Sex differences in verbal and spatial ability reconsidered in relation to body size, lung volume, and sex hormones.
Sex differences in verbal and nonverbal abilities were reconsidered in relation to bodily measures and sex hormones in Turkish university students. Perceptual-verbal ability was evaluated using As Test. To assess the nonverbal abilities, the mental rotation test and Cattell's Culture Fair Intelligence Test were used. As expected, the 53 women performed better than men on the As Test; 79 men had a higher mean than the 53 women on the mental rotation task; there was no sex difference on Cattell's IQ Test. Cattell IQs correlated only with tidal volume of lungs. Scores on the As Test did not show significant correlations with body size and lung capacities. Mental rotation was significantly correlated with height, weight, and lung volume. With covariates of height, weight, and vital capacity, sex differences in mental rotation completely disappeared, but the difference on the As Test increased while Cattell IQ remained sex-neutral. With testosterone as covariate, the sex difference on the As test increased but on the mental rotation task disappeared; Cattell IQ was sex-neutral. With covariates of estradiol and progesterone, sex differences on the As test disappeared; mental rotation scores and Cattell IQ were not influenced. Under a combined covariation of height, weight, and testosterone, sex differences in mental rotation reversed, women scoring better than men; after adding estradiol or progesterone instead of testosterone to this model, sex differences on mental rotation completely disappeared, but verbal ability and Cattell IQ were not changed. These results suggest that Cattell's Culture Fair Intelligence Test is unique in resistance to sex differences; perceptual-verbal ability was the most sex-specific mental trait but with dependence on estradiol; mental rotation, on the contrary, was least sex-specific, depending on body size, lung volume, sex hormones, and their combined actions, which explains women's better performance.


A population-based survey of eczema prevalence in the United States.
Eczema and atopic dermatitis (AD) are recognized as major health problems worldwide. Prevalence estimates are as high as one-third of the population, depending on the country studied, the age range of the subjects, and the diagnostic criteria used. National estimates of prevalence for the US population are lacking. To examine the public health problem posed by eczema, AD, and eczematous conditions in the United States by analyzing disease and symptom prevalence, estimating the number of undiagnosed cases, and assessing comorbidities. A self-administered questionnaire was sent to a sample of households (N = 60,000) representative of the US population. A designated member responded with information on symptoms, diagnoses, and impact for affected household members; 42,249 households (70%) responded, representing 116,202 individuals. Empirical eczema was defined by itching/scratching and red/inflamed rash or excessive dryness/scaling. Empirical AD was defined by itching/scratching and red/inflamed rash, excessive dryness/scaling, skinfold location, early onset, symptoms lasting or 14 days, or a physician diagnosis of asthma or of allergic rhinitis or hay fever. Of the population studied, 17.1% reported at least one of four eczematous symptoms; empirically defined eczema was found in 10.7%, and empirically defined AD was found in 6%. Prevalence decreased with increasing income. Approximately two-thirds of individuals with an empirical diagnosis of eczema or AD had moderate to severe symptoms, one-third had sleep disturbances, and one-quarter had chronic unremitting symptoms. Just over one-third (37.1%) of those with symptoms reported a physician diagnosis. Peak onset for empirical AD occurred in the group of subjects aged <or= 5 years. For empirical eczema, peak onset occurred in the group aged 18 to 29 years, and comorbid asthma and hay fever/allergic rhinitis were more prevalent. A substantial proportion of the US population has symptoms of eczema or eczematous conditions; 31.6 million met the empirical symptom criteria for eczema, and 17.8 million met the empirical criteria for AD. Most cases are not diagnosed by a physician, which indicates that these conditions are undertreated and/or managed with nonprescription remedies.


Evolutionary significance of cranial variation in Asian Homo erectus.
Homo erectus inhabited a wide geographic area of Asia, ranging from 40 degrees north latitude in China to 8 degrees south latitude in island Southeast Asia. Yet variation within Asian H. erectus and its relation to ecological and temporal parameters have been little studied. I synthesize the revised radiometric chronologies for hominid sites in Asia and their relation to new oxygen isotope curves (proxies for climatic fluctuations and landbridge connections). These data suggest substantial opportunities in the later Pleistocene for both regional isolation and gene flow between hominids in mainland and Southeast Asia. They also suggest that the most northerly located Chinese sites (Zhoukoudian and Nanjing) may have been occupied during sequential, interglacial periods. Probably reflecting these periods of isolation, nonmetric features and principal components analysis (PCA) of calvarial shape suggest regional differentiation between northern Asian and Southeast Asian H. erectus. The most recent Southeast Asian fossils (e.g., Ngandong) conform to the Southeast Asian pattern. Except perhaps in brain size, there is no evidence that the temporally intermediate Chinese fossils are intermediate in morphology between older and younger Indonesian fossils. In fact, northern Chinese calvaria are easier to exclude from the larger Asian H. erectus hypodigm than are the Ngandong fossils. The Chinese specimens differ from the others based on their narrower occipitals and frontals for their cranial size. The Chinese sample from Zhoukoudian alone is thus not a good proxy for the morphology and variation seen within Asian H. erectus. Both the Chinese and late Indonesian samples exhibit less variation than does the early Indonesian sample; this along with their shared morphological bauplan suggests a common origin and no more than subspecific differentiation. This shared morphology, despite regional differences, was likely maintained by the increasing intensity of multiple glaciations (and longer-lasting land bridge connections) between mainland and island Southeast Asia during the last million years.


Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance.
Diabetes is associated with defective beta cell function and altered beta cell mass. The mechanisms regulating beta cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory beta cell hyperplasia is achieved via proliferation of existing beta cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine beta cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents beta cell replication in 2 models of beta cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal beta cells. We propose that beta cell compensation to insulin resistance is a proliferative response of existing beta cells to growth factor signaling and requires FoxO1 nuclear exclusion.


Antimicrobial therapy for methicillin-resistant Staphylococcus aureus colonization in residents and staff of a Veterans Affairs nursing home care unit.
To evaluate the effect of antimicrobial therapy on patients and staff colonized with methicillin-resistant Staphylococcus aureus (MRSA) in a skilled nursing facility and to assess the role of the environment as a potential reservoir for MRSA in the nursing home setting. As part of a comprehensive program to control an MRSA outbreak in a nursing home, patients and staff colonized with MRSA received 1 of 3 antimicrobial decolonization regimens depending upon the site and extent of colonization. Followup cultures were performed during therapy and on days 2, 7, 14, and 30 following the completion of therapy. Cultures of the patients' inanimate environment (pajamas, sheet, and floor) were obtained during and after therapy. Antimicrobial susceptibility tests were performed on 54 MRSA isolates obtained before and 44 MRSA isolates recovered after therapy. A 120-bed Veterans Affairs nursing home care unit. Thirty-six patients and 7 staff nurses colonized with MRSA at 1 or more sites. Decolonization therapy with rifampin, trimethoprim-sulfamethoxazole, and clindamycin used alone or in various combinations for 5 or 10 days in conjunction with other infection control measures employed to combat the MRSA outbreak. Twenty (56%) of the 36 NHCU patients were either persistently colonized or became recolonized with MRSA during the 30-day followup period. Positive cultures on day 3 during therapy frequently identified patients who subsequently exhibited persistent or recurrent colonization. Before therapy, 92% of MRSA isolates were susceptible to rifampin, whereas only 43% of the isolates obtained after therapy were susceptible. Sixteen (80%) of 20 patients with persistent or recurrent colonization had rifampin-resistant strains of MRSA isolated after therapy. Twenty-three (18%) of 125 environmental cultures obtained during and after therapy from patients who exhibited persistent or recurrent colonization were positive for MRSA, in contrast to 9 (8%) of 107 from patients who were successfully decolonized. The decolonization component of the outbreak control program was judged to be ineffective and potentially hazardous because colonization persisted or recurred in more than half of the patients, and substantial antimicrobial resistance was noted in MRSA stains isolated after therapy. Resistance, especially to rifampin, and possibly re-acquisition of MRSA from other human or environmental sources were 2 factors that appeared to impede the decolonization effort.


Genetic architecture and genomic patterns of gene flow between hybridizing species of Picea.
Hybrid zones provide an opportunity to study the effects of selection and gene flow in natural settings. We employed nuclear microsatellites (single sequence repeat (SSR)) and candidate gene single-nucleotide polymorphism markers (SNPs) to characterize the genetic architecture and patterns of interspecific gene flow in the Picea glauca × P. engelmannii hybrid zone across a broad latitudinal (40-60 degrees) and elevational (350-3500 m) range in western North America. Our results revealed a wide and complex hybrid zone with broad ancestry levels and low interspecific heterozygosity, shaped by asymmetric advanced-generation introgression, and low reproductive barriers between parental species. The clinal variation based on geographic variables, lack of concordance in clines among loci and the width of the hybrid zone points towards the maintenance of species integrity through environmental selection. Congruency between geographic and genomic clines suggests that loci with narrow clines are under strong selection, favoring either one parental species (directional selection) or their hybrids (overdominance) as a result of strong associations with climatic variables such as precipitation as snow and mean annual temperature. Cline movement due to past demographic events (evidenced by allelic richness and heterozygosity shifts from the average cline center) may explain the asymmetry in introgression and predominance of P. engelmannii found in this study. These results provide insights into the genetic architecture and fine-scale patterns of admixture, and identify loci that may be involved in reproductive barriers between the species.


Squeezed hollow-core photonic Bragg fiber for surface sensing applications.
We propose to use squeezed hollow-core photonic bandgap Bragg fibers for surface sensing applications. We demonstrate theoretically and confirm experimentally that squeezing a section of the Bragg fiber core increases overlap between the optical fields of the core guided modes and the modes bound to the sensing layer, thus, significantly enhancing their interaction via anticrossing phenomenon, which, in turn, enhances surface sensitivity of the fiber sensor. As a practical demonstration, we apply our fiber sensor to in situ monitoring of the dissolution dynamics of a sub-micron-thick polyvinyl butyral (PVB) film coated on the surface of the liquid-filled Bragg fiber core. Strong spectral shift is observed during the dissolution of the PVB film, and a surface spectral sensitivity of ~0.07nm/nm is achieved experimentally with aqueous analytes. The proposed fiber sensor offers a new sensing modality and opens new sensing applications for photonic bandgap fibers, such as real-time detection of binding and affinity, study of kinetics, etc. for a range of chemical and biological samples.


Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells.
The study demonstrates that basic fibroblast growth factor (bFGF) serves as an inducer of radiation damage repair in bovine aortic endothelial cells (BAEC). Radiation dose-survival curves were generated with plateau-phase BAEC using culture dishes precoated with HR9-bFGF/extracellular matrix (ECM) for the postradiation colony formation assay. This natural basement membrane-like ECM is enriched with ECM-bound bFGF. Under these conditions the cells exhibited increased repair of radiation damage as compared to cells plated on top of the bFGF-free isotype of this extracellular matrix (the HR9/ECM). While the slopes of the curves did not differ significantly (Do 107 +/- 6.8 cGy on the HR9/ECM, compared to 112 +/- 1.3 cGy on the HR9-bFGF/ECM), there was a nearly complete elimination of the threshold shoulder in the curves generated on the bFGF-free HR9/ECM (Dq 29 +/- 19 cGy, compared to 174 +/- 22 cGy on the HR9-bFGF/ECM; P less than 0.05). Delayed plating experiments, in which the cells were irradiated under bFGF-free conditions (while adherent as contact-inhibited monolayers to the HR9/ECM in bFGF-free medium) and maintained after irradiation in the same culture for various periods of time, showed that the cells performed repair of potentially lethal damage (PLDR) and restored clonogenic ability, with a 24 h to immediate postradiation recovery ratio of 3.27. This expression of PLDR was inhibited by neutralizing monoclonal antibodies against bFGF, indicating that the irradiated cells secreted bFGF into their conditioned medium. Northern blot hybridization showed a 5.6-fold increase of the 3.7-kilobase species and a 4.7-fold increase of the 7.0-kilobase species of the bFGF-specific mRNA within 6 h after delivery of a single dose of 400 cGy. The data suggest that radiation induces a complete cycle of an autoregulated damage-repair pathway in BAEC, initiated by radiation-induced damage to cellular DNA and followed by stimulation of bFGF synthesis and its secretion into the medium. The newly synthesized bFGF stimulates the PLDR pathway, acting via an extracellular autocrine loop (inhibitable by specific anti-bFGF antibodies), leading to recovery of cells from radiation lesions and restoration of their clonogenic capacity.


Optical vector network analyzer for single-scan measurements of loss, group delay, and polarization mode dispersion.
We present a method for measuring the complete linear response, including amplitude, phase, and polarization, of a fiber-optic component or assembly that requires only a single scan of a tunable laser source. The method employs polarization-diverse swept-wavelength interferometry to measure the matrix transfer function of a device under test. We outline the theory of operation to establish how the transfer function is obtained. We demonstrate the enhanced accuracy, precision, and dynamic range of the technique through measurements of several components.


Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver.
Background: Fatty liver, a major health problem worldwide, is the earliest pathological change in the progression of alcohol-associated (AFL) and non-alcoholic fatty liver disease (NAFL). Though the causes of AFL and NAFL differ, both share similar histological and some common pathophysiological characteristics. In this study, we sought to examine mechanisms responsible for lipid dynamics in liver and adipose tissue in the setting of AFL and NAFL in response to 48 h of fasting. Methods: Male rats were fed Lieber-DeCarli liquid control or alcohol-containing diet (AFL model), chow or high-fat pellet diet (NAFL model). After 6-8 weeks of feeding, half of the rats from each group were fasted for 48 h while the other half remained on their respective diets. Following sacrifice, blood, adipose, and the liver were collected for analysis. Results: Though rats fed AFL and NAFL diets both showed fatty liver, the physiological mechanisms involved in the development of each was different. Here, we show that increased hepatic de novo fatty acid synthesis, increased uptake of adipose-derived free fatty acids, and impaired triglyceride breakdown contribute to the development of AFL. In the case of NAFL, however, increased dietary fatty acid uptake is the major contributor to hepatic steatosis. Likewise, the response to starvation in the two fatty liver disease models also varied. While there was a decrease in hepatic steatosis after fasting in ethanol-fed rats, the control, chow and high-fat diet-fed rats showed higher levels of hepatic steatosis than pair-fed counterparts. This diverse response was a result of increased adipose lipolysis in all experimental groups except fasted ethanol-fed rats. Conclusion: Even though AFL and NAFL are nearly histologically indistinguishable, the physiological mechanisms that cause hepatic fat accumulation are different as are their responses to starvation.


Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness.
To compare analgesic effects of phenylbutazone administered at a dosage of 4.4 mg/kg/d (2 mg/lb/d) or 8.8 mg/kg/d (4 mg/lb/d) in horses with chronic lameness. Controlled crossover study. Animals-9 horses with chronic forelimb lameness. Horses were treated i.v. with phenylbutazone (4.4 mg/kg/d or 8.8 mg/kg/d) or saline (0.9% NaCl) solution once daily for 4 days. All horses received all 3 treatments with a minimum of 14 days between treatments. Mean peak vertical force (mPVF) was measured and clinical lameness scores were assigned before initiation of each treatment and 6, 12, and 24 hours after the final dose for each treatment. Compared with values obtained after administration of saline solution, mPVF was significantly increased at all posttreatment evaluation times when phenylbutazone was administered. Clinical lameness scores were significantly decreased 6 and 12 hours after administration of the final dose when phenylbutazone was administered at the low or high dosage but were significantly decreased 24 hours after treatment only when phenylbutazone was administered at the high dosage. No significant differences in mPVF and clinical lameness scores were found at any time when phenylbutazone was administered at the low versus high dosage. Results suggest that the high dosage of phenylbutazone was not associated with greater analgesic effects, in terms of mPVF or lameness score, than was the low dosage. Considering that toxicity of phenylbutazone is related to dosage, the higher dosage may not be beneficial in chronically lame horses.


Growth, Survival and Reproduction of the Giant Clam Tridacna maxima (Röding 1798, Bivalvia) in Two Contrasting Lagoons in French Polynesia.
Shell growth, reproduction, and natural mortality of the giant clam Tridacna maxima were characterized over a two-year-period in the lagoon of the high island of Tubuai (Austral Archipelago) and in the semi-closed lagoon of Tatakoto (Tuamotu Archipelago) in French Polynesia. We also recorded temperature, water level, tidal slope, tidal range, and mean wave height in both lagoons. Lower lagoon aperture and exposure to oceanic swells at Tatakoto than at Tubuai was responsible for lower lagoon water renewal, as well as higher variability in temperature and water level at Tatakoto across the studied period. These different environmental conditions had an impact on giant clams. Firstly, spawning events in the lagoon of Tatakoto, detected by gonad maturity indices in June and July 2014, were timed with high oceanic water inflow and a decrease in lagoon water temperature. Secondly, temperature explained differences in shell growth rates between seasons and lagoons, generating different growth curves for the two sites. Thirdly, local mortality rates were also found to likely be related to water renewal patterns. In conclusion, our study suggests that reef aperture and lagoon water renewal rates play an integral role in giant clam life history, with significant differences in rates of shell growth, mortality and fertility found between open versus semi-closed atoll lagoons in coral reef ecosystems.


Efficacy of ribavirin against malignant glioma cell lines.
Ribavirin (1-β-D-ribofuranosy-1,2,4-triazole-3-carboxamide) has been widely administered as an antiviral agent against RNA and DNA viruses. Ribavirin, in combination with interferon, has predominantly been applied in the treatment of the hepatitis C virus infection and its potential antitumor efficacy has recently become a point of interest. The aim of the present study was to evaluate the effect of ribavirin on the growth of malignant glioma cells, to identify novel predictive genes in malignant glioma cells (by analyzing gene expression profiles) and to assess the influence of ribavirin on the cell cycle of malignant glioma cells. The present study evaluated the antitumor efficacy of ribavirin against various malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13). After culturing the cells in ribavirin-containing culture medium (final concentration, 0-1,000 μM) for 72 h, the viable proliferated cells were harvested and counted. The half maximal inhibitory concentration of ribavirin, with regard to the growth of the malignant glioma cell lines, was determined from the concentration of ribavirin required for 50% growth inhibition in comparison to the untreated control cells. Furthermore, the current study identified the genes in which the gene expression levels correlated with the ribavirin sensitivity of the malignant glioma cells lines, using a high-density oligonucleotide array. Finally, cell cycle analysis was performed on the U-87MG cell line. It was identified that ribavirin inhibited the growth of all of the malignant glioma cell lines in a dose-dependent manner, although the ribavirin sensitivity varied between each cell line. Of the extracted genes, PDGFRA demonstrated the strongest positive correlation between gene expression level and ribavirin sensitivity. Cell cycle analysis of the U-87MG cell line demonstrated that ribavirin treatment induces G0/G1 arrest and thus may be an effective agent for inhibiting malignant glioma cell growth. Therefore, the results of the current study indicate that ribavirin may have potential as a therapeutic agent in the treatment of malignant gliomas.


Shipboard dialysis.
With better understanding of the pathophysiology of uremia, the development of more efficient dialysis techniques and more portable machinery, a larger number of patients on maintenance dialysis are not stable enough to undertake travel to places where a regular hemodialysis center may not be availabel or to travel on a ship for a relatively long period of time. Ten stable patients were taken on a 7 day cruise utilizing the relatively lightweight and portable REDY Dialysis System. The medical team consisted of 2 nurses, 2 technicians and 1 physician. The ship's infirmary was converted to a 4 bed hemodialysis unit. Complications were minimal and easily handled by the medical staff.


Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy.
Urachal carcinoma (UrC) is a rare malignancy, and patients with this disease have a poor prognosis. In this article, the authors report 50 years of experience with this tumor at the Mayo Clinic. A urachal mass was described in 130 patients, and 66 of those masses were malignant. The authors identified multivariate predictors of malignancy in clinically diagnosed urachal masses and predictors of UrC-specific survival. This report presents a novel 4-category staging system for UrC along with the treatment history of this tumor and the results of salvage therapy. Twenty women and 46 men were identified with UrC. The strongest predictors of malignancy in a urachal mass were hematuria and age older than 55 years. The 5-year cancer-specific survival rate was 49%. The new Mayo staging system was less complicated than the Sheldon system, although both systems predicted cancer-specific mortality equally well. Positive surgical margins (hazard ratio [HR], 4.7), high tumor grade (HR, 3.6), positive local lymph nodes (HR, 5.1), metastases at diagnosis (HR, 3.3), advanced tumor stage (HR, 4.8), failure to perform umbilectomy (HR, 3.0), and primary radiation therapy (HR, 2.9) were all univariately associated with death (P <.05). Only grade and margins were significant in the multivariate analysis. No survival benefit was noted for lymphadenectomy or adjuvant therapy. Salvage surgery resulted in a long-term cure for 50% of patients who had local recurrences. No effective treatment was identified for patients with metastatic UrC. Early and complete extended partial cystectomy, including umbilectomy, is critical to the survival of patients with UrC. The authors recommend using the Mayo staging system in future studies because of its simplicity. The current results indicated that the most important predictors of prognosis were tumor grade and surgical margin status.


Adverse Events Detection Through Global Trigger Tool Methodology: Results From a 5-Year Study in an Italian Hospital and Opportunities to Improve Interrater Reliability.
Global Trigger Tool (GTT) has been proposed as a low-cost method to detect adverse events (AEs). The validity of the methodology has been questioned because of moderate interrater agreement. Continuous training has been suggested as a means to improve consistency over time. We present the main findings of the implementation of the Italian version of the GTT and evaluate efforts to improve the interrater reliability over time. The Italian version of the GTT was developed and implemented at the San Bonifacio Hospital, a 270-bed secondary care acute hospital in Verona, Italy. Ten clinical records randomly selected every 2 weeks were reviewed from 2009 to 2014. Two-stage interrater reliability assessment between team members was conducted on 2 subsamples of 50 clinical records before and after the implementation of specific review rules and staff training. Among 1320 medical records reviewed, a total of 366 AEs were found with at least 1 AE on 20.2% of all discharges, 27.7 AEs/100 admissions, and 30.6 AEs/1000 patient-days. Adverse events with harm score E and F were respectively 58.2% (n = 213) and 38.8% (n = 142). First round interrater reliability was comparable with other international studies. The interrater agreement improved significantly after intervention (κ interrater I = 0.52, κ interrater II = 0.80, P < 0.001). Despite the improvements in the interrater consistency, overall results did not show any significant trend in AEs over time. Future studies may be directed to apply and adapt the GTT methodology to more specific settings to explore how to improve its sensitivity.


Malignant human papillomavirus type 16-transformed human keratinocytes exhibit altered expression of extracellular matrix glycoproteins.
We found that keratinocytes immortalized with human papillomavirus (HPV) type 16 DNA and malignantly converted by H-ras transfection (HPK-1A/ras) exhibit an enhanced ability to synthesize a fibronectin-containing extracellular matrix. Gene expression of fibronectin and thrombospondin was increased in tumorigenic keratinocytes compared to control and immortalized keratinocytes, 6- and 9-fold, respectively. Increased production of soluble and cell surface-associated fibronectin was not specific for HPV 16 transformed keratinocytes. Ad12-SV40-immortalized keratinocytes malignantly converted by H-ras transfection (RHEK-1/ras) also exhibited enhanced expression of fibronectin and thrombospondin, as well as pro-alpha 1 type I collagen. Steady state mRNA levels for autocrine growth-regulatory factors, transforming growth factors alpha and beta 1, were increased in Ad12-SV40 but not HPV 16-transformed human keratinocytes. We then determined whether increased production of fibronectin was associated with aberrant differentiation of transformed keratinocytes. Less than 10% of the HPV 16-transformed cells produced cornified envelopes after suspension-induced differentiation compared to 70% of normal keratinocytes. However, immortalization by HPV 16 DNA was sufficient to confer a differentiation-defective phenotype. Both involucrin mRNA and protein levels were decreased 8-fold in HPV 16-immortalized keratinocytes compared to normal cells and malignant conversion further attenuated involucrin levels. These studies demonstrate that aberrant differentiation is an early event in the transformation of the human keratinocytes and is not the result of enhanced expression of the extracellular matrix proteins. Unlike transformed fibroblastic cell types, up-regulation of fibronectin gene expression and matrix formation is a consistent characteristic of malignantly converted human keratinocytes.


A new test of the construct validity of the CarerQol instrument: measuring the impact of informal care giving.
Most economic evaluations of health care programmes do not consider the effects of informal care, while this could lead to suboptimal policy decisions. This study investigates the construct validity of the CarerQol instrument, which measures and values carer effects, in a new population of informal caregivers. A questionnaire was distributed by mail (n = 1,100, net response rate = 21%) to regional informal care support centers throughout the Netherlands. Two types of construct validity, i.e., convergent and clinical validity, have been analyzed. Convergent validity was assessed with Spearman's correlation coefficients and multivariate correlation between the burden dimensions (CarerQol-7D) and the valuation component (CarerQol-VAS) of the CarerQol. Additionally, convergent validity was analyzed with Spearman's correlation coefficients between the CarerQol and other measures of subjective caregiver burden (SRB, PU). Clinical validity was evaluated with multivariate correlation between CarerQol-VAS and CarerQol-7D, characteristics of caregivers, care recipients and care situation among the whole sample of caregivers and subgroups. The positive (negative) dimensions of CarerQol-7D were positively (negatively) related to CarerQol-VAS, and almost all had moderate strength of convergent validity. CarerQol-VAS was positively associated with PU and negatively with SRB. The CarerQol-VAS reflects differences in important background characteristics of informal care: type of relationship, age of the care recipient and duration of care giving were associated with higher CarerQol-VAS scores. These results confirmed earlier tests of the construct validity of the CarerQol. Furthermore, the dimensions of CarerQol-7D significantly explained differences in CarerQol-VAS scores among subgroups of carers. Notwithstanding the limitations of our study, such as the low response rate, this study shows that the CarerQol provides a valid means to measure carer effects for use in economic evaluations. Future research should derive a valuation set for the CarerQol and further address the instrument's content validity, sensitivity and reliability.


The problems reported by cancer patients with major depression.
To describe the problems reported by people with cancer and major depressive disorder as elicited before starting problem-solving therapy (PST). Ninety-eight outpatients, with a variety of cancers who met criteria for major depression, received PST as part of a system of treatment called 'Depression Care for People with Cancer' within a randomized trial. During the first session of PST, each patient was asked to provide an exhaustive list of problems defined as 'anything that was bothering them'. A coding system, based on thematic content, was developed to categorize the problems listed. Each problem was then coded by two raters independently (κ=0.81). The resulting categories were organized into larger conceptual domains using a card-sorting task. Thirty-six problem categories were generated which were in turn organized into 11 larger conceptual domains. Patients reported problems in a mean of 9.2 different categories (range 3-21) and 5.7 domains (range 2-9). The most common problem categories were 'concerns about other people's well-being' (65%), 'problems in interpersonal relations' (61%), 'loss of interest' (56%), 'low mood' (55%), and 'cancer recurrence or relapse' (54%). People with cancer and major depression report a wide variety of problems that include, but go beyond concerns about, both cancer and depression. The large number of problems related to concerns about other people's well-being and difficulties in interpersonal relationships, stresses the importance of these topics to patients and should be given more weight in the assessment and management of depressed cancer patients.


Sense of hyper-positive self and response to cognitive therapy in bipolar disorder.
Cognitive therapy (CT) for bipolar disorder emphasizes the monitoring and regulation of mood, thoughts and behaviour. The Sense of Hyper-Positive Self Scale (SHPSS) measures the extent to which bipolar patients value themselves and perceive themselves to possess personal attributes (e.g. dynamism, persuasiveness and productiveness) associated with a state of being 'mildly high', which does not reach the severity of clinical hypomania. It is hypothesized that patients who score highly on the SHPSS do not respond well to cognitive therapy. One hundred and three bipolar-I patients were randomized into CT and control groups. The SHPSS was administered at baseline and at a 6-month follow-up. The SHPSS had good test-retest reliability after 6 months. At baseline, the Goal-Attainment Dysfunctional Attitudes contributed significantly to the SHPSS scores after the mood measures were controlled for in a regression analysis. There was a significant interaction between baseline SHPSS scores and group allocation in predicting relapse during therapy. Patients who scored highly on the SHPSS had a significantly increased chance of relapse after controlling for mood scores, levels of social functioning at recruitment, and the previous number of bipolar episodes. Not all patients benefited from CT. For patients with high SHPSS scores, CT was less efficacious. The results also indicate that future studies could evaluate targeting these attributes and dysfunctional beliefs with intensive cognitive behavioural techniques.


Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report. Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in approximately 12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in approximately 0.4%, and leukemia occurs in approximately 0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking.


Circadian locomotor rhythms in the cricket, Gryllodes sigillatus. II. Interactions between bilaterally paired circadian pacemakers.
The optic lobe is essential for circadian locomotor rhythms in the cricket, Gryllodes sigillatus. We examined potential interactions between the bilaterally paired optic lobes in circadian rhythm generation. When one optic lobe was removed, the free-running period of the locomotor rhythm slightly but significantly lengthened. When exposed to light-dark cycles (LD) with 26 hr period, intact and sham operated animals were clearly entrained to the light cycle, but a large number of animals receiving unilateral optic nerve severance showed rhythm dissociation. In the dissociation, two rhythmic components appeared; one was readily entrained to the given LD and the other free-ran with a period shorter than 24 hr, and activity was expressed only when they were inphase. The period of the free-running component was significantly longer than that of the animals with a single blinded pacemaker kept in LD13:13, suggesting that the pacemaker on the intact side had some influence on the blinded pacemaker even in the dissociated state. The ratio of animals with rhythm dissociation was greater with the lower light intensity of the LD. The results suggest that the bilaterally distributed pacemakers are only weakly coupled to one another but strongly suppress the activity driven by the partner pacemaker during their subjective day. The strong suppression of activity would be advantageous to keep a stable nocturnality for this cricket living indoors.


Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews.
This study aims to summarise the evidence on more than 140 pharmacological and non-pharmacological treatment options for major depressive disorder (MDD) and to evaluate the confidence that patients and clinicians can have in the underlying science about their effects. This is a review of systematic reviews. This study used MEDLINE, Embase, Cochrane Library, PsycINFO and Epistemonikos from 2011 up to February 2017 for systematic reviews of randomised controlled trials in adult patients with acute-phase MDD. We dually reviewed abstracts and full-text articles, rated the risk of bias of eligible systematic reviews and graded the strength of evidence. Nineteen systematic reviews provided data on 28 comparisons of interest. For general efficacy, only second-generation antidepressants were supported with high strength evidence, presenting small beneficial treatment effects (standardised mean difference: -0.35; 95% CI -0.31 to -0.38), and a statistically significantly higher rate of discontinuation because of adverse events than patients on placebo (relative risk (RR) 1.88; 95% CI 1.0 to 3.28).Only cognitive behavioural therapy is supported by reliable evidence (moderate strength of evidence) to produce responses to treatment similar to those of second-generation antidepressants (45.5% vs 44.2%; RR 1.10; 95% CI 0.93 to 1.30). All remaining comparisons of non-pharmacological treatments with second-generation antidepressants either led to inconclusive results or had substantial methodological shortcomings (low or insufficient strength of evidence). In contrast to pharmacological treatments, the majority of non-pharmacological interventions for treating patients with MDD are not evidence based. For patients with strong preferences against pharmacological treatments, clinicians should focus on therapies that have been compared directly with antidepressants. International Prospective Register of Systematic Reviews (PROSPERO) registration number: 42016035580.


Kaempferol inhibits the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes by blocking activation of the MAPK pathway.
In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) play an essential role in cartilage destruction. Aggressive migration and invasion by FLSs significantly affect RA pathology. Kaempferol has been shown to inhibit cancer cell migration and invasion. However, the effects of kaempferol on RA FLSs have not been investigated. Our study aimed to determine the effects of kaempferol on RA both in vitro and in vivo. In vitro, cell migration and invasion were measured using scratch assays and the Boyden chamber method, respectively. The cytoskeletal reorganization of RA FLSs was evaluated by immunofluorescence staining. Matrix metalloproteinase (MMP) levels were measured by real-time PCR, and protein expression levels were measured by western blotting. In vivo, the effects of kaempferol were evaluated in mice with CIA. The results showed that kaempferol reduced migration, invasion and MMP expression in RA FLSs. In addition, we demonstrated that kaempferol inhibited reorganization of the actin cytoskeleton during cell migration. Moreover, kaempferol dramatically suppressed tumor necrosis factor (TNF)-α-induced MAPK activation without affecting the expression of TNF-α receptors. We also demonstrated that kaempferol attenuated the severity of arthritis in mice with CIA. Taken together, these results suggested that kaempferol inhibits the migration and invasion of FLSs in RA by blocking MAPK pathway activation without affecting the expression of TNF-α receptors.


Glucosamine abrogates the acute phase of experimental autoimmune encephalomyelitis by induction of Th2 response.
Glucosamine, a natural glucose derivative and an essential component of glycoproteins and proteoglycans, has been safely used to relieve osteoarthritis in humans. Recent studies have shown that glucosamine also possesses immunosuppressive properties and is effective in prolonging graft survival in mice. Whether this reagent is effective in human multiple sclerosis (MS), an inflammatory demyelination in the CNS, is not known. We thus investigated the therapeutic effect of glucosamine on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We demonstrated that oral, i.p., or i.v. administration of glucosamine significantly suppressed acute EAE, with reduced CNS inflammation and demyelination. A significant, albeit not strong, blockade of Th1 response and an up-regulation of Th2 cytokines (IL-5 and IL-10) are observed in the splenocytes of glucosamine-treated mice. Glucosamine also regulates IL-5 and IL-10 in vitro. As glucosamine is able to effectively suppress acute EAE, has low or absent toxicity, and has been safely used in humans orally, our study suggests a potential use for this drug alone or in combination with other disease-modifying immunotherapies to enhance their efficacy and reduce their doses in MS and possibly other autoimmune disorders. Furthermore, because glucosamine functions not simply as an immunosuppressant, but as a mild immunomodulator, administration of glucosamine provides a novel immunoregulatory approach for autoimmune disorders.


Ultra-low background Raman sensing using a negative-curvature fibre and no distal optics.
Measuring Raman spectra through an optical fibre is usually complicated by the high intrinsic Raman scatter of the fibre material. Common solutions such as the use of multiple fibres and distal optics are complex and bulky. We demonstrate the use of single novel hollow-core negative-curvature fibres (NCFs) for Raman and surface-enhanced Raman spectroscopy (SERS) sensing using no distal optics. The background Raman emission from the silica in the NCF was at least 1000× smaller than in a conventional solid fibre, while maintaining the same collection efficiency. We transmitted pump light from a 785-nm laser through the NCF, and we collected back the weak Raman spectra of different distal samples, demonstrating the fibre probe can be used for measurements of weak Raman and SERS signals that would otherwise overlap spectrally with the silica background. The lack of distal optics and consequent small probe diameter (<0.25 mm) enable applications that were not previously possible.


Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy.
Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.


A contrast of the three more common illnesses with the ten less common in a study and 18-month follow-up of 314 psychiatric emergency room patients.
An 18-month follow-up of 314 randomly selected psychiatric emergency room patients showed that, although there were 15 possible diagnostic groups the diagnoses made at initial interviews proved to be largely accurate. Follow-up results showed the prediction based on those initial diagnoses was 84% correct in the 299 patients (95%) that could be followed up. Follow-up results also showed that 88% of the individual diagnoses (as opposed to diagnosed patients) were correct. The kappa coefficients were high, all of them being above 0.60, some between 0.80 and 0.90. In addition to the relatively high diagnostic validity, the results also demonstrated a high item reliability for the more than 400 separate items for which kappa coefficients were calculated. Less than 15% of these items had a kappa coefficient of less than 0.60. This study thus demonstrated a high diagnostic reliability and a high diagnostic validity The basis of these diagnoses in a heterogeneous psychiatric population was the application of precisely defined and applied diagnostic criteria. The diagnostic process was blind in that the follow-up diagnosis was made in the absence of knowledge of the initial diagnosis. The use of precisely defined and systematically applied criteria may prove to be superior to multivariate analysis, cluster analysis, or other statistical techniques.


Radiation From Kidney-Ureter-Bladder Radiographs Is Not Trivial.
To estimate effective dose of kidney-ureter-bladder (KUB) radiographs in a contemporary population of patients with urolithiasis. A retrospective review was performed to identify patients visiting a urology clinic for urolithiasis where a KUB was obtained and whom had a recent computed tomography (CT). Effective dose for KUBs was estimated using a Monte Carlo based simulation program and for CT utilizing the reported dose-length-product. Age, gender, body mass index, and abdominal diameter were analyzed for association with effective dose. KUBs performed at outside facilities in referred patient were compared to those obtained locally when available. Fifty-four patients were identified meeting criteria. The majority (92.6%) of KUBs contained multiple radiographs. Mean effective dose was 2.15 mSv ± 1.67 mSv. Only 26% of examinations effective dose was under 1 mSv. Body mass index, abdominal thickness, and image count were all associated with an increase in dose (P < .01 each). Similar to local KUBs, 88% of outside examinations contained multiple images. KUB examinations in this contemporary setting are associated with a 2-fold higher effective dose then is often referenced. Increased effective dose is associated with increased patient size and number of images acquired. Nearly 1 in 5 patient's KUB effective dose was similar to a low-dose CT. KUBs role should be re-examined given its limited sensitivity, specificity, associated radiation, and other available imaging options.


Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.
To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC). PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated. PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI) = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth. Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.


Participation without representation? Senior opinion, legislative behavior, and federal health reform.
Why do legislators sometimes engage in behavior that deviates from the expressed policy preferences of constituents who participate in politics at high rates? We examine this puzzle in the context of Democratic legislators' representation of their senior citizen constituents on the Patient Protection and Affordable Care Act of 2010 (ACA). We find that legislators' roll-call votes on the ACA did not reflect the stated preferences of their respective senior constituents; by contrast, these roll-call votes did reflect the preferences of nonsenior adults. We draw upon a theoretical framework developed by Mansbridge to explain this apparent nonresponsiveness to seniors on the ACA. This framework distinguishes between promissory representation, whereby legislators merely respond to constituents' preferences, and anticipatory representation, whereby legislators respond to constituents' underlying policy interests, even when such interests conflict with expressed preferences. By considering the Medicare provisions in the ACA and analyzing Democratic legislators' floor speeches on health reform, we provide preliminary evidence that members of Congress engaged in anticipatory representation of their senior constituents by attempting to educate seniors about how the ACA serves their policy interests.


Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: An IMI-DIRECT study.
Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.


Gastric ulcers with and without associated duodenal ulcer have different pathophysiology.
1. Maximal acid output after pentagastrin stimulation, and fasting and postprandial serum gastrin concentrations were determined in 25 normal subjects, 30 patients with corpus gastric ulcers, 10 patients with prepyloric ulcers and 30 patients with both duodenal and gastric ulcers. 2. Corpus ulcers and prepyloric ulcers formed one distinct group. Maximal acid output was abnormally low in the corpus ulcer patients and no different from normal in prepyloric ulcer patients, whereas fasting serum gastrin and postprandial integrated gastrin response was abnormally high in the former and no different from the normal in the latter. Furthermore, as in the normal subjects, a significant negative correlation between maximal acid output expressed in mmol h(-1) kg(-1) body weight and postprandial integrated gastrin response was observed in the corpus and prepyloric ulcer patients taken as a group. 3. In complete contrast patients with both duodenal and gastric ulcers, in whom postprandial integrated gastrin response was statistically highest amongst the three types of gastric ulcers, had a significantly positive correlation between maximal acid output and the integrated gastrin response. 4. These findings suggest the operation of different pathophysiological mechanisms in gastric ulcers with and without associated duodenal ulcers.


SU-E-T-174: Synopsis of the Experimental and Monte Carlo Calculated Values of the Radial EPOM Shift of Cylindrical Ionization Chambers for Photon-Beam Dosimetry.
According to the concept of the effective point of measurement (EPOM), the values of depth z serving as the variable of photon-beam depth dose distributions in water measured with cylindrical ionization chambers are commonly corrected according to the formula zeff=zR+▵z, were zeff is the depth of the EPOM, zR the depth of the reference point of the chamber, i.e. of its symmetry axis, and Az the EPOM shift. Agreed-upon values of the EPOM shift are for instance ▵z=-0.6r (IAEA TRS 398, 2000) and ▵z=-0.5r (DIN6800-2,2008) with r=radius of the air-filled volume. The EPOM concept holds in the falling as well as in the rising curve branch. The Az versus r relationship is currently reviewed. Measurements of the EPOM shift of cylindrical ionization chambers for 6/15 MV photons had been based upon a comparison with depth dependent dose distributions in water measured with the Roos chamber (PTW Freiburg). Its EPOM position (1.5 mm below the front face) had been determined by comparison with radiochrome films. (Looe et al, Phys.Med.Biol. 2011;56:4267-4290). Available are also the experimental EPOM shift values by Huang et al, Physica Medica 2010;26:126-131 and the classical value of Johansson et al, IAEA -SM-222/35,243-270(1978). Accurate Monte Carlo values had been supplied by Tessier and Kawrakow, Med.Phys. 2010;37:96-107. As shown by the graphical display of Az versus r, the relationship is nonlinear, shaped as a hockey stick, with values around -0.2 mm for the "pinpoint" chambers and with values near -1.4 mm for the often-used chambers with radii near 3 mm. For r ranging from 1 to 4 mm, the relationship can be approximated by ▵z = -(2.25 mm)×[1-exp(-0.0122 r̂4)] with r in mm. Time has come for a nonlinear updating of the EPOM shift versus radius relationship of cylindrical ionization chambers applied in photon-beam dosimetry.


Infantile spasms: A prognostic evaluation.
Few papers address the comprehensive prognosis in infantile spasms and look into the seizure profile and psychomotor outcome. We aimed to follow up children with infantile spasms to study: a) the etiology, demographics, semiology, electroencephalogram (EEG), and radiological pattern; b) seizure control, psychomotor development, and EEG resolution with treatment; c) the effects of various factors on the control of spasms, resolution of EEG changes, and psychomotor development at 3-year follow-up. Fifty newly diagnosed cases with a 1-12 month age of onset and who had hypsarrhythmia in their EEG were recruited and 43 were followed up for 3 years. Of the children followed up, 51% were seizure-free and 37% had a normal EEG at the 3-year follow-up. Autistic features were seen in 74% of the children. Only 22.7% among the seizure-free (11.6% of the total) children had normal vision and hearing, speech with narration, writing skills, gross and fine motor development, and no autism or hyperactivity. On multivariate analysis, two factors could predict bad seizure outcome - the occurrence of other seizures in addition to infantile spasms and no response to 28 days of adrenocorticotropic hormone (ACTH). No predictor could be identified for abnormal psychomotor development. In our study, we could demonstrate two factors that predict seizure freedom. The cognitive outcome and seizure control in this group of children are comparable to the existing literature. However, the cognitive outcome revealed by our study and the survey of the literature are discouraging.


Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease: a cohort study.
The staging system for chronic kidney disease relies almost exclusively on estimated glomerular filtration rate (eGFR), although proteinuria is also associated with adverse outcomes. To validate a 5-category system for risk stratification based on the combination of eGFR and proteinuria. Retrospective cohort study. A provincial laboratory registry in Alberta, Canada, and a representative sample of noninstitutionalized U.S. adults. A derivation data set of 474 521 adult outpatients, 2 independent internal validation cohorts with 51 356 and 460 623 patients, and an external validation cohort of 14 358 patients. Glomerular filtration rate, estimated by using the Modification of Diet in Renal Disease Study equation, and proteinuria, measured by using urine albumin-to-creatinine ratio or dipstick urinalysis. Outcomes included all-cause mortality and a composite renal outcome of kidney failure or doubling of serum creatinine level. Over a median follow-up of 38 months in the internal validation cohorts, higher risk categories (indicating lower eGFR or more proteinuria) were associated with a graded increase in the risk for the composite renal outcome. The projected number of U.S. adults assigned to risk categories 3 and 4 in the alternate system was 3.9 million, compared with 16.3 million assigned to stage 3 and 4 in the current staging system. The alternate system was more likely to correctly reclassify persons who did not develop the renal outcome than those who did, although some persons developed the renal outcome despite reclassification to a lower category. However, all analyses of patients reclassified to a lower category showed that substantially fewer such patients developed the renal outcome than did not. Correct reclassification by the alternate system was more likely when proteinuria was measured by using albumin-to-creatinine ratio than with dipstick testing, and also more likely for the composite renal outcome than for mortality. The study had a short follow-up time. Using proteinuria in combination with eGFR may reduce unnecessary referrals for care at the cost of not referring or delaying referral for some patients who go on to develop kidney failure. Alberta Heritage Foundation for Medical Research interdisciplinary research team grant.


Analysis of bovine viral diarrhoea virus: Biobank and sequence database to support eradication in Scotland.
Samples from bovine viral diarrhoea virus (BVDV)-positive cattle were gathered by Scottish diagnostic laboratories and used to produce a Biobank of samples with associated location and identification data in support of the Scottish BVDV eradication scheme. The samples were subject to direct amplification and sequencing of the 5'-untranslated region (5'-UTR) to define the viral types and subtypes present. From 2693 samples collected prior to 2016, approximately 2300 sequences were obtained, representing 8 BVDV type 1 subtypes. No BVDV type 2 samples were detected. The samples came from all regions of the UK but 66 per cent were from Scotland. Analysis of the sequences showed great diversity in the 5'-UTR, with 1206 different sequences. Many samples carried virus with identical 5'-UTR sequences; often from single locations, but there were also examples of the same sequence being obtained from samples at several different locations. This work provides a resource that can be used to analyse the movement of BVDV strains both within Scotland and between Scotland and other nations, particularly in the latter stages of the Scottish eradication programme, and so inform the advice available to both livestock keepers and policymakers.


In vitro response to EPA, DPA, and DHA: Comparison of effects on ruminal fermentation and biohydrogenation of 18-carbon fatty acids in cows and ewes.
The modulation of milk fat nutritional quality through fish oil supplementation seems to be largely explained by the action of n-3 very long chain polyunsaturated fatty acids (PUFA) on ruminal biohydrogenation (BH) of C18 fatty acids (FA). However, relationships among this action, disappearance of those PUFA in the rumen, and potential detrimental consequences on ruminal fermentation remain uncertain. This study compared the effect of 20:5n-3 (eicosapentaenoic acid; EPA), 22:5n-3 (docosapentaenoic acid; DPA), and 22:6n-3 (docosahexaenoic acid; DHA) on rumen fermentation and BH of C18 FA and was conducted simultaneously in cows and sheep to provide novel insights into interspecies differences. The trial was performed in vitro using batch cultures of rumen microorganisms with inocula collected from cannulated cows and ewes. The PUFA were added at a dose of 2% incubated dry matter, and treatment effects on ruminal C18 FA concentrations, PUFA disappearances, and fermentation parameters (gas production, ammonia and volatile FA concentrations, and dry matter and neutral detergent fiber disappearances) were examined after 24 h of incubation. A principal component analysis suggested that responses to PUFA treatments explained most of the variability; those of ruminant species were of lower relevance. Overall, EPA and DHA were equally effective for inhibiting the saturation of trans-11 18:1 to 18:0 and had a similar influence on ruminal fermentation in cows and sheep (e.g., reductions in gas production and acetate:propionate ratio). Nevertheless, DHA further promoted alternative BH pathways that lead to trans-10 18:1 accumulation, and EPA seemed to have specific effects on 18:3n-3 metabolism. Only minor variations attributable to DPA were observed in the studied parameters, suggesting a low contribution of this FA to the action of marine lipids. Although most changes due to the added PUFA were comparable in bovine and ovine, there were also relevant specificities, such as a stronger inhibition of 18:0 formation in cows and a greater increase in 18:3n-3 metabolites in sheep. No direct relationship between in vitro disappearance of the incubated PUFA and effect on BH (in particular, inhibition of the last step) was found in either cows or ewes, calling into question a putative link between extent of disappearance and toxicity for microbiota. Conversely, an association between the influence of these PUFA on ruminal lipid metabolism and fermentation may exist in both species. In vivo verification of these findings would be advisable.


Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice.
Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.


Using the XCS classifier system for multi-objective reinforcement learning problems.
We investigate the performance of a learning classifier system in some simple multi-objective, multi-step maze problems, using both random and biased action-selection policies for exploration. Results show that the choice of action-selection policy can significantly affect the performance of the system in such environments. Further, this effect is directly related to population size, and we relate this finding to recent theoretical studies of learning classifier systems in single-step problems.


Ramadan model of intermittent fasting for 28 d had no major effect on body composition, glucose metabolism, or cognitive functions in healthy lean men.
There has been a parallel increase in the incidence of obesity and diabetes as well as the number of daily meals. However, evidence is lacking regarding the role of intermittent fasting. The aim of this study was to determine the effects of a Ramadan model of intermittent fasting (RIF; 14 h of daytime abstinence from food and drinking) for 28 d on body composition, glucose metabolism, and cognitive function. Ten healthy, lean men were included in a nonrandomized, crossover, intervention study. Testing was performed before a control period of 28 d, as well as before and after 28 d of RIF. Whole-body dual-energy x-ray absorptiometry, magnetic resonance imaging of the abdomen, fitness test, oral glucose tolerance test, and cognitive function tests were performed. As secondary outcome, the participants' physical activity and 72-h glycemic responses were monitored 6 d within each of the periods. Dietary intake, appetite, and mood questionnaires also were assessed. Comparing Δ differences from testing days; body mass index changes from the control period (Δ mean: 0.2 kg/m2, 95% confidence interval [CI], -2 to 0.5) and the RIF period (Δ mean: -0.3 kg/m2, 95% CI, -0.6 to -0.1) were significantly different (P < 0.05). Secondary outcomes within the RIF period showed an increased area under curve (AUC) for hunger accompanied by a reduced AUC for satiety (both, P < 0.05), less mean steps per day (P < 0.05), and less positive feelings in the afternoon (P < 0.01) compared with the control period. No changes were observed in any of the other evaluated parameters. Free-living participants were able to comply with 14 h of daily daytime abstinence from food and drinking for 28 d with only a minor effect on body mass index and without any effects on body composition, glucose metabolism, and cognitive function.


Role played by NaV 1.7 channels on thin-fiber muscle afferents in transmitting the exercise pressor reflex.
Voltage-gated sodium channels (NaV) 1.7 are highly expressed on the axons of somatic afferent neurons and are thought to play an important role in the signaling of inflammatory pain. NaV 1.7 channels are classified as tetrodotoxin (TTX)-sensitive, meaning that they are blocked by TTX concentrations of less than 300 nM. These findings prompted us to determine in decerebrated, unanesthetized rats, the role played by NaV 1.7 channels in the transmission of muscle afferent input evoking the exercise pressor reflex. We first showed that the exercise pressor reflex, which was evoked by static contraction of the triceps surae muscles, was reversibly attenuated by application of 50 nM TTX, but not 5 nM TTX, to the L4-L5 dorsal roots (control: 21 ± 1 mmHg, TTX: 8 ± 2 mmHg, recovery: 21 ± 3 mmHg; n = 6; P < 0.01). We next found that the peak pressor responses to contraction were significantly attenuated by dorsal root application of 100 nM Ssm6a, a compound that is a selective NaV 1.7 channel inhibitor. Removal of Ssm6a restored the reflex to its control level (control: 19 ± 3 mmHg, Ssm6a: 10 ± 1 mmHg, recovery: 19 ± 4 mmHg; n = 6; P < 0.05). Compound action potentials recorded from the L4 and L5 dorsal roots and evoked by single-pulse stimulation of the sciatic nerve showed that both TTX and Ssm6a attenuated input from group III, as well as group IV afferents. We conclude that NaV 1.7 channels play a role in the thin-fiber muscle afferent pathway evoking the exercise pressor reflex.


PPARγ controls Dectin-1 expression required for host antifungal defense against Candida albicans.
We recently showed that IL-13 or peroxisome proliferator activated receptor gamma (PPARgamma) ligands attenuate Candida albicans colonization of the gastrointestinal tract. Here, using a macrophage-specific Dectin-1 deficient mice model, we demonstrate that Dectin-1 is essential to control fungal gastrointestinal infection by PPARgamma ligands. We also show that the phagocytosis of yeast and the release of reactive oxygen intermediates in response to Candida albicans challenge are impaired in macrophages from Dectin-1 deficient mice treated with PPARgamma ligands or IL-13. Although the Mannose Receptor is not sufficient to trigger antifungal functions during the alternative activation of macrophages, our data establish the involvement of the Mannose Receptor in the initial recognition of non-opsonized Candida albicans by macrophages. We also demonstrate for the first time that the modulation of Dectin-1 expression by IL-13 involves the PPARgamma signaling pathway. These findings are consistent with a crucial role for PPARgamma in the alternative activation of macrophages by Th2 cytokines. Altogether these data suggest that PPARgamma ligands may be of therapeutic value in esophageal and gastrointestinal candidiasis in patients severely immunocompromised or with metabolic diseases in whom the prevalence of candidiasis is considerable.


A two-dimensional hydrogen bonded organic framework self-assembled from a three-fold symmetric carbamate.
A flexible organic sheet spontaneously assembled under mild conditions from a tri-carbamate. By introducing cyclohexyl side chains as 'pillars' between the sheets, a hydrogen bonded organic framework was formed which displayed a capacity for accommodating and releasing guest molecules. The guest size/shape selectivity of the lamellar framework was demonstrated by testing with various guests.


The relevance framework for category-based induction: Evidence from garden-path arguments.
Relevance theory (Sperber & Wilson, 1995) suggests that people expend cognitive effort when processing information in proportion to the cognitive effects to be gained from doing so. This theory has been used to explain how people apply their knowledge appropriately when evaluating category-based inductive arguments (Medin, Coley, Storms, & Hayes, 2003). In such arguments, people are told that a property is true of premise categories and are asked to evaluate the likelihood that it is also true of conclusion categories. According to the relevance framework, reasoners generate hypotheses about the relevant relation between the categories in the argument. We reasoned that premises inconsistent with early hypotheses about the relevant relation would have greater effects than consistent premises. We designed three premise garden-path arguments where the same 3rd premise was either consistent or inconsistent with likely hypotheses about the relevant relation. In Experiments 1 and 2, we showed that effort expended processing consistent premises (measured via reading times) was significantly less than effort expended on inconsistent premises. In Experiment 2 and 3, we demonstrated a direct relation between cognitive effect and cognitive effort. For garden-path arguments, belief change given inconsistent 3rd premises was significantly correlated with Premise 3 (Experiment 3) and conclusion (Experiments 2 and 3) reading times. For consistent arguments, the correlation between belief change and reading times did not approach significance. These results support the relevance framework for induction but are difficult to accommodate under other approaches.


SOURCE 3 Registry: Design and 30-Day Results of the European Postapproval Registry of the Latest Generation of the SAPIEN 3 Transcatheter Heart Valve.
The SOURCE 3 Registry (SAPIEN Aortic Bioprosthesis European Outcome) is a European multicenter, observational registry of the latest generation of transcatheter heart valve, the SAPIEN 3 (Edwards Lifesciences, Irvine, CA). Its purpose is to document outcomes of clinical safety and performance after European approval was given. Here, we present the 30-day outcome of the SOURCE 3 Registry. All data are self-reported, and all participating centers have committed to support their consecutive experience with the SAPIEN 3 transcatheter heart valve, dependent on patient consent, before the start of the study. Adverse events are defined with Valve Academic Research Consortium 2 criteria and adjudicated by an independent clinical events committee. A total of 1950 patients from 80 centers in 10 countries were enrolled between July 2014 and October 2015. Of those, 1947 patients underwent transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 (mean age, 81.6±6.6 years; 48.1% female). Main comorbidities included coronary artery disease (51.5%), renal insufficiency (27.4%), diabetes mellitus (29.5%), chronic obstructive pulmonary disease (16.0%), and a mean logistic EuroSCORE of 18.3±13.2. Transfemoral access was used in 87.1% (n=1695); nontransfemoral, in 252 patients. Conscious sedation was used in 59.9% of transfemoral procedures, and in 50% of patients, TAVI was performed without aortic balloon valvuloplasty. Implantation success (1 valve in the intended location) was 98.3%. Conversion to conventional surgery (0.6%) and use of cardiopulmonary bypass (0.7%) were rare. Adverse events were low, with site-reported 30-day all-cause mortality of 2.2%, cardiovascular mortality of 1.1%, stroke of 1.4%, major vascular complications of 4.1%, life-threatening bleeding of 5%, and post-TAVI pacemaker implantation of 12%. Moderate or greater paravalvular regurgitation was observed in 3.1% of reporting patients. Results from the SOURCE 3 Registry demonstrate contemporary European trends and good outcomes of TAVI in daily practice when this third-generation TAVI device is used.


Chair-boat transitions in single polysaccharide molecules observed with force-ramp AFM.
Under a stretching force, the sugar ring of polysaccharide molecules switches from the chair to the boat-like or inverted chair conformation. This conformational change can be observed by stretching single polysaccharide molecules with an atomic force microscope. In those early experiments, the molecules were stretched at a constant rate while the resulting force changed over wide ranges. However, because the rings undergo force-dependent transitions, an experimental arrangement where the force is the free variable introduces an undesirable level of complexity in the results. Here we demonstrate the use of force-ramp atomic force microscopy to capture the conformational changes in single polysaccharide molecules. Force-ramp atomic force microscopy readily captures the ring transitions under conditions where the entropic elasticity of the molecule is separated from its conformational transitions, enabling a quantitative analysis of the data with a simple two-state model. This analysis directly provides the physico-chemical characteristics of the ring transitions such as the width of the energy barrier, the relative energy of the conformers, and their enthalpic elasticity. Our experiments enhance the ability of single-molecule force spectroscopy to make high-resolution measurements of the conformations of single polysaccharide molecules under a stretching force, making an important addition to polysaccharide spectroscopy.


Preoperative identification of the facial nerve in patients with large cerebellopontine angle tumors using high-density diffusion tensor imaging.
Facial nerve paresis can be a devastating complication following resection of large (> 2.5 cm) cerebellopontine angle (CPA) tumors. The authors have developed and used a new high-density diffusion tensor imaging (HD-DT imaging) method, aimed at preoperatively identifying the location and course of the facial nerve in relation to large CPA tumors. Their study objective was to preoperatively identify the facial nerve in patients with large CPA tumors and compare their HD-DT imaging method with a traditional standard DT imaging method and correlate with intraoperative findings. The authors prospectively studied 5 patients with large (> 2.5 cm) CPA tumors. All patients underwent preoperative traditional standard- and HD-DT imaging. Imaging results were correlated with intraoperative findings. Utilizing their HD-DT imaging method, the authors positively identified the location and course of the facial nerve in all patients. In contrast, using a standard DT imaging method, the authors were unable to identify the facial nerve in 4 of the 5 patients. The HD-DT imaging method that the authors describe and use has proven to be a powerful, accurate, and rapid method for preoperatively identifying the facial nerve in relation to large CPA tumors. Routine integration of HD-DT imaging in preoperative planning for CPA tumor resection could lead to improved facial nerve preservation.


Effect of phalloidin on structure and permeability of rete capillaries in the normal and hypoxic state.
The effects of 10(-6) M phalloidin on reperfusion-injured blood capillary structure and permeability were studied in the countercurrent perfused rete mirabile of the eel swim bladder. In the normal rete, the addition of phalloidin to the perfusion medium did not induce morphological or functional changes. When flow was arrested for 30 minutes, during which time the capillaries were exposed to inhibitors of ATP generation, and flow was then resumed with an oxygenated medium, cell membrane blebs and vacuolization, mitochondrial swelling, pericyte shrinkage, and interstitial space edema were observed. The permeability coefficients for labeled albumin, sucrose, and sodium increased to three to four times baseline values, whereas the permeability to water was not significantly modified. When the same protocol was repeated with phalloidin present in the medium throughout the experiment, the structural integrity of the endothelial cells was completely preserved and pericyte shrinkage was abolished, but interstitial space edema still occurred. The permeability to albumin, sucrose, and sodium increased only to 1.5 times baseline values, a significantly decreased increment in comparison with the experiments performed without phalloidin. We concluded that although phalloidin does not improve the capillary barrier of the normal rete, it provides protection against the structural and functional damage induced by hypoxia and reperfusion.


Chromatin Accessibility Impacts Transcriptional Reprogramming in Oocytes.
Oocytes have a remarkable ability to reactivate silenced genes in somatic cells. However, it is not clear how the chromatin architecture of somatic cells affects this transcriptional reprogramming. Here, we investigated the relationship between the chromatin opening and transcriptional activation. We reveal changes in chromatin accessibility and their relevance to transcriptional reprogramming after transplantation of somatic nuclei into Xenopus oocytes. Genes that are silenced, but have pre-existing open transcription start sites in donor cells, are prone to be activated after nuclear transfer, suggesting that the chromatin signature of somatic nuclei influences transcriptional reprogramming. There are also activated genes associated with new open chromatin sites, and transcription factors in oocytes play an important role in transcriptional reprogramming from such genes. Finally, we show that genes resistant to reprogramming are associated with closed chromatin configurations. We conclude that chromatin accessibility is a central factor for successful transcriptional reprogramming in oocytes.


Distributed Patterns of Brain Activity Underlying Real-Time fMRI Neurofeedback Training.
Neurofeedback (NF) based on real-time functional magnetic resonance imaging (rt-fMRI) is an exciting neuroimaging application. In most rt-fMRI NF studies, the activity level of a single region of interest (ROI) is provided as a feedback signal and the participants are trained to up or down regulate the feedback signal. NF training effects are typically analyzed using a confirmatory univariate approach, i.e., changes in the target ROI are explained by a univariate linear modulation. However, learning to self-regulate the ROI activity through NF is mediated by distributed changes across the brain. Here, we deploy a multivariate decoding model for assessing NF training effects across the whole brain. Specifically, we first explain the NF training effect by a posthoc multivariate model that leads to a pattern of coactivation based on 90 functional atlas regions. We then use cross validation to reveal the set of brain regions with the best fit. This novel approach was applied to the data from a rt-fMRI NF study where the participants learned to down regulate the auditory cortex. We found that the optimal model consisted of 16 brain regions whose coactivation patterns best described the training effect over the NF training days. Cross validation of the multivariate model showed that it generalized across the participants. Interestingly, the participants could be clustered into two groups with distinct patterns of coactivation, potentially reflecting different NF learning strategies. Overall, our findings revealed that multiple brain regions are involved in learning to regulate an activity in a single ROI, and thus leading to a better understanding of the mechanisms underlying NF training.


Recommended number of participants in iodine nutrition studies is similar before and after an iodine fortification programme.
Iodine fortification programs have been applied in many iodine deficient regions. Iodine excess is also unfavourable, and it is recommended to monitor iodine status by measuring urinary iodine concentration (UIC). The number of samples needed in such monitoring depends on the variation in UIC. However, it is not known if variation in UIC differs according to iodine levels. We aimed to describe the effect of an iodisation program on the individual and group-based variation in UIC in spot urine samples. Group 1 (G1, n = 16) was studied before, and group 2 (G2, n = 21) was studied after an iodine fortification program was implemented. Individual urine samples were collected monthly for one year, 13 samplings. G1s (207 samples) median (interquartile range) UIC was 50 (37-67) μg/L, and G2 (265 samples) was 98 (69-139) μg/L. Median individual coefficient of variation (CV) was 38% in G1 and 40 % in G2 (p = 0.55), whereas the group-based CV was 50% in G1 and 53% in G2. No trend was seen between mean UIC and variation in UIC, neither at the individual (p = 0.36) nor at the group level (p = 0.43). Based on data from both groups, approximately 100 samples were needed to reliably estimate the UIC in a population. In two groups studied before and after an iodine fortification program was implemented and with different UIC levels, variation in UIC was comparable both at the individual level and according to UIC level. When mild iodine deficiency is corrected, the number of samples needed to reliably estimate the UIC in a population is unaffected.


T cell receptor repertoire diversity and clonal expansion in human neonates.
Newborn human infants, particularly those born prematurely, are susceptible to infection with a variety of microorganisms. We questioned whether limitations in the T cell repertoire contribute to the neonatal immunocompromised state. To describe developmental changes of the T cell repertoire, cDNA segments corresponding to third complementarity regions (CDR3) of human umbilical cord blood T cell receptors (TCR) from 24-41-wk gestational age were amplified with TCR family-specific probes. The resulting amplified CDRs were visualized by fingerprinting and single strand conformation polymorphism (SSCP) analysis. At 24-wk gestation there were no limitations in TCRBV family usage, and the degree of CDR3 size heterogeneity was not different from the adult. However, earlier in gestation, CDR3s were shorter for all families and gradually increased in size until term. The extent of oligoclonal expansion observed in cord blood was greater than in adult peripheral blood (p = 0.03). T cell oligoclonal expansion was greatest at 29-33-wk gestation and declined toward term. Expansions were detectable in both CD4+ and CD8+ subpopulations. Our findings indicate that the genetic mechanisms of repertoire diversification appear intact as early as 24 wk of gestation, but repertoire diversity is limited as a result of smaller CDR3 sizes. In addition, there was a developmentally regulated progression of oligoclonally expanded T cells. These differences in the TCRBV repertoire add to the body of evidence demonstrating immaturity of the neonatal immune system. However, the role that these subtle differences are likely to play in the relative immunodeficiency of the neonate remains to be determined.


Clinical and cost-effectiveness of a New psychosocial intervention to support Independence in Dementia (NIDUS-family) for family carers and people living with dementia in their own homes: a randomised controlled trial.
Most people living with dementia want to remain living in their own homes and are supported to do so by family carers. No interventions have consistently demonstrated improvements to people with dementia's life quality, functioning, or other indices of living as well as possible with dementia. We have co-produced, with health and social care professionals and family carers of people with dementia, a new intervention (NIDUS-family). To our knowledge, NIDUS-family is the first manualised intervention that can be tailored to personal goals of people living with dementia and their families and is delivered by facilitators without clinical training. The intervention utilizes components of behavioural management, carer support, psychoeducation, communication and coping skills training, enablement, and environmental adaptations, with modules selected to address dyads' selected goals. We will evaluate the effect of NIDUS-family and usual care on goal attainment, as measured by Goal Attainment Scaling (GAS) rated by family carers, compared to usual care alone at 12-month follow-up. We will also determine whether NIDUS-family and usual care is more cost-effective than usual care alone over 12 months. A randomised, two-arm, single-masked, multi-site clinical trial involving 297 people living with dementia-family carer dyads. Dyads will be randomised 2:1 to receive the NIDUS-family intervention with usual care (n = 199) or usual care alone (n = 98). The intervention group will be offered, over 1 year, via 6-8 video call or telephone sessions (or face to face if COVID-19 restrictions allow in the recruitment period) in the initial 6 months, followed by telephone follow-ups every 1-2 months to support implementation, with a trained facilitator. Increasing the time lived at home by people living with dementia is likely to benefit lives now and in the future. Our intervention, which we adapted to include remote delivery prior to trial commencement due to the COVID-19 pandemic, aims to address barriers to living as well and as independently as possible that distress people living with dementia, exacerbate family carer(s) stress, negatively affect relationships, lead to safety risks, and frequently precipitate avoidable moves to a care home. International Standard Randomised Controlled Trials Number ISRCTN11425138 . Registered on 7 October 2019.


Reproductive fitness and quinone content of Caenorhabditis elegans clk-1 mutants fed coenzyme Q isoforms of varying length.
Caenorhabditis elegans clk-1 mutants lack coenzyme Q9 and accumulate the biosynthetic intermediate demethoxy-Q9. A dietary source of ubiquinone (Q) is required for larval growth and development of the gonad and germ cells. We considered that uptake of the shorter Q8 isoform present in the Escherichia coli food may contribute to the Clk phenotypes of slowed development and reduced brood size observed when the animals are fed Q-replete E. coli. To test the effect of isoprene tail length, N2 and clk-1 animals were fed E. coli engineered to produce Q7, Q8, Q9, or Q10. Wild-type nematodes showed no change in reproductive fitness regardless of the Qn isoform fed. clk-1(e2519) fed the Q9 diet showed increased egg production; however, this diet did not improve reproductive fitness of the clk-1(qm30) animals. Furthermore, animals with the more severe clk-1(qm30) allele become sterile and their progeny inviable when fed Q7-containing bacteria. The content of Q7 in the mitochondria of clk-1 animals was decreased relative to Q8, suggesting less effective transport of Q7 to the mitochondria, impaired retention, or decreased stability. Additionally, regardless of E. coli diet, clk-1(qm30) animals contain a dysfunctional dense form of mitochondria. The gonads of clk-1(qm30) worms fed Q7-containing food were severely shrunken and disordered. The differential fertility of clk-1 mutant nematodes fed Q isoforms may result from changes in Q localization, altered recognition by Q-binding proteins, and/or potential defects in mitochondrial function resulting from the mutant CLK-1 polypeptide itself.


Photon superbunching from a generic tunnel junction.
Generating time-correlated photon pairs at the nanoscale is a prerequisite to creating highly integrated optoelectronic circuits that perform quantum computing tasks based on heralded single photons. Here, we demonstrate fulfilling this requirement with a generic tip-surface metal junction. When the junction is luminescing under DC bias, inelastic tunneling events of single electrons produce a stream of visible photons of plasmonic origin whose superbunching index is 17 (improved to a record of 70 by the authors during publication) when measured with a 53-ps instrumental resolution limit. The effect is driven electrically, rather than optically. This discovery has immediate and profound implications for quantum optics and cryptography, notwithstanding its fundamental importance to basic science and its ushering in of heralded photon experiments on the nanometer scale.


Changes in the Epilimnetic Bacterial Community Composition, Production, and Protist-Induced Mortality along the Longitudinal Axis of a Highly Eutrophic Reservoir.
We studied changes in the epilimnetic bacterial community composition (BCC), bacterial biomass and production, and protistan succession and bacterivory along the longitudinal axis of the canyon-shaped, highly eutrophic Sau Reservoir (NE Spain) during two sampling campaigns, in April and July 1997. Longitudinal changes in BCC from the river inflow to the dam area of the reservoir were detected by using oligonucleotide probes targeted to the kingdom Bacteria, to the alpha, beta, and gamma subclasses (ALFA, BETA, and GAMA) of the class Proteobacteria, and to the Cytophaga/Flavobacterium (CF) cluster. In general, the inflow of the organically loaded Ter river, with highly abundant allochthonous bacterial populations, induced a clearly distinguishable longitudinal succession of the structure of the microbial food web. The most dynamic changes in microbial parameters occurred at the plunge point, the mixing area of river water and the reservoir epilimnion. Changes within members of BETA and CF were the most important in determining changes in BCC, bacterial abundance and biomass. Much less relevant changes occurred within the less abundant ALFA and GAMA bacteria. From the plunge point downstream, we described a significant shift in BCC in the form of decreased proportions of BETA and CF. This shift spatially coincided with the highest values of heterotrophic nanoflagellate bacterivory (roughly doubled the bacterial production). CF numerically dominated throughout the reservoir without any marked longitudinal changes in their mean cell volume. In contrast, very large cells affiliated to BETA clearly dominated in the allochthonous bacterial biomass brought by the river. BETA showed a marked downstream trend of decreasing mean cell volume. We conclude that the observed BCC shift and the longitudinal shift in food web structure (bacteria-heterotrophic nanoflagellates-ciliates) resulted from highly complex interactions brought about by several major factors: varying hydrology, the high localized allochthonous input of organic matter brought by the river, downstream changing substrate availability, and selective protistan bacterivory.