Pupillary light reflex is altered in adolescent depression.
Major depressive disorder is associated with abnormal autonomic regulation which could be noninvasively studied using pupillometry. However, the studies in adolescent patients are rare. Therefore, we aimed to study the pupillary light reflex (PLR), which could provide novel important information about dynamic balance between sympathetic and parasympathetic nervous system in adolescent patients suffering from major depression. We have examined 25 depressive adolescent girls (age 15.2+/-0.3 year) prior to pharmacotherapy and 25 age/gender-matched healthy subjects. PLR parameters were measured separately for both eyes after 5 min of rest using Pupillometer PLR-2000 (NeurOptics, USA). The constriction percentual change for the left eye was significantly lower in depressive group compared to control group (-24.12+/-0.87 % vs. -28.04+/-0.96 %, p<0.01). Furthermore, average constriction velocity and maximum constriction velocity for the left eye were significantly lower in depressive group compared to control group (p<0.05, p<0.01, respectively). In contrast, no significant between-groups differences were found for the right eye. Concluding, this study revealed altered PLR for left eye indicating a deficient parasympathetic activity already in adolescent major depression. Additionally, the differences between left and right eye could be related to functional lateralization of autonomic control in the central nervous system.


Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration.
Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited. To understand regenerative heterogeneity, we conducted patch-based single-cell RNA sequencing on rare regenerating CST neurons at high depth following PTEN and SOCS3 deletion. Supervised classification with Garnett gave rise to a Regeneration Classifier, which can be broadly applied to predict the regenerative potential of diverse neuronal types across developmental stages or after injury. Network analyses highlighted the importance of antioxidant response and mitochondrial biogenesis. Conditional gene deletion validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in CST regeneration. Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronal populations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.


Multimodality Imaging Assessment of Tetralogy of Fallot: From Diagnosis to Long-Term Follow-Up.
Tetralogy of Fallot (TOF) is the most common complex congenital heart disease with long-term survivors, demanding serial monitoring of the possible complications that can be encountered from the diagnosis to long-term follow-up. Cardiovascular imaging is key in the diagnosis and serial assessment of TOF patients, guiding patients' management and providing prognostic information. Thorough knowledge of the pathophysiology and expected sequalae in TOF, as well as the advantages and limitations of different non-invasive imaging modalities that can be used for diagnosis and follow-up, is the key to ensuring optimal management of patients with TOF. The aim of this manuscript is to provide a comprehensive overview of the role of each modality and common protocols used in clinical practice in the assessment of TOF patients.


Hepatitis C-positive donor liver transplantation for hepatitis C seronegative recipients.
The opioid crisis has led to an increase in hepatitis C virus-positive donors in the past decade. Whereas historically hepatitis C seropositive organs were routinely discarded, the advent of direct-acting antiviral agents has notably expanded the utilization of organs from donors with hepatitis C. There has been growing experience with liver transplantation (LT) from hepatitis C seropositive donors to hepatitis C seropositive recipients. However, data remain limited on LT from hepatitis C seropositive or hepatitis C ribonucleic acid positive donors to hepatitis C seronegative recipients. We performed a retrospective study of 26 hepatitis C seronegative recipients who received hepatitis C seropositive donor livers followed by preemptive antiviral therapy with direct-acting antiviral treatment at the Johns Hopkins Hospital Comprehensive Transplant Center from January 1, 2017, to August 31, 2019. Twenty-five of the 26 recipients are alive with proper graft function; 20 of them received livers from hepatitis C nucleic acid testing positive donors. All 12 recipients who completed their direct-acting antiviral courses and have reached sufficient follow-up for sustained virologic response have achieved sustained virologic response. Nine of our recipients have either completed direct-acting antiviral treatment without sufficient follow-up time for sustained virologic response or are undergoing direct-acting antiviral treatment. One patient is awaiting antiviral treatment initiation pending insurance approval. Of note, 11 of 12 patients with sustained virologic response received a hepatitis C nucleic acid testing positive donor liver. Hepatitis C seronegative patients who receive a hepatitis C seropositive or hepatitis C nucleic acid testing positive liver allograft can enjoy good short-term outcomes with hepatitis C cure following direct-acting antiviral treatment.


A dynamics and stability framework for avian jumping take-off.
Jumping take-off in birds is an explosive behaviour with the goal of providing a rapid transition from ground to airborne locomotion. An effective jump is predicated on the need to maintain dynamic stability through the acceleration phase. The present study concerns understanding how birds retain control of body attitude and trajectory during take-off. Cursory observation suggests that stability is achieved with relatively little cost. However, analysis of the problem shows that the stability margins during jumping are actually very small and that stability considerations play a significant role in the selection of appropriate jumping kinematics. We use theoretical models to understand stability in prehensile take-off (from a perch) and also in non-prehensile take-off (from the ground). The primary instability is tipping, defined as rotation of the centre of gravity about the ground contact point. Tipping occurs when the centre of pressure falls outside the functional foot. A contribution of the paper is the development of graphical tipping stability margins for both centre of gravity location and acceleration angle. We show that the nose-up angular acceleration extends stability bounds forward and is hence helpful in achieving shallow take-offs. The stability margins are used to interrogate simulated take-offs of real birds using published experimental kinematic data from a guinea fowl (ground take-off) and a diamond dove (perch take-off). For the guinea fowl, the initial part of the jump is stable; however, simulations exhibit a stuttering instability not observed experimentally that is probably due to the absence of compliance in the idealized joints. The diamond dove model confirms that the foot provides an active torque reaction during take-off, extending the range of stable jump angles by around 45°.


Evaluation of treatment results and prognostic factors in early-stage cervical carcinoma patients treated with postoperative radiotherapy or radiochemotherapy.
To investigate the clinical features, prognostic factors, and treatment outcome in early-stage cervical carcinoma patients treated with postoperative radiotherapy (RT)/radiochemotherapy (RCT). The records of 256 Stage IB and II cervical cancer patients treated with postoperative RT/RCT from 1992-2007 were retrospectively reviewed. Median age of the patients was 47 (range: 25-78). Two hundred one (78.6%) patients had squamous cell carcinoma and 29 (11.3%) had adenocarcinoma. One hundred and eighty-seven (73.0%) had FIGO Stage IB and 69 (27%) had Stage II disease. Concomitant cisplatin-based chemotherapy was administered to 47 (18.4%) patients. Metastatic lymph node ratio (MLNR), defined as number of metastatic lymph nodes divided by the number of dissected lymph nodes, was 0 in 142 (55.5%) patients, from 1% to 10% in 27 (10.5%) and > 10% in 31 (12.1%) patients. Median follow-up duration was 60.5 months (range: 6-202 months). Five-year locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS) rates were 90.8%, 83.4%, 91.2%, and 85%, respectively. In multivariate analysis; bulky tumor (> 4 cm) was shown as an important prognostic factor for LRC, DFS and DSS. Pretreatment hemoglobin level (< 10 g/dl) was associated with lower OS rate. Endometrial involvement was associated with lower LRC and DFS. Treatment break > 14 days showed significance for DFS and DSS. MLNR was found as a valuable prognostic factor for all endpoints (LRC, DFS, DSS and OS). The rate of grade 3-4 late toxicity was 3.6% and 2%, respectively. Postoperative RT/RCT is an effective treatment modality for early-stage cervical cancer patients with unfavorable features and provides satisfactory local control and survival rates with low morbidity.


Cardiac troponin T and cardiac troponin I: relative values in short-term risk stratification of patients with acute coronary syndromes. GUSTO-IIa Investigators.
We compared cardiac troponins T (cTnT) and I (cTnI) collected within 3.5 h of ischemic symptoms for predicting clinical outcomes in 770 patients. cTnT (cutoff > 0.1 microgram/L) and cTnI (cutoff > 1.5 micrograms/L) were concordant (both positive or negative) in 90.4% of patients. Among discordant results, 66 were cTnT positive and cTnI negative vs 8 who showed the reverse (P < 0.001). Five cTnT-positive and cTnI-negative patients died within 30 days; none who were cTnT negative and cTnI positive died. cTnT showed a slightly greater association (chi 2 = 18.0, P < 0.001) with 30-day mortality than cTnI (chi 2 = 12.5, P = 0.002). The area of the ROC curve for predicting 30-day mortality was significantly larger (Z = 2.08; P = 0.0375) for cTnT, at 0.68 [95% confidence interval (CI) 0.60-0.75], compared with cTnI, at 0.64 (95% CI 0.56-0.72). When cTnI and the electrocardiogram (ECG) were put in a logistic multiple regression model, cTnT added significant information (chi 2 = 8.03, P = 0.045); however, cTnI did not add to a model containing cTnT and the ECG (chi 2 = 0.84, P = 0.657). cTnT provided more information than cTnI for predicting 30-day mortality early after presentation with acute coronary syndromes.


Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4).
Epidermolysis bullosa with pyloric atresia (EB-PA; OMIM 226730) is a clinically and genetically heterogeneous autosomal recessive blistering disorder, including lethal and nonlethal variants. Recently, expression of alpha6beta4 integrin, a transmembrane protein of the epithelial basement membranes, has been shown to be altered in these patients. In this work, we have explored the molecular pathology of the lethal form of EB-PA, and we describe novel ITGB4 mutations in five alleles of three patients. The mutation detection strategy included polymerase chain reaction amplification of each exon of ITGB4, followed by heteroduplex analysis and direct nucleotide sequencing. The novel mutations included a homozygous 2-bp deletion in exon 34 (4501delTC), compound heterozygosity for a 2-bp deletion within the paternal allele (120delTG) within exon 3 and a cysteine substitution in the maternal allele (C245G) within exon 7, and the paternal nonsense mutation within exon 4 (Q73X). Thus, three of four distinct mutations predicted truncated polypeptide chains, whereas the missense mutation in the extracellular domain of beta4 integrin may affect ligand binding or dimerization of alpha6 and beta4 integrin subunits. These mutations emphasize the critical importance of the alpha6beta4 integrin in providing stability to the association of epidermis to the underlying dermis at the cutaneous basement membrane zone.


Microfractures in the head of the femur.
Microfractures of the trabeculae were studied in the femoral heads of three different population groups. The femoral heads were sliced and then examined with a dissecting microscope. Microfractures were found in large numbers in specimens from British patients who had suffered femoral-neck fracture, and in smaller numbers in femoral heads -aken routine autopsy in India and in China (Hong Kong). There were many more microfractures in the thinner, lightly stressed trabeculae than in the thicker weight-bearing trabeculae in the fractured femoral-neck specimens. The significance of these findings is discussed in the light of current concepts regarding the pathogenesis and significance of trabecular microfractures.


Host sex discrimination by an egg parasitoid on Brassica leaves.
Egg parasitoids are able to find their hosts by exploiting their chemical footprints as host location cues. In nature, the apolar epicuticular wax layer of plants that consists of several classes of hydrocarbons serves as the substrate that retains these contact kairomones. However, experiments on chemical footprints generally have used filter paper as substrate to study insect behavior. Here, we explored the ability of Trissolcus basalis (Scelionidae) females to discriminate between footprint cues left by male and female Nezara viridula (Pentatomidae) on leaves of their host plant Brassica oleracea (broccoli). Furthermore, we analyzed the chemical composition of the outermost wax layer of broccoli leaves to evaluate the degree of overlap in insect and plant cuticular hydrocarbons that could lead to masking effects in the detection of footprint cues. Our results showed that B. oleracea epicuticular wax retains the chemical footprints of adult bugs and allows T. basalis females to differentiate hosts of different sex. Traces of female bugs elicited more extensive searching behavior in egg parasitoids than traces of males. The application of n-nonadecane, a compound specific to male N. viridula, on the tarsi of female bugs prevented parasitoid females from distinguishing between host male and host female footprints. Analyses of B. oleracea leaves revealed that epicuticular waxes were mainly composed of linear alkanes, ketones, and secondary alcohols. Alkanes were dominated by n-nonacosane (nC29) and n-hentriacontane (nC31), while male-specific n-nonadecane (nC19) was absent. The ecological significance of these results for parasitoid host location behavior is discussed.


Shark fisheries in the Southeast Pacific: A 61-year analysis from Peru.
Peruvian waters exhibit high conservation value for sharks. This contrasts with a lag in initiatives for their management and a lack of studies about their biology, ecology and fishery. We investigated the dynamics of Peruvian shark fishery and its legal framework identifying information gaps for recommending actions to improve management. Further, we investigated the importance of the Peruvian shark fishery from a regional perspective. From 1950 to 2010, 372,015 tons of sharks were landed in Peru. From 1950 to 1969, we detected a significant increase in landings; but from 2000 to 2011 there was a significant decrease in landings, estimated at 3.5% per year. Six species represented 94% of landings: blue shark ( Prionace glauca), shortfin mako ( Isurus oxyrinchus), smooth hammerhead ( Sphyrna zygaena), common thresher ( Alopias vulpinus), smooth-hound ( Mustelus whitneyi) and angel shark ( Squatina californica). Of these, the angel shark exhibits a strong and significant decrease in landings: 18.9% per year from 2000 to 2010. Peru reports the highest accumulated historical landings in the Pacific Ocean; but its contribution to annual landings has decreased since 1968. Still, Peru is among the top 12 countries exporting shark fins to the Hong Kong market. Although the government collects total weight by species, the number of specimens landed as well as population parameters (e.g. sex, size and weight) are not reported. Further, for some genera, species-level identification is deficient and so overestimates the biomass landed by species and underestimates the species diversity. Recently, regional efforts to regulate shark fishery have been implemented to support the conservation of sharks but in Peru work remains to be done.


[Surgical treatment of cholecystitis and cholecystopancreatitis].
The treatment of 3539 patients has shown that patients with the unquestionable diagnosis of acute cholecystitis (cholecystopancreatitis) without aggravating circumstances must be operated upon in earlier time - within 3--6 days from the onset of the disease, in spite of the improved general condition. Other conditions being equal, the question of surgical treatment must be solved earlier in elderly and senile patients with acute cholecystitis and cholecystopancreatitis.


Late stage benzylic C-H fluorination with [¹⁸F]fluoride for PET imaging.
We describe the first late-stage (18)F labeling chemistry for aliphatic C-H bonds with no-carrier-added [(18)F]fluoride. The method uses Mn(salen)OTs as an F-transfer catalyst and enables the facile labeling of a variety of bioactive molecules and building blocks with radiochemical yields (RCY) ranging from 20% to 72% within 10 min without the need for preactivation of the labeling precursor. Notably, the catalyst itself can directly elute [(18)F]fluoride from an ion exchange cartridge with over 90% efficiency. Using this feature, the conventional and laborious dry-down step prior to reaction is circumvented, greatly simplifying the mechanics of this protocol and shortening the time for automated synthesis. Eight drug molecules, including COX, ACE, MAO, and PDE inhibitors, have been successfully [(18)F]-labeled in this way.


Health TAPESTRY: Exploring the Potential of a Nursing Student Placement Within a Primary Care Intervention for Community-Dwelling Older Adults.
The increasing prevalence of chronic diseases in aging places demands on primary care. Nurses are the major nonphysician primary care workforce. Baccalaureate nursing programs should expose students to primary care and older adults to support these demands and help recruit new graduates to this setting. However, many baccalaureate nursing programs focus on acute care and placements aimed at older adults are viewed negatively. To address these curriculum challenges, third-year Canadian baccalaureate nursing students were placed in an innovative primary care program-Health TAPESTRY-for community-dwelling older adults. Health TAPESTRY involves an interprofessional primary care team, trained lay volunteers conducting home visits, system navigation, and an online software application. The goal of this study was to explore third-year baccalaureate nursing students' perceptions of this unique clinical primary care placement. This qualitative descriptive study explored students' perceptions of this placement's strengths, weaknesses, opportunities, threats (SWOT), and outcomes. Nursing students participated in focus groups (n = 14) or an interview (n = 1) and five completed narrative summaries following visits. Qualitative content analysis was supported by NVivo 10. Strengths of the clinical placement included training for the intervention; new insights about older adults; and experience with home visiting, interprofessional team functions, and community resources. Weaknesses included limited exposure to older adult clients, lack of role clarity, lack of registered nurse role models, and technology challenges. Opportunities included more exposure to primary care, interprofessional teams, and community resources. No threats were described. Nursing students' clinical experiences can be enhanced through engagement in innovative primary care programs. Adequate exposure to clients, including older adults; interprofessional teams; mentoring by registered nurses or advanced practice nurse preceptors; and role clarity for students in the primary care team should be considered in supporting baccalaureate nursing students in primary care clinical placements.


Complexities and uncertainties of neuronal network function.
The nervous system generates behaviours through the activity in groups of neurons assembled into networks. Understanding these networks is thus essential to our understanding of nervous system function. Understanding a network requires information on its component cells, their interactions and their functional properties. Few networks come close to providing complete information on these aspects. However, even if complete information were available it would still only provide limited insight into network function. This is because the functional and structural properties of a network are not fixed but are plastic and can change over time. The number of interacting network components, their (variable) functional properties, and various plasticity mechanisms endows networks with considerable flexibility, but these features inevitably complicate network analyses. This review will initially discuss the general approaches and problems of network analyses. It will then examine the success of these analyses in a model spinal cord locomotor network in the lamprey, to determine to what extent in this relatively simple vertebrate system it is possible to claim detailed understanding of network function and plasticity.


Effects of Radiotherapy in Early-Stage, Low-Recurrence Risk, Hormone-Sensitive Breast Cancer.
Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality. We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided. The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other). Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death.


Destabilization of ultrafine bubbles in water using indirect ultrasonic irradiation.
Ultrafine bubble (UFB) is a bubble with a diameter of less than 1 μm. Little attention has been paid to the defoaming and removal of UFBs. This study proposes a method to destabilize UFBs by using indirect ultrasonic irradiation. Besides, the destabilization mechanism of UFB was investigated. The ultrasonic frequency was 1.6 MHz and the dissipated power was 30 W. UFB dispersions were prepared using two different types of bubble generators: pressurized dissolution method and swirling liquid flow method. The effects of ultrasonic irradiation on the stability of UFBs were evaluated by particle tracking analysis (PTA) and electrophoretic zeta potential measurement. Results showed that the indirect ultrasonic irradiation for 30 min reduced the number concentration of UFBs by 90% regardless of the generation method. This destabilization was attributed to a decrease in the magnitude of zeta potential of UFBs due to the changes in pH and electrical conductivity. These changes in the electrochemical properties were caused by the formation of nitric acid. To study the destabilization mechanism, the pH of the UFB dispersions were modified by titration; the chemical and mechanical effects of ultrasound were separately examined. It was found that not only the chemical effect caused by the formation of nitric acid but also the mechanical effect contributed to the destabilization of UFB. Feasibility studies were also performed for UFBs in an aqueous surfactant solution and UFBs in a solid particle dispersion. The proposed method selectively destabilized UFBs in the solutions.


Electron- and photon-stimulated desorption: probes of structure and bonding at surfaces.
Techniques for analyzing the structure and composition of solid surfaces with electron and photon beams often cause radiation damage in samples. Damage-producing processes compete with information-producing events during measurements, and beam damage can be a serious perturbation in quantitative surface analysis. There are, however, substantial benefits of electron- and photonstimulated damage processes for studying molecules adsorbed on surfaces. Direct information about the geometric structure of surface molecules can be obtained from measurements of the angular distributions of ions released by electron- or photon-stimulated desorption. The directions of ion emission are determined by the orientation of the surface bonds that are ruptured by beam irradiation. Moreover, photon-stimulated desorption studies that make use of synchrotron radiation reveal the fundamental electronic excitations that lead to bondbreaking processes at surfaces. These measurements provide new insights into radiation-damage processes in areas as diverse as x-ray optics and semiconductor electronics.


Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial.
Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245. 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39-1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06-0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02-0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. Bill & Melinda Gates Foundation and US National Institutes of Health.


Study protocol for prevention of falls: a randomized controlled trial of effects of vitamin D and exercise on falls prevention.
Falls are the leading cause of unintentional injury and injury-related death among older people. In addition to physical activity, vitamin D also may affect balance and neuromuscular function. Low serum 25-hydroksivitamin D level increases the risk of bone loss, falls and fractures. Thus, an appropriate exercise program and sufficient vitamin D intake may significantly improve not only functional balance, but also balance confidence. Balance represents a complex motor skill determined by reaction time, muscle strength, and speed and coordination of movement. A 2-year randomized double-blind placebo-controlled vitamin D and open exercise trial of 409 home-dwelling women 70 to 80 years of age comprising four study arms: 1) exercise + vitamin D (800 IU/d), 2) exercise + placebo, 3) no exercise + vitamin D (800 IU/d), 4) no exercise + placebo. In addition to monthly fall diaries, general health status, life style, bone health, physical functioning, and vitamin D metabolism will be assessed. The primary outcomes are the rate of falls and fall-related injuries. Secondary outcomes include changes in neuromuscular functioning (e.g. body balance, muscle strength), ADL- and mobility functions, bone density and structure, cardiovascular risk factors, quality of life and fear of falling. The successful completion of this trial will provide evidence on the effectiveness of exercise and vitamin D for falls reduction. ClinicalTrial.gov -register (NCT00986466).


Risk of Stroke in Patients With Heart Failure: A Population-Based 30-Year Cohort Study.
The long-term risk of specific stroke subtypes among heart failure patients is largely unknown. We examined short-term and long-term risk of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in heart failure patients and in a general population comparison cohort. In this nationwide cohort study (1980-2012), we used Danish population-based medical registries to identify and follow (1) all patients hospitalized for the first time with heart failure and (2) a birth year-, sex-, and calendar year-matched general population comparison cohort. Age-, sex-, and comorbidity-adjusted stroke rate ratios were computed based on Cox regression analysis. We included 289 353 patients with heart failure and 1 446 765 individuals from the general population in the analysis. One- and 5-year risks among heart failure patients were 1.4% and 3.9% for ischemic stroke, 0.2% and 0.5% for ICH, and 0.03% and 0.07% for SAH. The 30-day adjusted stroke rate ratio was increased markedly for ischemic stroke (5.08; 95% confidence interval, 4.58-5.63] and was also elevated for ICH (2.13; 95% confidence interval, 1.53-2.97) and SAH (3.52; 95% confidence interval, 1.54-8.08). Between 31 days and 30 years, risk of all stroke subtypes remained positively associated with heart failure (1.5- to 2.1-fold for ischemic stroke, 1.4- to 1.8-fold for ICH, and 1.1- to 1.7-fold for SAH) in comparison with the general population cohort. Heart failure was associated with increased short-term and long-term risk of all stroke subtypes, suggesting that heart failure is a potent and persistent risk factor for ischemic stroke, ICH, and SAH.


[Precise minimally invasive surgery of lower lumbar spine].
The fast development of minimally invasive spine surgery in recent years is based on the advance of endoscopic microsurgery techniques, computer science and medical imaging, as well as the growing concerning of medical humanities. The concept of minimally invasive and precise targeting therapy has been penetrating into various areas of surgery, and minimal tissue damage and fewer complications are the new directions of minimally invasive spine surgery. In this article we review some advances in precise spinal surgery including percutaneous lumbar discectomy, microendoscopic discectomy, computer-assisted orthopedic surgery and robot surgery.


Variation in the Genetic Repertoire of Viruses Infecting Micromonas pusilla Reflects Horizontal Gene Transfer and Links to Their Environmental Distribution.
Prasinophytes, a group of eukaryotic phytoplankton, has a global distribution and is infected by large double-stranded DNA viruses (prasinoviruses) in the family Phycodnaviridae. This study examines the genetic repertoire, phylogeny, and environmental distribution of phycodnaviruses infecting Micromonas pusilla, other prasinophytes and chlorophytes. Based on comparisons among the genomes of viruses infecting M. pusilla and other phycodnaviruses, as well as the genome from a host isolate of M. pusilla, viruses infecting M. pusilla (MpVs) share a limited set of core genes, but vary strongly in their flexible pan-genome that includes numerous metabolic genes, such as those associated with amino acid synthesis and sugar manipulation. Surprisingly, few of these presumably host-derived genes are shared with M. pusilla, but rather have their closest non-viral homologue in bacteria and other eukaryotes, indicating horizontal gene transfer. A comparative analysis of full-length DNA polymerase (DNApol) genes from prasinoviruses with their overall gene content, demonstrated that the phylogeny of DNApol gene fragments reflects the gene content of the viruses; hence, environmental DNApol gene sequences from prasinoviruses can be used to infer their overall genetic repertoire. Thus, the distribution of virus ecotypes across environmental samples based on DNApol sequences implies substantial underlying differences in gene content that reflect local environmental conditions. Moreover, the high diversity observed in the genetic repertoire of prasinoviruses has been driven by horizontal gene transfer throughout their evolutionary history, resulting in a broad suite of functional capabilities and a high diversity of prasinovirus ecotypes.


Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor.
Corticosterone is known to suppress levels of 5-HTA(1A) receptor mRNA in rat hippocampus. We describe hippocampal 5-HT(1A) receptor mRNA regulation in mice that have a targeted disruption of the glucocorticoid receptor gene. 5-HT(1A) receptor mRNA levels as well as binding of [3H]8-OH-DPAT, were measured in the hippocampus of heterozygous and homozygous GR-deficient mice and in wild-type control mice. The effect of adrenalectomy in wild-type mice and heterozygous knockouts was also studied. We hypothesized that if the glucocorticoid receptor is important as a mediator of the suppressive effect of corticosterone, this would be revealed by changed (enhanced) expression of 5-HT(1A) receptor mRNA in mice with a genetically changed glucocorticoid receptor status. It was found that 5-HT(1A) receptor mRNA levels and 5-HT(1A) receptor binding were not different in GR-deficient mice. The 5-HT(1A) receptor mRNA levels were responsive to corticosterone, as adrenalectomy led to increased levels of hippocampal 5-HT(1A) receptor mRNA both in wild-type as in heterozygous knockout mice. These increases were paralleled by small but statistically significant changes in [3H]8-OH-DPAT binding. These results support a suppressive control of B over 5-HT(1A) receptor expression in the hippocampus of the mouse, which is predominantly mediated via the mineralocorticoid receptor. The data indicates that no interaction between the two corticosteroid receptors is required for this effect of corticosterone, and that mineralocorticoid receptor-mediated suppression of gene expression can take place in the complete absence of glucocorticoid receptor.


99mTc-DMSA absolute uptake: normal pediatric values at 2-4 hours.
This study aims to determine if normal absolute uptake values of dimercaptosuccinic acid (DMSA) can be predicted accurately over the optimal time for imaging. Eighty-eight normal kidneys were analyzed from 44 children with a median age of 4 y. The mean time between injection and scan was 171.7 min. The absolute uptake of DMSA in milligrams was calculated for each kidney. A strong positive linear relationship was found between the absolute uptake of DMSA and the amount of DMSA injected in milligrams (corr = 0.940 [P< 0.0005]), and the age of the child (corr = 0.770 (P<0.0005)). Multiple linear regression showed that these 2 factors accounted for 92.2% of the change in absolute DMSA uptake. The absolute uptake of DMSA can be accurately predicted using a linear regression equation incorporating the amount of DMSA injected in milligrams and the patient's age. Time between injection and scan appears to play little role in the absolute uptake of DMSA over 2-4 h.


Polarization fatigue of organic ferroelectric capacitors.
The polarization of the ferroelectric polymer P(VDF-TrFE) decreases upon prolonged cycling. Understanding of this fatigue behavior is of great technological importance for the implementation of P(VDF-TrFE) in random-access memories. However, the origin of fatigue is still ambiguous. Here we investigate fatigue in thin-film capacitors by systematically varying the frequency and amplitude of the driving waveform. We show that the fatigue is due to delamination of the top electrode. The origin is accumulation of gases, expelled from the capacitor, under the impermeable top electrode. The gases are formed by electron-induced phase decomposition of P(VDF-TrFE), similar as reported for inorganic ferroelectric materials. When the gas barrier is removed and the waveform is adapted, a fatigue-free ferroelectric capacitor based on P(VDF-TrFE) is realized. The capacitor can be cycled for more than 10(8) times, approaching the programming cycle endurance of its inorganic ferroelectric counterparts.


[Estimation of glycosaminoglycan hydrolases in liver tissue].
Optimal enzyme/substrate ratios were studied to estimate the activity of lysosomal glycosaminoglycan (GAG) hydrolases in homogenate and supernatant fractions of liver tissue. The modified procedures enabled, without any loss in sensitivity, to decrease the amount of biological material in samples on estimation of hyaluronidase, beta-glucuronidase and N-acetyl-beta-D-hexosaminidase; concentration of substrate was also decreased in mixtures containing hexosaminidase. Under conditions of experimental cirrhosis total and, especially, non-sedimented activities of GAG-hydrolases as well as the rate of the enzymes penetration through lysosomal membranes were increased in liver tissue.


A Fluorometric Method of Measuring Carboxypeptidase Activities for Angiotensin II and Apelin-13.
Degradation of the biologically potent octapeptide angiotensin Ang II-(1-8) is mediated by the activities of several peptidases. The conversion of Ang II to the septapeptide Ang-(1-7) is of particular interest as the latter also confers organ protection. The conversion is catalyzed by angiotensin-converting enzyme 2 and other enzymes that selectively cleave the peptide bond between the proline and the phenylalanine at the carboxyl terminus of Ang II. The contribution of various enzyme activities that collectively lead to the formation of Ang-(1-7) from Ang II, in both normal conditions and in disease states, remains only partially understood. This is largely due to the lack of a reliable and sensitive method to detect these converting activities in complex samples, such as blood and tissues. Here, we report a fluorometric method to measure carboxypeptidase activities that cleave the proline-phenylalanine dipeptide bond in Ang II. This method is also suitable for measuring the conversion of apelin-13. The assay detects the release of phenylalanine amino acid in a reaction with the yeast enzyme of phenylalanine ammonia lyase (PAL). When used in cell and mouse organs, the assay can robustly measure endogenous Ang II and apelin-13-converting activities involved in the renin-angiotensin and the apelinergic systems, respectively.


Robotic assisted simple prostatectomy: recent advances.
Robotic assisted simple prostatectomy (RASP) represents a minimally invasive evolution of traditional open simple prostatectomy for the surgical treatment of severe lower urinary tract symptoms (LUTS) because of benign prostatic enlargement (BPE). Aim of the present review is to summarize the most recent evidence on this novel procedure, and to better define its current role in the surgical armamentarium for the treatment of BPE. Several studies demonstrated that RASP can be safely and effectively performed in centers with sufficient expertise. The procedure can duplicate its open counterpart with the advantage of lower perioperative morbidity, and ultimately faster patient recovery. Overall, the status of RASP seems to be well beyond that of an 'investigational' procedure, and guidelines should be amended accordingly.Nevertheless, it remains to be determined what the place of the RASP procedure in the surgical armamentarium for the treatment of symptomatic BPE will be. Over the most recent years, few comparative studies have been reported, allowing in part to draw some conclusions. RASP seems to be attractive when compared with open simple prostatectomy as it can offer less blood loss, and shorter hospital stay. However, its advantages over transurethral enucleation techniques - such as HoLEP - remain unclear. There are some specific indications, such as the presence of concomitant bladder diverticula or stones, for example, where a robotic approach could represent an appealing solution. Ultimately, further research should look at a cost analysis to determine which technique can be more cost effective. Last, the issue of the learning curve for the different procedures for symptomatic BPE remain to be further scrutinized. RASP offers potential advantages over other available techniques for the treatment of large prostate glands. In centers, wherever a solid robotic program is already in place, this procedure is likely to be increasingly implemented.


Is plasma arginine concentration decreased in patients with sepsis? A systematic review and meta-analysis.
L-arginine is a conditionally essential amino acid that plays an important role in immune and vascular function in sepsis. Plasma concentrations of L-arginine are decreased after trauma or surgery but have been variably reported to be normal or decreased in patients with sepsis. We searched MEDLINE and Embase from database inception until January 2010 for the MESH terms "arginine," "amino acids," and "sepsis" and reviewed all studies that reported plasma arginine concentrations in humans with sepsis. Studies were grouped according to the presence or absence of trauma and surgery. We performed a pooled quantitative analysis on the subset of studies that reported appropriate data. We identified 285 citations, of which 16 met inclusion criteria and 10 were included in the quantitative analysis. Plasma arginine concentration was lower in sepsis patients compared with concurrent or historical controls in three of four studies of surgical sepsis, one of four of sepsis after trauma, and all eight studies of predominantly medical sepsis. In the quantitative analysis, mean plasma L-arginine concentration was 33.9 μmol/L (95% confidence interval, 41.2-26.6) lower in sepsis patients than in concurrent nonseptic controls (p < .001), which is a relative decrease of 41%. Plasma concentrations of plasma L-arginine are substantially decreased in patients with sepsis in the absence of trauma or surgery. There are not enough studies of sufficient quality to determine whether this is also the case for trauma-associated or surgery-associated sepsis.


Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients - a retrospective study of clinical and tumor characteristics.
Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity.


Gas chromatography with diode array detection in series with flame ionisation detection.
We introduce a gas chromatography detection approach that uses diode array detection operated in series with flame ionisation detection and demonstrate the utility of the detection approach for determination of volatile organic compounds. Diode array detection brings ultraviolet - visible spectroscopy (over a range of 190-640nm) onto the capillary gas chromatography time-scale, where average peak widths of analytes are on the order of 3-5s. The non-destructive nature of the diode array detector affords serially-coupled flame ionisation detection. This arrangement delivers near-simultaneous selective and universal detection without incurring additional analytical time, and without recourse to column flow splitting. The hyphenated technique is shown to be effective for chromatographic applications spanning an equivalent volatility range from C1 to C7n-paraffin hydrocarbons. The approach introduced herein provides increased sensitivity and selectivity for classes of compounds amenable to electronic spectroscopy such as alkenes, dienes, sulfurs, and aromatic compounds. The approach is demonstrated for direct measurement of carbon disulfide in work place atmospheres with a detection limit of 93pg on column and for the direct measurement of 1,3-butadiene in hydrocarbon matrices and ambient air with a detection of 73pg on column, each in less than 5min.


Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients.
Hepatocellular carcinoma (HCC) is a major liver malignancy possessing a high mortality rate and is particularly prevalent in China and Asia. While surgery is the most effective treatment for liver tumor, about 80% of HCC patients are inoperable at presentation and die early due to late diagnosis. For early cancer detection, we employed a proteomic expression profiling approach to identify biomarkers for early stages of HCC and subsequently assessed the clinical feasibility of a novel marker in plasma. Frozen liver tissues from a retrospective cohort of 75 liver patients (39 HCCs, 20 cirrhosis, and 16 nondiseased subjects) were subjected to proteome-wide expression profiling by 2-DE. MALDI-TOF/TOF was used to identify differentially expressed proteins, which were further confirmed by immunoblotting, qPCR, and immunohistochemistry. Conventional RT-PCR was employed to further analyze the abundance of selected biomarker at mRNA level in a separate cohort of 63 plasma samples (35 HCCs, 16 liver cirrhosis, 12 healthy individuals). We successfully identified lamin B1 (LMNB1) that was significantly upregulated in HCC tumors and present in patients' plasma. LMNB1 functions in nuclear envelope lamina and possesses a transcriptional coregulatory activity having an important role in DNA replication, cellular aging, and stress responses. Clinically, the expression level of lamin B1 correlated positively with tumor stages, tumor sizes, and number of nodules. Our findings further showed elevation of circulating LMNB1 marker in plasma could detect early stages of HCC patients, with 76% sensitivity and 82% specificity. In conclusion, lamin B1 is a clinically useful biomarker for early stages of HCC in tumor tissues and plasma, and warrants further clinical investigation.


Diabetes screening with hemoglobin A1c prior to a change in guideline recommendations: prevalence and patient characteristics.
In January 2010, the American Diabetes Association recommended the use of hemoglobin A1c (Hgb A1c) to screen and diagnose diabetes. This study explored the prevalence and clinical context of Hgb A1c tests done for non-diabetic primary care patients for the three years prior to the release of the new guidelines. We sought to determine the provision of tests in non-diabetic patients age 19 or over, patients age 45 and over (eligible for routine diabetes screening), the annual change in the rate of this screening test, and the patient characteristics associated with the provision of Hgb A1c screening. We conducted a retrospective study using data routinely collected in Electronic Medical Records. The participants were thirteen community-based family physicians in Toronto, Ontario. We calculated the proportion of non diabetic patients who had at least one Hbg A1c done in three years. We used logistic generalized estimating equation with year treated as a continuous variable to test for a non-zero slope in yearly Hbg A1c provision. We modelled screening using multivariable logistic regression. There were 11,792 non-diabetic adults. Of these, 1,678 (14.2%; 95%CI 13.6%-14.9%) had at least one Hgb A1c test done; this was higher for patients 45 years of age or older (20.2%; 95% CI 19.3% - 21.2%). The proportion of non-diabetic patients with an A1c test increased from 5.2% in 2007 to 8.8% in 2009 (p < 0.0001 for presence of slope). Factors associated with significantly greater adjusted odds ratios of having the test done included increasing diastolic blood pressure, increasing fasting glucose, increasing body mass index, increasing age, as well as male gender and presence of hypertension, but not smoking status or LDL cholesterol. Patients living in the highest income quintile neighbourhoods had significantly lower odds ratios of having this test done than those in the lowest quintile (p < 0.001). A large and increasing proportion of the non-diabetic patients we studied have had an Hgb A1c for screening prior to guidelines recommending the test for this purpose. Several risk factors for cardiovascular disease or diabetes were associated with the provision of the Hgb A1c. Early uptake of the test may represent appropriate utilization.


Chromosomal Instability in Gastric Cancer: Role in Tumor Development, Progression, and Therapy.
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.


The inhibitory effect of reduced glutathione on the lipid peroxidation of the microsomal fraction and mitochondria.
1. GSH efficiently inhibited the ascorbate-stimulated lipid peroxidation of the unsaturated fatty acids in the fresh microsomal fraction and mitochondria of rat liver, whereas the peroxidation in heat-denatured particles was little inhibited. 2. Cysteamine and diethyldithiocarbamate inhibited the peroxidation in both fresh and boiled particles. Thioglycollate and 2-mercaptoethanol had no inhibiting effect. Cysteine and homocysteine both stimulated the lipid peroxidation even in the absence of ascorbate. 3. The added GSH disappeared at nearly the same rate in the presence of fresh and of boiled particles to which ascorbate had been added, although considerably more malonaldehyde was formed in the boiled particles. In the absence of ascorbate little GSH disappeared. 4. It is suggested that the protective effect of GSH against lipid peroxidation depends on the preservation of heat-labile structures in the microsomal fraction and mitochondria.


Inheritance of delta 9-tetrahydrocannabinol seizure susceptibility in rabbits.
Delta 9-Tetrahydrocannabinol (THC), the major psychoactive ingredient of marijuana, causes nonfatal convulsions in rabbits of a closed colony of New Zealand White rabbits (Uaz: NZW). The convulsive phenotype appears to be associated with homozygous expression of a single autosomal recessive gene with full penetrance. We propose the symbol thc for the gene responsible for this condition. We also propose that this closed colony of New Zealand White rabbits at the University of Arizona, in which the thc gene is segragating, be designated Uaz:NZW-thc.


Differential expression of MHC class II antigens in chronic B-cell disorders.
Cells from the peripheral blood of 22 patients with chronic B-cell disorders were examined for the expression of surface MHC class II antigens. We made use of well-characterized monoclonal antibodies (McAbs) specific for HLA-DP, -DQ and -DR molecules (B7/21, Tü22, RFDR1 and RFDR2) and of another McAb, RFD1, associated with the class II system. By using indirect immunofluorescence and flow cytometry we found both non-coordination and heterogeneity in expression of MHC class II antigens but generally with a hierarchy of positivity: DR greater than DQ greater than DP. This suggests a sequence of gradual acquisition of HLA-D antigens and indicates distinct differences in maturation arrest of the individual cases. However, after treatment with phorbol ester TPA and calcium ionophore A23187, all cases expressed the previously absent molecules indicating that the structural genes for these products remained intact. TPA and A23187 increased both the number of positive cells in most cases and the fluorescence staining intensities of all class II markers including RFD1. Thus, leukaemic cells may express different combinations of class II antigens reflecting: (i) a predetermined order of gradual acquisition of class II molecules; (ii) differences in the stages of maturation arrest; and (iii) in the cases of disordered expression a desynchronized regulation of these markers.


The role of sex hormones and receptors in HBV infection and development of HBV-related HCC.
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.


Evaluation of a novel bioprosthetic heart valve incorporating anticalcification and antimicrobial technology in a sheep model.
The St. Jude Medical (SJM) Epic valve has been designed to diminish the risk of prosthetic valve endocarditis by the use of silver-coated polyester fabric, and to inhibit dystrophic calcification by the use of ethanol pretreatment. A 20-week juvenile sheep mitral valve implant model was used to determine safety and efficacy of the device, as well as the rate of silver release and degree of dystrophic calcification. The SJM Epic valves were compared with SJM Biocor porcine valves (not ethanol-pretreated, not silver-modified polyester fabric) and Baxter Carpentier-EdwardsR standard valves. Blood concentrations of silver reached a maximum of 40 p.p.b. within 10 days of SJM Epic valve implantation, and were well below toxic levels (300 p.p.b.). Blood silver concentrations returned to baseline within 30 days after surgery. Maximal silver accumulation occurred in the liver (16.75 mg/g dry weight); concentrations in the brain, spleen, kidney and lung were similar to those reported for other silver-modified prosthetic valves. No statistically significant difference was found in calcium content between SJM Epic and Biocor valves. The fibrous response to the sewing cuff was similar among the three valve types. At all times tested, silver release from the SJM Epic valve led to blood concentrations well below toxic levels. Although calcification in the two SJM valve groups was extremely low, the 20-week sheep model may be insufficiently sensitive to detect differences in calcium accumulation in modern bioprosthetic valves.


Motexafin gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a Children's Oncology Group phase I study.
The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin gadolinium (MGd) with involved field radiation therapy in children with newly diagnosed intrinsic pontine gliomas. MGd was administered as a 5-min intravenous bolus 2-5 h prior to standard radiation. The starting dose was 1.7 mg/kg. After first establishing that 5 doses/week for 6 weeks was tolerable, the dose of MGd was escalated until dose-limiting toxicity was reached. Radiation therapy was administered to 54 Gy in 30 once-daily fractions. Forty-four children received MGd at doses of 1.7 to 9.2 mg/kg daily prior to radiation therapy for 6 weeks. The maximum tolerated dose was 4.4 mg/kg. The primary dose-limiting toxicities were grade 3 and 4 hypertension and elevations in serum transaminases. Median elimination half-life and clearance values were 6.6 h and 25.4 ml/kg/h, respectively. The estimated median survival was 313 days (95% confidence interval, 248-389 days). The maximum tolerated dose of MGd and the recommended phase II dose was 4.4 mg/kg when administered as a daily intravenous bolus in conjunction with 6 weeks of involved field radiation therapy for pediatric intrinsic pontine gliomas.


Vinylazaarenes as dienophiles in Lewis acid-promoted Diels-Alder reactions.
Described are the first examples of Lewis acid-promoted Diels-Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels-Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.


A ribonuclease from human skeletal muscle.
1. A ribonuclease has been prepared from human muscle by ammonium sulphate fractionation, heat treatment and ion-exchange chromatography. 2. The enzyme degrades polycytidylic acid and polyuridylic acid to the nucleoside 3'-phosphates, with nucleoside 2':3'-cyclic phosphates as intermediates. Polyadenylic acid and polyguanylic acid are not attacked. 3. The enzyme has maximal activity at pH8.5. The molecular weight (by gel filtration) is between 11000 and 12000. It is relatively heat-stable. It exhibits optimum activity in a medium of high ionic strength, and is inhibited by several bivalent cations, particularly Zn(2+).


Does vascular endothelial dysfunction play a role in physical frailty and sarcopenia? A systematic review.
Frailty is strongly associated with adverse cardiovascular outcomes; however, the underlying pathophysiological processes are largely unknown. Vascular endothelial dysfunction (VED) is the earliest stage of cardiovascular disease (CVD) progression and predicts long-term CVD outcomes. Both these conditions share an elevated inflammatory state as a common pathological factor. Systematic literature review was conducted to examine the evidence supporting an association between VED and physical frailty and/or sarcopenia, in electronic databases including Scopus, Ovid Medline, CINAHL, ScienceDirect, ProQuest Health & Medicine and Embase from January 1980 to August 2019. A total of 18 studies met the inclusion criteria. VED is independently associated with increased frailty phenotypes and measures of sarcopenia. Several markers of VED, including higher levels of asymmetric dimethylarginine, abnormal ankle brachial index, pulse wave velocity, pulse pressure and lower levels of flow-mediated dilatation, peripheral blood flow and endothelial progenitor cell counts, have been associated with frailty/sarcopenia measurements. Some studies demonstrated the effect of inflammation on the association. Recent studies, although limited, showed that VED could be one of the underlying mechanisms of frailty. It is entirely possible that inflammation-related pathological changes in the vascular endothelium are involved in the early causative mechanisms in physical frailty. The exact mechanism(s) underlying this association are still unclear and will need to be evaluated. The outcomes of these future research studies could potentially inform early preventative strategies for physical frailty and sarcopenia.


[Acute myopathy and hyperthyroidism].
A 40 year-old woman with a rapidly progressive proximal muscle deficit of all four limbs had an acute myopathy secondary to hyperthyroidism. Biopsy of the quadriceps femoris revealed signs of non specific muscle impairment with type II fiber atrophy. Treatment with methimazole and correction of the thyroid condition led to rapid disappearance of the disorders. Eighteen months later the clinical status was normal and a second quadriceps femoris biopsy showed that the muscle had normalized.


Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study.
The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.


Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases.
Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34(+) cells in the peripheral blood (PB). We explored the possible mechanisms underlying this abnormal trafficking of CD34(+) cells. Plasma levels of neutrophil elastase (NE), total and active matrix metalloproteinase 9 (MMP-9), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were dramatically increased in IM. The absolute number of CD34(+) cells in the PB was correlated with the levels of sVCAM-1. Marked elevations of the levels of NE but not total and active MMP-9 as well as MMP-2 were detected in media conditioned by IM mononuclear cells (MNCs) as compared with that of healthy volunteers. IM MNC-conditioned media, however, was shown by zymographic analysis to contain increased gelatinolytic activity corresponding to the molecular weight of MMP-9. IM MNC-conditioned media also exhibited a greater ability to cleave VCAM-1 and c-kit in vitro, consistent with the biologic actions of NE. In addition, the increased ability of IM PB CD34(+) cells to migrate through a reconstituted basement membrane was diminished by several inhibitors of MMP-9 activity, indicating that these cells express increased levels of this MMP. These data indicate that a proteolytic environment exists in IM which might result in the sustained mobilization of CD34(+) cells.


Urinary N-acetyl-beta-D-glucosaminidase in children with diabetes as an early marker of diabetic nephropathy.
We investigated urinary N-acetyl-beta-D-glucosaminidase (NAG) levels in children with type 1 diabetes as an early marker of tubular damage and studied its correlation with microalbuminuria and glycaemic control. The study group comprised 42 children with type 1 diabetes and 20 healthy children as control. Urinary NAG to urinary creatinine ratio, microalbuminuria, glycated haemoglobin (Hb A1c), blood urea and serum creatinine were estimated. Urinary NAG levels in the children with diabetes were significantly higher than those of controls. There were positive correlations between urinary NAG levels and microalbuminuria, Hb A1c and systolic and diastolic blood pressure values. We found that 59.5% of diabetic children were positive for urinary NAG, while 38.1% of them were positive for microalbuminuria.


Imaging-based diagnosis of autosomal dominant polycystic kidney disease.
The clinical use of conventional ultrasonography (US) in autosomal dominant polycystic kidney disease (ADPKD) is currently limited by reduced diagnostic sensitivity, especially in at-risk subjects younger than 30 years of age. In this single-center prospective study, we compared the diagnostic performance of MRI with that of high-resolution (HR) US in 126 subjects ages 16-40 years born with a 50% risk of ADPKD who underwent both these renal imaging studies and comprehensive PKD1 and PKD2 mutation screening. Concurrently, 45 healthy control subjects without a family history of ADPKD completed the same imaging protocol. We analyzed 110 at-risk subjects whose disease status was unequivocally defined by molecular testing and 45 unaffected healthy control subjects. Using a total of >10 cysts as a test criterion in subjects younger than 30 years of age, we found that MRI provided both a sensitivity and specificity of 100%. Comparison of our results from HR US with those from a previous study of conventional US using the test criterion of a total of three or more cysts found a higher diagnostic sensitivity (approximately 97% versus approximately 82%) with a slightly decreased specificity (approximately 98% versus 100%) in this study. Similar results were obtained in test subjects between the ages of 30 and 40 years old. These results suggest that MRI is highly sensitive and specific for diagnosis of ADPKD. HR US has the potential to rival the diagnostic performance of MRI but is both center- and operator-dependent.


Pulsed Radiofrequency for Postherpetic Trigeminal Neuralgia: A Case Report.
Trigeminal postherpetic neuralgia has been reported to cause chronic headaches and facial pain. There are various modalities of treatment ranging from pharmacological to surgical treatment. However, these are frequently accompanied by undesirable side effects and minimal efficacy. Pulsed radiofrequency has been used to treat chronic pain but it is often seen as an unconventional treatment for postherpetic neuralgia. Nonetheless, the literature supports its use for alleviating pain with minimal complications. This case demonstrates that pulsed radiofrequency can successfully treat intractable pain secondary to postherpetic neuralgia affecting all three trigeminal dermatomes.


Propofol Induces Apoptosis of Neurons but Not Astrocytes, Oligodendrocytes, or Neural Stem Cells in the Neonatal Mouse Hippocampus.
It has been shown that propofol can induce widespread apoptosis in neonatal mouse brains followed by long-term cognitive dysfunction. However, selective brain area and cell vulnerability to propofol remains unknown. This study was aimed to dissect toxic effect of propofol on multiple brain cells, including neurons, astrocytes, oligodendrocytes, and neural stem cells (NSCs). Seven-day-old mice were intraperitoneally administrated propofol or intralipid as a vehicle control for 6 hours. To identify vulnerable cells undergoing apoptosis following propofol exposure, brain sagittal sections were co-stained with antibodies against an apoptosis marker along with neuron, astrocyte, oligodendrocyte, or NSC markers using immunofluorescence staining. The results showed widespread apoptosis in propofol-treated brains (apoptotic cells: 1.55 ± 0.04% and 0.06 ± 0.01% in propofol group and intralipid-treated control group, respectively). Apoptotic cell distribution exhibits region- and cell-specific patterns. Several brain regions (e.g., cerebral cortex and hippocampus) were more vulnerable to propofol than other brain regions. Most apoptotic cells in the hippocampus were located in the cornus ammonis 1 (CA1) subfield. These apoptotic cells were only detected in neurons and not astrocytes, oligodendrocytes, or NSCs. These data demonstrate that different brain regions, subfields, and different types of neuronal cells in mice exhibit various vulnerabilities to propofol. Understanding region- and cell-specific susceptibility to propofol will help to better understand cellular contribution to developmental neurotoxicity and further develop novel therapeutic targets.


Comparison of sutured versus non-sutured subcutaneous fat tissue in abdominal surgery. A prospective randomized study.
The aim of this prospective randomized study was to investigate the necessity of suturing subcutaneous fat tissue in elective abdominal surgery. 415 patients undergoing elective abdominal surgery were admitted to the trial. The patients were divided into two basic groups according to wound contamination: clean operations (n = 201) and clean-contaminated operation (n = 214). Subcutaneous suturing of the subcutaneous fat tissue was performed in half of the patients in each group, determined using the envelope method ('Suture Yes' or 'Suture No'). Wounds were checked on postoperative days 3, 7, 14, and 30. Infectious and non-infectious wound complications were charted in the records. Data were statistically analyzed. The percentages of complications in groups with and without subcutaneous suturing were statistically compared using Yates' corrected chi(2) two-tailed test. There were no statistically significant group differences in infectious and non-infectious wound complications. These results suggest that omission of subcutaneous fat tissue suturing does not increase the occurrence of infectious or non-infectious wound complications.


Psychiatric illness and length of stay in general hospitals: do case finding methods matter?
Several prior studies have investigated whether patients with "non-cognitive" mental disorders (i.e., organic disorders, substance abuse, delirium, and psychotic disorders excluded) have longer Length Of Stay (LOS) than mentally healthy individuals in nonpsychiatric hospital settings. These studies yielded contrasting results. The present paper aims to examine whether methods of psychiatric case finding can explain these differences. Using the Clinical Interview Schedule (CIS) and the General Health Questionnaire (GHQ), 462 in-patients of medical, surgical, gynecological, and rehabilitation departments were assessed for the presence of psychiatric disorders. In multiple regression analysis, all CIS-cases together did not show an association with LOS. Of the diagnostic groups assessed by CIS only major depression showed a significantly prolonged LOS. Using the GHQ sum-score as a continuous variable, LOS was significantly increased while using the GHQ as a dichotomous variable did not show such an association. After removing those suffering from multiple psychiatric diagnoses (such as major depression co-morbid with organic mental illness), none of the case definitions showed a significant association with LOS. It seems that different case finding methods yield different results concerning the association of psychiatric disorders with LOS. When interpreting these results the small size of some subsamples must be taken into consideration.


Validity and reliability of evaluating hip abductor strength using different normalization methods in a functional electromechanical device.
The hip abductor muscles are vitally important for pelvis stability, and common strength deficits can negatively affect functionality. The muscle strength can be measured using different dynamometers and be evaluated in three positions (side-lying, standing, and supine). Obtained strength data can be expressed in different ways, with data normalization providing more objective and comparable results. The aim of this study was to establish the validity and reliability of three protocols in evaluating the isometric strength of the hip abductor muscles. A new functional electromechanical dynamometer assessed strength in three positions, with findings subjected to three data normalization methods. In two identical sessions, the hip abductor strengths of 29 subjects were recorded in the side-lying, standing, and supine positions. Peak force was recorded in absolute terms and normalized against body mass, fat-free mass, and an allometric technique. The peak force recorded in the side-lying position was 30% and 27% higher than in the standing and supine positions, respectively, independent of data normalization methodology. High inter-protocol correlations were found (r: 0.72 to 0.98, p ≤ 0.001). The supine position with allometric data normalization had the highest test-retest reliability (0.94 intraclass correlation coefficient and 5.64% coefficient of variation). In contrast, the side-lying position with body mass data normalization had a 0.66 intraclass correlation coefficient and 9.8% coefficient of variation. In conclusion, the functional electromechanical dynamometer is a valid device for measuring isometric strength in the hip abductor muscles. The three assessed positions are reliable, although the supine position with allometric data normalization provided the best results.


Chronic daily headache: suggestion for the neuromuscular oral therapy.
Tweny patients (M: 4, F: 16, mean age 37 ± 11 years) with diagnosis of chronic daily headache (CDH), after drug withdrawal, were under electromyography, kinesiography and masticatory muscle deprogramming by TENS to identify the physiological rest position of the mandible. Our purpose was to clarify a possible role of the neuromuscular stomatognathic system. Examinations showed that 17 patients needed a neuromuscular orthosis, an occlusal device, to provisionally correct the detected discrepancies of jaw position. Of those, the 10 patients who showed an occlusal sagittal discrepancy higher than 2 mm and/or a lateral deviation higher than 0.4 mm, associated with more than three parafunctional activities, had a meaningful decrease on frequency/intensity of migraine crisis and/or of days of headache. VAS pain score during crisis decreased from 9.0 ± 0.9 to 4.9 ± 2.7; frequency of crisis were from 20.7 ± 5.2 to 9.5 ± 7.7. Baseline pain were from 5.3 ± 1.2 to 3.0 ± 1.3. Satisfying clinical results can be reached combining behavioural education and neuromuscular orthosis. This can be very helpful in patients who show significant discrepancy of jaw position that only TENS deprogramming can reveal and kinesiography can detect with such accuracy.


VTE Prophylaxis in Critically Ill Adults: A Systematic Review and Network Meta-analysis.
Critically ill adults are at increased risk of VTE, including DVT, and pulmonary embolism. Various agents exist for venous thromboprophylaxis in this population. What is the comparative efficacy and safety of prophylaxis agents for prevention of VTE in critically ill adults? Systematic review and network meta-analysis of randomized clinical trials (RCTs) evaluating efficacy of thromboprophylaxis agents among critically ill patients. We searched six databases (including PubMed, EMBASE, and Medline) from inception through January 2021 for RCTs of patients in the ICU receiving pharmacologic, mechanical, or combination therapy (pharmacologic agents and mechanical devices) for thromboprophylaxis. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. We included 13 RCTs (9,619 patients). Compared with control treatment (a composite of no prophylaxis, placebo, or compression stockings only), low-molecular-weight heparin (LMWH) reduced the incidence of DVT (OR, 0.59 [95% credible interval [CrI], 0.33-0.90]; high certainty) and unfractionated heparin (UFH) may reduce the incidence of DVT (OR, 0.82 [95% CrI, 0.47-1.37]; low certainty). LMWH probably reduces DVT compared with UFH (OR, 0.72 [95% CrI, 0.46-0.98]; moderate certainty). Compressive devices may reduce risk of DVT compared with control treatments; however, this is based on low-certainty evidence (OR, 0.85 [95% CrI, 0.50-1.50]). Combination therapy showed unclear effect on DVT compared with either therapy alone (very low certainty). Among critically ill adults, compared with control treatment, LMWH reduces incidence of DVT, whereas UFH and mechanical compressive devices may reduce the risk of DVT. LMWH is probably more effective than UFH in reducing incidence of DVT and should be considered the primary pharmacologic agent for thromboprophylaxis. The efficacy and safety of combination pharmacologic therapy and mechanical compressive devices were unclear. Open Science Framework; URL: https://osf.io/694aj.


Microfibril structure masks fibrillin-2 in postnatal tissues.
Fibrillin microfibrils are polymeric structures present in connective tissues. The importance of fibrillin microfibrils to connective tissue function has been demonstrated by the multiple genetic disorders caused by mutations in fibrillins and in microfibril-associated molecules. However, knowledge of microfibril structure is limited, largely due to their insolubility. Most previous studies have focused on how fibrillin-1 is organized within microfibril polymers. In this study, an immunochemical approach was used to circumvent the insolubility of microfibrils to determine the role of fibrillin-2 in postnatal microfibril structure. Results obtained from studies of wild type and fibrillin-1 null tissues, using monoclonal and polyclonal antibodies with defined epitopes, demonstrated that N-terminal fibrillin-2 epitopes are masked in postnatal microfibrils and can be revealed by enzymatic digestion or by genetic ablation of Fbn1. From these studies, we conclude that fetal fibrillin polymers form an inner core within postnatal microfibrils and that microfibril structure evolves as growth and development proceed into the postnatal period. Furthermore, documentation of a novel cryptic site present in EGF4 in fibrillin-1 underscores the molecular complexity and tissue-specific differences in microfibril structure.


Isolation of two novel myb-like genes from Arabidopsis and studies on the DNA-binding properties of their products.
Two novel myb-like genes (atmyb6 and atmyb7) were isolated from an Arabidopsis thaliana cDNA library. The entire proteins or the Myb domains encoded by the genes were expressed as fusion proteins in Escherichia coli. The DNA-binding domain of the murine c-Myb was also expressed in the same way for use in comparative studies. The fusion proteins were examined for their DNA-binding activity using the animal c-Myb DNA-binding site (MBS) and the binding site of the maize P gene product (PBS). The Myb domain of Atmyb6 bound to PBS more efficiently than to MBS. Complete Atmyb6 and Atmyb7 proteins preferentially bound to PBS but not MBS. This suggests that the in vitro binding consensus sequences for both Atmyb6 and Atmyb7 are similar to PBS. The binding of the Myb domain of Atmyb6 to both PBS and MBS raises the possibility that the protein recognizes multiple sequences in vivo. The third alpha-helix and three adjacent amino acids in the third repeat (R3) of c-Myb was replaced with the analogous sequence of Atmyb6 to create a chimeric Myb protein. This chimeric protein bound to PBS with a low affinity but failed to bind to MBS. Thus the binding pattern of the chimeric Myb protein is similar to that of the Atmyb6. This result suggests that the last 20 amino acids in the R3 repeat of Atmyb6 play a major role in DNA-binding.


In vivo activities of newer rifamycin analogs against Mycobacterium avium infection.
The comparative activities of newer rifamycin analogs and the activity of rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex.


Differential transfer of dietary flavour compounds into human breast milk.
Transfer of dietary flavour compounds into human milk is believed to constitute the infant's early flavour experiences. This study reports on the time-dependent transfer of flavour compounds from the mother's diet to her breast milk using a within-subject design. Eighteen lactating mothers completed three test days on which they provided a baseline milk sample prior to ingestion of capsules containing 100 mg d-carvone, l-menthol, 3-methylbutyl acetate and trans-anethole. Milk samples were collected 2, 4, 6 and 8 h post-ingestion and analysed by a dynamic headspace method and gas chromatography-mass spectroscopy. The recovery quantities were adjusted for variations in milk fat content. Concentration-time profiles for d-carvone and trans-anethole revealed a maximum around 2 h post-ingestion, whereas the profile for l-menthol showed a plateau pattern. The ester 3-methylbutyl acetate could not be detected in the milk, but a single determination showed traces (<0.4 ppb) in a 1 h milk collection. Flavour compounds appeared to be transmitted differentially from the mother's diet to her milk. The results imply that human milk provides a reservoir for time-dependent chemosensory experiences to the infant; however, volatiles from the diet are transferred selectively and in relatively low amounts.


Protein Mass-Modulated Effects in Alkaline Phosphatase.
Recent experimental studies engaging isotopically substituted protein (heavy protein) have revealed that many, but not all, enzymatic systems exhibit altered chemical steps in response to an altered mass. The results have been interpreted as femtosecond protein dynamics at the active site being linked (or not) to transition-state barrier crossing. An altered enzyme mass can influence several kinetic parameters (kcat, Km, and kchem) in amounts of ≤30% relative to light enzymes. An early report on deuterium-labeled Escherichia coli alkaline phosphatase (AP) showed an unusually large enzyme kinetic isotope effect on kcat. We examined steady-state and chemical step properties of native AP, [2H]AP, and [2H,13C,15N]AP to characterize the role of heavy enzyme protein dynamics in reactions catalyzed by AP. Both [2H]- and [2H,13C,15N]APs showed unaltered steady-state and single-turnover rate constants. These findings characterize AP as one of the enzymes in which mass-dependent catalytic site dynamics is dominated by reactant-linked atomic motions. Two catalytic site zinc ions activate the oxygen nucleophiles in the catalytic site of AP. The mass of the zinc ions is unchanged in light and heavy APs. They are essentially linked to catalysis and provide a possible explanation for the loss of linkage between catalysis and protein mass in these enzymes.


Molecular Hydrogen Therapy-A Review on Clinical Studies and Outcomes.
With its antioxidant properties, hydrogen gas (H2) has been evaluated in vitro, in animal studies and in human studies for a broad range of therapeutic indications. A simple search of "hydrogen gas" in various medical databases resulted in more than 2000 publications related to hydrogen gas as a potential new drug substance. A parallel search in clinical trial registers also generated many hits, reflecting the diversity in ongoing clinical trials involving hydrogen therapy. This review aims to assess and discuss the current findings about hydrogen therapy in the 81 identified clinical trials and 64 scientific publications on human studies. Positive indications have been found in major disease areas including cardiovascular diseases, cancer, respiratory diseases, central nervous system disorders, infections and many more. The available administration methods, which can pose challenges due to hydrogens' explosive hazards and low solubility, as well as possible future innovative technologies to mitigate these challenges, have been reviewed. Finally, an elaboration to discuss the findings is included with the aim of addressing the following questions: will hydrogen gas be a new drug substance in future clinical practice? If so, what might be the administration form and the clinical indications?


Metabolomic method: UPLC-q-ToF polar and non-polar metabolites in the healthy rat cerebellum using an in-vial dual extraction.
Unbiased metabolomic analysis of biological samples is a powerful and increasingly commonly utilised tool, especially for the analysis of bio-fluids to identify candidate biomarkers. To date however only a small number of metabolomic studies have been applied to studying the metabolite composition of tissue samples, this is due, in part to a number of technical challenges including scarcity of material and difficulty in extracting metabolites. The aim of this study was to develop a method for maximising the biological information obtained from small tissue samples by optimising sample preparation, LC-MS analysis and metabolite identification. Here we describe an in-vial dual extraction (IVDE) method, with reversed phase and hydrophilic liquid interaction chromatography (HILIC) which reproducibly measured over 4,000 metabolite features from as little as 3mg of brain tissue. The aqueous phase was analysed in positive and negative modes following HILIC separation in which 2,838 metabolite features were consistently measured including amino acids, sugars and purine bases. The non-aqueous phase was also analysed in positive and negative modes following reversed phase separation gradients respectively from which 1,183 metabolite features were consistently measured representing metabolites such as phosphatidylcholines, sphingolipids and triacylglycerides. The described metabolomics method includes a database for 200 metabolites, retention time, mass and relative intensity, and presents the basal metabolite composition for brain tissue in the healthy rat cerebellum.


Proteolytic Degradation and Inflammation Play Critical Roles in Polypoidal Choroidal Vasculopathy.
Polypoidal choroidal vasculopathy (PCV) is a common subtype of wet age-related macular degeneration in Asian populations, whereas choroidal neovascularization is the typical subtype in Western populations. The cause of PCV is unknown. By comparing the phenotype of a PCV mouse model expressing protease high temperature requirement factor A1 (HTRA1) in retinal pigment epithelium with transgenic mice expressing the inactive HTRA1S328A, we showed that HTRA1-mediated degradation of elastin in choroidal vessels is critical for the development of PCV, which exhibited destructive extracellular matrix remodeling and vascular smooth muscle cell loss. Compared with weak PCV, severe PCV exhibited prominent immune complex deposition, complement activation, and infiltration of inflammatory cells, suggesting inflammation plays a key role in PCV progression. More important, we validated these findings in human PCV specimens. Intravitreal delivery of an HTRA1 inhibitor (DPMFKLboroV) was effective (36% lesion reduction; P = 0.009) in preventing PCV initiation but ineffective in treating existing lesions. Anti-inflammatory glucocorticoid was effective in preventing PCV progression but ineffective in preventing PCV initiation. These results suggest that PCV pathogenesis occurs through two stages. The initiation stage is mediated by proteolytic degradation of extracellular matrix proteins attributable to increased HTRA1 activity, whereas the progression stage is driven by inflammatory cascades. This study provides a basis for understanding the differences between PCV and choroidal neovascularization, and helps guide the design of effective therapies for PCV.


Exploring nursing faculty, managers, newly graduated nurses, and students' experiences of nursing internship program implementation in Iran: a descriptive qualitative study.
Nursing students are required to acquire the necessary clinical knowledge and skills to provide safe and quality care. The method of providing training, particularly for final-year nursing students, is of utmost importance. An internship is a program during which students work in shifts similar to nurses employed in a hospital; however, the number of their shifts and patients is less than nurses; a nurse and the faculty supervise the care they provide, and they are paid a monthly salary. This study was conducted to explore nursing faculty, managers, new graduates, and students' experiences of nursing internship program implementation. This descriptive qualitative study was conducted from November 2021 to March 2022. The participants were selected from among nursing managers, newly graduated nurses, nursing internship students (final-year undergraduate), and faculty of Iran. Data were collected using in-depth semi-structured interviews. The qualitative content analysis approach was used for data analysis. Participants in this study included 17 nursing internship students, 12 nursing managers, three faculty members, ten nursing preceptors, and five newly graduated nurses from the internship program, 47 participants in total. After analyzing the data, five themes, including 'facilitation of socialization process,' 'filling the gap between theory and practice,' 'improving self-confidence and independence,' 'an opportunity for clinical skill training,' and 'Achilles' heel of the clinical setting,' and nineteen subthemes were extracted from the participants' experiences. Implementation of an internship program for final-year nursing students plays a role in preparing them for better professional performance, enhancing clinical skills, increasing self-confidence and independence, inspiring the nursing profession, strengthening professional commitment, and improving the chances of employment after graduation. In order to alleviate the identified challenges of the internship program, holding a briefing meeting with managers, supervisors, and faculty to determine working hours, performance standards, and amenities such as lunch, dinner, and resting place is efficient.


Coupling of Spinons with Defects and Phonons in the Spin Chain Compound Ca_{2}CuO_{3}.
Extrinsic spinon scattering by defects and phonons instead of intrinsic spinon-spinon coupling is responsible for resistive magnetic heat transport in one-dimensional (1D) quantum magnets. Here we report an investigation of the elusive extrinsic effect in the 1D Heisenberg S=1/2 spin chain compound Ca_{2}CuO_{3}, where the defect concentration is determined from the measured specific heat and first-principles calculations are used to separate the lattice component of the measured thermal conductivity to isolate a large magnetic contribution (κ_{m}). The obtained temperature-dependent spinon-defect and spinon-phonon mean free paths can enable a quantitative understanding of both κ_{m} and the spinon-induced spin Seebeck effect.


Cell to cell interactions contributing to the "oxygen paradox".
Intact rat hearts demonstrate a sudden release of cytoplasmic proteins when they are subjected to reoxygenation following anoxic injury (oxygen paradox). Reoxygenation enzyme release is associated with cellular swelling and contraction band necrosis. Reoxygenation damage is reduced by mitochondrial inhibitors, and DMSO which prevent cellular hypercontracture. An oxygen paradox also occurs during reperfusion of ischemic hearts but has not been reported to occur in isolated adult myocyte preparations. The absence of cell interactions in reoxygenated isolated cell preparations could allow unrestrained contracture to occur without transmission of disruptive forces to cell membranes. Other equally plausible explanations have not, however, been ruled out. Future studies will be required to establish the pathogenesis of the oxygen paradox and explain its apparent absence in the isolated adult myocyte model of cell injury.