Can erosions on MRI of the sacroiliac joints be reliably detected in patients with ankylosing spondylitis? - A cross-sectional study.
Erosions of the sacroiliac joints (SIJ) on pelvic radiographs of patients with ankylosing spondylitis (AS) are an important feature of the modified New York classification criteria. However, radiographic SIJ erosions are often difficult to identify. Recent studies have shown that erosions can be detected also on magnetic resonance imaging (MRI) of the SIJ early in the disease course before they can be seen on radiography. The goals of this study were to assess the reproducibility of erosion and related features, namely, extended erosion (EE) and backfill (BF) of excavated erosion, in the SIJ using a standardized MRI methodology. Four readers independently assessed T1-weighted and short tau inversion recovery sequence (STIR) images of the SIJ from 30 AS patients and 30 controls (15 patients with non-specific back pain and 15 healthy volunteers) ≤ 45 years old. Erosions, EE, and BF were recorded according to standardized definitions. Reproducibility was assessed by percentage concordance among six possible reader pairs, kappa statistics (erosion as binary variable) and intraclass correlation coefficient (ICC) (erosion as sum score) for all readers jointly. SIJ erosions were detected in all AS patients and six controls by ≥ 2 readers. The median number of SIJ quadrants affected by erosion recorded by four readers in 30 AS patients was 8.6 in the iliac and 2.1 in the sacral joint portion (P < 0.0001). For all 60 subjects and for all four readers, the kappa value for erosion was 0.72, 0.73 for EE, and 0.63 for BF. ICC for erosion was 0.79, 0.72 for EE, and 0.55 for BF, respectively. For comparison, the kappa and ICC values for bone marrow edema were 0.61 and 0.93, respectively. Erosions can be detected on MRI to a comparable degree of reliability as bone marrow edema despite the significant heterogeneity of their appearance on MRI.


The role of the nervous system in neuromuscular fatigue induced by ultra-endurance exercise.
Ultra-endurance events are not a recent development but they have only become very popular in the last 2 decades, particularly ultramarathons run on trails. The present paper reviews the role of the central nervous system in neuromuscular fatigue induced by ultra-endurance exercise. Large decreases in voluntary activation are systematically found in ultra-endurance running but are attenuated in ultra-endurance cycling for comparable intensity and duration. This indirectly suggests that afferent feedback, rather than neurobiological changes within the central nervous system, is determinant in the amount of central fatigue produced. Whether this is due to inhibition from type III and IV afferent fibres induced by inflammation, disfacilitation of Ia afferent fibers owing to repeated muscle stretching or other mechanisms still needs to be determined. Sleep deprivation per se does not seem to play a significant role in central fatigue although it still affects performance by elevating ratings of perceived exertion. The kinetics of central fatigue and recovery, the influence of muscle group (knee extensors vs plantar flexors) on central deficit as well as the limitations related to studies on central fatigue in ultra-endurance exercise are also discussed in the present article. To date, no study has quantified the contribution of spinal modulations to central fatigue in ultra-endurance events. Future investigations utilizing spinal stimulation (i.e., thoracic stimulation) must be conducted to assess the role of changes in motoneuronal excitability on the observed central fatigue. Recovery after ultra-endurance events and the effect of sex on neuromuscular fatigue must also be studied further.


A mixture model for expression deconvolution from RNA-seq in heterogeneous tissues.
RNA-seq, a next-generation sequencing based method for transcriptome analysis, is rapidly emerging as the method of choice for comprehensive transcript abundance estimation. The accuracy of RNA-seq can be highly impacted by the purity of samples. A prominent, outstanding problem in RNA-seq is how to estimate transcript abundances in heterogeneous tissues, where a sample is composed of more than one cell type and the inhomogeneity can substantially confound the transcript abundance estimation of each individual cell type. Although experimental methods have been proposed to dissect multiple distinct cell types, computationally "deconvoluting" heterogeneous tissues provides an attractive alternative, since it keeps the tissue sample as well as the subsequent molecular content yield intact. Here we propose a probabilistic model-based approach, Transcript Estimation from Mixed Tissue samples (TEMT), to estimate the transcript abundances of each cell type of interest from RNA-seq data of heterogeneous tissue samples. TEMT incorporates positional and sequence-specific biases, and its online EM algorithm only requires a runtime proportional to the data size and a small constant memory. We test the proposed method on both simulation data and recently released ENCODE data, and show that TEMT significantly outperforms current state-of-the-art methods that do not take tissue heterogeneity into account. Currently, TEMT only resolves the tissue heterogeneity resulting from two cell types, but it can be extended to handle tissue heterogeneity resulting from multi cell types. TEMT is written in python, and is freely available at https://github.com/uci-cbcl/TEMT. The probabilistic model-based approach proposed here provides a new method for analyzing RNA-seq data from heterogeneous tissue samples. By applying the method to both simulation data and ENCODE data, we show that explicitly accounting for tissue heterogeneity can significantly improve the accuracy of transcript abundance estimation.


Instrumented Four-Level Anterior Cervical Discectomy and Fusion: Long-Term Clinical and Radiographic Outcomes.
There is a paucity of data on outcomes following four-level anterior cervical discectomy and fusions (ACDFs), especially the sagittal balance (SB) parameters. We aimed to review the long-term clinical and radiographic outcomes for 41 consecutive patients that underwent instrumented four-level ACDF. Records of 27 men and 14 women, aged 40-68 years, who underwent instrumented four-level ACDF and plating at C3-C7 (n = 37) or C4-T1 (n = 4) were retrospectively analyzed. Clinical outcomes that were assessed were the visual analog scale (VAS) for pain, neck disability index (NDI), Odom's criteria, improvement of symptoms, intraoperative and postoperative complications, SB, and need for revision surgery. The mean follow-up was 65 ± 36.3 months. The mean VAS for arm and neck pain significantly improved from 7.7 ± 1.4 to 3.5 ± 1.7 (P < 0.001). The NDI score significantly improved from 31 ± 8.2 to 19.3 ± 8.1 (P < 0.001). Concerning Odom's criteria, the grades were excellent (14), good (17), fair (9), and poor (1). Concerning intraoperative and postoperative complications, 10 cases developed dysphagia, 3 cases developed temporary dysphonia, 2 cases developed a postoperative hematoma, 1 patient developed C5 palsy, 1 vertebral artery (VA) injury, and 1 case had superficial infection. The average length of stay (LOS) was 2.9 ± 3.7 days. Three patients needed another surgery (one adjacent segment and two posterior foraminotomies). Regarding the mean change in SB parameters, Cobb's angle (CA) (C2-C7) was 14° ± 8.3°, fusion angle (FA) was 10.9 ± 10.9°, cervical straight vertical alignment (cSVA) was 0.6 ± 0.5 cm, T1 slope was 2.3° ± 3.4°, and disc height (DH) was 1.3 ± 0.9 mm. Instrumented four-level ACDF is safe with a satisfactory outcome and supplementary posterior fusion was not required in any case.


The association between fracture site and obesity in men: a population-based cohort study.
A site-dependent association between obesity and fracture has been reported in postmenopausal women. In this study we investigated the relationship between body mass index (BMI) and fracture at different skeletal sites in older men (≥65 years). We carried out a population-based cohort study using data from the Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP(Q) ) database. SIDIAP(Q) contains the primary care and hospital admission computerized medical records of >1300 general practitioners (GPs) in Catalonia (Northeast Spain), with information on a representative 30% of the population (>2 million people). In 2007, 186,171 men ≥65 years were eligible, of whom 139,419 (74.9%) had an available BMI measurement. For this analysis men were categorized as underweight/normal (BMI < 25 kg/m(2) , n = 26,298), overweight (25 ≤ BMI < 30 kg/m(2) , n = 70,851), and obese (BMI ≥ 30 kg/m(2) , n = 42,270). Incident fractures in the period 2007 to 2009 were ascertained using International Classification of Diseases, 10th edition (ICD-10) codes. A statistically significant reduction in clinical spine and hip fractures was observed in obese (relative risk [RR], 0.65; 95% confidence interval [CI], 0.53-0.80 and RR, 0.63; 95% CI, 0.54-0.74, respectively), and overweight men (RR, 0.77; 95% CI, 0.64-0.92 and RR, 0.63; 95% CI 0.55-0.72, respectively) when compared with underweight/normal men. Additionally, obese men had significantly fewer wrist/forearm (RR, 0.77; 95% CI, 0.61-0.97) and pelvic (RR, 0.44; 95% CI, 0.28-0.70) fractures than underweight/normal men. Conversely, multiple rib fractures were more frequent in overweight (RR, 3.42; 95% CI, 1.03-11.37) and obese (RR, 3.96; 95% CI, 1.16-13.52) men. In this population-based cohort of older men, obesity was associated with a reduced risk of clinical spine, hip, pelvis, and wrist/forearm fracture and increased risk of multiple rib fractures when compared to normal or underweight men. Further work is needed to identify the mechanisms underlying these associations.


Correlates of overall and central obesity in adults from seven European countries: findings from the Food4Me Study.
To identify predictors of obesity in adults and investigate to what extent these predictors are independent of other major confounding factors. Data collected at baseline from 1441 participants from the Food4Me study conducted in seven European countries were included in this study. A food frequency questionnaire was used to measure dietary intake. Accelerometers were used to assess physical activity levels (PA), whereas participants self-reported their body weight, height and waist circumference via the internet. The main factors associated (p < 0.05) with higher BMI per 1-SD increase in the exposure were age (β:1.11 kg/m2), intakes of processed meat (β:1.04 kg/m2), red meat (β:1.02 kg/m2), saturated fat (β:0.84 kg/m2), monounsaturated fat (β:0.80 kg/m2), protein (β:0.74 kg/m2), total energy intake (β:0.50 kg/m2), olive oil (β:0.36 kg/m2), sugar sweetened carbonated drinks (β:0.33 kg/m2) and sedentary time (β:0.73 kg/m2). In contrast, the main factors associated with lower BMI per 1-SD increase in the exposure were PA (β:-1.36 kg/m2), intakes of wholegrains (β:-1.05 kg/m2), fibre (β:-1.02 kg/m2), fruits and vegetables (β:-0.52 kg/m2), nuts (β:-0.52 kg/m2), polyunsaturated fat (β:-0.50 kg/m2), Healthy Eating Index (β:-0.42 kg/m2), Mediterranean diet score (β:-0.40 kg/m2), oily fish (β:-0.31 kg/m2), dairy (β:-0.31 kg/m2) and fruit juice (β:-0.25 kg/m2). These findings are important for public health and suggest that promotion of increased PA, reducing sedentary behaviours and improving the overall quality of dietary patterns are important strategies for addressing the existing obesity epidemic and associated disease burden.


Colouring the human landscapes. Lennart Nilsson and the spectacular world of scanning electron micrographs.
This article explores the relationship between Swedish photographer Lennart Nilsson's scanning electron micrographs and commercial culture from the late 1960s to the mid-1980s. By retracing how Nilsson's micrographs of the internal structures of the human body were made, circulated, and received, its aim is to investigate three aspects of this relationship. First, it highlights how the complex and sometimes conflicting interplay between the photographer and various actors in science, industry and the media shaped the pictures and their trajectories. Second, it analyses the processes used to colour Nilsson's original black-and-white micrographs in relation to tendencies in the media and the advertising industry during this period. Third, it examines what motivated Nilsson and his collaborators in their use of colour and also the critical debates concerning the spectacular and commercial qualities of his pictures. In the concluding section, the implications of this analysis for the history of the objectivity of scientific images is discussed.


Functional connectivity differences in autism during face and car recognition: underconnectivity and atypical age-related changes.
Face recognition abilities improve between adolescence and adulthood over typical development (TD), but plateau in autism, leading to increasing face recognition deficits in autism later in life. Developmental differences between autism and TD may reflect changes between neural systems involved in the development of face encoding and recognition. Here, we focused on whole-brain connectivity with the fusiform face area (FFA), a well-established face-preferential brain region. Older children, adolescents, and adults with and without autism completed the Cambridge Face Memory Test, and a matched car memory test, during fMRI scanning. We then examined task-based functional connectivity between the FFA and the rest of the brain, comparing autism and TD groups during encoding and recognition of face and car stimuli. The autism group exhibited underconnectivity, relative to the TD group, between the FFA and frontal and primary visual cortices, independent of age. Underconnectivity with the medial and rostral lateral prefrontal cortex was face-specific during encoding and recognition, respectively. Conversely, underconnectivity with the L orbitofrontal cortex was evident for both face and car encoding. Atypical age-related changes in connectivity emerged between the FFA and the R temporoparietal junction, and R dorsal striatum for face stimuli only. Similar differences in age-related changes in autism emerged for FFA connectivity with the amygdala across both face and car recognition. Thus, underconnectivity and atypical development of functional connectivity may lead to a less optimal face-processing network in the context of increasing general and social cognitive deficits in autism.


Weyl Double Copy for Gravitational Waves.
We establish the status of the Weyl double copy relation for radiative solutions of the vacuum Einstein equations. We show that all type N vacuum solutions, which describe the radiation region of isolated gravitational systems with appropriate falloff for the matter fields, admit a degenerate Maxwell field that squares to give the Weyl tensor. The converse statement also holds, i.e., if there exists a degenerate Maxwell field on a curved background, then the background is type N. This relation defines a scalar that satisfies the wave equation on the background. We show that for nontwisting radiative solutions, the Maxwell field and the scalar also satisfy the Maxwell equation and the wave equation on Minkowski spacetime. Hence, nontwisting solutions have a straightforward double copy interpretation.


The skeleton flight apparatus of North American bluebirds (Sialia): phylogenetic thrushes or functional flycatchers?
To better understand ecological traits of organisms, one can study them from two, not necessarily mutually exclusive perspectives: how the traits evolved, and their current adaptive utility. In birds, foraging behavior and associated morphological traits generally are explained by a combination of adaptive and phylogenetic predictors. The avian skeleton and more specifically, the skeletal flight apparatus is under well-known functional and phylogenetic constraints. This is an interesting area to partition the relative contributions of adaptive correlated evolution and phylogenetic constraint to species clustering in morphological space. A prediction of convergent evolution is that nonphylogenetic morphological clustering is a characteristic of ecological similarity. We tested this using representatives of North American birds from two clades, one with a mixture of foraging modes (Turdid thrushes, solitaires, and bluebirds) and one with more canalized foraging behaviors (Tyrannid flycatchers). Nine characters on the skeletal flight apparatus from 19 species were used to characterize the morphological space and test for ecomorphological clustering. When body size and phylogeny are considered, the three bluebird species and Townsend's solitaire cluster with the ecologically similar flycatchers rather than with their phylogenetic close relatives. Furthermore, sit-and-wait foragers tend to exhibit relatively long distal elements and a long keel while active ground foragers have deeper keels and a longer humerus. Distal elements, expected to be relatively shorter and more bowed in the flycatchers and bluebirds, were actually longer and narrower. A reduction of distal element mass may be more important for facilitating maneuverability than surface area for insertion of wing-rotational musculature.


Effects of temperament on growth, plasma cortisol concentrations and puberty attainment in Nelore beef heifers.
Excitable temperament disrupts physiological events required for reproductive development in cattle, but no research has investigated the impacts of temperament on growth and puberty attainment in Bos indicus females. Hence, this experiment evaluated the effects of temperament on growth, plasma cortisol concentrations and puberty attainment in B. indicus heifers. A total of 170 Nelore heifers, weaned 4 months before the beginning of this experiment (days 0 to 91), were managed in two groups of 82 and 88 heifers each (mean ± SE; initial BW=238±2 kg, initial age=369±1 days across groups). Heifer temperament was evaluated via exit velocity on day 0. Individual exit score was calculated within each group by dividing exit velocity into quintiles and assigning heifers with a score from 1 to 5 (1=slowest; 5=fastest heifer). Heifers were classified according to exit score as adequate (ADQ, n=96; exit score⩽3) or excitable temperament (EXC, n=74; exit score>3). Heifer BW, body condition score (BCS) and blood samples were obtained on days 0, 31, 60 and 91. Heifer exit velocity and score were recorded again on days 31, 60 and 91. Ovarian transrectal ultrasonography was performed on days 0 and 10, 31 and 41, 60 and 70, 81 and 91 for puberty evaluation. Heifer was declared pubertal at the first 10-day interval in which a corpus luteum was detected. Exit velocity and exit score obtained on day 0 were correlated (r⩾0.64, P<0.01) with evaluations on days 31, 60 and 91. During the experiment, ADQ had greater (P<0.01) mean BCS and BW gain, and less (P<0.01) mean plasma cortisol concentration compared with EXC heifers. Temperament × time interactions were detected (P<0.01) for exit velocity and exit score, which were always greater (P<0.01) in EXC v. ADQ heifers. A temperament × time interaction was also detected (P=0.03) for puberty attainment, which was delayed in EXC v. ADQ heifers. At the end of the experiment, a greater (P<0.01) proportion of ADQ were pubertal compared with EXC heifers. In summary, B. indicus heifers classified as EXC had reduced growth, increased plasma cortisol concentrations and hindered puberty attainment compared to ADQ heifers. Moreover, exit velocity may serve as temperament selection criteria to optimize development of B. indicus replacement heifers.


Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction.
Saw Palmetto Berry Extract (SPBE) is applied for prostate health and treatment of urinary tract infections, nonbacterial prostitis and Benign Prostatic Hyperplasia (BPH) in man. An assumption is that SPBE affects tumor cell progression and migration in breast and prostate tissue. In this work, DU-145 cells were used to demonstrate that SPBE and its sterol components, beta-sitosterol and stigmasterol, inhibit prostate cancer growth by increasing p53 protein expression and also inhibit carcinoma development by decreasing p21 and p27 protein expression. In the presence of cholesterol, these features are not only reversed but increased significantly. The results show for the first time the potential of SPBE, beta-sitosterol and stigmasterol as potential anti-tumor agents. Since the protein p53 is also regarded as nuclear matrix protein facilitating actin cytoskeletal binding, 2D tractions were measured. The cell adhesion strength in the presence of SPBE, beta-sitosterol and cholesterol and the observation was that the increase in p53 expression triggered an increase in the intracellular force generation. The results suggest a dual function of p53 in cells.


Use of the polymerase chain reaction for the diagnosis of asymptomatic Leishmania infection in a visceral leishmaniasis-endemic area.
The diagnosis of asymptomatic infection with Leishmania (Leishmania) chagasi has become more important over recent years. Expansion of visceral leishmaniasis might be associated with other routes of transmission such as transfusion, congenital or even vector transmission, and subjects with asymptomatic infection are potential reservoirs. Moreover, the identification of infection may contribute to the management of patients with immunosuppressive conditions (HIV, transplants, use of immunomodulators) and to the assessment of the effectiveness of control measures. In this study, 149 subjects living in a visceral leishmaniasis endemic area were evaluated clinically and submitted to genus-specific polymerase chain reaction (PCR), serological testing, and the Montenegro skin test. Forty-nine (32.9%) of the subjects had a positive PCR result and none of them developed the disease within a follow-up period of three years. No association was observed between the results of PCR, serological and skin tests. A positive PCR result in subjects from the endemic area did not indicate a risk of progression to visceral leishmaniasis and was not associated with a positive result in the serological tests.


Use of aerobic treadmill exercises on nerve regeneration after sciatic nerve injury in spontaneously hypertensive rats.
Various postoperative protocols have been proposed to improve outcomes and accelerate nerve regeneration. Recently, the use of physical exercise in a post-surgical neurorraphy procedure has shown good results when started early. We experimentally investigated the hypothesis that post-operative exercise speeds up results and improves clinical and morphologic parameters. Isogenic rats were randomly divided into four groups: 1 SHAM; 2 SHAM submitted to the exercise protocol (EP); 3 Grafting of the sciatic nerve; and 4 Grafting of the sciatic nerve associated with the EP. The EP was based on aerobic activities with a treadmill, with a progressive increase in time and intensity during 6 weeks. The results were evaluated by the sciatic functional index (SFI), morphometric and morphologic analysis of nerve distal to the lesion, and the number of spinal cord motor neurons, positive to the marker Fluoro-Gold (FG), captured retrogradely through neurorraphy. Functional analysis (SFI) did not show a statistical difference between the group grafted with (-50.94) and without exercise (-65.79) after 90 days. The motoneurons count (Spinal cord histology) also showed no diference between these groups (834.5 × 833 respectively). Although functionally there is no difference between these groups, morphometric study showed a greater density (53.62) and larger fibers (7.762) in GRAFT group. When comparing both operated groups with both SHAM groups, all values were much lower. The experimental model that this aerobic treadmill exercises protocol did not modify nerve regeneration after sciatic nerve injury and repair with nerve graft.


[Anesthetic management for elective cesarean section for a woman with beriberi].
Beriberi is a disease caused by thiamine (vitamin B1) deficiency. Peripheral and central nerve involvement causes psychosis and memory loss as well as cardiocirculatory effects. We report the case of a 35-year-old woman 8 weeks pregnant who came to the emergency department after bouts of nausea and vomiting over a period of 6 days, with intolerance of both solids and liquids. The initial diagnosis of gastroenteritis was later changed to hyperemesis gravidarum. Episodes of vomiting and nausea continued 48 hours after admission, accompanied by vertical nystagmus, ataxia, and diminished osteotendinous reflexes. Evaluation of the clinical picture confirmed vitamin B1 deficiency, leading to a diagnosis of Wernicke-Korsakoff syndrome. Symptoms improved with thiamine therapy but did not entirely disappear. The patient was admitted for elective cesarean section at 37 weeks' gestation. Examination revealed neurological involvement (horizontal and vertical nystagmus) and general anesthesia was therefore chosen to assure adequate hemodynamic control given the possibility of cardiocirculatory alteration.


Ethnic differences in the relationships between obesity and glucose-metabolic abnormalities: a cross-sectional population-based study.
To evaluate whether body mass index (BMI) and other anthropometric indices of visceral obesity vary by ethnic group in their distribution and their relationship to metabolic abnormalities. Cross-sectional study. Canadian men and women, aged 35-75 years, of South Asian (n=342), Chinese (n=317), European (n=326) and Aboriginal (n=301) descent were recruited using stratified random sampling. Anthropometric indices (BMI, waist to hip ratio (WHR) and waist circumference (WC)), metabolic markers (fasting glucose, HbA1c, the ratio of total cholesterol/HDL) and clinical markers (systolic blood pressure) were assessed. In subjects with BMI<30 kg/m2, the mean marker levels in people with elevated WC (>88 cm in women, >102 cm in men) vs people with normal WC were 6.16 vs 5.34 mmol/l for fasting glucose, 6.05 vs 5.66% for HbA1c and 5.46 vs 4.68 for the ratio of total cholesterol to HDL (P<0.001 in each case). At nearly every given level of BMI, non-European ethnic groups displayed significantly higher marker levels than Europeans. For example, for a given BMI, age and sex, the difference between European and non-European groups in HbA1c levels was 0.53% (95% confidence interval (CI): 0.37-0.69) for South Asians, 0.37% (95% CI: 0.2-0.54) for Chinese and 0.95% (95% CI: 0.78-1.12) for Aboriginal People. Uniform cut-points for the classification of obesity using BMI, WHR or WC result in marked variation in the levels of glucose-metabolic abnormalities between ethnic groups. Existing action thresholds for these anthropometric indices do not apply to non-European ethnic groups and warrant revision.


Selecting Goals and Target Muscles for Botulinum Toxin A Injection Using the Goal Oriented Facilitated Approach to Spasticity Treatment (GO-FAST) Tool.
The objective of this article is to introduce the GO-FAST Tool (developed by the Toxnet group) to clinicians working in the field of neurological rehabilitation, specifically post-stroke spasticity management. The concepts utilized in the Tool and described in this article can be broadly grouped into five topics: the principles of patient-centred goal-setting; an algorithm for setting SMART (specific, measurable, attainable, realistic, and timed) treatment goals; goal-related target muscles and botulinum toxin type A dose determinants; goal attainment follow-up, scoring, and interpretation; and the multimodal approach to spasticity management. The Tool can enhance clinical practice by providing guided assistance with goal-setting and target muscle selection for botulinum toxin type A treatment. It also provides support with the follow-up evaluation of goal attainment and calculation of treatment success. The Tool is designed to be used by clinicians with varying levels of expertise in the field of neurological rehabilitation and post-stroke spasticity management, from those who are new to the field to those with many years of experience. A case study is presented in the Results Section of the article to illustrate the utility of the Tool in setting SMART treatment goals in the management of patients with post-stroke spasticity.


Social Behaviour in Zoo Bachelor Groups: A Case Study of Related South American Fur Seals.
Appropriate management of social groups is one of the greatest challenges that face zoos and aquaria worldwide. To facilitate breeding programmes, particularly in polygynous species, there is a need to house surplus males in bachelor groups, yet for pinnipeds, the social impact of this management strategy is unknown. The aim of this research was to enhance understanding of sociality in South American fur seals (SAFSs), with a particular focus on social dynamics in a related bachelor group, and consider implications for evidence-based management of this species in zoos. The subjects were four related male seals housed at Bristol Zoo Gardens. Social interaction and nearest neighbour data were collected between February and July 2019. Individuals engaged in both positive and negative social interactions. Positive interactions were more frequent than negative interactions, and no excessive negative interactions were observed. Temporal dynamics were observed in social relationships, and negative interactions did not increase with the onset of the breeding season. Reciprocity in dyadic relationships was variable across the study months, and nearest neighbours were not necessarily reflective of social partners. This research highlights the importance of longitudinal monitoring of social relationships and establishment of baseline social behaviour profiles to support evidence-based species management. We advocate that this research is extended, to further develop our understanding of SAFS social needs within zoo environments, to understand the differences between single-sex and mixed-sex groups and to identify the degree to which the extensive research conducted in other polygynous species (e.g., gorillas) is applicable in the social management of South American fur seals moving forwards.


Heating and eating: brown adipose tissue thermogenesis precedes food ingestion as part of the ultradian basic rest-activity cycle in rats.
Laboratory rats, throughout the 24 hour day, alternate between behaviorally active and non active episodes that Kleitman called the basic rest-activity cycle (BRAC). We previously demonstrated that brown adipose tissue (BAT), body and brain temperatures and arterial pressure and heart rate increase in an integrated manner during behaviorally active phases. Studies show that eating is preceded by increases in body and brain temperature, but whether eating is integrated into the BRAC has not been investigated. In the present study of chronically instrumented, unrestrained Sprague-Dawley rats, peaks in BAT temperature occurred every 96 ± 7 and 162 ± 16 min (mean ± SE, n=14 rats) in dark and light periods respectively, with no apparent underlying regularity. With food available ad libitum, eating was integrated into the BRAC in a temporally precise manner. Eating occurred only after an increase in BAT temperature, commencing 15 ± 1 min (mean ± SE) after the onset of an increase, with no difference between dark and light phases. There were either no or weak preprandial and postprandial relations between intermeal interval and amount eaten during a given meal. Remarkably, with no food available the rat still disturbed the empty food container 16 ± 1 min (p>0.05 versus ad libitum food) after the onset of increases in BAT temperature, and not at other times. Rather than being triggered by changes in levels of body fuels or other meal-associated factors, in sedentary laboratory rats with ad libitum access to food eating commences as part of the ultradian BRAC, a manifestation of intrinsic brain activity.


A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT).
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.


The impact of the Shanley Pressure Ulcer Prevention Programme on older persons' knowledge of, and attitudes and behaviours towards, pressure ulcer prevention.
Pressure ulcers (PUs) have a profound impact on individuals, with studies demonstrating that compared with similarly aged persons, those living with a PU have a significantly lower quality of life. The aim of this study was to explore the impact of the Shanley Pressure Ulcer Prevention Programme (SPUPP) on older persons' knowledge of, and attitudes and behaviours towards, PU prevention. This was a multi-centre, open-label, randomised controlled trial. The population of interest was older persons living in the community who attended either a day care centre or a retirement group and were deemed to be at risk of PUs due to reduced mobility. Stratified random sampling was used to randomise based on days of attendance at day care centre/retirement group. Pretest and post-test were applied to the intervention and control groups. The SPUPP is a multimedia programme delivered using electronic media, hard copy materials, activities, and patient diaries and addresses the key tenets of PU prevention as described by the SKIN bundle. The programme contains five separate sessions delivered over 5 weeks. The impact of the SPUPP was assessed using the patient knowledge of and attitude and behaviour towards PU prevention instrument (KPUP). A total of 64 persons, 32 in each group, took part in the study. Of these, 75% (n = 48) were female, with a mean age of 81.9 years (SD: 5.56 years). Further, 68.8% (n = 44) were either overweight or obese and 40.6% (n = 26) were usually incontinent of urine. There were no differences between the intervention and control groups in mean scores during the pretest stage. However, at post-test, the mean scores for the intervention group were higher than the control group, 16.87 (SD: 1.88) versus 12.41 (SD: 3.21), respectively. For the post-test stage, mean differences between the two groups in favour of the intervention group (∆ = 4.46) were statistically significant, as t = 6.76, P = .0001, and equal variances were not assumed. The SPUPP impacted positively on knowledge scores of the participants and positively influenced attitudes and behaviours towards PU prevention. Thus, this research provides information regarding the potential to enhance patient involvement in PU prevention.


A national study confirms that Escherichia coli from Australian commercial layer hens remain susceptible to critically important antimicrobials.
Controlling the use of the most critically important antimicrobials (CIAs) in food animals has been identified as one of the key measures required to curb the transmission of antimicrobial resistant bacteria from animals to humans. Expanding the evidence demonstrating the effectiveness of restricting CIA usage for preventing the emergence of resistance to key drugs amongst commensal organisms in animal production would do much to strengthen international efforts to control antimicrobial resistance (AMR). As Australia has strict controls on antimicrobial use in layer hens, and internationally comparatively low levels of poultry disease due to strict national biosecurity measures, we investigated whether these circumstances have resulted in curtailing development of critical forms of AMR. The work comprised a cross-sectional national survey of 62 commercial layer farms with each assessed for AMR in Escherichia coli isolates recovered from faeces. Minimum inhibitory concentration analysis using a panel of 13 antimicrobials was performed on 296 isolates, with those exhibiting phenotypic resistance to fluoroquinolones (a CIA) or multi-class drug resistance (MCR) subjected to whole genome sequencing. Overall, 53.0% of isolates were susceptible to all antimicrobials tested, and all isolates were susceptible to cefoxitin, ceftiofur, ceftriaxone, chloramphenicol and colistin. Resistance was observed for amoxicillin-clavulanate (9.1%), ampicillin (16.2%), ciprofloxacin (2.7%), florfenicol (2.4%), gentamicin (1.0%), streptomycin (4.7%), tetracycline (37.8%) and trimethoprim/sulfamethoxazole (9.5%). MCR was observed in 21 isolates (7.0%), with two isolates exhibiting resistance to four antimicrobial classes. Whole genome sequencing revealed that ciprofloxacin-resistant (fluoroquinolone) isolates were devoid of both known chromosomal mutations in the quinolone resistance determinant regions and plasmid-mediated quinolone resistance genes (qnr)-other than in one isolate (ST155) which carried the qnrS gene. Two MCR E. coli isolates with ciprofloxacin-resistance were found to be carrying known resistance genes including aadA1, dfrA1, strA, strB, sul1, sul2, tet(A), blaTEM-1B, qnrS1 and tet(A). Overall, this study found that E. coli from layer hens in Australia have low rates of AMR, likely due to strict control on antimicrobial usage achieved by the sum of regulation and voluntary measures.


Economic evidence on integrated care for stroke patients; a systematic review.
Given the high incidence of stroke worldwide and the large costs associated with the use of health care resources, it is important to define cost-effective and evidence-based services for stroke rehabilitation. The objective of this review was to assess the evidence on the relative cost or cost-effectiveness of all integrated care arrangements for stroke patients compared to usual care. Integrated care was defined as a multidisciplinary tool to improve the quality and efficiency of evidence-based care and is used as a communication tool between professionals to manage and standardize the outcome-orientated care. A systematic literature review of cost analyses and economic evaluations was performed. Study characteristics, study quality and results were summarized. Fifteen studies met the inclusion criteria; six on early-supported discharge services, four on home-based rehabilitation, two on stroke units and three on stroke services. The follow-up per patient was generally short; one year or less. The comparators and the scope of included costs varied between studies. Six out of six studies provided evidence that the costs of early-supported discharge are less than for conventional care, at similar health outcomes. Home-based rehabilitation is unlikely to lead to cost-savings, but achieves better health outcomes. Care in stroke units is more expensive than conventional care, but leads to improved health outcomes. The cost-effectiveness studies on integrated stroke services suggest that they can reduce costs. For future research we recommend to focus on the moderate and severely affected patients, include stroke severity as variable, adopt a societal costing perspective and include long-term costs and effects.


A report of children with spinal dysraphism managed conservatively.
This investigation is a retrospective study of 12 patients with spinal dysraphism. There were 5 males and 7 females in the cohort. Their ages ranged from 4 to 13 years at the time of their last assessment. Initial presentation included one or more of the following--a blemish on the back in the midline (lump, hairy patch, sinus and/or angioma), abnormal neurological signs and symptoms in one or both legs, and in one case dribbling of urine. Investigations performed included plain X-rays of the spine, CT scans alone or in combination with a myelogram and MR scans. Findings included thickened filum terminale, low lying cord, lipoma, syringomyelia, diastematomyelia, spina bifida occulta and sacral agenesis. The children were followed up for between 2 and 10 years. During the period of observation, none developed new symptoms or signs, and there was no progression of existing neurological deficits. This preliminary report suggests that there is no justification for prophylactic surgery in this group of patients.


Longitudinal associations between psychological capital and problem-solving among social workers: A two-wave cross-lagged study.
Social workers are tasked with the heavy responsibility of addressing societal problems and helping people in need, so the ability to solve a wide range of problems efficiently and effectively is essential for their daily responsibilities. Although recent studies have provided evidence for the salutary effects of psychological capital (PsyCap), including hope, efficacy, resilience and optimism, on job performance and well-being, the mechanism through which PsyCap operates has not been empirically examined. Adopting the social problem-solving theory, this study proposes that PsyCap is a positive psychological resource that enhances the ability to solve work problems, which provides an explanation for how PsyCap can produce work-related benefits. Due to hopeful, efficacious, resilient and optimistic attributes, social workers who possess a high level of PsyCap are expected to engage in rational problem-solving. Since social workers who possess a low level of PsyCap have less psychological resources to deal with job demands, they are expected to engage in impulsivity-carelessness and avoidance strategies. A 2-wave longitudinal study with a 3-month interval was conducted on a sample of 400 full-time social workers in Hong Kong. Cross-lagged analysis showed that PsyCap at T1 increased rational problem-solving and decreased avoidance at T2. These effects were nonreciprocal. A follow-up qualitative study was conducted to contextualise and enrich the quantitative findings. In-depth interviews revealed that social workers faced task-related, interpersonal and organisational problems. They took an active or passive approach to problems depending on their level of PsyCap. Theoretical and practical implications for the social service sector are discussed.


Proinflammatory role of monocytes in SARS-CoV-2 infection in chronic hemodialysis patients.
Fully mature monocytes that express CD14, but not CD16, undergo phagocytosis within tissues, whereas non-classical monocytes, CD14-low CD16+, represent <11% of peripheral monocytes and have primary pro-inflammatory functions. Inflammation plays a major role in Covid-19 disease and adds to the inflammation caused by chronic hemodialysis. The aim of our study was to monitor monocyte subsets in five patients with end-stage kidney disease (ESKD) over a 1-year period after a mild Covid-19 infection. Five ESKD patients with a mild Covid-19 infection were monitored using CD14, CD16, CD300e, HLA-DR, CD64, and CD45 panels using a BD FACS Canto flow cytometer. CD14-low CD16+ was dramatically (p=0,001) decreased in patients during Covid-19 infection, as previously described for patients without chronic renal failure. In addition, CD14-low CD16+ monocytes remained decreased for 10 months after recovery from Covid. Intermediate monocytes increased during Covid-19 infection and decreased 10 months after infection but this subtype of monocytes retained their inflammatory activity with a significant increase in HLA-DR expression after recovery from Covid infection. Our study shows that ESKD patients had a pro-inflammatory profile induced by Covid 19, but this status was prolonged significantly over a 10-month period. Thus, advanced renal failure treated by hemodialysis did not dramatically change the inflammatory response against to SARS Covid 2. It seems that monocytes retain their inflammatory status for many months in ESKD patients after a Covid-19 infection.


Genome-wide reprogramming of metabolism and regulatory networks of Arabidopsis in response to phosphorus.
Affymetrix ATH1 arrays, large-scale real-time reverse transcription PCR of approximately 2200 transcription factor genes and other gene families, and analyses of metabolites and enzyme activities were used to investigate the response of Arabidopsis to phosphate (Pi) deprivation and re-supply. Transcript data were analysed with MapMan software to identify coordinated, system-wide changes in metabolism and other cellular processes. Phosphorus (P) deprivation led to induction or repression of > 1000 genes involved in many processes. A subset, including the induction of genes involved in P uptake, the mobilization of organic Pi, the conversion of phosphorylated glycolytic intermediates to carbohydrates and organic acids, the replacement of P-containing phospholipids with galactolipids and the repression of genes involved in nucleotide/nucleic acid synthesis, was reversed within 3 h after Pi re-supply. Analyses of 22 enzyme activities revealed that changes in transcript levels often, but not always, led to changes in the activities of the encoded enzymes in P-deprived plants. Analyses of metabolites confirmed that P deprivation leads to a shift towards the accumulation of carbohydrates, organic acids and amino acids, and that Pi re-supply leads to use of the latter. P-deprived plants also showed large changes in the expression of many genes involved in, for example, secondary metabolism and photosynthesis. These changes were not reversed rapidly upon Pi re-supply and were probably secondary in origin. Differentially expressed and highly P-specific putative regulator genes were identified that presumably play central roles in coordinating the complex responses of plants to changes in P nutrition. The specific responses to Pi differ markedly from those found for nitrate, whereas the long-term responses during P and N deprivation share common and non-specific features.


The growing dependency in health care. Recent changes in medical technology imports and exports in Turkey.
This study investigates recent changes related to the import and export of medical technology and their results in Turkey. Between 1980 and 1993 the number of medical technology imports in Turkey rose, and there was a parallel rise in its ratio to total imports and health expenditures. In contrast the ratio of medical technology exports to total exports decreased significantly in the same period. The liberalization of foreign trade and the changes of health services toward free market policy has caused growing import of medical technology in Turkey.


Pathology of female mice experimentally infected with an in vitro cultured strain of Trypanosoma equiperdum.
Dourine, caused by infection with Trypanosoma equiperdum, is one of the trypanosomiasis in equids. The clinical course of dourine is long-term, ranging from 1-2 months to several years. Since the pathogenesis of dourine has not yet been elucidated, experimental studies using mouse infection models are needed. Although mice are not susceptible to most T. equiperdum strains, some strains can infect mice. Even in such strains, infected mice develop rapidly transient parasitemia and die within 2-8 days. Therefore, mice experimentally infected with these T. equiperdum strains are not suitable for mouse infection models to analysis the pathogenesis of dourine. A sequential method of isolating parasites from dourine-affected horses and adapting them to in vitro cultures using soft agarose media was recently developed. Various T. equiperdum strains adapted to in vitro conditions have been established using this technique. We used one of these strains, the T. equiperdum IVM-t2 strain. In the present study, T. equiperdum IVM-t2 strain inoculated mice developed periodic parasitemia during the experimental period of 60 days. Histopathologically, vaginitis and dermatitis were observed. These findings were comparable to those of dourine-affected horses. Therefore, mice infected with T. equiperdum IVM-t2 strain may be a valuable tool for pathological, immunological, and parasitological in vivo research, and will contribute to investigations on the mechanisms underlying the disease process and the host-parasite relationship.


Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2022.
The National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), provides a family of database resources to support global research in both academia and industry. With the explosively accumulated multi-omics data at ever-faster rates, CNCB-NGDC is constantly scaling up and updating its core database resources through big data archive, curation, integration and analysis. In the past year, efforts have been made to synthesize the growing data and knowledge, particularly in single-cell omics and precision medicine research, and a series of resources have been newly developed, updated and enhanced. Moreover, CNCB-NGDC has continued to daily update SARS-CoV-2 genome sequences, variants, haplotypes and literature. Particularly, OpenLB, an open library of bioscience, has been established by providing easy and open access to a substantial number of abstract texts from PubMed, bioRxiv and medRxiv. In addition, Database Commons is significantly updated by cataloguing a full list of global databases, and BLAST tools are newly deployed to provide online sequence search services. All these resources along with their services are publicly accessible at https://ngdc.cncb.ac.cn.


Secretion and glycosylation of alpha-foetoprotein by the mouse yolk sac.
Secretion and glycosylation of alpha-foetoprotein (AFP) by mouse yolk sac were studied by using yolk-sac explants cultured in vitro. Yolk-sac explants rapidly incorporated [35S]methionine into AFP, whereas radioactively labelled AFP was not found in the medium until 30 min after incubation was initiated. Electrophoretic analysis revealed that microheterogeneity of AFP synthesized in explants increased in parallel with the gestational age of the yolk sacs. The change in microheterogeneity was noted by the formation of increasingly acidic forms. Only the most acidic forms of AFP were found to be present in the medium on each gestational day studied. Tunicamycin reduced the incorporation of glucosamine into AFP with a concomitant decrease in molecular weight and microheterogeneity. However, the relative amount of AFP released into the medium was not altered by the presence of tunicamycin. The presence of under-glycosylated AFP in the medium indicates that glycosylation of AFP is not essential for its secretion from the yolk sac. In light of these and previous findings, it is suggested that the glycosylation of AFP may be important for the turnover of this glycoprotein in serum.


Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs.
Neonatal pigs are used as a model to study and optimize the clinical treatment of infants who are unable to maintain oral feeding. Using this model, we have shown previously that pulsatile administration of leucine during continuous feeding over 24 h via orogastric tube enhanced protein synthesis in skeletal muscle compared with continuous feeding alone. To determine the long-term effects of leucine pulses, neonatal piglets (n = 11-12/group) were continuously fed formula via orogastric tube for 21 days, with an additional parenteral infusion of either leucine (CON + LEU; 800 μmol·kg-1·h-1) or alanine (CON + ALA) for 1 h every 4 h. The results show that body and muscle weights and lean gain were ∼25% greater, and fat gain was 48% lower in CON + LEU than CON + ALA; weights of other tissues were unaffected by treatment. Fractional protein synthesis rates in longissimus dorsi, gastrocnemius, and soleus muscles were ∼30% higher in CON + LEU compared with CON + ALA and were associated with decreased Deptor abundance and increased mTORC1, mTORC2, 4E-BP1, and S6K1 phosphorylation, SNAT2 abundance, and association of eIF4E with eIF4G and RagC with mTOR. There were no treatment effects on PKB, eIF2α, eEF2, or PRAS40 phosphorylation, Rheb, SLC38A9, v-ATPase, LAMTOR1, LAMTOR2, RagA, RagC, and LAT1 abundance, the proportion of polysomes to nonpolysomes, or the proportion of mRNAs encoding rpS4 or rpS8 associated with polysomes. Our results demonstrate that pulsatile delivery of a leucine supplement during 21 days of continuous enteral feeding enhances lean growth by stimulating the mTORC1-dependent translation initiation pathway, leading to protein synthesis in skeletal muscle of neonates.


[Decade of genomics--methods for genome investigation in yeast Saccharomyces cerevisiae].
The last ten years, since yeast Saccharomyces cerevisiae genome was sequenced, brought a big impact in genome-wide techniques. The tenth anniversary of genomic era provokes the following resume: a lot of new methods were invented. The yeast strains libraries carrying transposon insertions, gene deletions or tagged proteins have been created. Using them, the phenotypes of gene deletions, as well as the biological activity, cellular localization and possible modifications of their protein products were elucidated. SAGE analysis and DNA microarray experiments showed gene expression profiles and allowed to build interaction networks of gene regulation. The two dimensional gels, mass spectrometry, protein arrays and two-hybrid system carry information about protein interactions, modifications, and biochemical activities. All these methods permit to increase the number of genes with known cellular functions. Moreover, testing these techniques on yeast S. cerevisiae--a model eukaryotic organism--opened the door for their usage in all other species.


The relationship between the stretching capability of the anterior capsule and zonules.
The stretching capability of the zonules was studied in 40 human eyes obtained postmortem from 27 patients. A continuous circular capsulorhexis (CCC) (2.2-6.8 mm) was performed, and the lenses were removed by either phacoemulsification (26 eyes) or planned extracapsular cataract extraction (ECCE) (14 eyes). Maximal zonular stretch was calculated as the difference in distance between the ciliary processes and the zonular insertion at rest and after maximal stretch. This zonular stretch test showed that zonules can stretch to a mean distance of 3.82 mm before rupturing. Capsular elasticity was measured in 35 of the eyes by gradually opening a modified caliper until the capsular opening was torn. The ratio between the circumference at rupture and the circumference at rest was used as an index of capsular elasticity. Circumference of the intact capsulorhexis could be enlarged an additional 62% before a radial tear occurred. In most cases, no significant correlation was seen between the capsular and zonular capability to stretch. Maximal zonular stretch decreased significantly with age by approximately 0.5 mm for every 5 yr, whereas capsular elasticity did not show a significant correlation with age. Two eyes with pseudoexfoliation had relatively friable zonules but the capsular elasticity was within normal limits. Patient age is probably the best indicator of the stretching capability of the zonules.


Haeme-regulated degradation of delta-aminolevulinate synthase 1 in rat liver mitochondria.
Protein turnover, which occurs at various rates, is critical for the homeostasis of cellular protein levels. However, the proteolysis systems that determine the turnover rate of mitochondrial proteins are largely unknown. Delta-aminolevulinic acid synthase (ALAS) 1, a rate-limiting enzyme in the haeme biosynthesis, is one of the mitochondrial proteins that have a very short lifetime. In this study, to reveal the regulatory mechanisms for ALAS1 degradation, we examined the turnover rates of ALAS1 in rat liver under several conditions. In primary rat hepatocytes, the degradation of ALAS1 was stimulated by haeme, and suppressed by inhibition of haeme biosynthesis. Furthermore, the haeme-stimulated degradation of ALAS1 was observed in the isolated mitochondria. These results suggested that, in mitochondria, there exists an ALAS1 degradation system that is regulated by cellular haeme level and plays a crucial role in the regulation of haeme biosynthesis.


Cost savings and clinical improvement through disease management.
Cystic fibrosis is an expensive chronic illness that has not historically demonstrated cost savings and quality of care improvement potential by alternate care plans using comprehensive disease management treatment modalities. This case study describes care provided over a 45-month period to an adolescent female with severe cystic fibrosis involving multiple hospitalizations and $396,000 in total cost of care. Treatment plans before and after the initiation of a comprehensive home care disease management program are described. Clinical improvement outcomes and savings of 33.4% in total costs were documented using longitudinal analysis of paid claims data and medical chart review. Guidelines are suggested for case managers desiring to initiate similar programs of care.


Changing profile of disease in leprosy patients diagnosed in a tertiary care centre during years 1995-2000.
A hospital based retrospective study was carried out to determine change in the profile of disease in leprosy patients taking 1995 as baseline and compared with the profile seen in year 2000. A total of 2149 and 1703 cases were studied respectively of year 1995 and 2000. Male to female ratio slightly increased from 2.95:1 in year 1995 to 3.4:1 in year 2000. Majority of patients were of borderline type in both years. Proportion of cases with MB leprosy was nearly same in females (60.8%) and males (63.1%) in year 1995 and in year 2000 (64.8% females and 67.6% males). Proportion of highly bacillary cases has decreased over the years in females (from 20.95% in 1995 to 11.7% in year 2000, p=0.03) as well as in males (from 25% in 1995 to 15.5% in year 2000, p=0.001). Incidence of total reactions increased from 27.6% to 35.4% over the years which is significant (p<0.01). Proportion of type 1 reactions were more in reproductive age group in females in both years (p<0.05) and of type 2 reactions were significantly (p > or = 0.05) more in males in both years. Incidence of disability (both grade 1 and grade 2) was significantly more in males than in females in both years (p > or = 0.04). Grade 1 disability has significantly increased over years in females from 10.11% to 14.8%(p<0.03) as well as in males from 13.27% to 21.3%(p<0.001). Onset of reactions was associated with pregnancy/lactation in 62% of cases and with menopause in 21% of cases in 2000, which suggests strong correlation with hormonal imbalance. To conclude while leprosy incidence has declined after MDT, recognition and management of reactions in women around changes in their hormonal levels should be properly monitored for early and effective management.


Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design.
Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIα) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIα, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIα-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD.


A new pediatric protocol for rapid desensitization to monoclonal antibodies.
Monoclonal antibodies are important therapeutic tools, but their usefulness may be limited when patients experience acute hypersensitivity reactions. Patients reporting a history of adverse allergic reaction are likely to discontinue their therapeutic protocol or be switched to an alternative drug, which is sometimes less effective than that originally prescribed. Drug desensitization has proven to be a highly effective strategy to readminister a drug in a patient who has experienced a hypersensitivity reaction. It involves forcing the patient's immune system to accept and tolerate the allergen. Nevertheless, such a procedure is still empiric for monoclonal antibodies and not common in the pediatric population. The aim of our study is to demonstrate the clinical success of a new protocol of rapid desensitization to infliximab in a pediatric patient affected by ulcerative colitis, who developed an anaphylaxis to the drug. We used a protocol of rapid desensitization consisting of 13 steps, with the first being 1/1,000,000 of the cumulative and total dose. Such a protocol has proven to be able to induce a temporary tolerance to infliximab, allowing the patient to achieve complete control of his disease.


Trajectories of entering the metabolic syndrome: the framingham heart study.
We evaluated the progression of the metabolic syndrome (MetS) and its components, the trajectories followed by individuals entering MetS, and the manner in which different trajectories predict cardiovascular disease and mortality. Using data from 3078 participants from the Framingham Offspring Study (a cohort study) who attended examinations 4 (1987), 5 (1991), and 6 (1995), we evaluated the progression of MetS and its components. MetS was defined according to the Adult Treatment Panel III criteria. Using logistic regression, we evaluated the predictive ability of the presence of each component of the MetS on the subsequent development of MetS. Additionally, we examined the probability of developing cardiovascular disease or mortality (until 2007) by having specific combinations of 3 that diagnose MetS. The prevalence of MetS almost doubled in 10 years of follow-up. Hyperglycemia and central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and the presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold (hazard ratio, 2.36; 95% confidence interval, 1.54 to 3.61) increase of incident cardiovascular events and a 3-fold (hazard ratio, 3.09, 95% confidence interval, 1.93 to 4.94) increased risk of mortality. Particular trajectories and combinations of factors on entering the MetS confer higher risks of incident cardiovascular disease and mortality in the general population and among those with MetS. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.


Molecular Basis of the Antioxidant Capability of Glutathione Unraveled via Aerosol VUV Photoelectron Spectroscopy.
Glutathione (GSH), the most abundant nonenzymatic antioxidant in living systems, actively scavenges various exogenous/endogenous oxidizing species, defending important biomolecules against oxidative damages. Although it is well established that the antioxidant activity of GSH originates from the cysteinyl thiol (-SH) group, the molecular origin that makes the thiol group of GSH a stronger reducing agent than other thiol-containing proteins is unclear. To gain insights into the molecular basis underlying GSH's superior antioxidant capability, here we report, for the first time, the valence electronic structures of solvated GSH in the aqueous aerosol form via the aerosol vacuum ultraviolet photoelectron spectroscopy technique. The pH-dependent electronic evolution of GSH is obtained, and the possible correlations between GSH and its constituting amino acids are interrogated. The valence band maxima (VBMs) for GSH aqueous aerosols are found at 7.81, 7.61, 7.52, and 5.51 ± 0.10 eV at a pH of 1.00, 2.74, 7.00, and 12.00, respectively, which appear to be lower than the values of their corresponding hybrid counterparts collectively contributed from the three isolated constituting amino acids of GSH. An additional photoelectron feature is observed for GSH aqueous aerosols at pH = 12.00, where the thiol group on its Cys residue becomes deprotonated and the relatively well-separated feature allows its vertical ionization energy (VIE) to be determined as 6.70 ± 0.05 eV. Compared to a VIE of 6.97 ± 0.05 eV obtained for a similar thiolate feature observed previously for isolated Cys aqueous aerosols ( Su et al. VUV Photoelectron Spectroscopy of Cysteine Aqueous Aerosols: A Microscopic View of Its Nucleophilicity at Varying pH Conditions . J. Phys. Chem. Lett. 2015 , 6 , 817 - 823 ), a 0.27 eV reduction in the VIE is found for GSH, indicating that the outermost electron corresponding to the nonbonding electron on the thiolate group can be removed more readily from the GSH tripeptide than that from Cys alone. The possible origins underlying the decrease in the VBM of GSH with respect to that of each corresponding hybrid counterpart and the decrease in the VIE of the thiolate feature of GSH with respect to that of the isolated Cys are discussed, providing hints to understand the superior antioxidant capability of GSH from a molecular level.


Biocompatible indocyanine green loaded PLA nanofibers for in situ antimicrobial photodynamic therapy.
Chronic wounds and their associated bacterial infections are major issues in modern health care systems. Therefore, antimicrobial resistance (AMR), treatment costs, and number of disability-adjusted life-years have gained more interest. Recently, photodynamic therapy emerged as an effective approach against resistant and naïve bacterial strains with a low probability of creating AMR. In this study, needleless electrospinning was used to produce an indocyanine green (ICG) loaded poly(d,l-lactide) nanofibrous mesh as a photoresponsive wound dressing. The non-woven mesh had a homogeneous nanofibrous structure and showed long-term hydrolytic stability at different pH values. The antimicrobial activity was tested against several bacterial strains, namely Staphylococcus saprophyticus subsp. bovis, Escherichia coli DH5 alpha, and Staphylococcus aureus subsp. aureus. Upon irradiation with a laser of a specific wavelength (λ = 810 nm), the bacterial viability was significantly reduced by 99.978% (3.66 log10), 99.699% (2.52 log10), and 99.977% (3.64 log10), respectively. The nanofibrous mesh showed good biocompatibility, which was confirmed by the proliferation of mouse fibroblasts (L929) on the surface and into deeper parts of the mesh. Furthermore, a favorable proangiogenic effect was observed in ovo using the chorioallantoic membrane assay. In general, it can be concluded that ICG loaded nanofibers as an innovative wound dressing represent a promising strategy against chronic wounds associated with skin infections.


Ultra-deep pyrosequencing analysis of the hepatitis B virus preCore region and main catalytic motif of the viral polymerase in the same viral genome.
Hepatitis B virus (HBV) pregenomic RNA contains a hairpin structure (ε) located in the preCore region, essential for viral replication. ε stability is enhanced by the presence of preCore variants and ε is recognized by the HBV polymerase (Pol). Mutations in the retrotranscriptase domain (YMDD) of Pol are associated with treatment resistance. The aim of this study was to analyze the preCore region and YMDD motif by ultra-deep pyrosequencing (UDPS). To evaluate the UDPS error rate, an internal control sequence was inserted in the amplicon. A newly developed technique enabled simultaneous analysis of the preCore region and Pol in the same viral genome, as well as the conserved sequence of the internal control. Nucleotide errors in HindIII yielded a UDPS error rate <0.05%. UDPS study confirmed the possibility of simultaneous detection of preCore and YMDD mutations, and demonstrated the complexity of the HBV quasispecies and cooperation between viruses. Thermodynamic stability of the ε signal was found to be the main constraint for selecting main preCore mutations. Analysis of ε-signal variability suggested the essential nature of the ε structural motif and that certain nucleotides may be involved in ε signal functions.


Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin.
The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [(125)I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (+/-standard deviation) body mass index was 46.2 +/- 5.5 kg/m(2) or 21.8 +/- 1.9 kg/m(2) for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.


[THE CHROMOGENIC SYNTHETIC MEDIUM "KLEBSIELLA 5-ASK CHROM-C" FOR ISOLATION AND IDENTIFICATION OF KLEBSIELLAE].
The chromogenic synthetic medium "Klebsiella 5-ASK CHROM-C was developedfor isolation and identification of klebsiellae of species of K. pneumoniae subsp. pneumoniae K. oxytoca, K. mobilis according chromogenic reaction to enzyme 5-aminosalycilate decarboxylase as a unique marker of genus Klebsiella. The L-proline and L-calcium glutamate are used as a source of nitrogen and carbon in medium. The consistency of composition of growth medium that ensure its regularity. The diagnostic sensitivity of chromogenic medium is 95.3 ± 1.7%; diagnostic specificity is 100%; analytical sensitivity is 1-2 colony-forming units per ml-1. The identification of Klebsiella is achieved simultaneously with their isolation during 24 = 48 hours. The test of 5-ASK decarboxylase using two chromogenic mediums "Klebsiella 5-ASK CHROM-C" permits identifying additionally K. pneumoniae subsp, ozaenae, K .pneumoniae subsp. Rhinoscleromatis.


Complete solvation response of coumarin 153 in ionic liquids.
The dynamic Stokes shift of coumarin 153, measured with a combination of broad-band fluorescence upconversion (80 fs resolution) and time-correlated single photon counting (to 20 ns), is used to determine the complete solvation response of 21 imidazolium, pyrrolidinium, and assorted other ionic liquids. The response functions so obtained show a clearly bimodal character consisting of a subpicosecond component, which accounts for 10-40% of the response, and a much slower component relaxing over a broad range of times. The times associated with the fast component correlate with ion mass, confirming its origins in inertial solvent motions. Consistent with many previous studies, the slower component is correlated to solvent viscosity, indicating that its origins lie in diffusive, structural reorganization of the solvent. Comparisons of observed response functions to the predictions of a simple dielectric continuum model show that, as in dipolar solvents, solvation and dielectric relaxation involve closely related molecular dynamics. However, in contrast to dipolar solvents, dielectric continuum predictions systematically underestimate solvation times by factors of at least 2-4.


Hypergravity within a critical period impacts on the maturation of somatosensory cortical maps and their potential for use-dependent plasticity in the adult.
We investigated experience-dependent plasticity of somatosensory maps in rat S1 cortex during early development. We analyzed both short- and long-term effects of exposure to 2G hypergravity (HG) during the first 3 postnatal weeks on forepaw representations. We also examined the potential of adult somatosensory maps for experience-dependent plasticity after early HG rearing. At postnatal day 22, HG was found to induce an enlargement of cortical zones driven by nail displacements and a contraction of skin sectors of the forepaw map. In these remaining zones serving the skin, neurons displayed expanded glabrous skin receptive fields (RFs). HG also induced a bias in the directional sensitivity of neuronal responses to nail displacement. HG-induced map changes were still found after 16 wk of housing in normogravity (NG). However, the glabrous skin RFs recorded in HG rats decreased to values similar to that of NG rats, as early as the end of the first week of housing in NG. Moreover, the expansion of the glabrous skin area and decrease in RF size normally induced in adults by an enriched environment (EE) did not occur in the HG rats, even after 16 wk of EE housing in NG. Our findings reveal that early postnatal experience critically and durably shapes S1 forepaw maps and limits their potential to be modified by novel experience in adulthood.


Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion.
Mesangial cells maintain normal glomerular function by mediating ECM remodeling and immune complex disposal. We have recently identified megsin, a novel member of the serine protease inhibitor (serpin) superfamily predominantly expressed in the mesangium. While our previous studies suggested a role for megsin in the pathogenesis of human glomerular diseases, its exact biological significance remained unknown. Here we produced two lines of megsin transgenic mice. Overexpression of megsin led to progressive mesangial matrix expansion and an increase in the number of mesangial cells. These glomerular lesions were accompanied by an augmented immune complex deposition, together with Ig's and complement. Binding and functional assays in vitro identified plasmin as one biological substrate of megsin and confirmed its activity as a proteinase inhibitor. Transgenic animals exhibiting nephritis as a result of treatment with anti--glomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial ECM than was seen in parental mice. Megsin therefore exerts a biologically relevant influence on mesangial function, and on the mesangial microenvironment, such that simple overexpression of this endogenous serpin engenders elementary mesangial lesions.


Associations among prenatal stress, maternal antioxidant intakes in pregnancy, and child temperament at age 30 months.
Prenatal stress and prenatal nutrition each have demonstrable impact on fetal development, with implications for child neurodevelopment and behavior. However, few studies have examined their joint influences despite evidence of potential interactive effects. We examined associations among prenatal stress, prenatal antioxidant intakes, and child temperament in a sociodemographically diverse pregnancy cohort (N=137 mother-child dyads). In mid-pregnancy, mothers completed an assessment of recent negative life events as a measure of prenatal stress and an assessment of prenatal diet. When the children were 30 months of age, mothers completed the Early Childhood Behavior Questionnaire-Very Short form, which provides scores on child Negative Affectivity, Effortful Control, and Surgency/Extraversion. Linear regressions tested associations between maternal prenatal negative life events and child temperament, and effect modification by maternal prenatal antioxidant intakes (vitamins A, C, and E, magnesium, zinc, selenium, β-carotene). Analyses revealed that increased maternal prenatal negative life events were associated with higher child Negative Affectivity (β=0.08, P=0.009) but not with child Effortful Control (β=-0.03, P=0.39) or Surgency/Extraversion (β=0.04, P=0.14). Prenatal intakes of zinc and selenium modified this effect: Maternal exposure to prenatal negative life events was associated with higher child Negative Affectivity in the presence of lower intakes of zinc and selenium. Modification effects approached significance for vitamins A and C. The results suggest that the combination of elevated stress exposures and lower antioxidant intakes in pregnancy increases the likelihood of heightened child temperamental negative affectivity. Increased antioxidant intakes during pregnancy may protect against influences of prenatal stress on child temperament.


Clinical review of acute, recurrent, and chronic pancreatitis: Recent updates of 2013-2019 literature.
The increasing prevalence of pancreatic disorders worldwide has provided challenges in its clinical care and management. This review was aimed to evaluate recent literature on diagnosis, treatment, and management of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), as well as chronic pancreatitis (CP) documented during the past 5-6 years. An extensive literature review was carried out based on studies within the last 6 years (2013-2019). Articles were selected based on updates and therapeutic management. Critical appraisal of literature was performed using the Mixed Methods Appraisal Tool (MMAT), and a PRISMA flowchart was used to avoid bias. The study identified recent updates on the prophylactic treatment in preventing RAP. The risk factors and the therapeutic management options were evaluated and discussed. The findings show that although many lifesaving new protocols are available for implementation in clinical practice, current literature lacks detailed and comprehensive guidelines that cover special populations and comorbidities. The literature evaluated showed that eight genes were involved in pancreatitis, CASR, CFTR, CLDN2, CPA1, CTRC, PRSS1, SBDS, and SPINK1, but the most common gene implicated was found to be CFTR, at 11%. Therefore, it is recommended that a comprehensive guideline should be formulated to facilitate the diagnosis, management, treatment, and prophylactic measures of pancreatic disease. This could in turn reduce disease complications and hospitalization time, and improve clinical practice for management of pancreatitis.


SX-fraction: Promise for novel treatment of type 2 diabetes.
SX-fraction (SXF) is a bioactive glycoprotein with anti-diabetic and hypoglycemic activities that have been documented in several reports. We have reviewed those studies herein and also explored the possible mechanism of its hypoglycemic activity. The early animal studies of SXF using diabetic mice showed the significant reduction in the three diabetic parameters, serum glucose, insulin, and triglyceride, suggesting its anti-diabetic activity. The limited clinical studies also showed that SXF led to the significant reduction in the fasting blood glucose levels of type 2 diabetic patients within 2 wk or a month, suggesting its hypoglycemic activity. To explore the hypoglycemic mechanism of SXF, its possible effects on the insulin signal transduction pathway was examined in vitro. Particularly, activities of insulin receptor, insulin receptor substrate 1, and protein kinase B, which are essential elements playing a key regulatory role in the signal pathway, were studied using skeletal muscle L6 cells. The status of these three parameters were examined under a high glucose (35 mmol/L) milieu with SXF and assessed using the enzyme-linked immunosorbent assay. Such studies revealed that all three parameters (insulin receptor, insulin receptor substrate 1, and protein kinase B) were inactivated by high glucose, indicating a disruption of the signal pathway. However, such an inactivation was reversed or re-activated by SXF to successfully carry out the sequential signaling events. In fact, a measurement of glucose uptake in cells showed that SXF did increase a glucose uptake while high glucose decreased it. Therefore, SXF has anti-diabetic and hypoglycemic activities through activation of the insulin signal pathway and appears to be a safe, natural agent for lowering the serum glucose levels in type 2 diabetic patents and improving their diabetic conditions.


Health resource utilization and multidisciplinary impact of endoscopic ultrasonography in a tertiary referral medical center.
Endoscopic ultrasound (EUS) is a resource-intensive endoscopic procedure, but may result in high downstream health resource utilization and multispecialty impact. Our aim was to examine the downstream impact of EUS by specialty and by indication. A retrospective chart review was performed at an academic medical center for patients for whom EUS represented the first point of contact at the study institution within a 20-month period. A total of 552 EUS procedures were reviewed and 208 represented the first point of contact. The most common principle indication involved the pancreas (n = 117, 56%). Downstream health utilization was calculated for an average of 313 days postprocedure (range: 35-632 days). Following unique referral for endoscopic ultrasound, 52% of the patients in the study were retained within the institution for further management and, of these, 34% had a major intervention in the form of surgery or chemoradiotherapy. Compared with other indications, patients presenting with a pancreatic mass were significantly more likely to remain in the study institution for further management (62% versus 39%, p = 0.005), were more likely to have a downstream surgery (29% versus 14%, p = 0.020) and were more likely to have downstream chemo-radiotherapy (11% versus 3%, p = 0.012). EUS represents a unique portal of entry into tertiary referral medical centers. First point of contact EUS referrals are associated with major downstream health resource utilization and significantly increased utilization for mass lesions of the pancreas.


Efficacy of sirolimus-eluting stents compared with paclitaxel-eluting stents in an unselected population with coronary artery disease: 24-month outcomes of patients in a prospective non-randomized registry in Southern Turkey.
The efficacy of drug-eluting stents has been shown in randomized trials, but some controversy exists regarding which stent sirolimus-eluting or paclitaxel-eluting is more effective in unselected Turkish patients. Therefore, we investigated the clinical outcomes of patients who were treated with one type of these drug-eluting stents in the real world. We created a registry and prospectively analyzed data on a consecutive series of all patients who presented to our institution with symptomatic coronary artery disease between February 2005 and March 2007 and who were treated with the sirolimus- or the paclitaxel-eluting stent. The follow-up period after stent implantation was approximately 24 months. The primary end point was a major cardiac event, and the secondary end point was stent thrombosis. Informed consent was obtained from all subjects, and the study protocol was approved by the local ethical committee. In total, 204 patients were treated with either the sirolimus-eluting stent (n = 103) or the paclitaxel-eluting stent (n = 101). The lesions in the 2 arms of the study were treated similarly by conventional technique. At 24-month follow-up, patients who received the paclitaxel-eluting stent showed significantly higher rates of non-Q-wave myocardial infarction (1.9% vs 5.9%; P: .002), target vessel revascularization (1.9% vs 4.9%; P: .002), coronary artery bypass graft surgery (1.9% vs 6.9%; P: .001), and late stent thrombosis (1.9% vs 3.9%, P: .002). Patients who received the sirolimus-eluting stent showed better clinical outcomes compared with those who had the paclitaxel-eluting-stent.


SID1-1: a mutation affecting meiotic sister-chromatid association in yeast.
Meiotic chromosome segregation must occur with high fidelity in order to prevent the generation of deleterious aneuploidies. In meiosis I, homologous chromosomes pair, then migrate to opposite poles of the spindle. This process uses a collection of unique structures and mechanisms that have yet to be thoroughly characterized. To acquire a collection of informative meiotic mutants, we carried out a novel genetic screen in Saccharomyces cerevisiae. This screen was designed to identify dominant mutants in which meiosis I chromosome segregation occurs with decreased fidelity. One mutant recovered using this screen, SID1-1 (sister disjunction), showed an incidence of spores disomic for a marked chromosome III that was 25-fold greater than the wild-type level. Crossing-over is slightly, but not dramatically, reduced in SID1-1. Both recombinant and nonrecombinant chromosomes segregate with reduced fidelity in the presence of SID1-1. We present evidence that the mutant is defective in sister-chromatid association.


alpha-Actinin and vinculin in normal and thrombasthenic platelets.
Recently, the contractile protein alpha-actinin was identified in normal human platelets by its antigenic cross-reaction with a monospecific antibody to purified muscle alpha-actinin. In this study, we extend that preliminary identification of platelet alpha-actinin. Amino acid analysis, one-dimensional peptide maps, and silver stain analysis on polyacrylamide gels demonstrate that human platelet alpha-actinin shows a greater degree of similarity to smooth muscle alpha-actinin than to striated muscle alpha-actinin. There is no evidence to suggest that alpha-actinin is a glycoprotein. In addition, we find that thrombasthenic platelets, which are deficient in glycoproteins IIb and IIIa (GPIIb and GPIIIa) contain normal amounts of alpha-actinin, confirming the recent finding that alpha-actinin and GPIIIa are different proteins in human platelets. We demonstrate that both normal and thrombasthenic platelets also contain vinculin, a 130,000-dalton polypeptide found in many cell types at sites of end-on attachment of microfilaments to the plasma membrane. Thus, the thrombasthenic defect in GPIIb and GPIIIa does not diminish the content of either alpha-actinin or vinculin.


Additive value of 3T cardiovascular magnetic resonance coronary angiography for detecting coronary artery disease.
The purpose of the work was to evaluate the incremental diagnostic value of free-breathing, contrast-enhanced, whole-heart, 3 T cardiovascular magnetic resonance coronary angiography (CE-MRCA) to stress/rest myocardial perfusion imaging (MPI) and late gadolinium enhancement (LGE) imaging for detecting coronary artery disease (CAD). Fifty-one patients with suspected CAD underwent a comprehensive cardiovascular magnetic resonance (CMR) examination (CE-MRCA, MPI, and LGE). The additive diagnostic value of MRCA to MPI and LGE was evaluated using invasive x-ray coronary angiography (XA) as the standard for defining functionally significant CAD (≥ 50% stenosis in vessels > 2 mm in diameter). 90.2% (46/51) patients (54.0 ± 11.5 years; 71.7% men) completed CE-MRCA successfully. On per-patient basis, compared to MPI/LGE alone or MPI alone, the addition of MRCA resulted in higher sensitivity (100% vs. 76.5%, p < 0.01), no change in specificity (58.3% vs. 66.7%, p = 0.6), and higher accuracy (89.1% vs 73.9%, p < 0.01) for CAD detection (prevalence = 73.9%). Compared to LGE alone, the addition of CE-MRCA resulted in higher sensitivity (97.1% vs. 41.2%, p < 0.01), inferior specificity (83.3% vs. 91.7%, p = 0.02), and higher diagnostic accuracy (93.5% vs. 54.3%, p < 0.01). The inclusion of successful free-breathing, whole-heart, 3 T CE-MRCA significantly improved the sensitivity and diagnostic accuracy as compared to MPI and LGE alone for CAD detection.


Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers.
One of the major intracellular barriers to nonviral gene delivery is efficient endosomal escape. The incorporation of histidine residues into polymeric constructs has been found to increase endosomal escape via the proton sponge effect. Statistical and diblock copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA), oligolysine, and oligohistidine were synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization and tested for in vitro transfection efficiency, buffering ability, and polyplex uptake mechanism via the use of chemical endocytic inhibitors. Interestingly, histidine-containing statistical and diblock polymers exhibited increased buffer capacity in different endosomal pH ranges. Statistical copolymers transfected better than block copolymers that contained similar amounts of histidine. In addition, only the polymer containing the highest incorporation of oligohistidine residues led to increases in transfection efficiency over the HPMA-oligolysine base polymer. Thus, for these polymer architectures, high histidine incorporation may be required for efficient endosomal escape. Furthermore, inhibitor studies indicate that nonacidified caveolae-mediated endocytosis may be the primary route of transfection for these copolymers, suggesting that alternative approaches for increasing endosomal escape may be beneficial for enhancing transfection efficiency with these HPMA-oligolysine copolymers.


Reliability of the NK dexterity board.
The NK computerized hand evaluation system includes a dexterity board that can be used to measure patients' ability to manipulate small, medium, and large objects. This study evaluated the test-retest reliability of the NK dexterity test. Thirty-seven healthy subjects aged 20 to 54 years completed two occasions of dexterity testing. Each occasion included bilateral dexterity tests consisting of two trials of each of three subtests. Intraoccasion intraclass correlation coefficients (ICCs) indicated fair to excellent reliability (ICC, 0.53-0.86). Interoccasion ICCs tended to be lower and ranged from 0.39 to 0.83, depending on the subtest. Reliability tended to be higher with the dominant hand than with the nondominant hand. Improvements in equipment design and alternative testing protocols may be needed to ensure consistently excellent reliability in dexterity scores with this test.


Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear locations.
Much of the success of Plasmodium falciparum in establishing persistent infections is attributed to immune evasion through antigenic variation. This process involves periodically exchanging variants of the major surface antigen PfEMP1, a protein also responsible for parasite cytoadherence. PfEMP1 is encoded by genes of the 60-member var family, located at subtelomeric and internal chromosome loci. The active or silenced state of var genes is heritable, and its control by nonsequence information remains puzzling. Using FISH analysis, we demonstrate that both internal and subtelomeric var genes are positioned at the nuclear periphery in their repressed state. Upon activation, the same var genes are still found in the periphery, indicating that this zone can be transcriptionally competent, rather than uniformly silenced. However, activation of a var gene is linked with altered positioning at the nuclear periphery, with subtelomeric var loci exiting chromosome end clusters and being relocated to distinct nuclear sites. Serial sectioning of parasite nuclei reveals areas of both condensed and noncondensed chromatin at the nuclear periphery. Our results demonstrate that regulation of antigenic variation is associated with subnuclear position effects and point to the existence of transcriptionally permissive perinuclear zones for var genes.


Effects of mucosal thickness on the stress distribution and denture stability of mandibular implant-supported overdentures with unsplinted attachments in vitro.
The aim of this study was to compare the effects of mucosal thickness on the stress pattern around implants and movement of implant-supported overdentures with ball/female and three different types of magnetic attachments. After insertion of two root-form implants into a mandibular model, the surface of the model was covered with a 1.5- or 3-mm layer of impression material to simulate the oral mucosa, and removable overdentures were fabricated on each model. A 50-N vertical force was applied to the right first molar, and the resultant stress distribution and denture movement were measured. In the 1.5-mm mucosal model, the magnetic attachments showed significantly lower bending moments than did the ball attachment. The denture base displacement was the lowest on a magnetic attachment. In this study, use of magnetic attachments could be advantageous for mandibular implant-supported overdentures based on lower stress and better denture stability especially in the thin mucosal model.


New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections.
Carbapenem-resistant Acinetobacter baumannii (CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.


Inhibition of established subcutaneous and metastatic murine tumors by intramuscular electroporation of the interleukin-12 gene.
In vivo electroporation (EP) of the murine interleukin-12 (IL-12) gene in an expression plasmid (pIL-12) was evaluated for antitumor activity. EP transfer of pIL-12 into mouse quadriceps muscles elicited significant levels of serum IL-12 and interferon-gamma. Intramuscular EP of pIL-12 resulted in complete regression or substantial inhibition of 38C13 B-cell lymphoma, whereas pIL-12 delivered by gene gun or intramuscular injection without EP showed little therapeutic effect. Impressive antitumor activity by intramuscular EP was also demonstrated in animals with advanced malignant disease. At day 14 after 38C13 tumor inoculation, all animals were found to carry large tumors and to have metastases; without treatment, most died within a week. A single intramuscular EP of pIL-12 resulted in regression of 50% of large subcutaneous tumors and significantly prolonged the lifespan of these animals. Moreover, animals that were previously cured of 38C13 tumors by in vivo EP treatment significantly suppressed tumor growth when challenged 60 days later. In vivo EP of the IL-12 gene was also effective in suppressing subcutaneous and lung metastatic tumors of CT-26 colon adenocarcinoma and B16F1 melanoma cells. Together, these results show that intramuscular electrotransfer of the IL-12 gene may represent a simple and effective strategy for cancer treatment.