Premature aging in telomerase-deficient zebrafish.
The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio) as the second vertebrate model for human telomerase-driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second-generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC). Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC.


Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance.
High-fat diet (HFD)-induced obesity has emerged as a state of chronic low-grade inflammation characterised by a progressive infiltration of immune cells, particularly macrophages, into obese adipose tissue. Adipose tissue macrophages (ATM) present immense plasticity. In early obesity, M2 anti-inflammatory macrophages acquire an M1 pro-inflammatory phenotype. Pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β produced by M1 ATM exacerbate local inflammation promoting insulin resistance (IR), which consequently, can lead to type-2 diabetes mellitus (T2DM). However, the triggers responsible for ATM recruitment and activation are not fully understood. Adipose tissue-derived chemokines are significant players in driving ATM recruitment during obesity. Macrophage migration inhibitory factor (MIF), a chemokine-like inflammatory regulator, is enhanced during obesity and is directly associated with the degree of peripheral IR. This review focuses on the functional role of macrophages in obesity-induced IR and highlights the importance of the unique inflammatory cytokine MIF in propagating obesity-induced inflammation and IR. Given MIF chemotactic properties, MIF may be a primary candidate promoting ATM recruitment during obesity. Manipulating MIF inflammatory activities in obesity, using pharmacological agents or functional foods, may be therapeutically beneficial for the treatment and prevention of obesity-related metabolic diseases.


Removal of lead (II) from aqueous environment by a fibrous ion exchanger: polycinnamamide thorium (IV) phosphate.
The objective of the present research was to synthesize, characterize and to investigate the removal efficiency of lead (II) ion from synthetic lead solution by a hybrid fibrous ion exchanger. In the present study polycinnamamide thorium (IV) phosphate was synthesized by co-precipitation method and was characterized using SEM, XRD, FTIR and TGA-DSC. To know the practical applicability, a detailed removal study of lead ion was carried out using the material. The removal of lead was 81.2% under optimum conditions. Adsorption kinetic study revealed that the adsorption process followed first order kinetics. Adsorption data were fitted to linearly transformed Langmuir isotherm with R(2) (correlation coefficient) >0.99. Thermodynamic parameters were also calculated to study the effect of temperature on the removal process. In order to understand the adsorption type, equilibrium data were tested with Dubinin-Radushkevich isotherm.


Field-position dependent apodization in dark-field digital holographic microscopy for semiconductor metrology.
Measuring overlay between two layers of semiconductor devices is a crucial step during electronic chip fabrication. We present dark-field digital holographic microscopy that addresses various overlay metrology challenges that are encountered in the semiconductor industry. We present measurement results that show that the point-spread function of our microscope depends on the position in the field-of-view. We will show that this novel observation can be explained by a combination of the finite bandwidth of the light source and a wavelength-dependent focal length of the imaging lens. Moreover, we will also present additional experimental data that supports our theoretical understanding. Finally, we will propose solutions that reduce this effect to acceptable levels.


Chemical, in vitro, and in vivo evaluation of soybeans heat-treated by various processing methods.
In trial 1, eight Holstein heifers weighing 410 kg were used in an 8 x 8 Latin square and fed TMR containing 79.3% alfalfa silage and 20% soybeans. The first four treatments were raw soybeans, soybeans roasted and held for 3 h at the roasting temperature, extruded soybeans, and soybeans roasted in a California Pellet Mill Jet-Sploder. The remaining four treatments were obtained by altering the residence time of soybeans in the Jet Sploder. The temperatures of soybeans exiting the roaster were 117, 126, 138, and 154 degrees C for the last four treatments. The soybeans held 3 h postroasting and the extruded soybeans resulted in the highest estimate of postruminal available lysine. Blood plasma concentrations of essential and branched-chain AA were highest in heifers fed soybeans held 3 h postroasting. In trial 2, 44 Holstein heifers weighing 150 to 250 kg were assigned randomly to one of four TMR. Diets consisted of 91.8% alfalfa silage and 7.5% of one of four soybean treatments. Treatments were raw soybeans, soybeans roasted in a drum roaster with an exit temperature of 146 degrees C, and those roasted with exit temperatures of 141 or 146 degrees C and held for .5 h. Estimated postruminal available lysine was higher for soybeans roasted and held versus roasted or raw soybeans. However, BW gain for heifers was similar across diets, averaging .90 kg/d for 12 wk. Concentrations of AA in plasma were not affected by diet. Overall, results support the recommendation of holding soybeans for at least .5 h following roasting.


Obesity and Ovarian Cancer.
Ovarian cancer is the most fatal gynecologic cancer and is an important source of cancer-related mortality, particularly in developed countries. Despite substantial research examining adiposity (primarily adult body mass index [BMI]), the overall evidence suggests only a weak positive association between adiposity and risk of ovarian cancer, with stronger associations observed for population-based case-control studies compared to prospective studies. Ovarian cancer is not one disease and emerging data suggest that higher BMI may only be associated with risk of certain histologic subtypes, including low-grade serous and invasive mucinous tumors. Interestingly, some larger studies and meta-analyses have reported a stronger relationship with premenopausal ovarian cancers, which are more likely to be of these subtypes. Relatively few studies have conducted detailed examinations of other adiposity-related factors such as measures of abdominal adiposity, early-life body size and weight change. While the underlying mechanisms that may relate adiposity to risk are unclear, increased inflammatory biomarkers have been associated with risk and hormonal factors, including androgen levels, may be important for the development of mucinous tumors. Future research should leverage the large sample sizes of consortia to evaluate associations by key tumor characteristics as well as consider patterns of weight change over the life course with both ovarian cancer risk and survival.


Shortening-length diagram: a new method of modeling skeletal muscle performance.
Muscle shortening is usually characterized in terms of force-velocity and length-active tension properties. We have examined a third relationship, that between shortening and initial length to further characterize muscle performance. This analysis shows that optimal shortening is achieved at a length (Ls) different from the length (Lo) of optimal tension development. Moreover, the analysis reveals discrepancies between results expected (using classical modeling) and experimental findings and these discrepancies increase with age. This effect of age on shortening has not been previously identified. Diaphragm muscle strips were dissected from male Fischer 344 rats of 3 and 24 months of age. Muscles were subjected, in vitro, to isotonic loads of either 30% or 50% of peak isometric tension (Po*) and shortened from initial lengths ranging from 80% to 130%Lo. The relationship between shortening and initial length was fitted by a second order polynomial using linear regression analysis. Results at 30% P/Po* indicate a difference in ability to shorten of 7% at Lo between muscles of young and elderly rats. The age-related change was enhanced under a load of 50% P/Po*, with a 46% difference in ability to shorten between young and old rats. The results show an age-related decrease in shortening of the diaphragm that is not predicted using classical muscle mechanics. Factors other than the length-tension relation and load must therefore be explored to explain decrements of shortening with age.


Protective effects of Huang-Lian-Jie-Du-Tang and its component group on collagen-induced arthritis in rats.
Huang-Lian-Jie-Du-Tang is a famous Traditional Chinese medicine consisting of Rhizoma coptidis (Coptis chinensis Franch, Ranunculaceae), Radix scutellariae (Scutellaria baicalensis Georgi, Labiatae), Cortex phellodendri (Phellodendron amurense Rupr. Rutaceae) and Fructus gardeniae (Gardenia jasminoide Ellis, Rubiaceae) in a weight ratio of 3:2:2:3.This formula was described by Wang Tao (in the Chinese Tang Dynasty) in his treatise "Wai Tai Mi Yao". It has been used to treat inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases in the clinical practice of Traditional Chinese medicine, especially in treating inflammation for nearly two thousand years. However, the essential compounds in it have not been identified, and the mechanisms remain to be addressed. To investigate the protective effects of HLJDT and its component group (HLJDT-CG) on collagen-induced arthritis in rats. CIA was established in male Wistar rats with subcutaneous injection of type II bovine collagen at the base of the tail of animals. CIA rats were treated daily with oral administration of HLJDT aqueous extracts (270 mg/kg) or HLJDT-CG (40 mg/kg) once per day from day 6 to day 28. Rats in normal and vehicle control groups were given an equal volume of vehicle (0.9% saline) and 0.025 mg/kg Dexamethasone was given to the Standard group at the same time. The protective effect of them were assessed by measuring arthritis index, swelling, the cytokines such as TNF-α, IFN-γ and IL-17 in serum, type II collagen antibodies, splenocyte proliferation and so on. The results demonstrated that treatment of CIA rat with either HLJDT aqueous extracts or HLJDT-CG not only ameliorated the symptoms of arthritis, prevented joint damage but also reduced the serum levels of TNF-α, IFN-γ and IL-17 in CIA rats. Anti-CII antibodies showed the similar trend except that of IgG1. Furthermore, HLJDT aqueous extracts and HLJDT-CG administration also suppressed CII-induced proliferative response of splenocytes. More importantly, HLJDT-CG exhibited similar pharmacological activities as HLJDT aqueous extracts in all aforementioned experiments. HLJDT aqueous extracts and HLJDT-CG could effectively ameliorate CII-induced arthritis and significantly suppress the immune response against CII with similar pharmacological efficacy. These findings suggest that HLJDT has therapeutic potential in RA treatment and HLJDT-CG can represent the effective-composite of HLJDT.


COVID-19 and Psychological Distress: Racial Differences Among Middle-Aged and Older Adults.
COVID-19 has disproportionately impacted older adults and Black individuals. Research has focused on physical outcomes, with less attention to the psychological effects of COVID-19. The objective of this study was to examine the interplay between perceptions of the COVID-19 outbreak as a threat to one's day-to-day life, race, and psychological distress among middle-aged and older men and women. Analyses were conducted on a subsample of self-identified non-Latino Whites and Black individuals aged 50 and older (N = 3,834) from the American Trends Panel. Psychological distress was assessed with 5 items adapted from the Center for Epidemiologic Studies Depression Scale and Generalized Anxiety Disorder-7. Perceived COVID-19 day-to-day threat was assessed with a single question. Negative binomial regressions tested the study aim. Perceptions of COVID-19 day-to-day threat were positively associated with psychological distress. Black individuals reported lower distress than Whites. Regardless of gender, greater perceptions of COVID-19 day-to-day threats were associated with greater distress among both White respondents and Black respondents. However, this association was weaker among Black respondents than White respondents. Among men only, the association between COVID-19 day-to-day threat and distress varied by race, patterned similarly to the race differences identified in the total sample. This association did not vary by race among women. This study contributes to the emerging literature focused on older adults and COVID-19 related stressors and psychological distress. An intersectional lens shows how structural oppression may shape perceptions of the pandemic. Future work should consider coexisting intersections in marginalized identities and mental health during COVID-19.


The Gracillimus Orbitis Muscle.
The gracillimus orbitis muscle is an anomalous, accessory, or supernumerary extraocular muscle that, although is rarely seen clinically in the human orbit, has been identified in 5% to 14% of dissected cadaver orbits. It arises from the medial surface of the levator near its origin and runs forward between the levator and superior oblique muscles resembling one of the other extraocular muscles. More anteriorly, it becomes thinner, less well defined, and mostly fibrous. Its major insertion is into the fascia surrounding the trochlea, while other fibers may travel to the supratrochlear artery, intermuscular septum, the levator or medial rectus muscle, and the fascia surrounding the superior ophthalmic vein. The function of this anomalous muscle remains unknown in most cases. Knowledge of its presence is important as the oculoplastic/orbital surgeon may encounter it during an eyelid or orbital procedure.


Internet Search Alters Intra- and Inter-regional Synchronization in the Temporal Gyrus.
Internet search changed the way we store and recall information and possibly altered our brain functions. Previous studies suggested that Internet search facilitates the information-acquisition process. However, this process may cause individuals to lose the ability to store and recollect specific contents. Despite the numerous behavioral studies conducted in this field, little is known about the neural mechanisms underlying Internet searches. The present study explores potential brain activity changes induced by Internet search. The whole paradigm includes three phases, namely, pre-resting state fMRI (rs-fMRI) scan, 6-day Internet search training, and post rs-fMRI scan. We detected the functional integrations induced by Internet search training by comparing post- with pre-scan. Regional homogeneity (ReHo) and functional connectivity (FC) were used to detect intra- and interregional synchronized activity in 42 university students. Compared with pre-scan, post-scan showed decreased ReHo in the temporal gyrus, the middle frontal gyrus, and the postcentral gyrus. Further seed-based FC analysis showed that the temporal gyrus exhibited decreased FC in the parahippocampal cortex and the temporal gyrus after training. Based on the features of current task and functions exhibited by these brain regions, results indicate that short-term Internet search training changed the brain regional activities involved in memory retrieval. In general, this study provides evidence that supports the idea that Internet search can affect our brain functions.


Unravelling the enigma of cortical tremor and other forms of cortical myoclonus.
Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the 'spectrum of cortical myoclonus', i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.


Effect of summer season on milk protein fractions in Holstein cows.
Milk characteristics are affected by heat stress, but very little information is available on changes of milk protein fractions and their relationship with cheesemaking properties of milk. The main objective of the study was to evaluate the effect of hot season on milk protein fractions and cheesemaking properties of milk for Grana Padano cheese production. The study was carried out in a dairy farm with a cheese factory for transforming the milk to Grana Padano cheese. The study was carried out from June 2012 to May 2013. Temperature and relative humidity of the inside barn were recorded daily during the study period using 8 electronic data loggers programmed to record every 30 min. Constant managerial conditions were maintained during the experimental periods. During the experimental period, feed and diet characteristics, milk yield, and milk characteristics were recorded in summer (from June 29 to July 27, 2012), winter (from January 25 to March 8, 2013), and spring (from May 17 to May 31, 2013). Milk yield was recorded and individual milk samples were taken from 25 cows selected in each season during the p.m. milking. Content of fat, proteins, caseins (CN), lactose and somatic cell count (SCC), titratable acidity, and milk rennet coagulation properties were determined on fresh samples. Milk protein fraction concentrations were determined by the sodium dodecyl sulfate-PAGE. Data were tested for nonnormality by the Shapiro-Wilk test. In case of nonnormality, parameters were normalized by log or exponential transformation. The data were analyzed with repeated measures ANOVA using a mixed model procedure. For all the main milk components (fat, protein, total solids, and solids-not-fat), the lowest values were observed in the summer and the greatest values were observed in the winter. Casein fractions, with the exception of γ-CN, showed the lowest values in the summer and the greatest values in the winter. The content of IgG and serum albumin was greater in summer than in the winter and spring. A mild effect of season was observed for milk SCC, with greater values in summer than in the winter and spring. A worsening of milk coagulation properties was observed in summer season. The alteration of cheesemaking properties during hot season seems strictly linked with changes of milk protein fractions mainly with the decrease of αS-CN and β-CN and the increase of undefined proteins.


Outcomes following cholecystectomy in human immunodeficiency virus-positive patients treated with antiretroviral therapy: A retrospective cohort study.
The number of the human immunodeficiency virus (HIV)-positive patients are increasing worldwide, and more HIV-positive patients are undergoing urgent or elective cholecystectomy. There is still insufficient evidence on the relationship between surgical complications of cholecystectomy and antiviral status in HIV-positive patients. The purpose of the present study is to evaluate surgical outcomes after cholecystectomy in HIV-positive patients. Records of consecutive HIV-positive patients who underwent cholecystectomy between January 2010 and December 2020 were reviewed retrospectively. Patients were divided into urgent and elective surgery groups. Urgent surgery was defined as surgery within 48 hours of admission. Postoperative complications were evaluated according to the Clavien-Dindo classification. A total of 30 HIV-positive patients underwent urgent (n = 7) or elective (n = 23) cholecystectomy. Four complications (13.3%) occurred, and the rate was significantly higher in the urgent group than in the elective group (p = 0.008). However, all complications were minor (3 cases of grade I and one case of grade II), and there were no severe postoperative complications. There was no significant difference in CD4+ lymphocyte status in all patients and between the 2 groups before and after surgery (p = 0.133). No cases of postoperative deterioration in the control of HIV infection were observed. In conclusion, cholecystectomy in HIV-positive patients with controlled HIV under recent antiretroviral therapy may be performed safely even in an emergency situation.


Characterization of a murine model of non-lethal, symptomatic dengue virus infection.
The mosquito-borne disease dengue is caused by four serologically- and genetically-related viruses, termed DENV-1 to DENV-4. Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/β/γ receptors). Recently, our group established lethal AG129 mouse infection models of DENV-1, DENV-3, and DENV-4 using human isolates. Here we compare a non-lethal, disseminated model of DENV-3 infection using strain D83-144 to that of the lethal outcome following infection by strain C0360/94. Both strains belong to DENV-3 genotype II and differ by only 13 amino acids. Intraperitoneal inoculation of AG129 mice with strain D83-144 led to clinical signs of dengue infection, such as cytokine induction, thrombocytopenia, and systemic infection. However, C0360/94 infection led to features of severe human dengue, including coagulopathy and lethal outcome, whereas D83-144 infection does not. This study is the first to investigate a low passage, non-mouse lethal strain in AG129 mice and demonstrates that D83-144 infection induces milder features of human dengue than those induced by lethal C0360/94 infection. The results suggest that the AG129 mouse model has applications to investigate factors associated with mild or severe disease.


Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.
To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.


Drug-induced Hemolysis in G6PD Deficiency: an Unusual Presentation of a Common Clinical Condition.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency can present a diagnostic dilemma owing to the varying degrees of disease severity and the wide range of precipitating factors. Here, we report a case of a 56-year-old man who presented with signs and symptoms of heart failure and, during the course of treatment, developed intravascular hemolysis. On investigation, he was found to be G6PD deficient. Following discontinuation of the fixed-dose combination of isosorbide dinitrate and hydralazine, the clinical condition of the patient improved, and there were no further episodes of hemolysis. The case highlights the need for a high degree of suspicion of G6PD deficiency in patients with unexplained signs and symptoms of intravascular hemolysis.


Electrode Protection in High-Efficiency Li-O2 Batteries.
The aprotic Li-O2 battery possessing the highest theoretical energy density, approaching that of gasoline, has been regarded as one of the most promising successors to Li-ion batteries. Before this kind of battery can become a viable technology, a series of critical issues need to be conquered, like low round-trip efficiency and short cycling lifetime, which are closely related to the continuous parasitic processes happening at the cathode and anode during cycling. With an aim to promote the practical application of Li-O2 batteries, great effort has been devoted to identify the reasons for oxygen and lithium electrodes degradation and provide guidelines to overcome them. Thus, the stability of cathode and anode has been improved a lot in the past decade, which in turn significantly boosts the electrochemical performances of Li-O2 batteries. Here, an overlook on the electrode protection in high-efficiency Li-O2 batteries is presented by providing first the challenges of electrodes facing and then the effectiveness of the existing approaches that have been proposed to alleviate these. Moreover, new battery systems and perspectives of the viable near-future strategies for rational configuration and balance of the electrodes are also pointed out. This Outlook deepens our understanding of the electrodes in Li-O2 batteries and offers opportunities for the realization of high performance and long-term durability of Li-O2 batteries.


Macrophage migratory dysfunction in cancer. A mechanism for subversion of surveillance.
There is considerable evidence to suggest that macrophages participate in host resistance to the development and spread of cancer. We have, therefore, studied monocytemacrophage function in humans and animals with neoplasms. Approximately 60% of patients with various types of cancer were found to have abnormal monocyte chemotactic responsiveness in vitro, and abnormal chemotaxis was an indicator of poor prognosis in patients with melanoma. By studying patients before and after surgery, it was found that abnormal chemotactic responses normalized within weeks after removal of malignant tumors, indicating that a neoplasm itself might affect the host's monocyte chemotactic responsiveness. Subsequent studies using transplantable neoplasms in mice substantiated this hypothesis in that macrophage accumulation in vivo as well as macrophage chemotactic responsiveness in vitro was depressed in animals during the early phases of tumor growth. This depression of macrophage function could be attributed to a low-molecular-weight factor contained in murine neoplasms, which when given to normal mice was extremely potent in depressing peritoneal macrophage accumulation and chemotaxis but, paradoxically, enhanced phagocytosis. The serum of tumor-bearing mice also contained potent inhibitory activity for macrophage accumulation. In contrast to the effects on macrophages, granulocyte accumulation in vivo and chemotaxis in vitro was not depressed by the presence of a neoplasm or the administration of the factor from neoplasms. By releasing factors which depress macrophage migratory function, neoplasms may protect themselves from immunologically mediated host destruction during the early phases of tumor growth.


Limited V-shaped cement augmentation of the proximal femur to prevent secondary hip fractures.
Patients with a femoral fracture due to osteoporosis are at high risk of sustaining a secondary fracture on the contralateral side. A prophylactic mechanical reinforcement of the contralateral side during operation of the initial fracture could be of interest for such patients. This biomechanical in vitro study investigates the potential of a limited V-shaped bone cement augmentation to prevent secondary hip fractures by targeting the areas of the proximal femur with the highest stresses during a fall. Five pairs of human cadaveric proximal femora were tested in a configuration simulating a fall on the greater trochanter. The femoral neck of one specimen of each pair was augmented with 8-14 ml polymethylmethacrylate from the lateral cortex towards inferior and superior, spanning a V-shaped cement pattern. Clinical relevant fractures were generated with a 45 kg mass in controlled free fall. Load-displacement data were recorded and energy to fracture, fracture load, yield load and stiffness were statistically evaluated. Augmented samples absorbed 124% more energy until fracture compared to their controls (p = 0.043). No significant differences were found between the two groups for fracture load (p = 0.5), yield load (p = 0.35) and stiffness (p = 0.5). Biomechanically, a limited V-shaped prophylactic cement augmentation carries potential to prevent secondary hip fractures indicated by increased energy absorption until fracture. Further investigations are necessary to minimize interference with the biology and to maximize the mechanical benefit of prophylactic augmentation.


Synthesis and characterization of [Cu(NHC)2]X complexes: catalytic and mechanistic studies of hydrosilylation reactions.
The preparation of two series of [Cu(NHC)2]X complexes (NHC=N-heterocyclic carbene, X=PF6 or BF4) in high yields from readily available materials is reported. These complexes have been spectroscopically and structurally characterized. The activity of these cationic bis-NHC complexes in the hydrosilylation of ketones was examined, and both the ligand and the counterion showed a significant influence on the catalytic performance. Moreover, when compared with related [Cu(NHC)]-based systems, these cationic complexes proved to be more efficient under similar reaction conditions. The activation step of [Cu(NHC)2]X precatalysts towards hydrosilylation was investigated by means of 1H NMR spectroscopy. Notably, it was shown that one of the N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) ligands in [Cu(IPr)2]BF4 is displaced by tBuO(-) in the presence of NaOtBu, producing the neutral [Cu(IPr)(OtBu)]. This copper alkoxide is known to be a direct precursor of an NHC-copper hydride, the actual active species in this transformation. Furthermore, reagent loading and counterion effects have been rationalized in light of the species formed during the reaction.


Assessment of learning gains associated with independent exam analysis in introductory biology.
This study evaluates the impact of an independent postmidterm question analysis exercise on the ability of students to answer subsequent exam questions on the same topics. It was conducted in three sections (∼400 students/section) of introductory biology. Graded midterms were returned electronically, and each student was assigned a subset of questions answered incorrectly by more than 40% of the class to analyze as homework. The majority of questions were at Bloom's application/analysis level; this exercise therefore emphasized learning at these higher levels of cognition. Students in each section answered final exam questions matched by topic to all homework questions, providing a within-class control group for each question. The percentage of students who correctly answered the matched final exam question was significantly higher (p < 0.05) in the Topic Analysis versus Control Analysis group for seven of 19 questions. We identified two factors that influenced activity effectiveness: 1) similarity in topic emphasis of the midterm-final exam question pair and 2) quality of the completed analysis homework. Our data suggest that this easy-to-implement exercise will be useful in large-enrollment classes to help students develop self-regulated learning skills. Additional strategies to help introductory students gain a broader understanding of topic areas are discussed.


Domestication of self-splicing introns during eukaryogenesis: the rise of the complex spliceosomal machinery.
: The spliceosome is a eukaryote-specific complex that is essential for the removal of introns from pre-mRNA. It consists of five small nuclear RNAs (snRNAs) and over a hundred proteins, making it one of the most complex molecular machineries. Most of this complexity has emerged during eukaryogenesis, a period that is characterised by a drastic increase in cellular and genomic complexity. Although not fully resolved, recent findings have started to shed some light on how and why the spliceosome originated. In this paper we review how the spliceosome has evolved and discuss its origin and subsequent evolution in light of different general hypotheses on the evolution of complexity. Comparative analyses have established that the catalytic core of this ribonucleoprotein (RNP) complex, as well as the spliceosomal introns, evolved from self-splicing group II introns. Most snRNAs evolved from intron fragments and the essential Prp8 protein originated from the protein that is encoded by group II introns. Proteins that functioned in other RNA processes were added to this core and extensive duplications of these proteins substantially increased the complexity of the spliceosome prior to the eukaryotic diversification. The splicing machinery became even more complex in animals and plants, yet was simplified in eukaryotes with streamlined genomes. Apparently, the spliceosome did not evolve its complexity gradually, but in rapid bursts, followed by stagnation or even simplification. We argue that although both adaptive and neutral evolution have been involved in the evolution of the spliceosome, especially the latter was responsible for the emergence of an enormously complex eukaryotic splicing machinery from simple self-splicing sequences. This article was reviewed by W. Ford Doolittle, Eugene V. Koonin and Vivek Anantharaman.


Renin-angiotensin system in stroke-prone spontaneously hypertensive rats.
The development of malignant hypertension was studied in stroke-prone spontaneously hypertensive rats (SHR) kept on 1% NaCl as drinking water. Along with salt-loading, blood pressure gradually increased and reached a severe hypertensive level (greater than 230 mmHg), which was followed by increases in urinary protein (greater than 100 (mg/250 g body wt)/day) and plasma renin concentration (PRC, from 18.9 +/- 0.1 to 51.2 +/- 19.4 (ng/ml)/h, mean +/- SD). At this stage, renal small arteries and arterioles showed severe sclerosis and fibrinoid necrosis. Stroke was observed within a week after the onset of these renal abnormalities. The dose of exogenous angiotensin II (AII) producing 30 mmHg rise in blood pressure increased with the elevation of PRC, from 22 +/- 12 to 75 +/- 36 ng/kg, which was comparable to that in rats on water. The fall of blood pressure due to an AII inhibitor, [1-sarcosine, 8-alanine]AII (10(microgram/kg)/min for 40 min) became more prominent with the increase in PRC in salt-loaded rats, but was not detected in rats on water. These findings suggest that the activation of renin-angiotensin system participates in malignant hypertension of salt-loaded stroke-prone SHR rats that show stroke signs, proteinuria, hyperreninemia, and renovascular changes.


Mucin-like molecules as modulators of the survival and proliferation of primitive hematopoietic cells.
Current data suggest that interplay between two classes of molecules contributes to the regulation of hematopoiesis: hematopoietic growth factors, which regulate the survival, proliferation, and development of primitive hematopoietic cells and cell adhesion molecules (CAMs), which are responsible for the localization of hematopoiesis to the bone marrow (BM) and for mediating physical association between developing hematopoietic cells and marrow stromal tissue. A range of cell surface molecules representing several CAM superfamilies including integrins, selectins, the immunoglobulin gene superfamily and an emerging family of mucin-like molecules (the sialomucins) are involved in supporting cell-cell and cell-extracellular matrix (ECM) interactions between primitive hematopoietic cells and the stromal cell-mediated hematopoietic microenvironment (HM) of the bone marrow. There is abundant evidence in non-hematopoietic tissues that CAMs are signalling molecules which participate in a range of signal transduction events important not only for regulating cell adhesion and motility, but also for cell growth and survival. Although the signalling functions of CAMs have not been studied extensively in primitive hematopoietic progenitors (HPCs), extrapolation from burgeoning data in other systems is consistent with the hypothesis that hematopoiesis within the BM is regulated by interaction between signals generated locally by CAMs and those elicited by cytokines. Evidence in support of this notion was initially provided by studies on normal HPCs demonstrating cross-talk between members of the integrin superfamily and cytokine receptors. In this article we review recent reports that mucin-like molecules are also signalling molecules on primitive hematopoietic cells and that the signals they deliver potently inhibit hematopoiesis.


In vivo analysis of sequences required for translation of cytochrome b transcripts in yeast mitochondria.
Respiratory chain proteins encoded by the yeast mitochondrial genome are synthesized within the organelle. Mitochondrial mRNAs lack a 5' cap structure and contain long AU-rich 5' untranslated regions (UTRs) with many potential translational start sites and no apparent Shine-Dalgarno-like complementarity to the 15S mitochondrial rRNA. However, translation initiation requires specific interactions between the 5' UTRs of the mRNAs, mRNA-specific activators, and the ribosomes. In an initial step toward identifying potential binding sites for the mRNA-specific translational activators and the ribosomes, we have analyzed the effects of deletions in the 5' UTR of the mitochondrial COB gene on translation of COB transcripts in vivo. The deletions define two regions of the COB 5' UTR that are important for translation and indicate that sequence just 5' of the AUG is involved in selection of the correct start codon. Taken together, the data implicate specific regions of the 5' UTR of COB mRNA as possible targets for the mitochondrial translational machinery.


Perinatal and Maternal Outcomes According to the Accurate Term Antepartum Ultrasound Estimation of Extreme Fetal Weights.
(1) Background: The accuracy of ultrasound estimation of fetal weight (EFW) at term may be useful in addressing obstetric complications since birth weight (BW) is a parameter that represents an important prognostic factor for perinatal and maternal morbidity. (2) Methods: In a retrospective cohort study of 2156 women with a singleton pregnancy, it is verified whether or not perinatal and maternal morbidity differs between extreme BWs estimated at term by ultrasound within the seven days prior to birth with Accurate EFW (difference < 10% between EFW and BW) and those with Non-Accurate EFW (difference ≥ 10% between EFW and BW). (3) Results: Significantly worse perinatal outcomes (according to different variables such as higher rate of arterial pH at birth < 7.20, higher rate of 1-min Apgar < 7, higher rate of 5-min Apgar < 7, higher grade of neonatal resuscitation and need for admission to the neonatal care unit) were found for extreme BW estimated by antepartum ultrasounds with Non-Accurate EFW compared with those with Accurate EFW. This was the case when extreme BWs were compared according to percentile distribution by sex and gestational age following the national reference growth charts (small for gestational age and large for gestational age), and when they were compared according to weight range (low birth weight and high birth weight). (4) Conclusions: Clinicians should make a greater effort when performing EFW by ultrasound at term in cases of suspected extreme fetal weights, and need to take an increasingly prudent approach to its management.


Rapunzel Syndrome.
A bezoar refers to a mass of undigestible foreign material found in the gastrointestinal tract, mainly stomach. The second most common bezoar is the trichobezoar, which usually occurs in the young psychiatric female patients with history of trichotillomania and trichophagia. This is a case report of a 12 -year-old female patient came with complaints of diffuse abdominal pain, vomiting, and constipation. Ultrasound, Barium X-ray and Computed Tomography scan were done, which suggested trichobezoar. Thus, trichobezoar should be considered as differential diagnosis of abdominal pain in young female patients with associated psychiatric complaints. A review is presented here, as a high index of suspicion for better diagnostic facilities which can help in timely diagnosis and intervention, to prevent further complications like intestinal obstruction, perforation and mortality in such children.


Trachyonychia: case report and review of the literature.
Trachyonychia is the term used to describe nail plate roughness, pitting, and ridging that may affect 1 to 20 nails. Alopecia areata, psoriasis, lichen planus, atopic dermatitis, ichthyosis vulgaris, as well as other skin conditions have been associated with trachyonychia, but the causal relationship is often challenging to demonstrate histologically. Clinical evidence of these cutaneous disorders in conjunction with a nail matrix biopsy may help elucidate an etiology of trachyonychia, but many cases often remain idiopathic. Nail biopsy findings may match skin histology, but more commonly show spongiotic or nonspecific changes. We present an interesting case of a female with progressive development of trachyonychia in all 20 nails coinciding with a new diagnosis of sarcoidosis.


Prevalence, causes and socio-economic determinants of vision loss in Cape Town, South Africa.
To estimate the prevalence and causes of blindness and visual impairment in Cape Town, South Africa and to explore socio-economic and demographic predictors of vision loss in this setting. A cross sectional population-based survey was conducted in Cape Town. Eighty-two clusters were selected using probability proportionate to size sampling. Within each cluster 35 or 40 people aged 50 years and above were selected using compact segment sampling. Visual acuity of participants was assessed and eyes with a visual acuity less than 6/18 were examined by an ophthalmologist to determine the cause of vision loss. Demographic data (age, gender and education) were collected and a socio-economic status (SES) index was created using principal components analysis. Out of 3100 eligible people, 2750 (89%) were examined. The sample prevalence of bilateral blindness (presenting visual acuity <3/60) was 1.4% (95% CI 0.9-1.8). Posterior segment diseases accounted for 65% of blindness and cataract was responsible for 27%. The prevalence of vision loss was highest among people over 80 years (odds ratio (OR) 6.9 95% CI 4.6-10.6), those in the poorest SES group (OR 3.9 95% CI 2.2-6.7) and people with no formal education (OR 5.4 95% CI 1.7-16.6). Cataract surgical coverage was 68% in the poorest SES tertile (68%) compared to 93% in the medium and 100% in the highest tertile. The prevalence of blindness among people ≥50 years in Cape Town was lower than expected and the contribution of posterior segment diseases higher than previously reported in South Africa and Sub Saharan Africa. There were clear socio-economic disparities in prevalence of vision loss and cataract surgical coverage in this setting which need to be addressed in blindness prevention programs.


Herpes simplex viral infection of the mouse trigeminal ganglion. Immunohistochemical analysis of cell populations.
Several distinct populations of sensory neurons in the ophthalmic region of the mouse trigeminal ganglion have been identified by their reactivity to antibodies raised against substance P (SP), calcitonin gene-related peptide (CGRP), cell-surface glycoconjugates SSEA3 and LD2, and the plant lectin, Bandeiraea simplicifolia lectin 1, isolectin 4 (BSIL4). Thirty-six percent of the neurons in the ophthalmic portion of the mouse trigeminal ganglion express CGRP and 17%, SP. All neurons that express SP also express CGRP. Forty percent of the neurons in the ophthalmic region of the ganglion are recognized by monoclonal antisera to SSEA3, and 66% of this population also express the neuropeptides SP or CGRP. The neuronal population recognized by BSIL4 is identical to the population with the LD2 epitope. This population of cells (BSIL4/LD2) does not express the SSEA3 glycoconjugate and is largely nonpeptidergic. All four populations of sensory neurons (SP, CGRP, SSEA3, and LD2/BSIL4) can be infected by herpes simplex virus (HSV). However, the relative proportion of SSEA3- and LD2/BSIL4-labeled cells that were infected productively with HSV was much less than expected based on the relative size of the populations of these neurons in the ophthalmic region of the ganglion.


RAAS inhibition and renal protection.
Chronic kidney disease has become a major public health problem worldwide mainly as a consequence of the emerging epidemic of hypertension, diabetes, and obesity. It is currently estimated that nearly 15% of the general population has some degree of renal damage, a figure that reaches 50% in at-risk subgroups. Renin-angiotensin-aldosterone system (RAAS) inhibitors represent the agents of choice to control hypertension and reduce urinary albumin excretion, thereby delaying renal function deterioration. Greater blockade of the RAAS either by the combined use of multiple drugs or by supramaximal doses of single agents may provide greater renal protection. Furthermore, it has been proposed especially in the presence of proteinuria. However, at this time there is insufficient evidence to routinely recommend this therapeutic approach in patients with chronic kidney disease. The present article examines the currently available evidence and practical implications of pharmacological disruption of RAAS activity for renal protection.


Serological relationships among genotypic variants of betanodavirus.
Betanodaviruses, the causative agents of viral nervous necrosis or viral encephalopathy and retinopathy, are divided into 4 genotypes based on the coat protein gene (RNA2). In the present study, serological relationships among betanodavirus genotypic variants were examined by virus neutralization tests using rabbit antisera raised against purified virions of strains representative of each genotype. All 20 isolates examined shared epitopes for neutralizing, but they fell into 3 major serotypes (A, B, C). This sero-grouping is in part consistent with their genotypes, i.e. Serotype A for striped jack nervous necrosis virus (SJNNV) genotype, Serotype B for tiger puffer nervous necrosis virus (TPNNV) genotype, and Serotype C for both redspotted grouper nervous necrosis virus (RGNNV) and barfin flounder nervous necrosis virus (BFNNV) genotypes. The serological relatedness between RGNNV and BFNNV genotypes may result from their relatively higher similarity in RNA2 sequences. In neutralization tests using antisera of kelp grouper Epinephelus moara, which were raised against recombinant coat proteins representing each genotype, anti-SJNNV and anti-TPNNV sera neutralized only the homologous strain, and anti-RGNNV and anti-BFNNV sera reacted with both RGNNV and BFNNV strains. The present serological findings will be important in investigating the infectivity and host-specificity of betanodaviruses and in developing vaccines for the disease.


[Measurement of transdiaphragmatic pressure in pulmonary emphysema, a relevant contribution to clinical management?].
In 50 patients with advanced pulmonary emphysema, admitted for operative lung volume reduction, transdiaphragmatic pressure was measured by a double balloon catheter, using the sniff technique.Transdiaphragmatic pressure (pdi) is the difference between gastric pressure (pga) and esophageal pressure (pes). The mean value of pdi in the sitting position was 5,9 kPa (SD 1,6 kPa), in the lying position 5,6 kPa (SD 1,3 kPa). 94 % of the patients had a pathologic pdi (below 8,2 kPa). The reduction of diaphragm function in this patient group was quantified. No significant difference was found between sitting or lying position. There was no clear correlation between pdi and the reduction in lung function. Maybe there are other important factors, for example the influence of the deformation in the chest wall itself.


Safety and Efficacy of Brentuximab Vedotin in the Treatment of Classic Hodgkin Lymphoma.
Classical Hodgkin lymphoma (cHL) is a B-cell-derived lymphoid malignancy with the most favorable prognosis among various adult malignancies. However, once it becomes refractory disease to chemotherapy or relapses after high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT), it is difficult to manage with conventional cytotoxic chemotherapy. The introduction of brentuximab vedotin (BV) has changed the treatment landscape of cHL in the past decade. Several studies demonstrated high efficacy of BV monotherapy in heavily treated patients with cHL relapsed or refractory after HDC/ASCT. Recent studies also reported high efficacy of concurrent or sequential combination of BV and chemotherapy in patients with transplant-eligible relapsed/refractory cHL at the second-line setting. In addition, a randomized phase III trial ECHELON-1 reported a positive result of BV in combination with AVD (doxorubicin, vinblastine, and dacarbazine) in patients with newly diagnosed advanced-stage cHL. In this review, we summarize available data of BV for cHL and discuss the current and future role of BV in the management of cHL.


The 5-phosphatase OCRL mediates retrograde transport of the mannose 6-phosphate receptor by regulating a Rac1-cofilin signalling module.
Mutations in the OCRL gene encoding the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) 5-phosphatase OCRL cause Lowe syndrome (LS), which is characterized by intellectual disability, cataracts and selective proximal tubulopathy. OCRL localizes membrane-bound compartments and is implicated in intracellular transport. Comprehensive analysis of clathrin-mediated endocytosis in fibroblasts of patients with LS did not reveal any difference in trafficking of epidermal growth factor, low density lipoprotein or transferrin, compared with normal fibroblasts. However, LS fibroblasts displayed reduced mannose 6-phosphate receptor (MPR)-mediated re-uptake of the lysosomal enzyme arylsulfatase B. In addition, endosome-to-trans Golgi network (TGN) transport of MPRs was decreased significantly, leading to higher levels of cell surface MPRs and their enrichment in enlarged, retromer-positive endosomes in OCRL-depleted HeLa cells. In line with the higher steady-state concentration of MPRs in the endosomal compartment in equilibrium with the cell surface, anterograde transport of the lysosomal enzyme, cathepsin D was impaired. Wild-type OCRL counteracted accumulation of MPR in endosomes in an activity-dependent manner, suggesting that PI(4,5)P(2) modulates the activity state of proteins regulated by this phosphoinositide. Indeed, we detected an increased amount of the inactive, phosphorylated form of cofilin and lower levels of the active form of PAK3 upon OCRL depletion. Levels of active Rac1 and RhoA were reduced or enhanced, respectively. Overexpression of Rac1 rescued both enhanced levels of phosphorylated cofilin and MPR accumulation in enlarged endosomes. Our data suggest that PI(4,5)P(2) dephosphorylation through OCRL regulates a Rac1-cofilin signalling cascade implicated in MPR trafficking from endosomes to the TGN.


The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients.
Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at Euro 1,600 million. Cost-effectiveness evaluations have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4+/-2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7+/-2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62+/-0.15 with a treatment cost of Euro 26,517.62 and a QALY/cost of Euro 42,521.13. In the group methotrexate + etanercept the QALY gained was 0.64+/-0.26 with a treatment cost of Euro 25,020.96 and a QALY/cost of Euro 39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of Euro 50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.


Quality of Life in Lower-Limb Amputees 10 Years After the 2008 Sichuan Earthquake: A Cross-Sectional Study.
The aim of this study was to investigate the long-term outcome of quality of life (QOL) in the lower-limb amputees 10 years after the 2008 Sichuan earthquake. In the cross-sectional study, 66 lower-limb amputees were recruited. The prosthetics-related QOL was assessed using the Prosthetic Evaluation Questionnaire (PEQ) in terms of the scales of utility, appearance, sounds, residual limb health, perceived response, frustration, social burden, ambulation, and well-being. The score of each PEQ subscale was calculated and compared among the cohorts with different demographic characteristics. The PEQ scores showed that the scales of sounds, residual limb health, and frustration were still low in the lower-limb amputees 10 years after the 2008 Sichuan earthquake. The comparison of PEQ scales among cohorts with different demographic characteristics indicated that the potential demographic risk factors, namely, age, marital status, educational level, living independence, and comorbidity, were associated with prosthesis-related QOL. The prosthesis-related QOL of the lower-limb amputees 10 years after the 2008 Sichuan earthquake has been partly documented in this study. The potential demographic risk factors associated with QOL of amputees were also identified. These findings could enhance the understanding of prosthesis-related QOL of lower-limb amputees sustained in an earthquake and facilitate the optimization of post-disaster rehabilitation strategies.


Oral anticoagulants for nonvalvular atrial fibrillation in frail elderly patients: insights from the ARISTOPHANES study.
Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin. Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.


Structure and stability of Ricinus communis haemagglutinin.
The molecular properties of the haemagglutinin of Ricinus communis (RCA I or RCA 120) were evaluated by analytical ultracentrifugation, light-scattering, c.d. and fluorescence. The native molecule had a fairly expanded structure (f/f0 = 1.43) and dissociated into two subunits of equal size in 6 M-guanidinium chloride. This native structure was stable in alkali (up to pH 11) and resistant to thermal denaturation at neutrality. A pH-triggered change in the haemagglutinin conformation was observed and characterized by analytical ultracentrifugation, c.d. and fluorescence between pH 7 and 4.5, the range in which its affinity for galactosides decreased [Yamasaki, Absar & Funatsu (1985) Biochim, Biophys. Acta 828, 155-161]. These results are discussed in relation to those reported in the literature for other lectins and more especially ricin, for which a pH-dependent conformation transition has been observed in the same range of low pH.


Plasma Leptin Is Increased in Intensive Care Patients with COVID-19-An Investigation Performed in the PronMed-Cohort.
COVID-19 has shaken the world and intensive care units (ICU) have been challenged by numerous patients suffering from a previously unknown disease. Leptin is a polypeptide pleiotropic hormone, mainly expressed by adipocytes. It acts as a proinflammatory cytokine and is associated with several conditions, known to increase the risk of severe COVID-19. Very little is known about leptin in severe viral disorders. Plasma leptin was analyzed in 222 out of 229 patients with severe COVID-19 on admission to an ICU at Uppsala University Hospital, a tertiary care hospital in Sweden, and compared to plasma leptin in 25 healthy blood donors. COVID-19 was confirmed by positive PCR. Leptin levels were significantly higher in patients with COVID-19 (18.3 ng × mL-1; IQR = 30.4), than in healthy controls (7.8 ng × mL-1; IQR = 6.4). Women had significantly higher leptin values (22.9 ng × mL-1; IQR = 29.8) than men (17.5 ng × mL-1; IQR = 29.9). Mortality at 30 days was 23% but was not associated with increased leptin levels. Neither median duration of COVID-19 before admission to ICU (10 days; IQR = 4) or median length of ICU stay (8 days; IQR = 11) correlated with the plasma leptin levels. Leptin levels in COVID-19 were higher in females than in males. Both treatment (e.g., use of corticosteroids) and prophylaxis (vaccines) have been improved since the start of the COVID-19 pandemic, which may contribute to some difficulties in deciphering relations between COVID-19 and leptin.


A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative.
Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation.


Down syndrome passed from mother to child.
Down syndrome is the leading cause of inherited intellectual disability; it is characterized by mental retardation associated to physical growth delay and certain physical traits or features. It is caused by the presence of a third copy of chromosome 21, being this trisomy the most common chromosomal aneuploidy. Women with Down syndrome are less fertile, and pregnancy in these women is rare, although the information on exact statistics of reproduction in these patients is very limited, and they often have difficulties with miscarriage, premature birth, and difficult labor. We report the case of a preterm newborn with Down syndrome passed from her mother; this pregnancy was a result of sexual assault, which is an event that can and should be prevented in this population.


Job demand and control interventions: a stakeholder-centered best-evidence synthesis of systematic reviews on workplace disability.
Physical and psychological job demands in combination with the degree of control a worker has over task completion, play an important role in reducing stress. Occupational stress is an important, modifiable factor affecting work disability. However, the effectiveness of reducing job demands or increasing job control remains unclear, particularly for outcomes of interest to employers, such as absenteeism or productivity. This systematic review reports on job demand and control interventions that impact absenteeism, productivity and financial outcomes. A stakeholder-centered best-evidence synthesis was conducted with researcher and stakeholder collaboration throughout. Databases and grey literature were searched for systematic reviews between 2000 and 2012: Medline, EMBASE, the Cochrane Database of Systematic Reviews, DARE, CINAHL, PsycINFO, TRIP, health-evidence.ca, Rehab+, National Rehabilitation Information Center (NARIC), and Institute for Work and Health. Articles were assessed independently by two researchers for inclusion criteria and methodological quality. Differences were resolved through consensus. The search resulted in 3363 unique titles. After review of abstracts, 115 articles were retained for full-text review. 11 articles finally met the inclusion criteria and are summarized in this synthesis. The best level of evidence we found indicates that multimodal job demand reductions for either at-work or off-work workers will reduce disability-related absenteeism. In general, the impacts of interventions that aim to reduce job demands or increase job control can be positive for the organization in terms of reducing absenteeism, increasing productivity and cost-effectiveness. However, more high quality research is needed to further assess the relationships and quantify effect sizes for the interventions and outcomes reviewed in this study.


Polymorphisms of the MDR1 gene in the Czech population.
There exists a marked inter-individual variability of P-glycoprotein expression and activity, which can be of clinical importance due to the large number of drugs that are substrates for the transporter. Previously identified polymorphisms in the MDR1 gene belong to important factors causing this phenomenon. Our aim was to investigate the frequency of major functional SNPs of the MDR1 gene coding for P-glycoprotein in the Czech population. DNA was isolated from whole blood of 189 healthy, young and unrelated subjects (99 females and 90 males, aged from 23 to 28 years). The genotypes of polymorphic positions C3435T, G2677T/A, C1236T and T-76A were determined by PCR-RFLP. Observed allelic frequencies were 56.5%, 46.0%, 0.53%, 44.5% and 37.6% for the alleles 3435T, 2677T, 2677A, 1236T and -76A, respectively. We have found 64 subjects homozygous for 3435T, 42 for 2677T, 40 for 1236T and 31 for -76A alleles. The allelic distribution complies well with Hardy-Weinberg equilibrium. Allelic frequencies of functionally important MDR1 variants are in the Czech population similar to that of other Caucasian populations.


Suppression of experimental crescentic glomerulonephritis by deoxyspergualin.
Deoxyspergualin is an immunosuppressive drug which is effective in both preventing allograft rejection and suppressing steroid-resistant acute rejection. This study was designed to determine whether deoxyspergualin could suppress the development of rapidly progressive crescentic glomerulonephritis in antigen-primed animals. Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced by priming rats with rabbit immunoglobulin G (IgG), followed 5 days later by an injection of rabbit anti-rat GBM serum (day 0). Groups of five animals were treated with deoxyspergualin (5 mg/kg.day) or saline by daily ip injection from day 0 until euthanasia on days 1, 7, 14, or 21. Deoxyspergualin treatment resulted in a significant suppression of renal disease. Compared with saline-treated controls, deoxyspergualin treatment reduced proteinuria, resolved hematuria, and completely prevented a fall in creatinine clearance. Deposition of rabbit IgG along the GBM was unaffected by deoxyspergualin treatment, but glomerular deposition of rat IgG and C3 was significantly reduced from day 14 onwards, which was associated with a significant reduction of circulating rat anti-rabbit IgG. Deoxyspergualin treatment also produced a dramatic improvement in renal histology. Glomerular necrosis, fibrosis, and crescent formation were markedly suppressed, whereas tubulointerstitial lesions were completely prevented. This was associated with a marked suppression of mononuclear cell infiltration and activation. In the glomerulus, macrophage infiltration was suppressed by approximately 50%, whereas accumulation of macrophages and immune-activated (interleukin-2 receptor) T cells within the interstitium was almost completely abrogated by deoxyspergualin treatment. In conclusion, deoxyspergualin was found to be effective in suppressing the development of experimental crescentic glomerulonephritis in antigen-primed animals by acting on both the local cell-mediated response within the kidney and the systemic humoral immune response. Further work is warranted to determine whether this could be a useful drug for the treatment of human proliferative glomerulonephritis.


Lymphocytic-choriomeningitis virus in hamster tumor: spread to hamsters and humans.
A passage line of a spontaneous hamster fibrosarcoma is contaminated by the virus. of lymphocytic choriomeningitis. Tumors from animals receiving implants when newborn contain high titers of infectious lymphocytic-choriomeningitis virus and complement-fixing antigen, and hamsters receiving implants when weanlings develop high titers of complement-fixing antibody against lymphocytic-choriomeningitis virus. In contrast with the specific reactions of tumorous hamsters to the initiating virus in virus-induced tumors, the development of complement-fixing antibody to lymphocytic-choriomeningitis virus does not depend on the development of tumors. Infant hamsters bearing the tumor have a generalized subclinical infection and seem able to spread virus to other hamsters and to humans.


Immunomodulatory and Antitumoral Activity of Gold Nanoparticles Synthesized by Red Algae Aqueous Extracts.
This study reports on the green and cost-efficient synthesis of gold nanoparticles from three different red algae extracts. The nanoparticles synthesized were fully characterized by UV-Vis spectroscopy, HRTEM, and Z-potential. Relevant components occurring in the extracts, such as polysaccharides or phenolic content, were assessed by analytical techniques such as spectrophotometric assays and liquid chromatography. Finally, the antioxidant, antitumoral, and anti-inflammatory potential of both the extracts and the gold nanoparticles synthesized were analyzed in order to determine a possible synergistic effect on the nanoparticles. The results obtained confirmed the obtainment of gold nanoparticles with significant potential as immunotherapeutic agents. The therapeutic potential of these nanoparticles could be higher than that of inert gold nanoparticles loaded with bioactive molecules since the former would allow for higher accumulation into the targeted tissue.


[Three-dimensional planned radiotherapy in rectal cancer. Feasibility study and preliminary clinical results].
Since 1991 the use of three-dimensional planned radiation therapy for rectal cancer was evaluated as a part of a clinical project funded by the Deutsche Krebshilfe at the Radiological Department of the University of Heidelberg. First clinical experiences are reported. 32 patients who were irradiated loco-regional for rectal cancer were analysed retrospectively. Radiation therapy techniques: patient's position was prone by the use of a belly board. Three-dimensional treatment (3D) planning system was voxelplan. The radiation therapy was started using a 3-field-box technique modified by 3D-technique after 22 to 42 Gy, depending on therapeutic concept. On average 92% of the planning target volume were encompassed with the 80% isodose. The average maximum dose was 108% (isocenter = 100%), of the small bowel volume received less than 34% of the dose, 70% of the bladder volume less than 40% respectively. Total average dose was 52.4% Gy. Irregular fields were used in all patients, a non-coplanar field was used to optimize dose-distribution in 41% of the patients, 21 patients received chemotherapy simultaneously. Acute side effects according to gastrointestinal tract reached grade 1 (WHO) in 9 patients, grade 2 in 2 patients. Side effects according to bladder reached grade 1 in 5 patients grade 2 in 1 patient respectively. In 4 patients suffered from acute side effects concerning the bladder. In one patient acute side effects grade 1 concerning gastrointestinal tract was observed. Portal films were analysed to evaluate precision of radiation therapy. On average the error was 3.1/4.5/4.0 mm in the x/y/z direction respectively. The standard deviation was 4.4/6.8/6.3 mm for x/y/z respectively. A median time of 2 hours was necessary for all planning procedures. Three-dimensional treatment planning optimizes dose-distribution in a relevant number of patients. Its clinical use for treatment of large targets or in order to applicate high doses is justified. Planning target volume should cover the clinical target volume with a margin of 1.5 cm.


Exploring subgroup effects by socioeconomic position of three effective school-based dietary interventions: the European TEENAGE project.
The aim of this study was to explore subgroup effects by high and low socioeconomic position (SEP) of three previously conducted, effective European interventions. Reanalyses stratified by SEP were conducted by the research groups of each study. All studies were school-based: two multi-component interventions targeting intake of fat or fruit and vegetables (FV), and a free breakfast initiative. Computer-tailored advice affected fat intake among low, but not high SEP girls after 1 year. A multi-component intervention affected the total FV intake in both SEP groups, vegetable intake in low SEP and fruit intake in high SEP across three countries after 1 year, whereas free fruit affected total FV and fruit intake equally in both SEP groups in one country after 2 years. Providing a free healthy breakfast increased consumption of healthy food items only in the low SEP group. Reanalysing intervention studies by SEP is a quick and easy way to explore patterns in effects by SEP across interventions. Providing healthy food might be a promising strategy for decreasing social inequalities.


Abnormalities of heme biosynthesis in experimental acute renal failure.
Several abnormalities of porphyrin metabolism have been described in patients with end-stage renal failure. Because the heme biosynthetic pathway in acute renal failure has not been studied hitherto, an experimental model was therefore induced in 30 dogs by ligation and transection of both ureters. Forty-eight h after this procedure, anemia and uremia developed, erythrocyte aminolevulinate dehydratase activity decreased, and plasma porphyrins increased in these 30 dogs, whereas seven sham-operated animals did not exhibit any alteration of these parameters. Uremic plasma showed a capacity to inhibit aminolevulinate dehydratase activity (mean, 11.1 +/- 5.8%) when incubated in vitro with erythrocytes from healthy dogs. Such findings are similar to those reported in uremic patients on hemodialysis or on continuous ambulatory peritoneal dialysis. Twenty-three of the 30 animals underwent a hemodialysis session (180 min) 48 h after ureteral ligation, using a polyacrylonitrile membrane dialyzer. In addition to reducing serum creatinine and urea levels, this procedure significantly reduced plasma porphyrin values. However, the activity of erythrocyte aminolevulinate dehydratase and the plasma capacity to inhibit this enzyme were not modified after the hemodialysis session. This results described here show that some of the abnormalities of heme biosynthesis described in chronic renal failure are detected early in an experimental model of acute renal failure. This study also confirms that, although most plasma porphyrins circulate bound to proteins, hemodialysis may reduce levels of plasma porphyrins when a high permeability membrane is used.


[Accuracy of the rheographic method of evaluating stroke volume].
The results of stroke volume determination by means of integral tetrapolar body rheography (ITBR) and M-echocardiography were compared in 78 individuals, while Doppler cardiography was used as the reference method. Fairly high accuracy of stroke volume measurement by ITBR and its advantages over echocardiography, particularly the possibility of calculating the stroke volume irrespective of the heart size, are demonstrated. The accuracy of the ITBR determination declines in patients with severe heart failure.


Dilemmatic human-animal boundaries in Britain and Romania: post-materialist and materialist dehumanization.
Theories of dehumanization generally assume a single clear-cut, value-free and non-dilemmatic boundary between the categories 'human' and 'animal'. The present study highlights the relevance of dilemmas involved in drawing that boundary. In six focus groups carried out in Romania and Britain, 42 participants were challenged to think about dilemmas pertaining to animal and human life. Four themes were identified: rational autonomy, sentience, speciesism and maintaining materialist and post-materialist values. Sentience made animals resemble humans, while humans' rational autonomy made them distinctive. Speciesism underlay the human participants' prioritization of their own interests over those of animals, and a conservative consensus that the existing social system could not change supported this speciesism when it was challenged. Romanian participants appealed to Romania's lack of modernity and British participants to Britain's modernity to justify such conservatism. The findings suggest that the human-animal boundary is not essentialized; rather it seems that such boundary is constructed in a dilemmatic and post hoc way. Implications for theories of dehumanization are discussed.


Dynamic QTL analysis of protein content and glutamine synthetase activity in recombinant inbred wheat lines.
Protein content (PC) is a crucial factor that determines the end-use and nutritional quality of wheat (Triticum aestivum). Glutamine synthetase (GS), which is a major participant in nitrogen metabolism, can convert inorganic nitrogen into organic nitrogen. Although many studies have been conducted on PC and GS, a dynamic analysis of all of the filling stages has not been conducted. Therefore, 115 F9-10 recombinant inbred wheat lines of 'R131/R142' were used to analyze PC and GS activity during different developmental stages, using the conditional quantitative trait loci (QTL) mapping method. Twenty-two and six conditional QTL were detected for PC and GS activily, respectively. More QTL in leaf PC were detected during the early filling stages than in the later filling stages. Grain PC QTL displayed different dynamic variations to leaf PC QTL during the entire grain-filling stages. All of the QTL were expressed differently over time, and nine conditional QTL were detected across two filling stages. QTL with similar functions may have tended to group in specific locales. This study provides dynamic genetic information on protein accumulation during grain-filling stages.


Combined Application of Patient-Derived Cells and Biomaterials as 3D In Vitro Tumor Models.
Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over bi-dimensional (2D) cultures in evaluating the efficacy of chemotherapy. This commentary aims to highlight the potential of combined application of biomaterials with patient-derived cancer cells as a 3D in vitro model for the study and treatment of cancer patients. Five studies were discussed which demonstrate and provided early evidence to create 3D models with accurate microenvironments that are comparable to in vivo tumors. To date, the use of patient-derived cells for a more personalized approach to healthcare in combination with biomaterials to create a 3D tumor is still relatively new and uncommon for application in clinics. Although highly promising, it is important to acknowledge the current limitations and challenges of developing these innovative in vitro models, including the need for biologists and laboratory technicians to become familiar with biomaterial scaffolds, and the effort for bioengineers to create easy-to-handle scaffolds for routine assessment.


The Emerging Role of Polyphenols in the Management of Type 2 Diabetes.
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.


[Effect of temperature on the viability of Escherichia coli strains in seawater].
The survival and growth of E. coli strains were studied at different temperatures of sea water. The bacterial number for serotypes 055 and 078 was found to increase with a decrease in temperatue of sea water to 5 degrees C. The bacteria of serotype 015 did not grow in sea water whereas those of serotype 0115 were capable of growth only at 20 and 15 degrees C. The bacteria were able to survive from 4 to 98 days depending on the temperature of water and the strain of E. coli.


Metabolome-wide association study of neovascular age-related macular degeneration.
To determine if plasma metabolic profiles can detect differences between patients with neovascular age-related macular degeneration (NVAMD) and similarly-aged controls. Metabolomic analysis using liquid chromatography with Fourier-transform mass spectrometry (LC-FTMS) was performed on plasma samples from 26 NVAMD patients and 19 controls. Data were collected from mass/charge ratio (m/z) 85 to 850 on a Thermo LTQ-FT mass spectrometer, and metabolic features were extracted using an adaptive processing software package. Both non-transformed and log2 transformed data were corrected using Benjamini and Hochberg False Discovery Rate (FDR) to account for multiple testing. Orthogonal Partial Least Squares-Discriminant Analysis was performed to determine metabolic features that distinguished NVAMD patients from controls. Individual m/z features were matched to the Kyoto Encyclopedia of Genes and Genomes database and the Metlin metabolomics database, and metabolic pathways associated with NVAMD were identified using MetScape. Of the 1680 total m/z features detected by LC-FTMS, 94 unique m/z features were significantly different between NVAMD patients and controls using FDR (q = 0.05). A comparison of these features to those found with log2 transformed data (n = 132, q = 0.2) revealed 40 features in common, reaffirming the involvement of certain metabolites. Such metabolites included di- and tripeptides, covalently modified amino acids, bile acids, and vitamin D-related metabolites. Correlation analysis revealed associations among certain significant features, and pathway analysis demonstrated broader changes in tyrosine metabolism, sulfur amino acid metabolism, and amino acids related to urea metabolism. These data suggest that metabolomic analysis can identify a panel of individual metabolites that differ between NVAMD cases and controls. Pathway analysis can assess the involvement of certain metabolic pathways, such as tyrosine and urea metabolism, and can provide further insight into the pathophysiology of AMD.


Effect of early cryoprecipitate transfusion versus standard care in women who develop severe postpartum haemorrhage (ACROBAT) in the UK: a protocol for a pilot cluster randomised trial.
The incidence of severe postpartum haemorrhage (PPH) that requires blood transfusion is on the increase. Fibrinogen levels have been shown to drop early and significantly during PPH, which is associated with worse outcomes. Early fibrinogen replacement could potentially improve outcomes. No studies have investigated the clinical impact of early cryoprecipitate transfusion in PPH. Prior to performing a full-scale trial, a pilot study is needed to determine feasibility of the intervention and recruitment. ACROBAT is a cluster-randomised pilot study with a qualitative evaluation. Four large London maternity units are randomised to either the intervention or control group. The intervention group will adapt their major obstetric haemorrhage procedures to administer cryoprecipitate early for primary PPH. The control group will retain their standard of care.We include women at >24 weeks gestation who are actively bleeding within 24 hours of delivery and for whom transfusion of red blood cells (RBCs) has been started. We exclude women who decline blood transfusions in advance or have inherited Factor XIII or fibrinogen deficiency. Due to the emergency nature of the intervention, informed consent for administering the intervention is waived.The primary objective is to assess the feasibility of administering cryoprecipitate within 90 min of RBC request, as compared with standard treatment where cryoprecipitate is given later or not at all. Secondary objectives include the feasibility of recruitment and data collection, reasons for and barriers to consent, preliminary maternal clinical outcomes, identification of the optimal infrastructure pathways for study delivery, and acceptability of the intervention and outcomes. The trial has approvals from the London-Brighton & Sussex Research Ethics Committee (ref. 18/LO/2062), the Confidentiality Advisory Group (ref. 18/CAG/0199) and Health Research Authority (IRAS number 237959). Data analysis and publication of manuscripts will start in Q3 2020. ISRCTN12146519.


Multiscale high-speed photoacoustic microscopy based on free-space light transmission and a MEMS scanning mirror.
The conventional photoacoustic microscopy (PAM) system allows trade-offs between lateral resolution and imaging depth, limiting its applications in biological imaging in vivo. Here we present an integrated optical-resolution (OR) and acoustic-resolution (AR) multiscale PAM based on free-space light transmission and fast microelectromechanical systems (MEMS) scanning. The lateral resolution for OR is 4.9 µm, and the lateral resolution for AR is 114.5 µm. The maximum imaging depth for OR is 0.7 mm, and the maximum imaging depth for AR is 4.1 mm. The imaging speed can reach 50 k Alines per second. The high signal-to-noise ratios and wavelength throughput are achieved by delivering light via free-space, and the high speed is achieved by a MEMS scanning mirror. The blood vasculature from superficial skin to the deep tissue of a mouse leg was imaged in vivo using two different resolutions to demonstrate the multiscale imaging capability.


News from the future: health care summit caps decade of transformation, 1996-2005.
Many in academic medicine agree that its future will be very different from its past. Transformation, not tinkering, is needed if academic health science centers are to survive the challenges posed by federal and state budget constraints, the intense price competition of managed care, and the wide dispersion of information via the Internet. Academic medicine is like an ocean liner, stately and slow to turn from its charted course. But those who captain the huge, slow ship have seen the tip of the iceberg that looms in its path, and must turn to a new course now. The author presents a possible scenario of the future that describes new relationships among academic health centers, new roles for deans and department chairs, and a more collaborative approach to learning. In the scenario, set in the year 2002, the writer looks back on the changes of the period 1996-2005 and describes the relationships, management, priorities, and reward systems of the institutions responsible for health care, medical education, and biomedical research.


Classification of Individual Finger Movements from Right Hand Using fNIRS Signals.
Functional near-infrared spectroscopy (fNIRS) is a comparatively new noninvasive, portable, and easy-to-use brain imaging modality. However, complicated dexterous tasks such as individual finger-tapping, particularly using one hand, have been not investigated using fNIRS technology. Twenty-four healthy volunteers participated in the individual finger-tapping experiment. Data were acquired from the motor cortex using sixteen sources and sixteen detectors. In this preliminary study, we applied standard fNIRS data processing pipeline, i.e., optical densities conversation, signal processing, feature extraction, and classification algorithm implementation. Physiological and non-physiological noise is removed using 4th order band-pass Butter-worth and 3rd order Savitzky-Golay filters. Eight spatial statistical features were selected: signal-mean, peak, minimum, Skewness, Kurtosis, variance, median, and peak-to-peak form data of oxygenated haemoglobin changes. Sophisticated machine learning algorithms were applied, such as support vector machine (SVM), random forests (RF), decision trees (DT), AdaBoost, quadratic discriminant analysis (QDA), Artificial neural networks (ANN), k-nearest neighbors (kNN), and extreme gradient boosting (XGBoost). The average classification accuracies achieved were 0.75±0.04, 0.75±0.05, and 0.77±0.06 using k-nearest neighbors (kNN), Random forest (RF) and XGBoost, respectively. KNN, RF and XGBoost classifiers performed exceptionally well on such a high-class problem. The results need to be further investigated. In the future, a more in-depth analysis of the signal in both temporal and spatial domains will be conducted to investigate the underlying facts. The accuracies achieved are promising results and could open up a new research direction leading to enrichment of control commands generation for fNIRS-based brain-computer interface applications.


Periostin as a modulator of chronic cardiac remodeling after myocardial infarction.
After acute myocardial infarction, during the cardiac repair phase, periostin is released into the infarct and activates signaling pathways that are essential for the reparative process. However, the role of periostin in chronic cardiac remodeling after myocardial infarction remains to be elucidated. Therefore, the objective of this study was to investigate the relationship between tissue periostin and cardiac variables in the chronic cardiac remodeling induced by myocardial infarction. Male Wistar rats were assigned to 2 groups: a simulated surgery group (SHAM; n = 8) and a myocardial infarction group (myocardial infarction; n = 13). After 3 months, morphological, functional and biochemical analyses were performed. The data are expressed as means±SD or medians (including the lower and upper quartiles). Myocardial infarctions induced increased left ventricular diastolic and systolic areas associated with a decreased fractional area change and a posterior wall shortening velocity. With regard to the extracellular matrix variables, the myocardial infarction group presented with higher values of periostin and types I and III collagen and higher interstitial collagen volume fractions and myocardial hydroxyproline concentrations. In addition, periostin was positively correlated with type III collagen levels (r = 0.673, p = 0.029) and diastolic (r = 0.678, p = 0.036) and systolic (r = 0.795, p = 0.006) left ventricular areas. Considering the relationship between periostin and the cardiac function variables, periostin was inversely correlated with both the fractional area change (r = -0.783, p = 0.008) and the posterior wall shortening velocity (r = -0.767, p = 0.012). Periostin might be a modulator of deleterious cardiac remodeling in the chronic phase after myocardial infarction in rats.


Giant dual-mode graphene-based terahertz modulator enabled by Fabry-Perot assisted multiple reflection.
We report a high-performance terahertz (THz) modulator with dual operation mode. For the pulse operation mode, the proposed THz modulator has the advantage of high modulation depth (MD) and can operate in a broadband frequency range. We have experimentally achieved a MD larger than 90% for the fifth-order pulse THz echo at 0.8 THz, and the MD stays larger than 75% in a broadband frequency range larger than 1 THz, whereas, for the coherent operation mode, the Fabry-Perot (F-P) interference effect has been taken into consideration and a MD larger than 75% at 0.76 THz has also been realized.


Exercise-induced endocannabinoid signaling is modulated by intensity.
Endocannabinoids (eCB) are endogenous ligands for cannabinoid receptors that are densely expressed in brain networks responsible for reward. Recent work shows that exercise activates the eCB system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans. However, exercise-induced psychological changes reported by runners are known to be dependent on exercise intensity, suggesting that any underlying molecular mechanism should also change with varying levels of exercise intensity. Here, we examine circulating levels of eCBs following aerobic exercise (treadmill running) in recreationally fit human runners at four different intensities. We show that eCB signaling is indeed intensity dependent, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels). Our results are consistent with intensity-dependent psychological state changes with exercise and therefore support the hypothesis that eCB activity is related to neurobiological effects of exercise. Thus, future studies examining the role of exercise-induced eCB signaling on neurobiology or physiology must take exercise intensity into account.


Surface Coordination Chemistry of Metal Nanomaterials.
Surface coordination chemistry of nanomaterials deals with the chemistry on how ligands are coordinated on their surface metal atoms and influence their properties at the molecular level. This Perspective demonstrates that there is a strong link between surface coordination chemistry and the shape-controlled synthesis, and many intriguing surface properties of metal nanomaterials. While small adsorbates introduced in the synthesis can control the shapes of metal nanocrystals by minimizing their surface energy via preferential coordination on specific facets, surface ligands properly coordinated on metal nanoparticles readily promote their catalysis via steric interactions and electronic modifications. The difficulty in the research of surface coordination chemistry of nanomaterials mainly lies in the lack of effective tools to characterize their molecular surface coordination structures. Also highlighted are several model material systems that facilitate the characterizations of surface coordination structures, including ultrathin nanostructures, atomically precise metal nanoclusters, and atomically dispersed metal catalysts. With the understanding of surface coordination chemistry, the molecular mechanisms behind various important effects (e.g., promotional effect of surface ligands on catalysis, support effect in supported metal nanocatalysts) of metal nanomaterials are disclosed.