Preferences for genetic testing to identify hereditary colorectal cancer: perspectives of high-risk patients, community members, and clinicians.
The aim of this study was to establish key characteristics that patients, consumers, and health professionals value regarding genetic testing (GT) and personalized medicine using the example of GT for hereditary Lynch syndrome. We conducted a series of focus groups with individuals recruited from a clinic that follows those at high risk for hereditary cancer, individuals recruited from the community, physicians, and genetic counselors. Participants were presented with clinical scenarios about Lynch syndrome testing and asked to identify characteristics that they perceived as important in making decisions about GT. Forty-two participants (19 community members, 8 high-risk and cancer patients, 3 genetic counselors, and 8 physicians) participated. Among community members and patients, the most frequently discussed considerations were the personal impact of GT and family impact, respectively. Among physicians, the most frequently discussed topic was the characteristics of genomic services (e.g., test invasiveness); among genetic counselors, the most frequently discussed topic was evidence and recommendations. A variety of test characteristics were important in decision making about GT. High-risk patients, community members, and health care providers had different priorities. Health care professionals should be aware of differences between their own considerations about GT and those that are important to patients.


Genes and social behavior.
What genes and regulatory sequences contribute to the organization and functioning of neural circuits and molecular pathways in the brain that support social behavior? How does social experience interact with information in the genome to modulate brain activity? Here, we address these questions by highlighting progress that has been made in identifying and understanding two key "vectors of influence" that link genes, the brain, and social behavior: (i) Social information alters gene expression in the brain to influence behavior, and (ii) genetic variation influences brain function and social behavior. We also discuss how evolutionary changes in genomic elements influence social behavior and outline prospects for a systems biology of social behavior.


Quadriceps muscle tone, elasticity and stiffness in older males: reliability and symmetry using the MyotonPRO.
The MyotonPRO (Myoton Ltd; London) is a new portable device for measuring muscle mechanical properties (e.g. tone) and its reliability has yet to be established. Little is known about between-limb symmetry of mechanical properties in healthy older people, despite symmetry often being used as a measure of unilateral abnormalities in clinical assessment. Since quadriceps is important for mobility, it was selected for the present study. To investigate: (i) between-day intra-rater reliability of a novice user of MyotonPRO; (ii) between-side symmetry of mechanical properties of quadriceps in older males. Twenty healthy, community dwelling, right-lower-limb-dominant males (mean age 71.7, range 65-82 years) were studied. With the participant in relaxed supine lying, the MyotonPRO applied two consecutive sets of 10 taps to induce muscle oscillations of rectus femoris, from which measurements of decrement (elasticity), frequency (tone), and stiffness were obtained. Tests were performed on two occasions at the same time and day of the week, one week apart. Repeated measurements had very high within-day (intraclass correlation coefficient, ICC 3,1>0.90) and high between-day (ICC 3,2>0.70; mean of two measurement sets) reliability. There was no statistically significant difference between muscle mechanical properties of the dominant and non-dominant muscles (<2.5% difference; p>0.05), thereby indicating symmetry. High intra-rater reliability was established for MyotonPRO measurements of quadriceps in healthy older males, which were symmetrical between sides. These findings indicate that larger studies are warranted to establish normal reference ranges of data with which to compare patients with muscle abnormalities.


The Oncofertility Consortium--addressing fertility in young people with cancer.
The number of young cancer survivors is increasing owing to advances in cancer therapeutics, but many face infertility as a result of their treatment. Technologies that already exist for cancer patients concerned about their future fertility include sperm banking for men and hormonal intervention followed by in vitro fertilization and embryo cryopreservation for women. However, logistical barriers to timely patient referral and coordination of care between specialties can limit patient access to all the available options. Moreover, there are few alternatives for young women and girls who cannot delay their cancer treatment, or who are unable to undergo hormonal intervention. The Oncofertility Consortium is a network of researchers, physicians and scholars who are advancing fertility preservation options for young cancer patients. Research into the societal, ethical, and legal implications is also an important part of the work performed by the Oncofertility Consortium, which is providing new perspectives on patient decision-making about how to access these emerging reproductive technologies. Experts in the fields of oncology, reproductive medicine, the social sciences, law, education, and the humanities are working together to develop next-generation reproductive interventions and promote communication between scholars, clinicians, patients, and the public to ensure that young cancer patients are equipped with the most appropriate information and options for having a family in the future.


Heat and mass transport during microwave heating of mashed potato in domestic oven--model development, validation, and sensitivity analysis.
A 3-dimensional finite-element model coupling electromagnetics and heat and mass transfer was developed to understand the interactions between the microwaves and fresh mashed potato in a 500 mL tray. The model was validated by performing heating of mashed potato from 25 °C on a rotating turntable in a microwave oven, rated at 1200 W, for 3 min. The simulated spatial temperature profiles on the top and bottom layer of the mashed potato showed similar hot and cold spots when compared to the thermal images acquired by an infrared camera. Transient temperature profiles at 6 locations collected by fiber-optic sensors showed good agreement with predicted results, with the root mean square error ranging from 1.6 to 11.7 °C. The predicted total moisture loss matched well with the observed result. Several input parameters, such as the evaporation rate constant, the intrinsic permeability of water and gas, and the diffusion coefficient of water and gas, are not readily available for mashed potato, and they cannot be easily measured experimentally. Reported values for raw potato were used as baseline values. A sensitivity analysis of these input parameters on the temperature profiles and the total moisture loss was evaluated by changing the baseline values to their 10% and 1000%. The sensitivity analysis showed that the gas diffusion coefficient, intrinsic water permeability, and the evaporation rate constant greatly influenced the predicted temperature and total moisture loss, while the intrinsic gas permeability and the water diffusion coefficient had little influence. This model can be used by the food product developers to understand microwave heating of food products spatially and temporally. This tool will allow food product developers to design food package systems that would heat more uniformly in various microwave ovens. The sensitivity analysis of this study will help us determine the most significant parameters that need to be measured accurately for reliable model prediction.


Maternal modulation of infantile ovarian development and available ovarian luteinizing hormone-releasing hormone (LHRH) receptors via milk LHRH.
In the rat, ovarian LHRH receptor content, measured by the binding of [125I]D-Ala6-Pro9-LHRH ([125I]A-LHRH) to ovarian membranes, declines during the days preceding the first preovulatory LH surge. The present results show that LHRH receptor content is low during neonatal-infantile days (days 5-15) and increases markedly thereafter to a maximum by day 25. When ovarian membranes from 10-day-old rats were pretreated with MgCl2 to dissociate endogenously bound hormone, LHRH-binding capacity increased to levels similar to those in untreated ovaries from 25-day-old rats. No significant increase was observed in ovaries from the latter group after MgCl2 exposure. Equilibrium association constants were similar (6-8 X 10(9) M-1) in MgCl2-treated and control ovaries, indicating that the increase in binding was not due to a change in receptor affinity. Pups prevented from suckling for various time intervals (1-24 h) exhibited an increase in available ovarian LHRH-binding sites which was maximal by 4 h. When pups were allowed to suckle subsequent to a 6-h fast, available ovarian LHRH receptors decreased rapidly (1 h). This decline was not due to a local increase in LHRH triggered by a neural reflex in response to suckling and/or stomach distension. Intragastric administration of milk reproduced the decline in available receptors induced by suckling, whereas stomach distension produced by saline was ineffective. Concomitant with the decline in receptors, suckling produced a significant increase in both stomach content and plasma levels of an LHRH-like material. Fractionation of acid milk extracts in Sephadex G-25 yielded two peaks, one in a position similar to that of synthetic LHRH. Milk LHRH purified in a C-18 Sep-Pak column displaced binding of [125I]A-LHRH to ovarian membranes and yielded a parallel binding curve in the LHRH RIA. This milk LHRH also released LH and FSH from pituitaries in vitro and inhibited FSH-induced estradiol and progesterone secretion from granulosa cells in culture in a dose-related manner, comparable to A-LHRH. The suckling-induced decrease in available LHRH receptors was prevented by iv administration of a specific LHRH antiserum directed against all 10 amino acids of native LHRH, suggesting that milk LHRH reaches the ovary via the bloodstream. The results indicate that an LHRH-like substance of milk origin binds to LHRH receptors in the pup ovary, thereby controlling receptor availability.(ABSTRACT TRUNCATED AT 400 WORDS)


New insights into ROS dynamics: a multi-layered microfluidic chip for ecotoxicological studies on aquatic microorganisms.
Reactive oxygen species (ROS) play an important role in the life of every cell, including cellular defense and signaling mechanisms. Continuous and quantitative ROS sensing can provide valuable information about the cell state, but it remains a challenge to measure. Here, we introduce a multi-layered microfluidic chip with an integrated optical sensor for the continuous sensitive detection of extracellular hydrogen peroxide (H2O2), one of the most stable ROS. This platform includes hydraulically controlled microvalves and microsieves, which enable the precise control of toxicants and complex exposure sequences. In particular, we use this platform to study the dynamics of toxicity-induced ROS generation in the green microalga Chlamydomonas reinhardtii during short-term exposures, recovery periods, and subsequent re-exposures. Two cadmium-based toxicants with distinct internalization mechanisms are used as stress inducers: CdSe/ZnS quantum dots (Qdots) and ionic cadmium (Cd(2+)). Our results show the quantitative dynamics of ROS generation by the model microalga, the recovery of cell homeostasis after stress events and the cumulative nature of two consecutive exposures. The dissolution of quantum dots and its possible influence on toxicity and H2O2 depletion is discussed. The obtained insights are relevant from ecotoxicological and physiological perspectives.


Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.
An oncolytic, nonpathogenic ECHO-7 virus adapted for melanoma that has not been genetically modified (Rigvir) is approved and registered for virotherapy, an active and specific immunotherapy, in Latvia since 2004. The present retrospective study was carried out to determine the effectiveness of Rigvir in substage IB, IIA, IIB and IIC melanoma patients on time to progression and overall survival. White patients (N=79) who had undergone surgical excision of the primary melanoma tumour were included in this study. All patients were free from disease after surgery and classified into substages IB, IIA, IIB and IIC. Circulating levels of clinical chemistry parameters were recorded. Survival was analysed by Cox regression. Rigvir significantly (P<0.05) prolonged survival in substage IB-IIC melanoma patients following surgery compared with patients who were under observation (according to current guidelines). The hazard ratio for patients under observation versus treated with Rigvir was statistically significantly different: hazard ratio 6.27 for all, 4.39 for substage IIA-IIB-IIC and 6.57 for substage IIB-IIC patients. The follow-up period was not statistically different between both treatment groups. These results indicate that the patients treated with Rigvir had a 4.39-6.57-fold lower mortality than those under observation. In this study, there was no untoward side effect or discontinuation of Rigvir treatment. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 2 in Rigvir-treated patients. In conclusion, Rigvir significantly prolongs survival in early-stage melanoma patients without any side effect.


Analysis of cerebrovascular sympathetic nerve density in relation to stroke development in spontaneously hypertensive rats.
Previous studies have shown that elevating the K+ levels from 0.75% to 2.11% in the diet of stroke-prone spontaneously hypertensive rats significantly retards the development of stroke and increases their lifespan. On the other hand, stroke-resistant spontaneously hypertensive rats fail to develop stroke even if they are fed the low-K+ version of this diet. Since sympathetic nerves surrounding the cerebral vasculature play an important role in protecting the brain from stroke during hypertension, I studied whether changes in sympathetic nerve density accounted for the differing incidences of stroke in stroke-prone spontaneously hypertensive rats fed high- and low-K+ diets and in stroke-resistant and stroke-prone spontaneously hypertensive rats fed a low-K+ diet. At 14 weeks of age, all 11 stroke-prone rats fed the low-K+ diet had evidence of cerebral hemorrhage while such lesions were virtually absent in the 11 littermates fed the high-K+ diet and totally absent in the eight stroke-resistant rats fed the low-K+ diet. Stroke-prone (regardless of diet) but not stroke-resistant rats exhibited greater sympathetic nerve densities in the left hemisphere than in the right. When stroke-prone rats were compared, in some areas of the cerebrovasculature, rats fed the high-K+ diet had greater mean sympathetic nerve densities than those fed the low-K+ diet. On the other hand, stroke-resistant and stroke-prone rats fed the low-K+ diet exhibited comparable sympathetic nerve densities in most cerebral arteries studied.(ABSTRACT TRUNCATED AT 250 WORDS)


Alarms about structural alerts.
Structural alerts are widely accepted in chemical toxicology and regulatory decision support as a simple and transparent means to flag potential chemical hazards or group compounds into categories for read-across. However, there has been a growing concern that alerts disproportionally flag too many chemicals as toxic, which questions their reliability as toxicity markers. Conversely, the rigorously developed and properly validated statistical QSAR models can accurately and reliably predict the toxicity of a chemical; however, their use in regulatory toxicology has been hampered by the lack of transparency and interpretability. We demonstrate that contrary to the common perception of QSAR models as "black boxes" they can be used to identify statistically significant chemical substructures (QSAR-based alerts) that influence toxicity. We show through several case studies, however, that the mere presence of structural alerts in a chemical, irrespective of the derivation method (expert-based or QSAR-based), should be perceived only as hypotheses of possible toxicological effect. We propose a new approach that synergistically integrates structural alerts and rigorously validated QSAR models for a more transparent and accurate safety assessment of new chemicals.


Attention modulates initial stages of visual word processing.
Selective attention has the potential to enhance the initial processing of objects, their spatial locations, or their constituent features. The present study shows that this capacity to modulate initial stages of processing also applies to linguistic attributes. A cueing paradigm focused attention at different levels of word representations on a trial-by-trial basis to study the time course of attentional modulation on visual word processing by means of a high-density electrophysiology recording system. Attention to different linguistic attributes modulated components related to semantic, phonological, and orthographic stages of word processing. Crucially, the N200, associated with initial stages of orthographic decoding, was enhanced by attention to the letter pattern of words. These results suggest that top-down attention has the capacity to enhance initial perceptual stages of visual word processing and support the flexibility of attention in modulating different levels of information processing depending on task goals.


Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.
In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Janssen Research & Development.


WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway.
The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40-domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle-dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1α localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1's involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA-dependent epigenetic control mechanism that sustains centromere integrity and genomic stability.


On a vector space representation in genetic algorithms for sensor scheduling in wireless sensor networks.
Recent works raised the hypothesis that the assignment of a geometry to the decision variable space of a combinatorial problem could be useful both for providing meaningful descriptions of the fitness landscape and for supporting the systematic construction of evolutionary operators (the geometric operators) that make a consistent usage of the space geometric properties in the search for problem optima. This paper introduces some new geometric operators that constitute the realization of searches along the combinatorial space versions of the geometric entities descent directions and subspaces. The new geometric operators are stated in the specific context of the wireless sensor network dynamic coverage and connectivity problem (WSN-DCCP). A genetic algorithm (GA) is developed for the WSN-DCCP using the proposed operators, being compared with a formulation based on integer linear programming (ILP) which is solved with exact methods. That ILP formulation adopts a proxy objective function based on the minimization of energy consumption in the network, in order to approximate the objective of network lifetime maximization, and a greedy approach for dealing with the system's dynamics. To the authors' knowledge, the proposed GA is the first algorithm to outperform the lifetime of networks as synthesized by the ILP formulation, also running in much smaller computational times for large instances.


Correlation between multiple hydrogen bonding and alteration of the oxidation potential of the bacteriochlorophyll dimer of reaction centers from Rhodobacter sphaeroides.
The electronic absorption and vibrational Raman spectra of mutant reaction centers from Rhodobacter sphaeroides bearing multiple site-specific mutations near the primary electron donor (P), a bacteriochlorophyll dimer, are reported. These mutations bear double and triple combinations of single-point mutations that alter the H-bonding interactions between histidine residues and the C2- and C9-conjugated carbonyl groups of the primary donor [Mattioli, T.A., Williams, J.C., Allen, J.P., & Robert, B. (1994) Biochemistry 33, 1636-1643] and change the donor redox midpoint potential from 410 to 765 mV compared to 505 mV for wild type [Lin, X., Murchison, H.A., Nagarajan, V., Parson, W.W., Williams, J.C., & Allen, J.P. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10265-10269]. Near-infrared Fourier transform Raman spectroscopy was used to determine the changes in H-bonding interactions of the primary donor in these multiple mutants. The Fourier transform Raman spectra of the mutants exhibit the predicted changes in hydrogen bond interactions of the P carbonyl groups with the protein, and they are consistent with the designed mutations. Moreover, the Raman data verify that the H-bonds formed or broken in the multiple mutants are similar in strength to those observed in the corresponding single mutants. A correlation was observed between the change in P/P.+ redox midpoint potential and the total change in H-bonding interaction energy (from -207 to 364 meV relative to wild type) as gauged by the estimated enthalpy of each H-bond formed or broken on the four conjugated carbonyls of the primary donor. Only minor changes were observed in the optical spectra of the mutant reaction centers, indicating that the addition of H-bonds from histidines has little effect in destabilizing the first electronic excited state of the dimer relative to the ground state. However a blue shift in the dimer absorption band at ca. 890 nm at 20 K was associated with the removal of the H-bond to the C2 acetyl carbonyl group via His L168. A red shift of the oxidized dimer band at ca. 1250 nm was associated with the formation of each H-bond to the C9 keto carbonyl groups.


Examining local-level factors shaping school nutrition policy implementation in Ontario, Canada.
Increasing numbers of overweight and obese youth draw attention to the school as an important setting for targeted nutrition interventions, given that it is where they spend a majority of their waking time. The objective of the present study was to explore local-level factors shaping the implementation of a school nutrition policy. In-depth, semi-structured interviews were conducted in person or via the telephone (a maximum of 60 min). An interview guide was informed by the Analysis Grid for Environments Linked to Obesity (ANGELO) framework, research objectives and literature. Key themes centred on policy implementation, including facilitators and barriers (i.e. resources, capacity), user satisfaction (i.e. students) and communication strategies. Secondary schools in Ontario, Canada. Twenty-two participants from local agencies supporting school nutrition programming (n 8) and secondary-school principals, vice principals and teachers (n 14) from nine schools across three Ontario school boards. Results are organized according to environments outlined in the ANGELO framework. The cost of healthy food for sale, revenue loss (economic), proximity of schools to off-site food outlets (physical), the restrictive nature of policy, the role of key stakeholders (political), the role of stigma and school culture (sociocultural) act as local-level barriers to policy implementation. Gaps in policy implementation include the high cost of food for sale and subsequent revenue generation, the close proximity of internal and external food environments, the need for consultation and communication between stakeholders, and strategies to reduce stigma and improve the school nutrition culture.


Crystal structure of group II intron domain 1 reveals a template for RNA assembly.
Although the importance of large noncoding RNAs is increasingly appreciated, our understanding of their structures and architectural dynamics remains limited. In particular, we know little about RNA folding intermediates and how they facilitate the productive assembly of RNA tertiary structures. Here, we report the crystal structure of an obligate intermediate that is required during the earliest stages of group II intron folding. Composed of domain 1 from the Oceanobacillus iheyensis group II intron (266 nucleotides), this intermediate retains native-like features but adopts a compact conformation in which the active site cleft is closed. Transition between this closed and the open (native) conformation is achieved through discrete rotations of hinge motifs in two regions of the molecule. The open state is then stabilized by sequential docking of downstream intron domains, suggesting a 'first come, first folded' strategy that may represent a generalizable pathway for assembly of large RNA and ribonucleoprotein structures.


Improving consent in patients undergoing surgery for fractured neck of femur.
Background Neck of femur fractures and their subsequent operative fixation are associated with high rates of perioperative morbidity and mortality. Consenting in this setting is suboptimal with the Montgomery court ruling changing the perspective of consent. This quality improvement project assessed the adequacy of consenting against British Orthopaedic Association-endorsed guidance and implemented a series of changes to improve the documentation of risks associated with surgery for fractured neck of femur. Methods Seventy consecutive patients who underwent any operative fixation of a neck of femur fracture were included over a 6-month period at a single centre. Patients unable to consent or without electronic notes were excluded. Consent forms were analysed and the documented potential risks or complications associated with surgery were compared to British Orthopaedic Association-endorsed guidance. A series of changes (using the plan, do study, act (PDSA) approach) was implemented to improve the adequacy of consent. Results Documentation of four out of 12 potential risks or complications was recorded in <50% of cases for patients with intracapsular fractures (n=35), and documentation of seven out of 12 potential risks or complications was recorded in <50% of cases for patients with extracapsular fractures (n=35). Re-audit following raising awareness and attaching consent guidance showed 100% documentation of potential risks or complications in patients with intracapsular and extracapsular fractures (n=70). A neck of femur fracture-specific consent form has been implemented which will hopefully lead to sustained improvement. Conclusions Consenting patients with fractured neck of femur for surgery in the authors' unit was suboptimal when compared to British Orthopaedic Association-endorsed consent guidance. This project has shown that ensuring such guidance is readily available has improved the adequacy of consent. The authors hope that introduction of a neck of femur fracture-specific consent form within their unit will lead to sustained adequate documentation of risks associated with surgery.


Empowering individuals with psychiatric disabilities to work: Results of a randomized trial.
Supported employment has experienced immense growth as an evidence-based intervention targeting the disproportionately high rates of unemployment among individuals with psychiatric disabilities who actively want to work. However, employment services are often not available to individuals who are ambivalent about work or lack work self-efficacy. The purpose of this study was to pilot-test the efficacy of a new peer-run photography-based group intervention (Vocational Empowerment Photovoice [VEP]) designed to empower individuals with psychiatric disabilities to consider employment services and pursue work. A total of 51 individuals with serious mental illnesses enrolled at a university-based recovery center, who were not employed or enrolled in any vocational services, were randomly assigned to the VEP program or to a wait-list control group. Mixed-effects regression models were used to examine the impact of the VEP program on both extrinsic (enrollment in employment services and employment rates) and intrinsic (work hope, motivation and self-efficacy, vocational identity, overall empowerment and internalized stigma) work-related outcomes. Participation in the VEP program was associated with a significantly higher rate of engagement in employment services over the course of the intervention and with significantly higher overall empowerment and decrease of internalized stigma sustained through the 3-month follow-up assessment. Stronger engagement in the VEP program was associated with increased work hope, self-efficacy and sense of vocational identity. The study highlights the malleable nature of defeatist beliefs which prevent many individuals with mental illnesses from pursuing employment services despite their inherent interest in working. (PsycINFO Database Record


The Effect of Systemic Magnesium on Postsurgical Pain in Children Undergoing Tonsillectomies: A Double-Blinded, Randomized, Placebo-Controlled Trial.
Tonsillectomy is a frequently performed surgical procedure in children; however, few multimodal analgesic strategies have been shown to improve postsurgical pain in this patient population. Systemic magnesium infusions have been shown to reliably improve postoperative pain in adults, but their effects in pediatric surgical patients remain to be determined. In the current investigation, our main objective was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have less post-tonsillectomy pain than the children who received saline infusions. The study was a prospective, randomized, double-blinded, clinical trial. Subjects were randomly assigned using a computer-generated table of random numbers to 1 of the 2 intervention groups: systemic magnesium infusion (initial loading dose 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion 10 mg/kg/h) and the same volume of saline. The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC (Face, Legs, Activity, Cry, Consolability) pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method. Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the pediatric anesthesia emergence delirium scale), and parent satisfaction. Sixty subjects were randomly assigned and 60 completed the study. The area under pain scores (up to 90 minutes) was not different between the study groups, median (interquartile range [IQR]) of 30 (0-120) score × min and 45 (0-135) score × min for the magnesium and control groups, respectively (P = 0.74). Similarly, there was no clinically significant difference in the morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0-4.44) mg IV morphine, compared with the control, median (IQR) of 2.5 (0-4.99) mg IV morphine (P = 0.25). The serum level of magnesium was significantly lower in the control group than in the treatment group at the end of the surgery (P < 0.001). Despite a large number of studies demonstrating the efficacy of systemic magnesium for preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating multimodal analgesic strategies in children that have been demonstrated to be effective in the adult population.


Stepping down asthma treatment: how and when.
Guidelines suggest that asthma medication should be reduced once asthma control is sustained. Moderate-dose inhaled corticosteroids (ICS) can typically be reduced, but questions remain about the lowest effective ICS dose and the role of non-ICS controllers in treatment reduction. Long-acting beta agonist (LABA) safety concerns have created controversy about how to step down patients on ICS/LABA therapy. This review will focus on the current status of these issues. Intermittent ICS treatment, often in fixed combination with short-acting beta agonist, is an emerging strategy for control of mild asthma. Addition of leukotriene modifiers, LABAs, and omalizumab to ICS can allow for reduced ICS dosing. Doses of ICS that control symptoms may be inadequate to control exacerbations. Reducing ICS dose before discontinuing LABAs may be the more effective approach for patients on combination therapy. Use of non-ICS controllers allows for ICS dose reduction with superior outcomes. Tapering of ICS prior to LABA discontinuation may be the favored approach for patients on ICS/LABA therapy, but an understanding of long-term outcomes and further safety data are required. The lowest ICS dose that adequately controls both asthma impairment and risk remains to be determined.


Initial effects of the National PCV7 Childhood Immunization Program on adult invasive pneumococcal disease in Israel.
PCV7 was introduced as universal childhood vaccination in Israel in July 2009 and PCV13 in November 2010. Here we report data on adult invasive pneumococcal disease (IPD), two years post PCV7 implementation and before an expected effect of PCV13. An ongoing nationwide active-surveillance (all 27 laboratories performing blood cultures in Israel), providing all blood & CSF S. pneumoniae isolates from persons >18 y was initiated in July 2009. Capture-recapture method assured reporting of >95% cases. All isolates were serotyped in one central laboratory. IPD outcome and medical history were recorded in 90%. Second year post PCV implementation is compared to the first year. During July 2009 to June 2011, 970 IPD cases were reported (annual incidence [/100,000] of 9.17 and 10.16 in the two consecutive years, respectively). Respective case fatality rates (CFRs) were 20% and 19.1%. Incidence of IPD and CFR increased with age and number of comorbidities. Incidence rate was significantly greater during the second winter, 7.79/100,000 vs. 6.14/100,000 in first winter, p = 0.004, with a non-significant decrease during summer months (3.02 to 2.48/100,000). The proportion of IPD cases due to PCV7-serotypes decreased from 27.5% to 13.1% (first to second year) (p<0.001). Yet, non-PCV13-strains increased from 32.7% to 40.2% (p = 0.017). The increase in non-PCV13-strains was highly significant in immunocompromised patients and to a lesser degree in non-immunocompromised at risk or in older patients (>64 y). Among younger/healthier patients serotype 5 was the major increasing serotype. Penicillin and ceftriaxone resistance decreased significantly in the second year. While overall annual incidence of IPD did not change, the indirect effect of PCV7 vaccination was evident by the significant decrease in PCV7 serotypes across all age groups. Increase in non-VT13 strains was significant in immunocompromised patients. A longer follow-up is required to appreciate the full effect of infant vaccination on annual IPD.


Less than one-third of hip fracture patients return to their prefracture level of instrumental activities of daily living in a prospective cohort study of 480 patients.
A significant loss of instrumental activities of daily living (IADL) after a hip fracture has been reported. The aim of the present study was to identify specific predictors for low IADL after a hip fracture, in order to target better postoperative care for these patients. A prospective observational cohort study of 480 hip fracture patients was carried out. IADL was measured at baseline, and after 3 and 12 months using the Groningen Activity Restriction Scale. Multivariable logistic regression analysis was carried out using age, sex, American Society of Anesthesiologists classification, prefracture living with a partner, prefracture living situation, prefracture use of walking aids, type of fracture, type of anesthesia, length of hospital stay, postoperative complications and prefracture IADL as potential predictors for low IADL after a hip fracture. The correlation between IADL, mobility and living situation, both at admission, and 3 and 12 months postoperatively, were measured. Three months after hip fracture treatment, 24% of patients returned to their baseline IADL level, at 12 months postoperative this was 29%. Factors associated with a larger loss in IADL after a hip fracture were older age, prefracture living with a partner, prefracture living at home, prefracture use of walking aids and longer length of hospital stay. The correlation between IADL and living situation was 0.69, and between IADL and use of walking aids was 0.80. A return to prefracture IADL level was low. Healthier patients have a steeper decline in postoperative IADL. Geriatr Gerontol Int 2018; 18: 1244-1248.


Applicability of regular particle shapes in light scattering calculations for atmospheric ice particles.
We ascertain the usefulness of simple ice particle geometries for modeling the intensity distribution of light scattering by atmospheric ice particles. To this end, similarities and differences in light scattering by axis-equivalent, regular and distorted hexagonal cylindric, ellipsoidal, and circular cylindric ice particles are reported. All the results pertain to particles with sizes much larger than a wavelength and are based on a geometrical optics approximation. At a nonabsorbing wavelength of 0.55 µm, ellipsoids (circular cylinders) have a much (slightly) larger asymmetry parameter g than regular hexagonal cylinders. However, our computations show that only random distortion of the crystal shape leads to a closer agreement with g values as small as 0.7 as derived from some remote-sensing data analysis. This may suggest that scattering by regular particle shapes is not necessarily representative of real atmospheric ice crystals at nonabsorbing wavelengths. On the other hand, if real ice particles happen to be hexagonal, they may be approximated by circular cylinders at absorbing wavelengths.


Biomechanical properties across trabeculae from the proximal femur of normal and ovariectomised sheep.
The elastic behaviour of trabecular bone is a function not only of bone volume and architecture, but also of tissue material properties. Variation in tissue modulus can have a substantial effect on the biomechanical properties of trabecular bone. However, the nature of tissue property variation within a single trabecula is poorly understood. This study uses nanoindentation to determine the mechanical properties of bone tissue in individual trabeculae. Using an ovariectomised ovine model, the modulus and hardness distribution across trabeculae were measured. In both normal and ovariectomised bone, the modulus and hardness were found to increase towards the core of the trabeculae. Across the width of the trabeculae, the modulus was significantly less in the ovariectomised bone than in the control bone. However, in contrast to this hardness was found not to differ significantly between the two groups. This study provides valuable information on the variation of mechanical material properties in healthy and diseased trabecular bone tissue. The results of the current study will be useful in finite element modelling where more accurate values of trabecular bone modulus will enable the prediction of the macroscale behaviour of trabecular bone.


Prospective Predictors of Suicidal Ideation during Depressive Episodes among Older Adolescents and Young Adults.
Suicide is a leading cause of death among older adolescents and young adults; however, few studies have prospectively examined risk for suicidal ideation. The present study in older adolescents and young adults investigated whether two personality traits previously implicated in risk for suicidal ideation, neuroticism and extraversion, as well as certain aspects of interpersonal functioning, prospectively predicted endorsement of suicidal ideation during depressive episodes. Participants (n=117) are a subset of the Northwestern-UCLA Youth Emotion Project sample, which started with a group of high school juniors oversampled for high neuroticism. Baseline interpersonal functioning was measured using the Life Stress Interview. Baseline personality trait composite scores were created from multiple inventories. Depressive disorders and suicidal ideation were assessed at the baseline and three annual follow-up interviews using the SCID. Cox regression was employed to predict suicidal ideation during depressive episodes diagnosed at any follow-up interview. Results showed that baseline extraversion inversely predicts suicidal ideation in males only, and that baseline interpersonal problems in one's social circle, regardless of gender, predict suicidal ideation during depressive episodes.


Frailty and sarcopenia in elderly.
Frailty is a pre-disability syndrome where an older person can be identified as being at risk when exposed to stressors associated with high risk for disability or needing to be hospitalized. Two major frailty definitions exist. The physical phenotype of frailty and the multiple deficit model. A simple frailty screening tool-FRAIL-has been validated. Treatment of frailty involves resistance exercise, optimization of nutrition, and treatment of fatigue (sleep apnea, depression), treatable causes of weight loss and adjustment of polypharmacy. Sarcopenia (decline in function with low muscle mass) is a major cause of frailty. A simple sarcopenia screening tool-SARC-F-has been validated. The multiple causes of sarcopenia are reviewed. Optimal treatment is resistance exercise, leucine-enriched essential amino acids and vitamin D replacement.


Simple merging technique for improving resolution in qualitative single image phase contrast tomography.
For dynamic samples and/or for simple ease-of-use experiments, single-image phase contrast tomography is a very effective method for the 3D visualization of materials which would otherwise be indiscernible in attenuation based x-ray imaging. With binary samples (e.g. air-material) and monochromatic wavefields a transport-of-intensity (TIE)-based phase retrieval algorithm is known to retrieve accurate quantitative maps of the phase distribution. For mixed material samples and/or white beam radiation the algorithm can still produce useful qualitative tomographic reconstructions with significantly improved area contrast. The stability of the algorithm comes with a recognized associated loss of spatial resolution due to its essential behaviour as a low-pass filter. One possible answer to this is an image fusion technique that merges the slices reconstructed from raw phase contrast images and those after phase retrieval, where the improved contrast may be acquired without the associated loss of high-frequency information. We present this technique as a simple few-parameter Fourier method, which is easily tunable and highly compatible with current reconstruction steps.


Acute Acoustic Trauma among Soldiers during an Intense Combat.
During military actions, soldiers are constantly exposed to various forms of potentially harmful noises. Acute acoustic trauma (AAT) results from an impact, unexpected intense noise ≥140 dB, which generates a high-energy sound wave that can damage the auditory system. We sought to characterize AAT injuries among military personnel during operation "Protective Edge," to analyze the effectiveness of hearing protection devices (HPDs), and to evaluate the benefit of steroid treatment in early-diagnosed AAT injury. We retrospectively identified affected individuals who presented to military medical facilities with solitary or combined AAT injuries within 4 mo following an intense military operation, which was characterized with an abrupt, intensive noise exposure (July-December 2014). A total of 186 participants who were referred during and shortly after a military operation with suspected AAT injury. HPDs, oral steroids. Data extracted from charts and audiograms included demographics, AAT severity, worn HPDs, first and last audiograms and treatment (if given). The Student's independent samples t test was used to compare continuous variables. All tests were considered significant if p values were ≤0.05. A total of 186 participants presented with hearing complaints attributed to AAT: 122, 39, and 25 were in duty service, career personnel, and reservists, with a mean age of 21.1, 29.2, and 30.4 yr, respectively. Of them, 92 (49%) participants had confirmed hearing loss in at least one ear. Hearing impairment was significantly more common in unprotected participants, when compared with protected participants: 62% (74/119) versus 45% (30/67), p < 0.05. Tinnitus was more common in unprotected participants when compared with protected participants (75% versus 49%, p = 0.04), whereas vertigo was an uncommon symptom (5% versus 2.5%, respectively, p > 0.05). In the 21 participants who received steroid treatment for early-diagnosed AAT, bone-conduction hearing thresholds significantly improved in the posttreatment audiograms, when compared with untreated participants (p < 0.01, for 1-4 kHz). AAT is a common military injury, and should be diagnosed early to minimize associated morbidity. HPDs were proven to be effective in preventing and minimizing AAT hearing sequelae. Steroid treatment was effective in AAT injury, if initiated within 7 days after noise exposure.


PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas.
PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5'UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology.


The Pediatric Asthma Control and Communication Instrument for the Emergency Department (PACCI-ED) improves physician assessment of asthma morbidity in pediatric emergency department patients.
To determine whether the Pediatric Asthma Control and Communication Instrument for the Emergency Department (PACCI-ED), a 12-item questionnaire, can help ED attendings accurately assess a patient's asthma control and morbidity. This was a randomized-controlled trial performed at an urban pediatric ED of children aged 1-17 years presenting with an asthma exacerbation. Parents answered PACCI-ED questions about their children's asthma. Attendings were randomized to view responses to the PACCI-ED (intervention group) or to be blinded to the completed PACCI-ED (control group). The two groups were compared on their empirical clinical assessment of: (1) chronic asthma control categories, (2) asthma trajectory (stable, worsening or improving), (3) patient adherence to controller medications, and (4) burden of disease for the patient's family. The validated PACCI algorithm was used as the criterion standard for these four outcomes. Accuracy of clinical assessment was compared between intervention and control groups using chi-squared tests and an intention-to-treat approach. Seventeen ED attendings were enrolled in the study and 77 children visits were included in the analysis. There were no significant differences between the intervention and the control groups for child's gender, age, race, and asthma characteristics. Intervention group attendings were more accurate than control group attendings in assessing the category of chronic asthma control (43% versus 19%; p = 0.03), disease trajectory (72% versus 45%; p = 0.02), and the disease burden for families (74% versus 35%; p = 0.001) over the past 12 months. There was a trend towards more accuracy of intervention versus control attendings for estimating patient adherence to controller medications (72% versus 48%; p = 0.06). The PACCI-ED improves the assessment of asthma control, trajectory, and burden by ED attendings, and may help assessment of asthma medication adherence and prior asthma exacerbations. The PACCI-ED can be used to improve provider assessment of asthma morbidity during pediatric ED visits for asthma exacerbations, and to identify children who may benefit from interventions to reduce asthma morbidity.


Progression model tissue microarray (TMA) for the study of uterine carcinomas.
Cervical and endometrial uterine carcinomas are heterogeneous groups of cancers, which are preceded by preneoplastic lesions. More accurate tools are needed to improve the diagnosis and to define markers which may be relevant for the diagnosis, prediction of disease progression and therapeutic response.High throughput technologies for testing and validating molecular targets in cancer lesions and in their precursors are presently available. Among them, the tissue microarray (TMA) presents the advantage of a morphological control of the analyzed tissue fragment. In this article, we review the different aspects of the TMA technology with a special consideration to a uterine carcinogenesis model.


Quality assurance and the critical care nurse.
Care of the critically ill has become increasingly challenging due to demands from external sources to measure the quality and appropriateness of care provided. Quality assurance is the responsibility of every critical care nurse and requires vigilance as well as a knowledge of the principles of standards, monitoring and evaluation. Through quality assurance activities, the contribution of critical care nurses in the achievement of patient outcomes can be measured. Quality assurance challenges us to evaluate the way we practice, and assists us to continuously improve the way we provide care to critically ill patients.


Lower-Limb Passive Heat Maintenance Combined With Pre-cooling Improves Repeated Sprint Ability.
Pre-conditioning strategies to potentiate performance are a common feature of pre-competition routines. The elevation of muscle temperature is seen as a vital component of preparing for physical performance, while pre-cooling strategies have been adopted to offset fatigue during repeated efforts. We investigated the individual and combined effects of a passive heat maintenance strategy and the ingestion of an ice-water slurry on repeated sprint performance. In a random cross-over design, 12 professional male athletes performed 5 × 40 m maximal running sprints under one of four conditions following a standardized warm-up: 15-min passive rest (Control); wearing a lower-body survival garment (HEAT); consuming a 500 mL ice slushy (COLD); or wearing the survival garment and consuming the slushy (H+C). Measures of sprint speed, fatigue, heart rate, and rectal temperature were collected. Compared to COLD: HEAT improved Sprint 1 (ES: 0.84; p = 0.05), but negatively impacted Sprint 4 (ES: -0.87; p = 0.08), and Sprint 5 (ES: -1.57; p = 0.002). H+C was faster than Control for every sprint (ES: 0.28 to 0.66), clearly faster than COLD on Sprints 1-3 (ES: 0.73 to 0.54), and clearly faster than HEAT on Sprints 4 and 5 (ES: 1.31 and 1.87). Fatigue was greatest after the HEAT intervention with a large correlation between fatigue and rectal temperature (r = 0.66; p = 0.0204). While there are undoubtedly peripheral effects of cooling and heating on various aspects of muscle function and fatigue, understanding the integration of psychophysiological homeostatic feedback loops relating to a combined warming and cooling intervention may benefit sports in which repeat sprints are performed.


Concerted evolution of life stage performances signals recent selection on yeast nitrogen use.
Exposing natural selection driving phenotypic and genotypic adaptive differentiation is an extraordinary challenge. Given that an organism's life stages are exposed to the same environmental variations, we reasoned that fitness components, such as the lag, rate, and efficiency of growth, directly reflecting performance in these life stages, should often be selected in concert. We therefore conjectured that correlations between fitness components over natural isolates, in a particular environmental context, would constitute a robust signal of recent selection. Critically, this test for selection requires fitness components to be determined by different genetic loci. To explore our conjecture, we exhaustively evaluated the lag, rate, and efficiency of asexual population growth of natural isolates of the model yeast Saccharomyces cerevisiae in a large variety of nitrogen-limited environments. Overall, fitness components were well correlated under nitrogen restriction. Yeast isolates were further crossed in all pairwise combinations and coinheritance of each fitness component and genetic markers were traced. Trait variations tended to map to quantitative trait loci (QTL) that were private to a single fitness component. We further traced QTLs down to single-nucleotide resolution and uncovered loss-of-function mutations in RIM15, PUT4, DAL1, and DAL4 as the genetic basis for nitrogen source use variations. Effects of SNPs were unique for a single fitness component, strongly arguing against pleiotropy between lag, rate, and efficiency of reproduction under nitrogen restriction. The strong correlations between life stage performances that cannot be explained by pleiotropy compellingly support adaptive differentiation of yeast nitrogen source use and suggest a generic approach for detecting selection.


Pathogenetical subtypes of recurrent intracerebral hemorrhage: designations by SMASH-U classification system.
Pathogenetic classification of intracerebral hemorrhage (ICH), using systems such as SMASH-U (structural vascular lesions, medication, cerebral amyloid angiopathy [CAA], systemic disease, hypertension, or undetermined), is important in predicting functional outcomes and mortality in patients with ICH. This study aimed to compare pathogenetic subtypes between the first and recurrent ICH. This study obtained data related to 4578 consecutive acute patients with ICH from the National Taiwan University Hospital Stroke Registry during January 1995 to December 2013. Using the SMASH-U method, patients were classified into 6 subtypes. We then analyzed the outcomes of first-ever ICH cases and pathogenetic classification of recurrent ICH. Among 3785 patients who experienced first-ever ICH (male, 63.3%; mean age, 58.7±17.0 years), the most common cause was hypertensive angiopathy (54.9%), followed by CAA (12.2%), systemic disease (12.1%), undetermined (10.1%), structural vascular lesions (7.8%), and medication related (2.9%). In 185 cases of recurrent ICH, pathogenetic differences between the 2 ICH events were observed in 34 (18.4%) cases, most of which were CAA to hypertensive angiopathy (n=10) or vice versa (n=7). The rates of ICH recurrence were highest for systemic disease-related and CAA-related ICH at 1, 5, 10, and 15 years after the indexed ICH event. In approximately one fifth of the recurrent patients with ICH, pathogenetic differences were observed between initial and recurrent events, particularly among those with CAA. It is possible that some patients with ICH with concomitant hypertensive angiopathy and CAA may have been categorized as CAA by the SMASH-U method.


Mild congenital myopathy due to a novel variation in SPEG gene.
Centronuclear myopathies (CNMs) are a subgroup of congenital myopathies (CMs) characterized by muscle weakness, genetic heterogeneity, and predominant type 1 fibers and increased central nuclei in muscle biopsy. Mutations in CNM-causing genes such as MTM1, DNM2, BIN1, RYR1, CACNA1S, TTN, and extraordinary rarely SPEG (striated muscle preferentially expressed protein kinase) have been identified for about 60-80% of patients. Herein, we report a case of CM due to a novel variation in the SPEG gene, manifested by mild neonatal hypotonia, muscle weakness, delayed motor milestones, and ophthalmoplegia, without dilated cardiomyopathy. We identified a novel variation [c.153C>T (p.Asn51=) in exon 1] in the SPEG gene with whole-exome sequencing and confirmed by Sanger sequencing. Mild intellectual disability has not been associated with SPEG-related CM in the previous reports. We suggest that this report expands the phenotypic spectrum of SPEG-related CM, and further case reports are required to expand the genotype-phenotype correlations.


Systematic review of treatment modalities for gingival depigmentation: a random-effects poisson regression analysis.
Repigmentation variably occurs with different treatment methods in patients with gingival pigmentation. A systemic review was conducted of various treatment modalities for eliminating melanin pigmentation of the gingiva, comprising bur abrasion, scalpel surgery, cryosurgery, electrosurgery, gingival grafts, and laser techniques, to compare the recurrence rates (Rrs) of these treatment procedures. Electronic databases, including PubMed, Web of Science, Google, and Medline were comprehensively searched, and manual searches were conducted for studies published from January 1951 to June 2013. After applying inclusion and exclusion criteria, the final list of articles was reviewed in depth to achieve the objectives of this review. A Poisson regression was used to analyze the outcome of depigmentation using the various treatment methods. The systematic review was based on case reports mainly. In total, 61 eligible publications met the defined criteria. The various therapeutic procedures showed variable clinical results with a wide range of Rrs. A random-effects Poisson regression showed that cryosurgery (Rr = 0.32%), electrosurgery (Rr = 0.74%), and laser depigmentation (Rr = 1.16%) yielded superior result, whereas bur abrasion yielded the highest Rr (8.89%). Within the limit of the sampling level, the present evidence-based results show that cryosurgery exhibits the optimal predictability for depigmentation of the gingiva among all procedures examined, followed by electrosurgery and laser techniques. It is possible to treat melanin pigmentation of the gingiva with various methods and prevent repigmentation. Among those treatment modalities, cryosurgery, electrosurgery, and laser surgery appear to be the best choices for treating gingival pigmentation.


Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period.
Despite consistent evidence that abnormalities of fatty acid delivery and storage underlie the metabolic defects of insulin resistance, physiological pathways by which fat is stored in adipose tissue and skeletal muscle are not clear. We used a combination of stable isotope labeling and arteriovenous difference measurements to elucidate pathways of postprandial fat deposition in adipose tissue and skeletal muscle in healthy humans. A test meal containing [U-(13)C]palmitate was combined with intravenous infusion of [(2)H(2)]palmitate to label plasma fatty acids and VLDL-triglyceride. Both dietary (chylomicron) and VLDL-triglyceride were cleared across adipose tissue and muscle, though with greater fractional extraction of the chylomicron-triglyceride. In adipose tissue there was significant uptake of plasma nonesterified fatty acids (NEFAs) in the postprandial but not the fasting state. However, this was minor in comparison with chylomicron-triglyceride fatty acids. We modeled the fate of fatty acids released by lipoprotein lipase (LPL). There was clear preferential uptake of these fatty acids compared with plasma NEFAs. In muscle, there was unexpected evidence for release of LPL-derived fatty acids into the plasma. With this integrative physiological approach, we have revealed hidden complexities in pathways of fatty acid uptake in adipose tissue and skeletal muscle.


Amusia following resection of a Heschl gyrus glioma. Case report.
The incidence and character of neurological deficits following resection of glial neoplasms localized to the Heschl gyrus are currently unknown. In this series, the authors report the clinical presentation, management, and postoperative course of three patients with right hemisphere Heschl gyrus gliomas, one of whom developed difficulty with music production and comprehension postoperatively. Resection of right hemisphere Heschl gyms gliomas can result in deficits involving music comprehension. Preliminary evidence suggests that when these deficits occur, they may be transient in nature.


Bullying as a Developmental Precursor to Sexual and Dating Violence Across Adolescence: Decade in Review.
Adolescent bullying continues to be a major focus of scholarship across the globe. This article reviews research from 2010 to 2021 with a particular focus on longitudinal studies of the bully-sexual violence pathway (BSVP), where bullying serves as a precursor for sexual violence (SV) (e.g., sexual harassment, sexual coercion, and sexual assault) and teen dating violence via individual and socio-contextual mediators. Articles reviewed consisted of a total of 505, which included 17 meta-analyses and systematic reviews. Databases used for the search were Academic Search Complete, Education Full Text (H. W. Wilson), ERIC, National Criminal Justice Reference Service Abstracts, PsycINFO, PubMed (Medline), and Social Sciences Abstracts (H. W. Wilson). In total, 107 peer-reviewed articles were included in this review. Potential mechanisms underlying the BSVP include social dominance orientation, exposure to sexual education, and alcohol use. Several school-based intervention approaches have evidenced marginal success in reducing rates of bullying and SV by targeting factors undergirding both behaviors. The efficacy of international prevention approaches is summarized. Gaps in the literature are identified and future research is proposed.


Ampelopsin reduces the migration and invasion of ovarian cancer cells via inhibition of epithelial-to-mesenchymal transition.
Ampelopsin has displayed anticancer activity in several types of cancers. However, no evidence has been reported for the direct effect of ampelopsin on ovarian cancer cell migration and invasion, and the underling mechanisms have not yet been clearly established. The aim of the present study was to investigate the influence of ampelopsin on the migration and invasion of ovarian cancer. Proliferation and viability of the ovarian cancer cells were detected by MTT assay. Migration and invasion of the cells were detected, respectively, by scratch wound healing assay and Transwell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers were detected at the protein level after stimulation with ampelopsin. Then, the expression levels of NF-κB and p-IκBα were detected with western blot analysis. Meanwhile, an inhibitor of NF-κB was used to investigate the effect of ampelopsin. Finally, the expression of Snail was also detected. Proliferation, migration and invasion of the A2780 cells were all inhibited following the application of ampelopsin. Ampelopsin upregulated E-cadherin and downregulated N-cadherin and vimentin in a concentration- and time-dependent manner. Ampelopsin also exerted its ability to suppress the nuclear translocation of the NF-κB pathway. Administration of the inhibitor BAY11-7082 confirmed the roles of NF-κB in the expression of EMT markers and its transcription factor. These results demonstrated that ampelopsin inhibited EMT and reduced the invasion of ovarian cancer cells via the NF-κB/Snail pathway.


Predicting dispersal of auto-gyrating fruit in tropical trees: a case study from the Dipterocarpaceae.
Seed dispersal governs the distribution of plant propagules in the landscape and hence forms the template on which density-dependent processes act. Dispersal is therefore a vital component of many species coexistence and forest dynamics models and is of applied value in understanding forest regeneration. Research on the processes that facilitate forest regeneration and restoration is given further weight in the context of widespread loss and degradation of tropical forests, and provides impetus to improve estimates of seed dispersal for tropical forest trees. South-East Asian lowland rainforests, which have been subject to severe degradation, are dominated by trees of the Dipterocarpaceae family which constitute over 40% of forest biomass. Dipterocarp dispersal is generally considered to be poor given their large, gyration-dispersed fruits. However, there is wide variability in fruit size and morphology which we hypothesize mechanistically underpins dispersal potential through the lift provided to seeds mediated by the wings. We explored experimentally how the ratio of fruit wing area to mass ("inverse wing loading," IWL) explains variation in seed dispersal kernels among 13 dipterocarp species by releasing fruit from a canopy tower. Horizontal seed dispersal distances increased with IWL, especially at high wind speeds. Seed dispersal of all species was predominantly local, with 90% of seed dispersing <10 m, although maximum dispersal distances varied widely among species. We present a generic seed dispersal model for dipterocarps based on attributes of seed morphology and provide modeled seed dispersal kernels for all dipterocarp species with IWLs of 1-50, representing 75% of species in Borneo.


Imaging of bone metastases in prostate cancer: an update.
Assessing bone metastases is often beyond the scope of plain - film radiography, and nuclear imaging in particular with bone scintigraphy has proved the mainstay for detection of bony disease for over 40 years. Bone scanning with 99mTechnetium - labeled diphosphonates relies on the detection of pathological osteoblastic response elicited from malignant cells. This technique offers the advantage of whole body examination, low cost, availability and high sensitivity. However, it suffers from relative low specificity. The addition of single-photon emission computed tomography (SPECT) to bone scintigraphy has markedly improved the diagnostic benefit. Although the accuracy of SPECT is significantly higher than that of planar scintigraphy, there is still room for improvement of anatomic localization and morphological characterization, a limitation that has currently been mainly overcome with the upcoming of combined SPECT-CT (computed tomography). Positron emission tomography (PET), a modality with higher spatial resolution than that of SPECT can be particularly helpful in detecting small lesions. Moreover, PET imaging using various specific radiotracers has the advantage of detecting malignant disease in both bone and soft tissues. It is highly sensitive mainly in detecting early bone marrow as well as for diagnosing lytic bony metastases and can be also reliably used to monitor therapy response. In this review, we present the current role of SPECT and PET in the imaging of skeletal metastases from prostate cancer.


Spatial variations in growth rate within Klebsiella pneumoniae colonies and biofilm.
The use of acridine orange to visualize and quantify spatial variations in growth rate within Klebsiella pneumoniae colonies and biofilm was investigated. Bacterial colonies supported on polycarbonate filter membranes were grown on R2A agar plates. Some colonies were sampled for cell enumeration, while others were cryoembedded, sectioned, and stained with the fluorescent nucleic acid stain acridine orange. Spatial patterns of fluorescent color and intensity with depth in the colony were quantified using confocal microscopy and image analysis of stained cross sections. Colonies sampled in the midexponential phase were thin (20 microns), had high average specific growth rates (> 1 h-1), and had all the cells stained bright orange. Colonies sampled after more than 24 h of growth were thick (> 200 microns) and were growing slowly (mu < 0.15 h-1). These older colonies were characterized by distinct bands of orange at the colony edges and a dark green center. Stained biofilm cross sections displayed a similar orange band at the biofilm-bulk fluid interface and a green interior. Colony-average specific growth rates, determined by calculating the local slope of the cell accumulation versus time data, were correlated with colony-average fluorescence intensities. There was no correlation between average specific growth rate and orange or green intensity individually, but growth rate did correlate with the orange:green intensity ratio (r2 = 0.57). The resulting regression was used to predict specific growth rate profiles within colonies. These profiles indicated that bacteria were growing rapidly near the air and agar interfaces and more slowly in the center of the colonies when thicker than about 30 microns. The dimension of the orange bands ranged from 10 to 30 microns, which may indicate the thickness of growing regions. The inherent variability associated with this technique suggests that it is best applied in single species systems and that the results should be regarded as qualitative in nature.


Relaxation mode analysis and Markov state relaxation mode analysis for chignolin in aqueous solution near a transition temperature.
It is important to extract reaction coordinates or order parameters from protein simulations in order to investigate the local minimum-energy states and the transitions between them. The most popular method to obtain such data is principal component analysis, which extracts modes of large conformational fluctuations around an average structure. We recently applied relaxation mode analysis for protein systems, which approximately estimates the slow relaxation modes and times from a simulation and enables investigations of the dynamic properties underlying the structural fluctuations of proteins. In this study, we apply this relaxation mode analysis to extract reaction coordinates for a system in which there are large conformational changes such as those commonly observed in protein folding/unfolding. We performed a 750-ns simulation of chignolin protein near its folding transition temperature and observed many transitions between the most stable, misfolded, intermediate, and unfolded states. We then applied principal component analysis and relaxation mode analysis to the system. In the relaxation mode analysis, we could automatically extract good reaction coordinates. The free-energy surfaces provide a clearer understanding of the transitions not only between local minimum-energy states but also between the folded and unfolded states, even though the simulation involved large conformational changes. Moreover, we propose a new analysis method called Markov state relaxation mode analysis. We applied the new method to states with slow relaxation, which are defined by the free-energy surface obtained in the relaxation mode analysis. Finally, the relaxation times of the states obtained with a simple Markov state model and the proposed Markov state relaxation mode analysis are compared and discussed.


Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.
The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.


Peripheral Hole Acceptor Moieties on an Organic Dye Improve Dye-Sensitized Solar Cell Performance.
Investigation of charge transfer dynamics in dye-sensitized solar cells is of fundamental interest and the control of these dynamics is a key factor for developing more efficient solar cell devices. One possibility for attenuating losses through recombination between injected electrons and oxidized dye molecules is to move the positive charge further away from the metal oxide surface. For this purpose, a metal-free dye named E6 is developed, in which the chromophore core is tethered to two external triphenylamine (TPA) units. After photoinduced electron injection into TiO2, the remaining hole is rapidly transferred to a peripheral TPA unit. Electron-hole recombination is slowed down by 30% compared to a reference dye without peripheral TPA units. Furthermore, it is found that the added TPA moieties improve the electron blocking effect of the dye, retarding recombination of electrons from TiO2 to the cobalt-based electrolyte.


Quinolone treatment for pediatric bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin.
Trovafloxacin is a new fluoroquinolone that exhibits good penetration into the central nervous system and excellent antimicrobial activity against common meningeal pathogens, including beta-lactam-resistant pneumococci. A multicenter, randomized clinical trial was conducted in children with bacterial meningitis to compare the safety and efficacy of trovafloxacin with that of ceftriaxone with or without vancomycin therapy. A total of 311 patients, ages 3 months to 12 years, were enrolled, of whom 203 were fully evaluable, 108 treated with trovafloxacin and 95 with the conventional regimen. Both groups were comparable with regard to baseline characteristics: age; cerebrospinal fluid findings; use of dexamethasone; history of seizures; and etiologic agents. No significant differences between trovafloxacin and the comparator, respectively, were detected in any of the following outcome measures: clinical success at 5 to 7 weeks after treatment (79% vs. 81%); deaths (2% vs. 3%); seizures after enrollment (22% vs. 21%); and severe sequelae (14% vs. 14%). Only 4 of 284 children developed joint abnormalities up to 6 months after treatment, 1 (0.9%) child received trovafloxacin and 3 (3.1%) received the comparator regimen. None of the evaluable patients experienced significant abnormalities of liver function during treatment. One nonevaluable patient who received trovafloxacin for 5 days and ceftriaxone for 11 days was readmitted to the hospital with hepatitis of unknown etiology 1 day after discharge. The episode resolved with liver function tests returning to normal within 2 months. We conclude that trovafloxacin is an effective antibiotic for treatment of pediatric bacterial meningitis. These favorable results support further evaluation of fluoroquinolone therapy for children with meningitis or other serious bacterial infections.


Antimicrobial resistance surveillance in the genomic age.
The loss of effective antimicrobials is reducing our ability to protect the global population from infectious disease. However, the field of antibiotic drug discovery and the public health monitoring of antimicrobial resistance (AMR) is beginning to exploit the power of genome and metagenome sequencing. The creation of novel AMR bioinformatics tools and databases and their continued development will advance our understanding of the molecular mechanisms and threat severity of antibiotic resistance, while simultaneously improving our ability to accurately predict and screen for antibiotic resistance genes within environmental, agricultural, and clinical settings. To do so, efforts must be focused toward exploiting the advancements of genome sequencing and information technology. Currently, AMR bioinformatics software and databases reflect different scopes and functions, each with its own strengths and weaknesses. A review of the available tools reveals common approaches and reference data but also reveals gaps in our curated data, models, algorithms, and data-sharing tools that must be addressed to conquer the limitations and areas of unmet need within the AMR research field before DNA sequencing can be fully exploited for AMR surveillance and improved clinical outcomes.


Liver xeno-repopulation with human hepatocytes in Fah-/-Rag2-/- mice after pharmacological immunosuppression.
Functional human hepatocytes xeno-engrafted in mouse liver can be used as a model system to study hepatitis virus infection and vaccine efficacy. Significant liver xeno-repopulation has been reported in two kinds of genetically modified mice that have both immune deficiency and liver injury-induced donor hepatocyte selection: the uPA/SCID mice and Fah(-/-) Rag2(-/-)Il2rg(-/-) mice. The lack of hardy breeding and the overly elaborated technique in these two models may hinder the potential future application of these models to hepatitis virus infection and vaccination studies. Improving the transplantation protocol for liver xeno-repopulation from human hepatocytes will increase the model efficiency and application. In this study, we successfully apply immunosuppressive drug treatments of anti-asialo GM1 and FK506 in Fah(-/-)Rag2(-/-) mice, resulting in significant liver xeno-repopulation from human hepatocytes and human fetal liver cells. This methodology decreases the risk of animal mortality during breeding and surgery. When infected with hepatitis B virus (HBV) sera, Fah(-/-)Rag2(-/-) mice with liver xeno-repopulation from human hepatocytes accumulate significant levels of HBV DNA and HBV proteins. Our new protocol for humanized liver could be applied in the study of human hepatitis virus infection in vivo, as well as the pharmacokinetics and efficacy of potential vaccines.


A genomic storm in critically injured humans.
Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.


The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency.
The serine proteinase inhibitor α-1 anti-trypsin (AAT) provides an antiprotease protective screen throughout the body. Mutations in the AAT gene (SERPINA1) that lead to deficiency in AAT are associated with chronic obstructive pulmonary diseases. The Z mutation encodes a misfolded variant of AAT that is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum of hepatocytes and other AAT-producing cells. Until recently, it was thought that loss of antiprotease function was the major cause of ZAAT-related lung disease. However, the contribution of gain-of-function effects is now being recognized. Here we describe how both loss- and gain-of-function effects can contribute to ZAAT-related lung disease. In addition, we explore how SERPINA1 heterozygosity could contribute to smoking-induced chronic obstructive pulmonary diseases and consider the consequences.


I1 imidazoline receptor: novel potential cytoprotective target of TVP1022, the S-enantiomer of rasagiline.
TVP1022, the S-enantiomer of rasagiline (Azilect®) (N-propargyl-1R-aminoindan), exerts cyto/cardio-protective effects in a variety of experimental cardiac and neuronal models. Previous studies have demonstrated that the protective activity of TVP1022 and other propargyl derivatives involve the activation of p42/44 mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, we further investigated the molecular mechanism of action and signaling pathways of TVP1022 which may account for the cyto/cardio-protective efficacy of the drug. Using specific receptor binding and enzyme assays, we demonstrated that the imidazoline 1 and 2 binding sites (I(1) & I(2)) are potential targets for TVP1022 (IC(50) =9.5E-08 M and IC(50) =1.4E-07 M, respectively). Western blotting analysis showed that TVP1022 (1-20 µM) dose-dependently increased the immunoreactivity of phosphorylated p42 and p44 MAPK in rat pheochromocytoma PC12 cells and in neonatal rat ventricular myocytes (NRVM). This effect of TVP1022 was significantly attenuated by efaroxan, a selective I(1) imidazoline receptor antagonist. In addition, the cytoprotective effect of TVP1022 demonstrated in NRVM against serum deprivation-induced toxicity was markedly inhibited by efaroxan, thus suggesting the importance of I(1)imidazoline receptor in mediating the cardioprotective activity of the drug. Our findings suggest that the I(1)imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of TVP1022.


The efficacy of an intramedullary nitinol implant in the correction of claw toe or hammertoe deformities.
A multitude of procedures has been described in the literature for the treatment of lesser toe deformities and there is currently no general consensus on the optimal method of fixation. The aim of this study is to assess the clinical and radiological outcomes of an intramedullary nitinol implant for the correction of lesser toe deformities, and to determine if the distal interphalangeal (DIP) joint and metatarsophalangeal (MTP) joint are modified during patient follow-up after correction of the PIP joint. A prospective analysis of 36 patients with claw toe or hammertoe who were treated with an intramedullary nitinol implant. Clinical manifestations and angulation of the metatarsophalangeal, proximal and distal interphalangeal (MTP, PIP, DIP) joints were evaluated in radiographic studies preoperatively, at first medical revision post-surgery, and after a minimum of 1 year of follow-up. Complications such as non-union rate, implant rupture, and implant infection were also evaluated during follow-up. All patients were women with an average age of 65.5 (range 47-82) years. The average follow-up time was 2.4 (range 1-5.7) years. Fifty intramedullary nitinol implants were used. The MTP joint extension and PIP joint flexion decreased by 15.9° (95% CI - 19.11 to - 12.63) and 49.4° (95% CI - 55.29 to - 43.52), respectively, at the end of follow-up. Moreover, the DIP joint flexion increased progressively during follow-up (13.7° pre-surgery versus 35.6 in last medical check-up, 95% CI 13.24-30.57). There were four (8%) asymptomatic implant ruptures. The rate of fusion was 98%. The reduction of the PIP joint using an intramedullary nitinol implant is a good option in lesser toe deformities, with few complications and a high rate of arthrodesis. Moreover, the PIP joint reduction affects both the MTP and DIP joints.


Key principles and clinical applications of "next-generation" DNA sequencing.
Demand for fast, inexpensive, and accurate DNA sequencing data has led to the birth and dominance of a new generation of sequencing technologies. So-called "next-generation" sequencing technologies enable rapid generation of data by sequencing massive amounts of DNA in parallel using diverse methodologies which overcome the limitations of Sanger sequencing methods used to sequence the first human genome. Despite opening new frontiers of genomics research, the fundamental shift away from the Sanger sequencing that next-generation technologies has created has also left many unaware of the capabilities and applications of these new technologies, especially those in the clinical realm. Moreover, the brisk evolution of sequencing technologies has flooded the market with commercially available sequencing platforms, whose unique chemistries and diverse applications stand as another obstacle restricting the potential of next-generation sequencing. This review serves to provide a primer on next-generation sequencing technologies for clinical researchers and physician scientists. We provide an overview of the capabilities and clinical applications of DNA sequencing technologies to raise awareness among researchers about the power of these novel genomic tools. In addition, we discuss that key sequencing principles provide a comparison between existing and near-term technologies and outline key advantages and disadvantages between different sequencing platforms to help researchers choose an appropriate platform for their research interests.


Three-year financial analysis of minimally invasive radio-guided parathyroidectomy.
Minimally invasive radio-guided parathyroidectomy (MIRP) has had a high success rate in correcting hypercalcemia, along with a low morbidity rate and high patient satisfaction. Our study was conducted in an attempt to analyze the cost-effectiveness of MIRP in patients treated for primary hyperparathyroidism. We conducted a retrospective study of the total charges of three groups of patients undergoing surgery for previously untreated hyperparathyroidism in a single health care system. The three study groups included patients undergoing traditional bilateral neck exploration, MIRP, and neck exploration guided by intraoperative parathormone (PTH) assay. Charges were stratified into preoperative, intraoperative, and postoperative categories. The average total charge was $8,512 for MIRP, $12,723 for traditional neck exploration, and $13,011 for bilateral neck exploration with PTH assay. The decreased charge for MIRP was due to reduced operating room time, anesthesia costs, length of hospitalization, and an avoidance of the use of intraoperative tissue analysis and PTH assay. There was a greater than $4,000 savings with MIRP as compared with the more extensive neck exploration. These savings more than compensate for the cost of technology (preoperative sestamibi scan and intraoperative gamma probe) necessary to perform radio-guided parathyroidectomy.


Salt induction and activation of MtlD, the key enzyme in the synthesis of the compatible solute mannitol in Acinetobacter baumannii.
Mannitol is the major compatible solute, next to glutamate, synthesized by the opportunistic human pathogen Acinetobacter baumannii under low water activities. The key enzyme for mannitol biosynthesis, MtlD, was identified. MtlD is highly similar to the bifunctional mannitol-1-phosphate dehydrogenase/phosphatase from Acinetobacter baylyi. After deletion of the mtlD gene from A. baumannii ATCC 19606T cells no longer accumulated mannitol and growth was completely impaired at high salt. Addition of glycine betaine restored growth, demonstrating that mannitol is an important compatible solute in the human pathogen. MtlD was heterologously produced and purified. Enzyme activity was strictly salt dependent. Highest stimulation was reached at 600 mmol/L NaCl. Addition of different sodium as well as potassium salts restored activity, with highest stimulations up to 41 U/mg protein by sodium glutamate. In contrast, an increase in osmolarity by addition of sugars did not restore activity. Regulation of mannitol synthesis was also assayed at the transcriptional level. Reporter gene assays revealed that expression of mtlD is strongly dependent on high osmolarity, not discriminating between different salts or sugars. The presence of glycine betaine or its precursor choline repressed promoter activation. These data indicate a dual regulation of mannitol production in A. baumannii, at the transcriptional and the enzymatic level, depending on high osmolarity.


Structure of the Archaeoglobus fulgidus orphan ORF AF1382 determined by sulfur SAD from a moderately diffracting crystal.
The crystal structure of the 11.14 kDa orphan ORF 1382 from Archaeoglobus fulgidus (AF1382) has been determined by sulfur SAD phasing using a moderately diffracting crystal and 1.9 Å wavelength synchrotron X-rays. AF1382 was selected as a structural genomics target by the Southeast Collaboratory for Structural Genomics (SECSG) since sequence analyses showed that it did not belong to the Pfam-A database and thus could represent a novel fold. The structure was determined by exploiting longer wavelength X-rays and data redundancy to increase the anomalous signal in the data. AF1382 is a 95-residue protein containing five S atoms associated with four methionine residues and a single cysteine residue that yields a calculated Bijvoet ratio (ΔF(anom)/F) of 1.39% for 1.9 Å wavelength X-rays. Coupled with an average Bijvoet redundancy of 25 (two 360° data sets), this produced an excellent electron-density map that allowed 69 of the 95 residues to be automatically fitted. The S-SAD model was then manually completed and refined (R = 23.2%, R(free) = 26.8%) to 2.3 Å resolution (PDB entry 3o3k). High-resolution data were subsequently collected from a better diffracting crystal using 0.97 Å wavelength synchrotron X-rays and the S-SAD model was refined (R = 17.9%, R(free) = 21.4%) to 1.85 Å resolution (PDB entry 3ov8). AF1382 has a winged-helix-turn-helix structure common to many DNA-binding proteins and most closely resembles the N-terminal domain (residues 1-82) of the Rio2 kinase from A. fulgidus, which has been shown to bind DNA, and a number of MarR-family transcriptional regulators, suggesting a similar DNA-binding function for AF1382. The analysis also points out the advantage gained from carrying out data reduction and structure determination on-site while the crystal is still available for further data collection.


A Point System for Predicting 10-Year Risk of Developing Type 2 Diabetes Mellitus in Japanese Men: Aichi Workers' Cohort Study.
Relatively little evidence exists for type 2 diabetes mellitus (T2DM) prediction models from long-term follow-up studies in East Asians. This study aims to develop a point-based prediction model for 10-year risk of developing T2DM in middle-aged Japanese men. We followed 3,540 male participants of Aichi Workers' Cohort Study, who were aged 35-64 years and were free of diabetes in 2002, until March 31, 2015. Baseline age, body mass index (BMI), smoking status, alcohol consumption, regular exercise, medication for dyslipidemia, diabetes family history, and blood levels of triglycerides (TG), high density lipoprotein cholesterol (HDLC) and fasting blood glucose (FBG) were examined using Cox proportional hazard model. Variables significantly associated with T2DM in univariable models were simultaneously entered in a multivariable model for determination of the final model using backward variable selection. Performance of an existing T2DM model when applied to the current dataset was compared to that obtained in the present study's model. During the median follow-up of 12.2 years, 342 incident T2DM cases were documented. The prediction system using points assigned to age, BMI, smoking status, diabetes family history, and TG and FBG showed reasonable discrimination (c-index: 0.77) and goodness-of-fit (Hosmer-Lemeshow test, P = 0.22). The present model outperformed the previous one in the present subjects. The point system, once validated in the other populations, could be applied to middle-aged Japanese male workers to identify those at high risk of developing T2DM. In addition, further investigation is also required to examine whether the use of this system will reduce incidence.