration distributions of the carbon dioxide along the porous fixed bed are elaborated upon in detail. In addition, the MRT-LB simulation results show that the appearance time of the breakthrough point in the breakthrough curve is advanced as the mass transfer resistance in the linear driving force model increases; however, the saturation point is prolonged inversely.


A robust and modular synthesis of ynamides.
A flexible, modular ynamide synthesis is reported that uses trichloroethene as an inexpensive two carbon synthon. A wide range of amides and electrophiles can be converted to the corresponding ynamides, importantly including acyclic carbamates, hindered amides, and aryl amides. This method thus overcomes many of the limitations of other approaches to this useful functionality.


ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets.
Peripheral invariant NKT cells (iNKT) and CD8+ tissue-resident memory T cells (TRM) express high levels of the extracellular ATP receptor P2RX7 in mice. High extracellular ATP concentrations or NAD-mediated P2RX7 ribosylation by the enzyme ARTC2.2 can induce P2RX7 pore formation and cell death. Because both ATP and NAD are released during tissue preparation for analysis, cell death through these pathways may compromise the analysis of iNKT and CD8+ TRM Indeed, ARTC2.2 blockade enhanced recovery of viable liver iNKT and TRM The expression of ARTC2.2 and P2RX7 on distinct iNKT subsets and TRM is unclear, however, as is the impact of recovery from other nonlymphoid sites. In this study, we performed a comprehensive analysis of ARTC2.2 and P2RX7 expression in iNKT and CD8+ T cells in diverse tissues, at steady-state and after viral infection. NKT1 cells and CD8+ TRM express high levels of both ARTC2.2 and P2RX7 compared with NKT2, NKT17, and CD8+ circulating memory subsets. Using nanobody-mediated ARTC2.2 antagonism, we showed that ARTC2.2 blockade enhanced NKT1 and TRM recovery from nonlymphoid tissues during cell preparation. Moreover, blockade of this pathway was essential to preserve functionality, viability, and proliferation of both populations. We also showed that short-term direct P2RX7 blockade enhanced recovery of TRM, although to a lesser degree. In summary, our data show that short-term in vivo blockade of the ARTC2.2/P2RX7 axis permits much improved flow cytometry-based phenotyping and enumeration of murine iNKT and TRM from nonlymphoid tissues, and it represents a crucial step for functional studies of these populations.


Ultrasonographic examination of wound tracts.
To determine if ultrasonography is useful in evaluating penetrating injuries of the trunk to assess whether violation of the peritoneum or pleura has occurred. The study group was 29 patients who suffered gunshot (n = 17), stab (n = 10), or shotgun (n = 2) wounds. The abdomen was at risk in 21 injuries, the thorax in eight. The results of physical examination and plain x-rays suggested the pleura and or peritoneum might be intact in all patients. Using a 7-MHz transducer, wound tract(s) were images, looking for the presence of soft-tissue air and/or echolucent areas consistent with soft-tissue blood. Injuries were deemed extraperitoneal or extrapleural if (1) the entire tract was visualized; (2) it appeared superficial to the deepest fascial structure in that area; and (3) in shotgun injuries, all visible pellets on x-ray films were identified by ultrasound in the abdominal wall. Evidence of penetration occurred in four abdominal wounds and one thoracic wound. These were confirmed by operation in the abdominal cases and by subsequent chest x-ray examination in the one thoracic wound. The diagnosis of nonpenetration was confirmed in all the remainder by serial benign abdominal examination (n = 15), chest x-ray examination (n = 8), and laparoscopy (n = 1). Positive and negative predictive accuracy were thus 100% in this pilot series. Ultrasonographic exploration of penetrating truncal injuries is feasible and accurate. Ultrasonographic wound exploration may serve as a noninvasive and safe replacement for diagnostic laparoscopy, conventional local wound exploration, peritoneal lavage, and 6-hour chest x-rays (repeated chest x-rays taken 6 hours after initial chest x-ray examination). If used as part of the initial physical examination, cost-effectiveness can also be realized.


The impact of a palliative care unit on mortality rate and length of stay for medical intensive care unit patients.
This study evaluates the impact of a 10-bed inpatient palliative care unit (PCU) on medical intensive care unit (MICU) mortality and length of stay (LOS) for terminally ill patients following the opening of an inpatient PCU. We hypothesized that MICU mortality and LOS would be reduced through the creation of a more appropriate location of care for critically ill MICU patients who were dying. We performed a retrospective electronic database review of all MICU discharges from January 1, 2006 through December 31, 2009 (5,035 cases). Data collected included MICU mortality, MICU LOS, and mean age. The PCU opened on January 1, 2008. We compared location of death for MICU patients during the 2-year period before and the 2-year period after the opening of the PCU. Our data showed that the mean MICU mortality and MICU LOS both significantly decreased following the opening of the PCU, from 21 to 15.8% (p = 0.003), and from 4.6 to 4.0 days (p = 0.014), respectively. The creation of an inpatient PCU resulted in a statistically significant reduction in both MICU mortality rate and MICU LOS, as terminally ill patients were transitioned out of the MICU to the PCU for end-of-life care. Our data support the hypothesis that a dedicated inpatient PCU, capable of providing care to patients requiring mechanical ventilation or vasoactive agents, can protect terminally ill patients from an ICU death, while providing more appropriate care to dying patients and their loved ones.


The expression of novel membrane-type matrix metalloproteinase isoforms is required for normal development of zebrafish embryos.
Matrix metalloproteinases (MMPs) play important roles in the turnover of components of extracellular matrix (ECM) and in the processing of active and latent-signaling molecules bound to the ECM or associated with the cell surface. Through such actions, MMPs regulate a variety of cellular and developmental processes. Membrane-type matrix metalloproteinases (MT-MMPs) are of particular importance because they function in the immediate pericellular environment that modulates both cell-cell and cell-ECM interactions. In this study, we utilized zebrafish as a developmental model to study the role of MT-MMPs during early embryogenesis. We successfully isolated two isoforms of a MT-MMP homologue that are structurally similar to MT1-MMP. They have been named zebrafish MT-MMPalpha and beta. Zebrafish MT-MMPbeta is unique among vertebrate MT-MMPs in that it contains an Arg-Glu-Asp (RED) multiple-repeat motif in its linker region. Whole mount in situ analysis, RT-PCR, immunofluorescence, reporter analysis, Western blot analysis, and zymography indicated that MT-MMPalpha and beta were expressed through at least the first 72 h of development and that this expression was targeted to the cell surface. Functional studies using injection of either mRNA or morpholino antisense oligonucleotides resulted in a truncation of the cranial to caudal axis as monitored through 72 h post fertilization, indicating that zebrafish MT-MMPalpha and beta had an important role in embryonic development. Axis markers indicated that these effects likely involved processes occurring later than 10 h of embryogenesis.


Impact of Instructors' Caring on Students' Perceptions of Their Own Caring Behaviors.
The aim of this study was to identify the correlation between instructors' and students' caring behaviors and to explore the impact of instructors' caring on students' perceptions of their own caring behaviors. A descriptive, nonexperimental design was used in this study. A total of 586 student nurses from four countries (Greece, the Philippines, India, and Nigeria) were recruited to participate in this study during the months of September 2013 to January 2014. Data collection was based on interviews using two standardized questionnaires: the Nursing Students' Perception of Instructor Caring (NSPIC) and the Caring Behavior Inventory (CBI). Inferential statistics such as the Pearson r correlation and regression analysis were used to determine correlations between relevant variables. Student nurses perceived "instills confidence through caring" (mean = 4.275, SD = 0.755) as the most frequently demonstrated subscale, while "control vs. flexibility" (mean = 3.469, SD = 0.701) was the least demonstrated subscale. The highest self-reported subscale in the CBI was "assurance" (mean = 4.796, SD = 0.949), while "connectedness" (mean = 4.541, SD = 0.985) was the lowest self-rated subscale. The NSPIC correlated significantly with the CBI (r = .587, p < .001). Four of the five subscales in the NSPIC correlated significantly with the CBI when considered individually; the exception was the "Supportive learning climate" subscale (r = .009, p < .40). Among the NSPIC subscales, "instills confidence through caring" explained 32% in the CBI and "appreciation of life's meaning" explained 3% in the CBI. Instructors' caring behaviors influenced nursing students' caring behaviors positively. Through positive faculty modeling and role modeling, nursing students can be professionally trained to develop the competence of caring. The knowledge generated from this study provides direction in developing useful and effective caring strategies and curricular programs for nursing students. Understanding this concept in a cross-cultural context is necessary in order to develop an international perspective about caring, which is necessary in developing and formulating effective teaching and clinical strategies.


Atypia in nonneoplastic prostate glands after radiotherapy for prostate cancer: duration of atypia and relation to type of radiotherapy.
It is unknown how long postradiation atypia of benign prostate glands persists and whether the type of radiation is a factor. Forty-four cases consisting of 37 needle biopsies and 7 transurethral resections of the prostate seen in consultation (January 1997 to September 2000) were studied. In two men (5%), the cases were initially sent without a history of radiotherapy. Thirteen patients had minimal cancer (one core) with the remaining showing no residual tumor. Twenty patients were treated with interstitial radiotherapy (brachytherapy) (IRT), 17 with external beam radiation (XRT), and 7 with a combination of both (CT). The time interval between the treatment and tissue sampling ranged from 8 to 72 months (mean 3 months). Slides were reviewed blindly to the type of radiation and the time interval. Radiation-induced atypia in nonneoplastic glands, stromal fibrosis, and vascular changes was scored separately 0-3, with 0 showing no radiation injury and grade 3 showing prominent nuclear atypia, stromal fibrosis, and vascular hyalinization. We derived a combined score for the epithelial atypia from 0 to 300 (% of glands x grade) for each biopsy. For each case, an overall grade from 0 to 3 was given separately for the stromal and vascular changes. Cases were divided into three groups based on time between treatment and biopsy: <24 months (n = 14), between 24 and 48 months (n = 19), and >48 months (n = 11). Because the scores for epithelial atypia with IRT and CT were the same, we combined them into one group. There was more atypia in cases treated with IRT/CT (mean score 190) than XRT (mean score 105) (p <0.00001). There was also a greater degree of stromal fibrosis with IRT/CT than XRT (p <0.04). There was no correlation between the type of treatment and the effect on vessels. There was no change over time in epithelial atypia in men treated with IRT/CT. With XRT, there was less epithelial atypia in cases biopsied >48 months after treatment (mean score 57) compared with those with a shorter interval between biopsy and treatment (mean score 132) (p = 0.02). Radiation atypia in benign prostate glands may persist for a long time after the initial treatment, resulting in a significant pitfall in evaluating prostate biopsies. Prominent radiation effect (100% of the glands showing grade 2 and 3 atypia) was detected up to 72 months in one of the patients treated with IRT. In some cases, the clinician may not be aware of a prior remote history of radiation or does not relay this history to the pathologist. The pathologist must recognize radiation atypia without relying on the clinician to provide this history. The type of radiation therapy (IRT/CT vs XRT) is a major factor in the degree and duration of postradiation epithelial atypia.


Podoconiosis in Ethiopia: From Neglect to Priority Public Health Problem.
Podoconiosis is a geochemical disease occurring in individuals exposed to red clay soil of volcanic origin. This Neglected Tropical Disease (NTD) is highly prevalent in Ethiopia. According to the nationwide mapping in 2013, the disease is endemic in 345 districts, where an estimated 35 million people live. The government of Ethiopia prioritized podoconiosis as one of eight priority NTDs and included it in the national integrated master plan for NTDs. An integrated lymphoedema management guideline has been developed. Service expansion has continued in the last few years and lymphoedema management services have been expanded to over one hundred endemic districts. The last few years have been critical in generating evidence about the distribution, burden and effective interventions for podoconiosis in Ethiopia. Although the extent of the problem within Ethiopia is considerable, the country is well positioned to now scale-up elimination efforts. Given the extraordinary progress of the past ten years and the current commitment of government, private and third sectors, Ethiopia seems to be on course for the elimination of podoconiosis in our lifetime. We need continued strong partner commitment, evidence-building, and scale-up of activities to accomplish this.


[Positive interaction between immunosuppressive and antifungal drugs].
Immunosuppressive and antifungal drugs are frequently associated to treat solid organ transplant patients or patients with hematological malignancies. To cure invasive fungal infection (IFI), immunosuppression has to be reduced. However, immunosuppressive drugs such as cyclosporin A, tacrolimus, sirolimus (rapamycin) or mycophenolate mofetil possess antifungal properties. Indeed fungi and humans have in common calcineurin and TOR signalization pathways which are inhibited by these molecules. In vitro experiences suggest a positive interaction between immunosuppressive and antifungal drugs such as amphotericin B, azole and echinocandins. These results are confirmed by clinical findings and thus offer further therapeutic possibilities in the context of solid organ transplantation. double dagger.


Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection.
Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs.


Effects of phonological similarity and concurrent irrelevant articulation on short-term-memory recall of repeated and novel word lists.
The extent to which phonological similarity of list words impairs short-term-memory recall was investigated in two experiments. Experiment 1 showed that the phonological-similarity effect occurred both when list words were repeatedly sampled from a small set and when they were new on every trial, both when word-order information was required and when it was not. Furthermore, the adverse effect of phonological similarity on recall was apparent on the initial lists recalled, did not change over trials, and cannot be attributed to increasing levels of proactive inhibition across lists. In Experiment 2, subjects were required to count repeatedly to six during list presentation. Concurrent irrelevant articulation lowered recall and abolished the phonological-similarity effect for both repeated and novel word lists.


Lactobacillus helveticus Lafti L10 supplementation reduces respiratory infection duration in a cohort of elite athletes: a randomized, double-blind, placebo-controlled trial.
A randomized, double-blind, placebo-controlled study was conducted to evaluate if Lactobacillus helveticus Lafti L10 (Lallemand Health Solutions, Montreal, Que., Canada) supplementation during 14 weeks in winter can influence the duration, severity, and incidence of upper respiratory tract illness (URTI), as well as to monitor different immune parameters in the population of elite athletes. Before and after the treatment, cardiopulmonary testing and self-rated state of moods evaluation (by Profile of Mood States questionnaire) were performed and blood samples were collected. Thirty-nine elite athletes were randomized either to the placebo (n = 19) or the probiotic (n = 20) group. The probiotic group received L. helveticus Lafti L10, 2 × 10(10) Colony Forming Units. Lafti L10 significantly shortened the URTI episode duration (7.25 ± 2.90 vs. 10.64 ± 4.67 days, p = 0.047) and decreased the number of symptoms in the probiotic group (4.92 ± 1.96 vs. 6.91 ± 1.22, p = 0.035). Severity and incidence of URTI did not differ between the treatments. There were no significant changes in leukocyte subpopulation abundance, transforming growth factor-β serum levels, level of interleukin-10 secreted from peptidoglican stimulated peripheral blood mononuclear cells (PBMCs), interferon-γ level secreted from concanavalin A-stimulated PBMCs or viability/proliferation of PBMCs upon antigen stimulation. Group effect for CD4+/CD8+ ratio was significant (F[1,37] = 6.99, p = 0.020, η(2) = 0.350); this difference was not significant at baseline, but was evident after 14 weeks (p = 0.02). A significant interaction effect was noted for self-rated sense of vigor (F[1,37] = 11.76, p = 0.009, η(2) = 0.595). Self-rated sense of vigor increased in the probiotic group (18.5 ± 4.1 vs. 21.0 ± 2.6, p = 0.012). Probiotic strain Lafti L10 can be a beneficial nutritional supplement for the reduction of URTI length in elite athletes.


Generation and Oxidative Reactivity of a Ni(II) Superoxo Complex via Ligand-Based Redox Non-Innocence.
Metal ligand cooperativity is a powerful strategy in transition metal chemistry. This type of mechanism for the activation of O2 is best exemplified by heme centers in biological systems. While aerobic oxidations with Fe and Cu are well precedented, Ni-based oxidations are frequently less common due to less-accessible metal-based redox couples. Some Ni enzymes utilize special ligand environments for tuning the Ni(II)/(III) redox couple such as strongly donating thiolates in Ni superoxide dismutase. A recently characterized example of a Ni-containing protein, however, suggests an alternative strategy for mediating redox chemistry with Ni by utilizing ligand-based reducing equivalents to enable oxygen binding. While this mechanism has little synthetic precedent, we show here that Ni complexes of the redox-active ligand tBu,TolDHP (tBu,TolDHP = 2,5-bis((2-t-butylhydrazono)(p-tolyl)methyl)-pyrrole) activate O2 to generate a Ni(II) superoxo complex via ligand-based electron transfer. This superoxo complex is competent for stoichiometric oxidation chemistry with alcohols and hydrocarbons. This work demonstrates that coupling ligand-based redox chemistry with functionally redox-inactive Ni centers enables oxidative transformations more commonly mediated by metals such as Fe and Cu.


Why the embryo still matters: CSF and the neuroepithelium as interdependent regulators of embryonic brain growth, morphogenesis and histiogenesis.
The key focus of this review is that both the neuroepithelium and embryonic cerebrospinal fluid (CSF) work in an integrated way to promote embryonic brain growth, morphogenesis and histiogenesis. The CSF generates pressure and also contains many biologically powerful trophic factors; both play key roles in early brain development. Accumulation of fluid via an osmotic gradient creates pressure that promotes rapid expansion of the early brain in a developmental regulated way, since the rates of growth differ between the vesicles and for different species. The neuroepithelium and ventricles both contribute to this growth but by different and coordinated mechanisms. The neuroepithelium grows primarily by cell proliferation and at the same time the ventricle expands via hydrostatic pressure generated by active transport of Na(+) and transport or secretion of proteins and proteoglycans that create an osmotic gradient which contribute to the accumulation of fluid inside the sealed brain cavity. Recent evidence shows that the CSF regulates relevant aspects of neuroepithelial behavior such as cell survival, replication and neurogenesis by means of growth factors and morphogens. Here we try to highlight that early brain development requires the coordinated interplay of the CSF contained in the brain cavity with the surrounding neuroepithelium. The information presented is essential in order to understand the earliest phases of brain development and also how neuronal precursor behavior is regulated.


Defining "high quality" food resources of herbivores: the case for meadow voles (Microtus pennsylvanicus).
Food availability, food utilization patterns and levels of some nutritional factors in plants were studied in 1984-85 in an old-field community supporting low to moderate densities of meadow voles (Microtus pennsylvanicus). Food choice and preference indices were positively related to levels of proteins, and negatively related to levels of total phenolics and ADL fibers in plants. High quality resources for voles were resources that had the highest amount of proteins, and the lowest level of total phenolics and ADL fibers among available plant species. There were only two plants species among the available ones that possessed these characteristics, Festuca rubra and Vicia cracca and they represented 25 to 50% of the available biomass during summer. Vole densities of up to 64 animals/ha were therefore not limited by the availability of high quality resources. Fecal analyses performed on 267 animals in 1984 and 269 voles in 1985 showed that all voles ate high quality resources. Meadow voles appear to choose foods with high protein content and low levels of digestion inhibitors, and not on the basis of caloric content or availability. These observations contradict predictions arising from current antiherbivore hypotheses and lead us to reconsider these models in light of this new evidence.


DHA Reduces Oxidative Stress after Perinatal Asphyxia: A Study in Newborn Piglets.
Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurological morbidity in infants and children. Oxidative stress due to free radical formation and the initiation of abnormal oxidative reactions appears to play a key role. Docosahexanoic acid (DHA), a main component of brain membrane phospholipids, may act as a neuroprotectant after hypoxia-ischemia by regulating multiple molecular pathways and gene expression. The aims of this study were to test the hypothesis that DHA provides significant protection against lipoperoxidation damage in the cerebral cortex and hippocampus in a neonatal piglet model of severe hypoxia-reoxygenation. Newborn piglets, Noroc (LYLD), were subjected to severe global hypoxia. One group was resuscitated with ambient air (21% group, n = 11) and another also received 5 mg/kg of DHA 4 h after the end of hypoxia (21% DHA group, n = 10). After 9.5 h, tissues from the prefrontal cortex and hippocampus were sampled and the levels of isoprostanes, neuroprostanes, neurofurans, and F2-dihomo-isoprostanes were determined by the liquid chromatography triple quadrupole mass spectrometry technique. Lipid peroxidation biomarkers were significantly lower in both the cortex and hippocampus in the DHA-treated group compared with the untreated group. The present study demonstrates that DHA administration after severe hypoxia in newborn piglets has an antioxidative effect in the brain, suggesting a protective potential of DHA if given after injuries to the brain.


Polyfluorinated carba-closo-dodecaboranes with amino and ammonio substituents bonded to boron.
The inner salts x-H3N-closo-1-CB11H11 (x = 12, 2) and 7-H3N-12-F-closo-1-CB11H11 were fluorinated with elemental fluorine in anhydrous hydrogen fluoride to give the B-perfluorinated ammonio derivatives 1-H-x-H3N-closo-1-CB11F10 (x = 12, 7, 2). Deprotonation of the ammonio group yielded the corresponding amino-functionalized anions [1-H-x-H2N-closo-1-CB11F10](-) (x = 12, 7, 2) that were isolated as [Et4N](+) salts. Hydrolysis of the highly fluorinated inner salts 1-H-x-H3N-closo-1-CB11F10 (x = 12, 7, 2) is very slow in acidic aqueous solutions. This stability of the ammonio derivatives is unprecedented because the related fluorinated anion [1-H2N-closo-1-CB11F11](-) is immediately hydrolyzed to simple boron species in the presence of aqueous acids. The ammonio derivatives 1-H-x-H3N-closo-1-CB11F10 (x = 12, 7, 2) are much more acidic compared to their non-fluorinated counterparts as assessed from potentiometric titrations and DFT calculations. The inner salts and the anions were characterized by NMR and vibrational sepectroscopy. Solid-sate structures of 1-H-12-H3N-closo-1-CB11F10·H2O, 1-H-7-H3N-closo-1-CB11F10·diglyme, 1-H-2-H3N-closo-1-CB11F10·0.5H2O, 7-H3N-12-F-closo-1-CB11H10·(CH3)2CO and [Et4N][1-H-12-H2N-closo-1-CB11F10] were determined by single-crystal X-ray diffraction.


Structural and functional differences in two cyclic bacteriocins with the same sequences produced by lactobacilli.
Lactobacillus gasseri LA39 and L. reuteri LA6 isolated from feces of the same human infant were found to produce similar cyclic bacteriocins (named gassericin A and reutericin 6, respectively) that cannot be distinguished by molecular weights or primary amino acid sequences. However, reutericin 6 has a narrower spectrum than gassericin A. In this study, gassericin A inhibited the growth of L. reuteri LA6, but reutericin 6 did not inhibit the growth of L. gasseri LA39. Both bacteriocins caused potassium ion efflux from indicator cells and liposomes, but the amounts of efflux and patterns of action were different. Although circular dichroism spectra of purified bacteriocins revealed that both antibacterial peptides are composed mainly of alpha-helices, the spectra of the bacteriocins did not coincide. The results of D- and L-amino acid composition analysis showed that two residues and one residue of D-Ala were detected among 18 Ala residues of gassericin A and reutericin 6, respectively. These findings suggest that the different D-alanine contents of the bacteriocins may cause the differences in modes of action, amounts of potassium ion efflux, and secondary structures. This is the first report that characteristics of native bacteriocins produced by wild lactobacillus strains having the same structural genes are influenced by a difference in D-amino acid contents in the molecules.


Dementia special care units in residential care communities: United States, 2010.
In 2010, 17% of residential care communities had dementia special care units. Beds in dementia special care units accounted for 13% of all residential care beds. Residential care communities with dementia special care units were more likely than those without to have more beds, be chain-affiliated, and be purposely built as a residential care community, and less likely to be certified or registered to participate in Medicaid. Residential care communities with dementia special care units were more likely than those without to be located in the Northeast and in a metropolitan statistical area, and less likely to be in the West. Assisted living and similar residential care communities provide an alternative to nursing homes for individuals with dementia who can no longer live independently. In 2010, about 42% of individuals living in residential care communities had Alzheimer's disease or other dementia. Individuals with dementia can live in residential care communities that have dementia special care units, or in a more traditional setting where these residents are integrated with residents without dementia. Many states require residential care communities with dementia special care units to have certain physical features (e.g., locked door) and specially trained staff to care for residents with dementia. This report compares residential care communities with and without dementia special care units.


The functional recovery of peripheral nerves following defined acute crush injuries.
This study evaluates the effect of crushing load on functional recovery of the sciatic nerve. Male Sprague-Dawley rats were divided into five groups: sham operation, resected sciatic nerve, and 100 g (13 mm Hg/mm2), 500 g (50 mm Hg/mm2), and 15,000 g (1,000 mm Hg/mm2) of sciatic crush load (groups 1-5). In groups 3-5, a 5-mm segment of sciatic nerve was crushed for 10 min using a specially designed crushing device. Motor functional recovery was assessed from hind-limb walking tracks by calculating a sciatic functional index. There was no detectable functional deficit in the group receiving sham operations, while the resected sciatic nerve group exhibited complete dysfunction for the full duration of the experiment. All groups subjected to crush exhibited an initial deficit that gradually recovered to normal by day 14 (100-g crush), day 39 (500-g crush), and day 53 (15,000-g crush). Histological changes were also related to the initial crushing load and the length of the recovery period. Results indicate that the crushing device described is able to administer an adjustable, defined crush injury to the rat sciatic nerve, and that the functional deficit resulting from such an injury can be easily monitored with a sciatic functional index. The rate of recovery of crushed nerves was directly related to the initial load. All crushed nerves recovered in this experiment, even after the application of a 15,000-g load for 10 min.


Association of microvascular and capillary-lymphatic invasion with outcome in patients with renal cell carcinoma.
We evaluated the association of microvascular and capillary-lymphatic invasion with patient outcome after nephrectomy for renal cell carcinoma. We identified 1,433 patients surgically treated for sporadic, unilateral renal cell carcinoma between 2001 and 2008. All specimens were reviewed by a single uropathologist for microvascular and capillary-lymphatic invasion. Associations with time to metastasis and death from renal cell carcinoma were evaluated using Cox proportional hazards models, controlling for established clinicopathological prognostic variables. Microvascular invasion and capillary-lymphatic invasion were identified in 119 (11%) and 17 (2%) of the 1,103 patients with clear cell, 5 (2%) and 1 (less than 1%) of the 219 with papillary, and 1 (1%) and 0 of the 86 with chromophobe renal cell carcinoma, respectively. Median followup in survivors was 6.4 years (range 0 to 11). In clear cell renal cell carcinoma cases microvascular invasion was univariately associated with an increased risk of metastasis and cancer specific death (HR 3.5 and 3.0, respectively, each p <0.001). However, on multivariate analysis these associations were no longer statistically significant (HR 1.2, p = 0.4 and HR 1.3, p = 0.1, respectively). Capillary-lymphatic invasion remained significantly associated with an increased risk of metastasis and death on univariate analysis (HR 15.9 and 11.6) and on multivariate analysis (HR 3.2 and HR 3.1, respectively, each p <0.001). Microvascular invasion is associated with an increased risk of metastasis and cancer death in patients with clear cell renal cell carcinoma, although this did not remain significant after controlling for established prognostic variables. Capillary-lymphatic invasion appears to be independently associated with metastasis and cancer death even after controlling for known prognostic risk factors. However, given its rarity, this feature may prove to be of limited clinical significance.


New strong cement materials: chemically bonded ceramics.
New cements developed in recent years have strengths that are greater by an order of magnitude than those of conventional hydraulic cements. These low-temperature materials, whose strengths approach those of many traditional high-temperature ceramics, are termed chemically bonded ceramics. The different routes to generating strong cementitious materials, including warm pressing, chemical modification, high-shear mixing with polymer additions, and the making of fiber and particulate composites, are reviewed. Strength, toughness, durability, impermeability, and abrasion resistance of these new materials have been greatly improved, as have certain electrical and acoustical properties.


Cross-sectional validation of the Aging Perceptions Questionnaire: a multidimensional instrument for assessing self-perceptions of aging.
Self-perceptions of aging have been implicated as independent predictors of functional disability and mortality in older adults. In spite of this, research on self-perceptions of aging is limited. One reason for this is the absence of adequate measures. Specifically, there is a need to develop a measure that is theoretically-derived, has good psychometric properties, and is multidimensional in nature. The present research seeks to address this need by adopting the Self-Regulation Model as a framework and using it to develop a comprehensive, multi-dimensional instrument for assessing self-perceptions of aging. This study describes the validation of this newly-developed instrument, the Aging Perceptions Questionnaire (APQ). Participants were 2,033 randomly selected community-dwelling older (+65 yrs) Irish adults who completed the APQ alongside measures of physical and psychological health. The APQ assesses self-perceptions of aging along eight distinct domains or subscales; seven of these examine views about own aging, these are: timeline chronic, timeline cyclical, consequences positive, consequences negative, control positive, control negative, and emotional representations; the eighth domain is the identity domain and this examines the experience of health-related changes. Mokken scale analysis showed that the majority of items within the views about aging subscales were strongly scalable. Confirmatory factor analysis also indicated that the model provided a good fit for the data. Overall, subscales had good internal reliabilities. Hierarchical linear regression was conducted to investigate the independent contribution of APQ subscales to physical and psychological health and in doing so determine the construct validity of the APQ. Results showed that self-perceptions of aging were independently related to physical and psychological health. Mediation testing also supported a role for self-perceptions of aging as partial mediators in the relationship between indices of physical functioning and physical and psychological health outcomes. Findings support the complex and multifaceted nature of the aging experience. The good internal reliability and construct validity of the subscales suggests that the APQ is a promising instrument that can enable a theoretically informed, multidimensional assessment of self-perceptions of aging. The potential role of self-perceptions of aging in facilitating physical and psychological health in later life is also highlighted.


Profile of non-communicable disease risk factors among adults in the Republic of Palau: findings of a national STEPS survey.
Palau, similar to other Pacific island countries, is currently highly burdened with non-communicable diseases (NCDs). The WHO STEPS was launched in 2011 to comprehensively survey indicators for NCDs in the country. This paper aims to describe the prevalence of key NCD risk factors assessed by the survey. The WHO instrument, including behavioral, physical and biochemical measurements, was adopted to the nationwide survey for all residents aged 25 to 64 years. A cluster-based sampling method was performed to obtain a national representative data. Valid data from 2,184 individuals were selected for the analyses, of which 75% were Palauans and 19% were Filipinos. Prevalence of current cigarette smoking was 25% in men and 10% in women. Betel nut chewing with tobacco was prevalent particularly among Palauans (58% in men, 69% in women) compared to the other ethnic groups. In terms of all types of tobacco use, 60% of men and 58% of women were current users. Overweight or obesity was very common among Palauans (84% in men, 86% in women) as well as Filipinos (52% in men, 40% in women). Hypertension was found in 55% of men and 49% of women, with the stage 2 hypertension being 21% and 19%, respectively. The prevalence of diabetic level hyperglycemia was more than 20%. Raised total cholesterol was detected in 16% of men and 20% of women. This survey revealed an alarmingly high prevalence of NCD risk factors, especially tobacco use, obesity, hypertension and raised blood glucose. The data would be useful baseline information to develop effective NCD strategies in Palau.


A critical assessment of mortality statistics in Thailand: potential for improvements.
This study evaluates the collection and flow of mortality and cause-of-death (COD) data in Thailand, identifying areas of weakness and presenting potential approaches to improve these statistics. Methods include systems analysis, literature review, and the application of the Health Metrics Network (HMN) self-assessment tool by key stakeholders. We identified two weaknesses underlying incompleteness of death registration and inaccuracy of COD attribution: problems in recording events or certifying deaths, and problems in transferring information from death certificates to death registers. Deaths occurring outside health facilities, representing 65% of all deaths in Thailand, contribute to the inaccuracy of cause-of-death data because they must be certified by village heads with limited knowledge and expertise in cause-of-death attribution. However, problems also exist with in-hospital cause-of-death certification by physicians. Priority should be given to training medical personnel in death certification, review of medical records by health personnel in district hospitals, and use of verbal autopsy techniques for assessing internal consistency. This should be coupled with stronger collaboration with district registrars for the 65% of deaths that occur outside hospitals. Training of physicians and data coders and harmonization of death certificates and registries would improve COD data for the 35% of deaths that take place in hospital. Public awareness of the importance of registering all deaths and the application of registration requirements prior to funerals would also improve coverage, though enforcement would be difficult.


Assessing the progression of chronic periodontitis using subgingival pathogen levels: a 24-month prospective multicenter cohort study.
The diagnosis of the progression of periodontitis presently depends on the use of clinical symptoms (such as attachment loss) and radiographic imaging. The aim of the multicenter study described here was to evaluate the diagnostic use of the bacterial content of subgingival plaque recovered from the deepest pockets in assessing disease progression in chronic periodontitis patients. This study consisted of a 24-month investigation of a total of 163 patients with chronic periodontitis who received trimonthly follow-up care. Subgingival plaque from the deepest pockets was recovered and assessed for bacterial content of Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans using the modified Invader PLUS assay. The corresponding serum IgG titers were measured using ELISA. Changes in clinical parameters were evaluated over the course of 24 months. The sensitivity, specificity, and prediction values were calculated and used to determine cutoff points for prediction of the progression of chronic periodontitis. Of the 124 individuals who completed the 24-month monitoring phase, 62 exhibited progression of periodontitis, whereas 62 demonstrated stable disease. The P. gingivalis counts of subgingival plaque from the deepest pockets was significantly associated with the progression of periodontitis (p < 0.001, positive predictive value = 0.708). The P. gingivalis counts of subgingival plaque from the deepest pockets may be associated with the progression of periodontitis.


The quality of antimalarials available in Yemen.
Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine) available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only) in comparison to standard specifications for these products in the relevant pharmacopoeia. The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This appears to be due to non-compliance with Good Manufacturing Practice guidelines by manufacturers in the production of the antimalarials.


Early transcriptional changes in the reef-building coral Acropora aspera in response to thermal and nutrient stress.
Changes to the environment as a result of human activities can result in a range of impacts on reef building corals that include coral bleaching (reduced concentrations of algal symbionts), decreased coral growth and calcification, and increased incidence of diseases and mortality. Understanding how elevated temperatures and nutrient concentration affect early transcriptional changes in corals and their algal endosymbionts is critically important for evaluating the responses of coral reefs to global changes happening in the environment. Here, we investigated the expression of genes in colonies of the reef-building coral Acropora aspera exposed to short-term sub-lethal levels of thermal (+6°C) and nutrient stress (ammonium-enrichment: 20 μM). The RNA-Seq data provided hundreds of differentially expressed genes (DEGs) corresponding to various stress regimes, with 115 up- and 78 down-regulated genes common to all stress regimes. A list of DEGs included up-regulated coral genes like cytochrome c oxidase and NADH-ubiquinone oxidoreductase and up-regulated photosynthetic genes of algal origin, whereas coral GFP-like fluorescent chromoprotein and sodium/potassium-transporting ATPase showed reduced transcript levels. Taxonomic analyses of the coral holobiont disclosed the dominant presence of transcripts from coral (~70%) and Symbiodinium (~10-12%), as well as ~15-20% of unknown sequences which lacked sequence identity to known genes. Gene ontology analyses revealed enriched pathways, which led to changes in the dynamics of protein networks affecting growth, cellular processes, and energy requirement. In corals with preserved symbiont physiological performance (based on Fv/Fm, photo-pigment and symbiont density), transcriptomic changes and DEGs provided important insight into early stages of the stress response in the coral holobiont. Although there were no signs of coral bleaching after exposure to short-term thermal and nutrient stress conditions, we managed to detect oxidative stress and apoptotic changes on a molecular level and provide a list of prospective stress biomarkers for both partners in symbiosis. Consequently, our findings are important for understanding and anticipating impacts of anthropogenic global climate change on coral reefs.


Acupuncture as pain relief during delivery: a randomized controlled trial.
Many women need some kind of analgesic treatment to relieve pain during childbirth. The objective of our study was to compare the effect of acupuncture with transcutaneous electric nerve stimulation (TENS) and traditional analgesics for pain relief and relaxation during delivery with respect to pain intensity, birth experience, and obstetric outcome. A randomized controlled trial was conducted with 607 healthy women in labor at term who received acupuncture, TENS, or traditional analgesics. Primary outcomes were the need for pharmacological and invasive methods, level of pain assessed by a visual analogue scale, birth experience and satisfaction with delivery, and pain relief evaluated at 2 months postpartum. Secondary obstetric outcomes were duration of labor, use of oxytocin, mode of delivery, postpartum hemorrhage, Apgar score, and umbilical cord pH value. Analysis complied with the intention-to-treat principle. Use of pharmacological and invasive methods was significantly lower in the acupuncture group (acupuncture vs traditional, p < 0.001; acupuncture vs TENS, p = 0.031). Pain scores were comparable. Acupuncture did not influence the duration of labor or the use of oxytocin. Mean Apgar score at 5 minutes and umbilical cord pH value were significantly higher among infants in the acupuncture group compared with infants in the other groups. Acupuncture reduced the need for pharmacological and invasive methods during delivery. Acupuncture is a good supplement to existing pain relief methods.


Salivary cortisol levels in children adopted from romanian orphanages.
Six and a half years after adoption. 6- to 12-year-old children reared in Romanian orphanages for more than 8 months in their first years of life (RO. n = 18) had higher cortisol levels over the daytime hours than did early adopted (EA, < or = 4 months of age, n = 15) and Canadian born (CB, n = 27) children. The effect was marked, with 22% of the RO children exhibiting cortisol levels averaged over the day that exceeded the mean plus 2 SD of the EA and CB levels. Furthermore, the longer beyond 8 months that the RO children remained institutionalized the higher their cortisol levels. Cortisol levels for EA children did not differ in any respect from those of CB comparison children. This latter finding reduces but does not eliminate concerns that the results could be due to prenatal effects or birth family characteristics associated with orphanage placement. Neither age at cortisol sampling nor low IQ measured earlier appeared to explain the findings. Because the conditions in Romanian orphanages at the time these children were adopted were characterized by multiple risk factors, including gross privation of basic needs and exposure to infectious agents, the factor(s) that produced the increase in cortisol production cannot be determined. Nor could we determine whether these results reflected effects on the limbic-hypothalamic-pituitary-adrenal axis directly or were mediated by differences in parent-child interactions or family stress occasion by behavioral problems associated with prolonged orphanage care in this sample.


Newspaper reporting of screening mammography.
Continuing controversy surrounds screening mammography, particularly for women 40 to 49 years of age. Newspapers are potentially important sources of information on this topic, but it is not known whether they provide well-founded and objective information and recommendations. To examine how screening mammography is reported in newspapers. Cross-sectional descriptive study. 6 top-circulation U.S. newspapers, 1990 to 1997. Number of articles about screening mammography, issues covered by the articles, information sources, content and sources of quotes, recommendations cited in articles, and presentation of risks and benefits. The most common theme of newspaper articles about mammography was screening for women 40 to 49 years of age. Thirty-one percent of the articles presented information without citing a source or justification. Quotes and recommendations in the articles were approximately twice as likely to support as to express reservations about mammography for women aged 40 to 49 years. Recommendations changed little over time and rarely reflected changes in recommendations of national organizations. Of the 102 articles describing the benefits of mammography, 95% expressed them in relative terms and 11% expressed them in absolute terms. Newspapers tended to overrepresent support for screening mammography for women aged 40 to 49 years. Reports would have been improved by identification of all sources for information cited, less reliance on relatively few sources, and discussion of benefits in absolute as well as relative terms. Medical journalism may benefit from identification of standards similar to those used for reporting medical research.


A Histogram Transform for ProbabilityDensity Function Estimation.
The estimation of multivariate probability density functions has traditionally been carried out by mixtures of parametric densities or by kernel density estimators. Here we present a new nonparametric approach to this problem which is based on the integration of several multivariate histograms, computed over affine transformations of the training data. Our proposal belongs to the class of averaged histogram density estimators. The inherent discontinuities of the histograms are smoothed, while their low computational complexity is retained. We provide a formal proof of the convergence to the real probability density function as the number of training samples grows, and we demonstrate the performance of our approach when compared with a set of standard probability density estimators.


Complementation of antigen-presenting cells to generate T lymphocytes with broad target specificity.
Antigen-specific T cells provide a therapy for cancer that is highly specific, self-replicating, and potentially devoid of toxicity. Ideally, tumor-specific T cells should recognize multiple epitopes on multiple antigens to prevent tumor immune escape. However the large-scale expansion of such broad-spectrum T cells has been limited by the availability of potent autologous antigen-presenting cells that can present antigens on the polymorphic array of each patient's HLA allotype. We evaluated a novel antigen-presenting complex (KATpx) in which antigens in the form of peptide libraries can be presented by autologous activated T cells, whereas costimulation is complemented in trans by an HLA-negative K562 cell line genetically modified to express CD80, CD83, CD86, and 4-1BBL (K562cs). The additional costimulation provided by K562cs significantly enhanced T-cell expansion in culture over autologous activated T cells alone while maintaining antigen specificity. We validated this antigen-presenting system by generating Epstein-Barr virus (EBV) antigen-specific T cells from healthy donors and from patients with EBV-positive malignancies including nasopharyngeal carcinoma and multiply relapsed EBV-positive lymphoma. These T cells were specific for EBNA1, LMP1, and LMP2, the viral antigens expressed in these type 2 latency EBV-associated malignancies. The KATpx system consistently activated and expanded antigen-specific T cells both from healthy donors and from 5 of 6 patients with lymphoma and 6 of 6 with nasopharyngeal carcinoma, while simplifying the process for generating APCs by eliminating the need for live virus (EBV) or viral vectors to force expression of transgenic EBV antigens. Hence, KATpx provides a robust, reliable, and scalable process to expand tumor-directed T cells for the treatment of virus-associated cancers.


Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress.
Fibroblast growth factor (FGF) 1 is known to be released in response to stress conditions as a component of a multiprotein aggregate containing the p40 extravescicular domain of p65 synaptotagmin (Syt) 1 and S100A13. Since FGF1 is a Cu2+-binding protein and Cu2+ is known to induce its dimerization, we evaluated the capacity of recombinant FGF1, p40 Syt1, and S100A13 to interact in a cell-free system and the role of Cu2+ in this interaction. We report that FGF1, p40 Syt1, and S100A13 are able to bind Cu2+ with similar affinity and to interact in the presence of Cu2+ to form a multiprotein aggregate which is resistant to low concentrations of SDS and sensitive to reducing conditions and ultracentrifugation. The formation of this aggregate in the presence of Cu2+ is dependent on the presence of S100A13 and is mediated by cysteine-independent interactions between S100A13 and either FGF1 or p40 Syt1. Interestingly, S100A13 is also able to interact in the presence of Cu2+ with Cys-free FGF1 and this observation may account for the ability of S100A13 to export Cys-free FGF1 in response to stress. Lastly, tetrathiomolybdate, a Cu2+ chelator, significantly represses in a dose-dependent manner the heat shock-induced release of FGF1 and S100A13. These data suggest that S100A13 may be involved in the assembly of the multiprotein aggregate required for the release of FGF1 and that Cu2+ oxidation may be an essential post-translational intracellular modifier of this process.


Clinical Outcomes of Knee Osteoarthritis Treated With an Autologous Protein Solution Injection: A 1-Year Pilot Double-Blinded Randomized Controlled Trial.
Osteoarthritis (OA) is a debilitating disease resulting in substantial pain and functional limitations. A novel blood derivative has been developed to concentrate both growth factors and antagonists of inflammatory cytokines, with promising preliminary findings in terms of safety profile and clinical improvement. To investigate if one intra-articular injection of autologous protein solution (APS) can reduce pain and improve function in patients affected by knee OA in a multicenter, randomized, double-blind, saline-controlled study. Randomized controlled trial; Level of evidence, 2. Forty-six patients with unilateral knee OA (Kellgren-Lawrence 2 or 3) were randomized into the APS group (n = 31), which received a single ultrasound-guided injection of APS, and the saline (control) group (n = 15), which received a single saline injection. Patient-reported outcomes and adverse events were collected at 2 weeks and at 1, 3, 6, and 12 months through visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), Short Form-36 (SF-36), Clinical Global Impression of Severity/Change (CGI-S/C), Patient Global Impression of Severity/Change (PGI-S/C), and Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responder rate. Imaging evaluation was also performed with radiograph and magnetic resonance imaging (MRI) before and after treatment (12 months and 3 and 12 months, respectively). The safety profile was positive, with no significant differences in frequency and severity of adverse events between groups. The improvement from baseline to 2 weeks and to 1, 3, and 6 months was similar between treatments. At 12 months, improvement in WOMAC pain score was 65% in the APS group and 41% in the saline group ( P = .02). There were no significant differences in VAS pain improvement between groups. At 12 months, APS group showed improved SF-36 Bodily Pain subscale ( P = .0085) and Role Emotional Health subscale ( P = .0410), as well as CGI-C values ( P = .01) compared with saline control. Significant differences between groups were detected in change from baseline to 12 months in bone marrow lesion size as assessed on MRI and osteophytes in the central zone of the lateral femoral condyle, both in favor of the APS group ( P = .041 and P = .032, respectively). There were no significant differences between APS and control groups in other measured secondary endpoints. This study provides evidence to support the safety and clinical improvement at 1-year follow-up of a single intra-articular injection of APS in patients affected by knee OA. Treatment with APS or a saline injection provided significant pain relief over the course of the study with differences becoming apparent at between 6 and 12 months after treatment. NCT02138890 ( ClinicalTrials.gov identifier).


Magnetic Targeting of Stem Cell Derivatives Enhances Hepatic Engraftment into Structurally Normal Liver.
Attaining consistent robust engraftment in the structurally normal liver is an obstacle for cellular transplantation. Most experimental approaches to increase transplanted cells' engraftment involve recipient-centered deleterious methods such as partial hepatectomy or irradiation which may be unsuitable in the clinic. Here, we present a cell-based strategy that increases engraftment into the structurally normal liver using a combination of magnetic targeting and proliferative endoderm progenitor (EPs) cells. Magnetic labeling has little effect on cell viability and differentiation, but in the presence of magnetic targeting, it increases the initial dwell time of transplanted EPs into the undamaged liver parenchyma. Consequently, greater cell retention in the liver is observed concomitantly with fewer transplanted cells in the lungs. These highly proliferative cells then significantly increase their biomass over time in the liver parenchyma, approaching nearly 4% of total liver cells 30 d after transplant. Therefore, the cell-based mechanisms of increased initial dwell time through magnetic targeting combined with high rate of proliferation in situ yield significant engraftment in the undamaged liver.


Micro analysis of metals in dental restorations as part of a diagnostic approach in metal allergies.
In dentistry, a variety of potentially allergenic metals are used, such as mercury, palladium, nickel, gold, chromium, cobalt and other metals. This paper describes a diagnostic approach from a dentist's point of view, which enables analysis of metals in a patient's oral cavity. If metal allergy is suspected, a micro analysis can be used to determine which metals are present in the restorations. When the exact composition of the dental materials is known, the patient can be tested in vivo (patch test) and/or in vitro (lymphocyte proliferation test) to reveal sensitization. Two patients with nickel allergy are described where removal of nickel-containing materials (bridge and orthodontic wire) resulted in the marked alleviation of symptoms and improvement of health. Finally, if allergy to specific metals has been established, the restorations containing the implicated metals should be removed to discontinue the exposure and thus facilitate the patient's health.


Knowledge, attitude and practice about breast cancer and breast self-examination among women seeking out-patient care in a teaching hospital in central India.
Breast cancer (BC) continues to be a major cause of morbidity and mortality throughout the world. Early detection of BC and early treatment increases the chance of survival. According to Breast Health Global Initiative guidelines for low and middle income countries, diagnosing BCs early by promoting breast self-awareness; clinical breast examination (CBE) and resource adapted mammographic screening will reduce BC mortality. There is a paucity of data on the knowledge and awareness of BC and self-breast examination in India. We designed this hospital based cross sectional descriptive study to evaluate the current status of knowledge, awareness and practices related to BC and breast self-examination in the female rural population attending a teaching hospital. We did a random sampling to identify and enroll 360 women and their female relatives. We excluded a participant from the study if she had already undergone a screening mammography or had had a BC. The data was collected by a self-administered questionnaire in vernacular language. Our study population included 360 women with a mean age of 45.81 (±10.9) years. Only 5 (1.38%) females had a family history of BC. A whopping 81% of women did not have any knowledge about BC. All the women thought that CBE by doctors was the only way for screening BC. We concluded that with the results of this study, it is imperative to increase awareness about BC and its detection methods in the community through health education campaigns. We should have major policy changes to increase future screening programs and health education programs which would have an overall positive impact on reducing the disease burden.


Transvaginal Resection of a Rectal Gastrointestinal Stromal Tumor: A Case Report.
Gastrointestinal stromal tumors (GISTs) are a type of mesenchymal tumors. They are rare in rectum. This location is a surgical challenge due to the high morbidity after aggressive surgeries. We present the case of an 81-year-old female with a high-grade GIST treated with transvaginal excision and adjunctive therapy with imatinib. The postoperative period was uneventful without anal dysfunction. Within the types of surgical treatment available, transvaginal excision is an acceptable procedure in lesions located in the rectovaginal region.


Regulated expression of the small nuclear ribonucleoprotein particle protein SmN in embryonic stem cell differentiation.
The SmN protein is a component of small nuclear ribonucleoprotein particles and is closely related to the ubiquitous SmB and B' splicing proteins. It is expressed in a limited range of tissues and cell types, including several undifferentiated embryonal carcinoma cell lines and undifferentiated embryonic stem cells. The protein declines to undetectable levels when embryonal carcinoma or embryonic stem cells are induced to differentiate, producing primitive endoderm or parietal endoderm or yielding embryonal bodies. This decline is due to a corresponding decrease in the level of the SmN mRNA. The potential role of SmN in the regulation of alternative splicing in embryonic cell lines and early embryos is discussed.


A white matter lesion-filling approach to improve brain tissue volume measurements.
Multiple sclerosis white matter (WM) lesions can affect brain tissue volume measurements of voxel-wise segmentation methods if these lesions are included in the segmentation process. Several authors have presented different techniques to improve brain tissue volume estimations by filling WM lesions before segmentation with intensities similar to those of WM. Here, we propose a new method to refill WM lesions, where contrary to similar approaches, lesion voxel intensities are replaced by random values of a normal distribution generated from the mean WM signal intensity of each two-dimensional slice. We test the performance of our method by estimating the deviation in tissue volume between a set of 30 T1-w 1.5 T and 30 T1-w 3 T images of healthy subjects and the same images where: WM lesions have been previously registered and afterwards replaced their voxel intensities to those between gray matter (GM) and WM tissue. Tissue volume is computed independently using FAST and SPM8. When compared with the state-of-the-art methods, on 1.5 T data our method yields the lowest deviation in WM between original and filled images, independently of the segmentation method used. It also performs the lowest differences in GM when FAST is used and equals to the best method when SPM8 is employed. On 3 T data, our method also outperforms the state-of-the-art methods when FAST is used while performs similar to the best method when SPM8 is used. The proposed technique is currently available to researchers as a stand-alone program and as an SPM extension.


OpenSlice: an OpenFlow-based control plane for spectrum sliced elastic optical path networks.
A control plane is a key enabling technique for dynamic and intelligent end-to-end path provisioning in optical networks. In this paper, we present an OpenFlow-based control plane for spectrum sliced elastic optical path networks, called OpenSlice, for dynamic end-to-end path provisioning and IP traffic offloading. Experimental demonstration and numerical evaluation show its overall feasibility and efficiency.


A principal components analysis of factors associated with successful implementation of an LVAD decision support tool.
A central goal among researchers and policy makers seeking to implement clinical interventions is to identify key facilitators and barriers that contribute to implementation success. Despite calls from a number of scholars, empirical insights into the complex structural and cultural predictors of why decision aids (DAs) become routinely embedded in health care settings remains limited and highly variable across implementation contexts. We examined associations between "reach", a widely used indicator (from the RE-AIM model) of implementation success, and multi-level site characteristics of nine LVAD clinics engaged over 18 months in implementation and dissemination of a decision aid for left ventricular assist device (LVAD) treatment. Based on data collected from nurse coordinators, we explored factors at the level of the organization (e.g. patient volume), patient population (e.g. health literacy; average sickness level), clinician characteristics (e.g. attitudes towards decision aid; readiness for change) and process (how the aid was administered). We generated descriptive statistics for each site and calculated zero-order correlations (Pearson's r) between all multi-level site variables including cumulative reach at 12 months and 18 months for all sites. We used principal components analysis (PCA) to examine any latent factors governing relationships between and among all site characteristics, including reach. We observed strongest inclines in reach of our decision aid across the first year, with uptake fluctuating over the second year. Average reach across sites was 63% (s.d. = 19.56) at 12 months and 66% (s.d. = 19.39) at 18 months. Our PCA revealed that site characteristics positively associated with reach on two distinct dimensions, including a first dimension reflecting greater organizational infrastructure and standardization (characteristic of larger, more established clinics) and a second dimension reflecting positive attitudinal orientations, specifically, openness and capacity to give and receive decision support among coordinators and patients. Successful implementation plans should incorporate specific efforts to promote supportive and mutually informative interactions between clinical staff members and to institute systematic and standardized protocols to enhance the availability, convenience and salience of intervention tool in routine practice. Further research is needed to understand whether "core predictors" of success vary across different intervention types.


Vibrational multilevel quantum coherence due to anharmonic couplings in intermolecular hydrogen bonds.
Femtosecond three-pulse photon-echo studies of acetic acid dimers in solution reveal multilevel coherence of O-H stretching excitations caused by the anharmonic coupling between the high-frequency stretching and low-frequency hydrogen-bond motions. We demonstrate for the first time that such multilevel coherence determines the nonexponential decay of the macroscopic O-H stretching polarization, whereas spectral diffusion processes play a minor role. The dephasing time of individual vibrational transitions contributing to the overall polarization is approximately 200 fs.


[Restless legs due to ingestion of 'light' beverages containing saccharine; results of an N-of-1 trial].
To determine whether there was a connection between the complaint of restless legs and the ingestion of artificial sweeteners in a patient with these symptoms after drinking certain 'light' beverages. Randomised, double-blind, placebo-controlled N-of-1 trial with a cross-over design. During a period of 48 days, the patient took 4 capsules per day containing either 150 mg of cyclamate, 22.5 mg of saccharine, both sweeteners, or placebo on two successive days. Between each of these 2-day periods there was a 2-day rest period during which no capsules were taken. The hospital pharmacist had prepared the capsules and determined the sequence of the 2-day periods on a random basis. The patient did not know which capsules he was taking. Every day on arising, starting 3 weeks before the trial period, the patient noted the intensity and duration of the symptoms in the late evening and previous night. For this notation he used an 11-point scale, from 0 (= no restless legs) to 10 (= almost total inability to sleep because of restless legs). A score of 1-3 corresponded to mild symptoms that had no effect on the patient's sleep; at a score of 4-6 his sleep was disturbed and at a score of 7-10 the patient hardly slept at all. The patient had symptoms more often while using saccharine or the combination of saccharine and cyclamate than when taking the placebo (4 and 4 versus 2 ofthe 6 nights); moreover, the average score was then statistically significantly higher (5.2 and 5.8 versus 3.3). There was a connection between the patient's complaints of restless legs and the use of saccharine, but not the use of cyclamate.


Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells.
As the population ages, interest in identifying biomarkers of healthy aging and developing antiaging interventions has increased. DNA methylation has emerged as a potentially powerful molecular marker of aging. Methylation changes at specific sites in the human genome that have been identified in peripheral blood have been used as robust estimators of chronological age. Similar age-related DNA methylation signatures are also seen in various tissue types in rodents. However, whether these peripheral alterations in methylation status reflect changes that also occur in the central nervous system remains unknown. This study begins to address this issue by identifying age-related methylation patterns in the hippocampus and blood of young and old mice. Reduced-representation bisulfite sequencing (RBSS) was used to identify differentially methylated regions (DMRs) in the blood and hippocampus of 2- and 20-month-old C57/Bl6 mice. Of the thousands of DMRs identified genome-wide only five were both found in gene promoters and significantly changed in the same direction with age in both tissues. We analyzed the hippocampal expression of these five hypermethylated genes and found that three were expressed at significantly lower levels in aged mice [suppressor of fused homolog (Sufu), nitric oxide synthase 1 (Nos1) and tripartite motif containing 2 (Trim2)]. We also identified several transcription factor binding motifs common to both hippocampus and blood that were enriched in the DMRs. Overall, our findings suggest that some age-related methylation changes that occur in the brain are also evident in the blood and could have significant translational relevance.


Daily changes in synaptic innervation of VIP neurons in the rat suprachiasmatic nucleus: contribution of glutamatergic afferents.
The daily temporal organization of rhythmic functions in mammals, which requires synchronization of the circadian clock to the 24-h light-dark cycle, is believed to involve adjustments of the mutual phasing of the cellular oscillators that comprise the time-keeper within the suprachiasmatic nucleus of the hypothalamus (SCN). Following from a previous study showing that the SCN undergoes day/night rearrangements of its neuronal-glial network that may be crucial for intercellular phasing, we investigated the contribution of glutamatergic synapses, known to play major roles in SCN functioning, to such rhythmic plastic events. Neither expression levels of the vesicular glutamate transporters nor numbers of glutamatergic terminals showed nycthemeral variations in the SCN. However, using quantitative imaging after combined immunolabelling, the density of synapses on neurons expressing vasoactive intestinal peptide, known as targets of the retinal input, increased during the day and both glutamatergic and non-glutamatergic synapses contributed to the increase (+36%). This was not the case for synapses made on vasopressin-containing neurons, the other major source of SCN efferents in the non-retinorecipient region. Together with electron microscope observations showing no differences in the morphometric features of glutamatergic terminals during the day and night, these data show that the light synchronization process in the SCN involves a selective remodelling of synapses at sites of photic integration. They provide a further illustration of how the adult brain may rapidly and reversibly adapt its synaptic architecture to functional needs.


Morphology and spatial distribution of corticothalamic terminals originating from the cat auditory cortex.
In this paper we studied the morphology and spatial distribution of corticothalamic axons and terminals originating from the auditory cortical fields of the cat. The anterograde tracer biocytin was injected at electrophysiologically characterized loci in the primary (AI) (N = 2), anterior (AAF) (N = 1), posterior (PAF) (N = 1) and secondary (AII) (N = 2) auditory fields. In all cases, two different types of labeled terminals were found in the auditory thalamus: small spherical endings (1-2 microns) and giant, finger-like endings (5-10 microns). After biocytin injections in AI and AAF, the majority of anterogradely labeled axons terminated in the rostral half of the pars lateralis (LV) of the ventral division of the medial geniculate body (vMGB). In LV, the corticothalamic axons ramified profusely, giving rise to dense terminal fields forming well delineated curved stripes, with small spherical endings. Additional terminal fields formed by small endings were observed in the medial division of the medial geniculate body (mMGB). Giant endings were observed in a small area in the dorsal nucleus (D) of the dorsal division of the medial geniculate body (dMGB), near its border with the vMGB. PAF projections were located in the caudal half of vMGB and in mMGB, where only small terminals were found. Giant endings were seen in the superficial part of dMGB emerging from labeled corticothalamic axons oriented in parallel to the dorsal surface of the MGB. Projections from AII gave rise to a main terminal field of small endings in D; a second terminal field consisting of giant endings intermingled with small endings was found in the deep dorsal nucleus (DD) of dMGB. We conclude that small terminals serve the feedback projection to the thalamic nucleus from which the injected cortical field receives its main input, whereas giant terminals cross the borders between the parallel ascending auditory pathways.


The marsupial mitochondrial genome and the evolution of placental mammals.
The entire nucleotide sequence of the mitochondrial genome of the American opossum, Didelphis virginiana, was determined. Two major features distinguish this genome from those of other mammals. First, five tRNA genes around the origin of light strand replication are rearranged. Second, the anticodon of tRNA(Asp) is posttranscriptionally changed by an RNA editing process such that its coding capacity is altered. When the complete protein-coding region of the mitochondrial genome is used as an outgroup for placental mammals it can be shown that rodents represent an earlier branch among placental mammals than primates and artiodactyls and that artiodactyls share a common ancestor with carnivores. The overall rates of evolution of most of the mitochondrial genome of placentals are clock-like. Furthermore, the data indicate that the lineages leading to the mouse and rat may have diverged from each other as much as 35 million years ago.