Comparative genomic analysis of human and chimpanzee proteases.
Proteolytic enzymes are implicated in multiple physiological and pathological processes. The availability of the sequence of the chimpanzee genome has allowed us to determine that the chimpanzee degradome-the repertoire of protease genes from this organism-is composed of at least 559 protease and protease-like genes and is virtually identical to that of human, containing 561 genes. Despite the high degree of conservation between both genomes, we have identified important differences that vary from deletion of whole genes to small insertion/deletion events or single nucleotide changes that lead to the specific gene inactivation in one species, mostly affecting immune system genes. For example, the genes encoding PRSS33/EOS, a macrophage serine protease conserved in most mammals, and GGTLA1 are absent in chimpanzee, while the gene for metalloprotease MMP23A, located in chromosome 1p36, has been specifically duplicated in the human genome together with its neighbor gene CDC2L1. Other differences arise from single nucleotide changes in protease genes, such as NAPSB and CASP12, resulting in the presence of functional genes in chimpanzee and pseudogenes in human. Finally, we have confirmed that the Trypanosoma lytic factor HPR is inactive in chimpanzee, likely contributing to the susceptibility of chimpanzees to T. brucei infection. This study provides the first analysis of the chimpanzee degradome and might contribute to the understanding of the molecular bases underlying variations in host defense mechanisms between human and chimpanzee.


Corrigendum to "The global threat of antimicrobial resistance: science for intervention" [New Microbes New Infect 6 (2015): 22-29].
[This corrects the article DOI: 10.1016/j.nmni.2015.02.007.].


Middle East respiratory syndrome-related knowledge, preventive behaviours and risk perception among nursing students during outbreak.
The aim of this study was to survey nursing students' Middle East respiratory syndrome-related knowledge, preventive behaviours and risk perception to examine the correlations among the variables during a Middle East respiratory syndrome outbreak. Middle East respiratory syndrome is a new viral respiratory illness. Nursing students who engage in clinical practice at hospitals may have been exposed to Middle East respiratory syndrome infection during the Middle East respiratory syndrome outbreak. This study was a descriptive cross-sectional survey. Participants (n = 249) were nursing students in their third or fourth year of the programme who were engaged in clinical practice for eight hours per day at the tertiary hospitals with Middle East respiratory syndrome patients. Knowledge, preventive behaviours and risk perception related to Middle East respiratory syndrome were measured using scales developed through a preliminary survey and validity testing. The subjects' knowledge level of Middle East respiratory syndrome was 84·4%; their practice of preventive behaviours was rated at 44·5%; and their risk perception rating was 2·4 out of 5. Middle East respiratory syndrome-related risk perception was significantly different according to gender and Middle East respiratory syndrome education. Middle East respiratory syndrome-related knowledge was significantly correlated with preventive behaviours and risk perception. Considering the low scores for items regarding knowledge and preventive behaviours, it is necessary to develop effective and systematic publicity and education programmes for nursing students. Enhancing Middle East respiratory syndrome-related knowledge by considering cooperation between hospitals and universities will sharpen nursing students' risk perception of the disease and effectively increase their preventive behaviours. Similar to other emerging infectious diseases, Middle East respiratory syndrome outbreaks may occur in other countries. The results of this study can be used to develop and apply efficient and feasible Middle East respiratory syndrome education programmes for nursing students during Middle East respiratory syndrome outbreaks.


Anemia in patients with juvenile rheumatoid arthritis.
Patients with juvenile rheumatoid arthritis may have an anemia attributable to the chronic disease, to iron deficiency, or to a combination of the two. The contribution of iron deficiency is often difficult to determine by routine laboratory studies. We studied 51 patients with pauciarticular and polyarticular juvenile rheumatoid arthritis with red blood cell counts, indices, free erythrocyte protoporphyrin, and serum ferritin. Fifteen of the 18 who were anemic were restudied after a 3 to 6-month period of iron therapy. Thirteen of the 15 responded by these criteria: a rise in hemoglobin of 1.0 gm/dl or more and an increase in mean corpuscular volume of 3 fl or more; in 11 of these 13, hemoglobin values returned to the normal range for age. These findings indicate that iron deficiency can be a major component of the anemia that is commonly found in patients with active juvenile rheumatoid arthritis.


Echogenicity enhancement by end-fluorinated polylactide perfluorohexane nanocapsules: Towards ultrasound-activable nanosystems.
Polylactide (PLA) polymers containing five distinct lengths of fluorinated (from C3F7 to C13F27) and non-fluorinated (C6H13) end-groups were successfully synthesized by ring-opening polymerization of d,l-lactide. Fluorination was expected to increase the encapsulation efficiency of perfluorohexane (PFH). 150 nm nanocapsules were obtained and 19F nuclear magnetic resonance revealed that nanocapsules formulated with fluorinated polymers increased by 2-fold the encapsulation efficiency of PFH compared with non-fluorinated derivatives, without any effect of fluorine chain length. Fluorination of the polymers did not induce any specific in vitro cytotoxicity of nanocapsules towards HUVEC and J774.A1 cell lines. The echogenicity of fluorinated-shelled nanocapsules was increased by 3-fold to 40-fold compared to non-fluorinated nanocapsules or nanoparticles devoid of a perfluorohexane core for both conventional and contrast-specific ultrasound imaging modalities. In particular, an enhanced echogenicity and contrast-specific response was observed as the fluorinated chain-length increased, probably due to an increase of density and promotion of bubble nucleation. When submitted to focused ultrasound, both intact and exploded nanocapsules could be observed, also with end-group dependency, indicating that PFH was partly vaporized. These results pave the way to the design of theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound. We have synthesized novel fluorinated polyesters and formulated them into nanocapsules of perfluorohexane as ultrasound contrast agents. This nanosystem has been thoroughly characterized by several techniques and we show that fluorination of the biodegradable polymer favors the encapsulation of perfluorohexane without producing further reduction of cell viability. Contrary to nanocapsules of perfluoroctyl bromide formulated with the fluorinated polymers [32], the presence of the fluorinated moieties leads to an increase of echogenicity that is dependent of the length of the fluorinated moiety. Morevover, the ability of nanocapsules to explode when submitted to focused ultrasound also depends on the length of the fluorinated chain. These results pave the way to theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound.


Isorhynchophylline exerts anti-asthma effects in mice by inhibiting the proliferation of airway smooth muscle cells: The involvement of miR-200a-mediated FOXC1/NF-κB pathway.
Hyperplasia of airway smooth muscle cells (ASMCs) is key to the progression of asthma. Isorhynchophylline (IRN) derived from Uncaria rhynchophylla can inhibit the proliferation of AMSCs. The major purpose of the current study was to assess the effect of IRN on the asthma symptoms was assessed both in vitro and in vivo, and the associated mechanism of the effect was also explored by focusing on the function of miR-200a. Asthma model was induced using ovalbumin (OVA) method and AMSC hyperplasia model was induced using TGF-β1. The effect of IRN on allergic asthma mice and the effect of IRN on the proliferation of ASMCs were investigated as well, and the changes in miR-200a level and FOXC1/NF-κB pathway were detected. The administration of IRN attenuated the eosinophils recruitment in BALF, reduced collagen deposition in lung tissues, and suppressed production of IgE and pro-inflammation cytokines. IRN also inhibited the proliferation and induced the apoptosis of ASMCs. Moreover, the administration of IRN increased the level of miR-200a while inhibited the activation of FOXC1/NF-κB pathway. However, after the inhibition of miR-200a level, the function of IRN on ASMCs was impaired. Collectively, it was demonstrated that the effect of IRN on asthma relied on the up-regulation of miR-200a, which then deactivated FOXC1/NF-κB pathway.


Hospital admissions via the emergency department: implications for planning and patient flow.
In summary, there are important differences among patients admitted via the ED versus those admitted via other means in terms of both utilization and patient characteristics. When compared with patients admitted via other means, patients admitted via the ED are more likely to fall into the medical patient group, to be older and to have more complex and more diseases or health conditions. Medical patients admitted via the ED are more likely to become ALC patients than are other types of patients. As hospitals, health regions and policy makers focus on improving patient flow through Canada's EDs, it is important to consider the volume and characteristics of the patient population admitted via the ED.


Scalable fabrication of superhydrophobic hierarchical colloidal arrays.
Here we report a scalable bottom-up technology for assembling hierarchical colloidal arrays with superhydrophobic surface. Non-close-packed (NCP) colloidal multilayers, which facilitate the formation of more hydrophobic surface than close-packed arrays due to a higher fraction of entrapped air in between colloidal particles, are first fabricated by a simple spin-coating technology. Uniform silica nanoparticles are then assembled on the NCP microsphere arrays by a second spin-coating process. After surface functionalization of silica particles with fluorosilane, the resulting hierarchical colloidal arrays exhibit superhydrophobic surface with high apparent water contact angle (159°) and low contact angle hysteresis (4.7°). The experimental results on both the wettability and contact angle hysteresis can be qualitatively explained by adapting the Cassie's model. This spin-coating-based colloidal self-assembly technology is compatible with standard microfabrication and enables large-scale production of superhydrophobic coatings that could find important technological applications ranging from self-cleaning diffractive optics to microfluidic devices.


Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years.
The successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia. The authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores. We evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years). Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25% of deaths were caused by CHD and 16% by dementia. Approximately 64% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia. In subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133).


Myocardial Thermal Ablation with a Transesophageal High-Intensity Focused Ultrasound Probe: Experiments on Beating Heart Models.
Described here is a study of transesophageal thermal ablation of isolated and perfused beating hearts and non-human primates. An endoscope integrating a transesophageal echocardiography probe and a high-intensity focused ultrasound transducer was built and tested on five Langendorff-isolated hearts and three 30-kg baboons. B-Mode ultrasound, passive elastography and magnetic resonance imaging were performed to monitor thermal lesions. In isolated hearts, continuous and gated sonication parameters were evaluated with acoustic intensities of 9-12 W/cm2. Sonication parameters of gated exposures with 12 W/cm2 acoustic intensity for 5 min consistently produced visible lesions in the ventricles of isolated hearts. In animals, left atria and ventricles were exposed to repeated continuous sonications (4-15 times for 16 s) at an acoustic intensity at the surface of the transducer of 9 W/cm2. Clinical states of the baboons during and after the treatment were good. One suspected lesion in the left ventricle could be evidenced by elastography, but was not confirmed by magnetic resonance imaging. The transesophageal procedure therefore has the potential to create thermal lesions in beating hearts and its safety in clinical practice seems promising. However, further technical exploration of the energy deposition in the target would be necessary before the next pre-clinical experiments.


[POPULARIZATION OF TOURISM, HEALTHY LIFESTYLE, PHYSICAL AND SOCIAL ACTIVITY IN THE PROGRAMS OF ACTIVE LONGEVITY OF SENIOR CITIZENS].
The article presents data on sports, active forms of leisure, travel among elderly Russians. An important conclusion is made that health promotion by means of active recreation and sports among senior citizens in Russia is one of the directions of active longevity policy. An overview of charitable foundations for senior citizens of the Russian Federation and their activities in promoting an active lifestyle among elderly citizens is presented.


Positioning food standards programmes to protect public health: current performance, future opportunities and necessary reforms.
To assess current performance and identify opportunities and reforms necessary for positioning a food standards programme to help protect public health against dietary risk factors. A case study design in which a food standards programme's public health protection performance was analysed against an adapted Donabedian model for assessing health-care quality. The criteria were the food standards programme's structure (governance arrangements and membership of its decision-making committees), process (decision-making tools, public engagement and transparency) and food standards outcomes, which provided the information base on which performance quality was inferred. The Australia and New Zealand food standards programme.ParticipantsThe structure, process and outcomes of the Programme. The Programme's structure and processes produce food standards outcomes that perform well in protecting public health from risks associated with nutrient intake excess or inadequacy. The Programme performs less well in protecting public health from the proliferation and marketing of 'discretionary' foods that can exacerbate dietary risks. Opportunities to set food standards to help protect public health against dietary risks are identified. The structures and decision-making processes used in food standards programmes need to be reformed so they are fit for purpose for helping combat dietary risks caused by dietary excess and imbalances. Priorities include reforming the risk analysis framework, including the nutrient profiling scoring criterion, by extending their nutrition science orientation from a nutrient (reductionist) paradigm to be more inclusive of a food/diet (holistic) paradigm.


Establishment of Pediatric Subspecialty Advanced Practice Provider Fellowship Training Programs to Optimize Advanced Practice Utilization in Pediatric Specialty Care and Facilitate Interprofessional Integration.
In the setting of demand for health care providers exceeding the supply of physicians, shift toward value-based care, and institutional gaps in the understanding of advanced practice provider (APP) scope of practice, one urban academic pediatric hospital developed 12-month subspecialty post-graduate fellowship programs for APPs in 18 subspecialties in an effort to optimize APP utilization at top of license and increase access to high-quality care. [J Contin Educ Nurs. 2022;53(11):478-480.].


Serum Uric Acid Is Associated with Cerebral White Matter Hyperintensities in Patients with Acute Lacunar Infarction.
The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study showed a significant decrease in transcranial Doppler pulsatility index (PI) with cilostazol treatment after 90 days of acute lacunar infarction. The aim of this analysis was to perform a subgroup analysis of the ECLIPse study to explore the relationship between serum uric acid (UA) and the volume of white matter hyperintensities (WMH) in patients with acute lacunar infarction. The ECLIPse was a multicenter, randomized, double-blind, placebo-controlled study conducted in Korea. For this subgroup analysis, WMH volume was measured for those subjects for whom FLAIR or T2-weighted images were available using semiautomated computerized software. Of the 203 patients in 8 hospitals in the ECLIPse study, 130 in 6 hospitals were entered for this subgroup analysis. The mean age was 64.7 ± 9.95 years, and 20.8% were women. The mean WMH volume was 11.57 cm(3) (.13 to 68.45, median 4.86) and mean serum UA was 5.2 mg/dL (1.5 to 8.9). Multiple linear regression analysis revealed that age (P < .001) and serum UA (P = .013) were significantly associated with WMH volume. Age-adjusted scatterplots showed that serum UA level was positively related to WMH volume in patients with acute lacunar infarction (r = 0.275, P = .003). This study showed that serum UA was associated with cerebral WMH in patients with acute lacunar infarction.


Electron arc therapy of the postmastectomy prosthetic breast.
Reconstructive surgery of the postmastectomy breast presents new challenges to postoperative radiation therapy. This paper evaluates the dosimetric significance of oblique incidence of the electron field on the reconstructed mound during arc therapy. Using film densitometry, the relative dose distributions resulting from electron arc therapy incident on phantoms simulating the breast and chest wall dimensions of an actual patient are evaluated. Irradiation of the breast phantom in normal supine position results in constriction of the dose distribution at the junction of the reconstructed mound with the chest wall. Angulation of the phantom to provide a more normal incidence of the electron beam during arc reduces the constriction by minimizing obliquity of the incident electrons. These measurements suggest that, with proper positioning of the patient relative to the incident electron beam, electron arc therapy may be used as an alternative treatment technique for treatment of the postmastectomy reconstructed breast and chest wall.


Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus.
Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received. Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.


Intracellular GSH/GST antioxidants system change as an earlier biomarker for toxicity evaluation of iron oxide nanoparticles.
Glutathione (GSH) and glutathione-S-transferases (GSTs) are two frontlines of cellular defense against both acute and chronic toxicity of xenobiotics-induced oxidative stress. The contribution of GSH and GST enzymes to signaling pathways and the regulation of GSH homeostasis play a central role in the detoxification of numerous environmental toxins and impurities. Iron oxide nanoparticles stemmed from traffic exhaust, steel manufacturing, or welding as a potential environmental pollution can lead to adverse respiratory outcomes and aggravate the risk of chronic health conditions via persistent oxidative stress. In this work, two kinds of acute exposure experiments of iron oxide (Fe2O3 and Fe3O4) nanoparticles in cells and in vivo were conducted to evaluate the GSH levels and GST activity. Our current research presented Fe3O4 nanoparticles at lower concentrations (≤100 μg/ml) seem to be more toxic to the human bronchial epithelial cells as their consumption of GSH and decrease of GST activity. The catalysis activity of Fe3O4 nanoparticles per se may contribute to the intracellular GSH consumption along with inhibition of glutathione-S-transferase class mu 1 and P (GSTM1 and GSTP1) active site and expression decrease of GSTM1 and GSTP1. Accordingly, the GSH consumption and decrease in GST activity directed to the further lipid peroxidation regarded as an earlier marker for toxicity evaluation of iron oxide nanoparticles, and relevant intervention may be effective for prevention of respiratory exposure induced damage from iron oxide nanoparticles.


Multimeric analysis of von Willebrand factor in megakaryocytes.
Von Willebrand factor (vWF) is a glycoprotein that appears to play a major role in subserving the adhesion of platelets to subendothelium during hemostasis. Endothelial cells have been shown capable of synthesizing and releasing this large, multimeric glycoprotein that normally circulates in the plasma in association with the factor VIII coagulant molecule. Megakaryocytes, the precursor cells of blood platelets, also appear to possess vWF biosynthetic capacity, since cultured guinea pig megakaryocytes have been shown to produce a polypeptide precipitable by antibody to vWF. We now report a study of the multimeric structure of vWF in the megakaryocyte, as well as a quantitative comparison of megakaryocyte vWF with that of platelets and plasma in the guinea pig. Multimeric analysis on SDS agarose gels employing 125I-emu anti-human vWF revealed striking homology between human and guinea pig vWF. Platelets and megakaryocytes from the same guinea pigs contained vWF of highly comparable multimeric composition. Moreover, megakaryocytes and platelets both contained a subset of very high molecular weight multimers not present in plasma. Quantitation of vWF in megakaryocytes and platelets was achieved with a radioimmunoassay performed on detergent (NP-40) lysates of washed cells. These measurements showed that megakaryocytes and platelets contain 0.079 and 0.069 U of vWF per mg protein, respectively. The results of these studies suggest that megakaryocytes represent the primary, if in fact not sole, source of platelet vWF.


Human Microbiomes and Disease for the Biomedical Data Scientist.
The human microbiome is complex, variable from person to person, essential for health, and related to both the risk for disease and the efficacy of our treatments. There are robust techniques to describe microbiota with high-throughput sequencing, and there are hundreds of thousands of already-sequenced specimens in public archives. The promise remains to use the microbiome both as a prognostic factor and as a target for precision medicine. However, when used as an input in biomedical data science modeling, the microbiome presents unique challenges. Here, we review the most common techniques used to describe microbial communities, explore these unique challenges, and discuss the more successful approaches for biomedical data scientists seeking to use the microbiome as an input in their studies.


The association between wind-related variables and stroke symptom onset: A case-crossover study on Jeju Island.
Although several studies have investigated the effects of ambient temperature on the risk of stroke, few studies have examined the relationship between other meteorological conditions and stroke. Therefore, the aim of this study was to analyze the association between wind-related variables and stroke symptoms onset. Data regarding the onset of stroke symptoms occurring between January 1, 2006, and December 31, 2007 on Jeju Island were collected from the Jeju National University Hospital stroke registry. A fixed-strata case-crossover analysis based on time of onset and adjusted for ambient temperature, relative humidity, air pressure, and pollutants was used to analyze the effects of wind speed, the daily wind speed range (DWR), and the wind chill index on stroke symptom onset using varied lag terms. Models examining the modification effects by age, sex, smoking status, season, and type of stroke were also analyzed. A total of 409 stroke events (381 ischemic and 28 hemorrhagic) were registered between 2006 and 2007. The odds ratios (ORs) for wind speed, DWR, and wind chill among the total sample at lag 0-8 were 1.18 (95% confidence interval (CI): 1.06-1.31), 1.08 (95% CI: 1.02-1.14), and 1.22 (95% CI: 1.07-1.39) respectively. The ORs for wind speed, DWR, and wind chill for ischemic stroke patients were slightly greater than for patients in the total sample (OR=1.20, 95% CI: 1.08-1.34; OR=1.09, 95% CI: 1.03-1.15; and OR=1.22, 95% CI: 1.07-1.39, respectively). Statistically significant season-specific effects were found for spring and winter, and various delayed effects were observed. In addition, age, sex, and smoking status modified the effect size of wind speed, DWR, and wind chill. Our analyses showed that the risk of stroke symptoms onset was associated with wind speed, DWR, and wind chill on Jeju Island.


Surface Modification of Poly(lactide-co-glycolide) Nanoparticles for the Sustained in vitro Release and the Enhanced Cytotoxicity of Chelidonine.
Chelidonine is a potent anticancer against several cell lines. However, low bioavailability and water solubility restrict the clinical applications of this compound. The aim of this research was to develop a novel formulation of chelidonine encapsulated in the nanoparticles of poly(d l-lactic-co-glycolic acid) (PLGA) employing vitamin E D-α-tocopherol acid polyethylene glycol 1000 succinate (E TPGS) as a modifier to increase bioavailability. Chelidonine-encapsulated PLGA nanoparticles were fabricated using a single emulsion method and modified by various concentrations of E TPGS. Nanoparticles were recognized in terms of morphology, surface charge, drug release, size, drug loading, and encapsulation efficiency to obtain the optimized formulation. The cytotoxicity of different nanoformulations in HT-29 cells was evaluated using the MTT assay. The cells were stained with propidium iodide and annexin V solution to evaluate apoptosis using flow cytometry. Spherical nanoparticles prepared with 2% (w/v) of E TPGS had the optimum formulation in the nanometer size range (153 ± 12.3 nm), with a surface charge of -14.06 ± 2.21 mV, encapsulation efficiency of 95.58 ± 3.47%, drug loading of 33.13 ± 0.19%, and drug release profile of 73.54 ± 2.33. In comparison with non-modified nanoparticles and free chelidonine, E TPGS-modified nanoformulations improved anti-cancer capability even after three-months storage. Our results showed that E TPGS is an effective biomaterial for surface modification of nanoparticles, which can serve as a potential treatment for cancer.


Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism.
Methionine adenosyltransferases (MATs) are a family of enzymes in charge of synthesising S-adenosylmethionine (SAM), the most important methyl donor present in living organisms. These enzymes use methionine and ATP as reaction substrates, which react in a S(N)2 fashion where the sulphur atom from methionine attacks C5' from ATP while triphosphate chain is cleaved. A MAT liver specific isoenzyme has been detected, which exists in two distinct oligomeric forms, a dimer (MAT III) and a tetramer (MAT I). Our previously reported crystal structure of MAT I complexed with an inhibitor led to the identification of the methionine-binding site. We present here the results obtained from the complex of MAT I with a competitive inhibitor of methionine, (2S,4S)-amino-4,5-epoxypentanoic acid (AEP), which presents the same features at the methionine binding site reported before. We have also analysed several complexes of this enzyme with methionine and ATP and analogues of them, in order to characterise the interaction that is produced between both substrates. The crystal structures of the complexes reveal how the substrates recognise each other at the active site of the enzyme, and suggest a putative binding site for the product SAM. The residues involved in the interactions of substrates and products with MAT have been identified, and the results agree with all the previous data concerning mutagenesis experiments and crystallographic work. Moreover, all the information provided from the analysis of the complexes has allowed us to postulate a catalytic mechanism for this family of enzymes. In particular, we propose a key role for Lys182 in the correct positioning of the substrates, and Asp135(*), in stabilising the sulphonium group formed in the product (SAM).


Childhood leukemia--risk factors and the need for an interdisciplinary research agenda.
The International Agency for Research on Cancer (IARC) has classified high as well as low-frequency fields as "possibly carcinogenic to humans" (Group 2B). For high frequency fields the recent assessment is based mainly on weak positive associations described in some epidemiological studies between glioma and acoustic neuroma and the use of mobile and other wireless phones. Also for lowfrequency fields the evidence is based on epidemiological findings revealing a statistic association between childhood leukemia (CL) and low-level magnetic fields. The basic findings are already 10 years old. They have since been supported by further epidemiological studies. However, the knowledge on the main/crucial question of causality has not improved. This fact and in addition the small, but statistically significant increased incidence of CL in the surrounding of German nuclear power plants have motivated the German Office for Radiation Protection (BfS) to work toward a better understanding of the main causes of CL. A long-term strategic research agenda has been developed which builds on an interdisciplinary, international network and aims at clarifying the aetiology of childhood acute lymphoblastic leukemia.


LBP1C-2 from Lycium barbarum maintains skeletal muscle satellite cell pool by interaction with FGFR1.
Muscle stem cells, called satellite cells (SCs), are employed to repair and rebuild muscle. SC-based therapeutic strategies are urgently needed. In this study, we showed that Lycium barbarum extract (LBE) improved the number of SCs and enhanced muscle regeneration by promoting SC activation and self-renewal in both adult and aging mice. L. barbarum polysaccharide (LBP), the main component of LBE, also played a similar role. More importantly, LBP1C-2, a homogeneous polysaccharide isolated from LBP, was uncovered to be an active component in regulating SC function. Mechanism study revealed that LBP1C-2 might bind to FGFR1 to activate SCs and promote SC self-renewal through Spry1 upregulation. This might be the first study to show that LBE participated in the regulation of SCs, and the active components and targets of LBE were identified. This study lays a theoretical foundation for the medicinal or auxiliary medicinal use of L. barbarum in skeletal muscle.


Fibronectin-fibrin cross-linking: a regulator of cell behavior.
At sites of tissue injury or inflammation, extravasation of plasma proteins leads to the formation of a complex fibrillar matrix composed primarily of fibrin and plasma fibronectin (pFN). This protein meshwork serves not only to reestablish the integrity of the vascular system but also to provide a scaffold for cell migration and subsequent wound repair. The interactions between cell surface receptors and this provisional extracellular matrix (ECM) provide important cues that can modulate the cellular response at the injury site, leading to alterations in cell growth and gene expression. Key determinants of this response may lie in the structure and composition of this "injury-associated" ECM.


Generation of lentivirus vectors using recombinant baculoviruses.
In spite of advances in conventional four-plasmid transient transfection methods and development of inducible stable production cell lines, production of replication-defective lentiviral vectors in clinical scale has been challenging. Baculovirus technology offers an alternative to scalable virus production as a result of fast and easy production of baculoviruses, efficient transduction of mammalian cells and safety of the baculoviruses. As a first step toward scalable lentiviral production system, we have constructed four recombinant baculoviruses: the BAC-transfer virus expresses green fluorescent protein (GFP) as a transgene and BAC-gag-pol, BAC-vesicular stomatitis virus glycoprotein G and BAC-rev express all elements required for a safe lentivirus vector generation. Following 293T cell transduction with recombinant baculoviruses functional lentiviruses were produced. Different baculovirus concentrations, mediums and transduction times were used to find optimal conditions for lentivirus production. The unconcentrated lentiviral titers in cell culture mediums were on average 2.5 x 10(6) TU ml(-1), which are comparable to titers of the lentiviruses produced by conventional four-plasmid methods. Lentiviruses produced by baculovirus method transduced HeLa cells and showed sustained GFP expression. No evidence of the formation of replication competent lentiviruses was detected by p24 enzyme-linked immunosorbent assay. Our results show that baculoviruses are an attractive alternative for the production of lentiviruses in mammalian cells.


The effect of ethanol on spontaneous contractions and on the contraction produced by periarterial nerve stimulation and by acetylcholine in the rat isolated ileum.
1. The effect of ethanol (0.01-1000 mg.ml-1) on tone, contractility, and the contractions produced by periarterial nerve stimulation and by acetylcholine was studied in the rat isolated ileum. 2. In low concentrations, ethanol reduced the spontaneous contractions by 60 +/- 1.5% and in high concentrations, it produced a marked contraction in the muscle (3.2 +/- 0.3 g, mean +/- SE, n = 6). 3. In the presence of adrenergic, histaminergic, serotonin and prostaglandin antagonists, ethanol (1.8 mg.ml-1) reduced the contractions produced by periarterial nerve stimulation, at 1-100 Hz with 20 V and 0.2 msec pulse duration, by 80 +/- 3.4%. Ethanol also reduced the contractions produced by acetylcholine (0.001-1 microgram.ml-1), the mean EC50 values were 0.1 +/- 0.01 microgram.ml-1, control, and 0.96 +/- 0.1 microgram.ml-1, in ethanol, respectively. 4. Although the mechanism of action of ethanol at the gut smooth muscle is not clear, it is known that it may block conduction, depolarize the cell membrane and cause release of intracellular calcium, which is, in part, responsible for the contraction produced by ethanol in the rat ileum.


Risk factors for adverse events occurring after recovery from stereotactic brain biopsy in dogs with primary intracranial neoplasia.
Stereotactic brain biopsy (SBB) allows for histopathologic diagnosis of brain tumors. Adverse events (AE) occur in 5 to 29% of dogs after SBB, but risk factors associated with developing AE are poorly described. Identify clinicopathologic, diagnostic imaging, or procedural variables that are associated with AE in dogs after SBB. Twenty-nine dogs with brain tumors. Retrospective, case-control study. Dogs had laboratory investigations performed before SBB, as well as clinical examinations and diagnostic imaging of the brain before and after SBB. Cases experienced AE after SBB including transient exacerbation of preexisting neurologic deficits, transient new deficits, or permanent neurologic deficits. Controls had SBB performed without AE. Fisher's exact and Student's t tests were used to examine associations between the postulated risk factors and AE. Adverse events occurred in 8/29 (27%) dogs, and 7/8 AE (88%) were transient. Cases were significantly more likely to have T2W-heterogenous tumors (88 versus 38%; P = .04) and lower platelet counts (194.75 ± 108.32 versus 284.29 ± 68.54 ×103 /mm3 , P = .006). Dogs with gradient echo signal voids present on baseline imaging were significantly more likely to have hemorrhage present after biopsy, and 7/8 (88%) of cases had hemorrhage on imaging after SBB. Twenty-seven percent of dogs undergoing SBB experience AE, with the majority of AE resolving with 1 week. Platelet counts should be ≥185 000/mm3 to minimize risk of SBB-associated AE. Observation of intracranial hemorrhage after biopsy can have important clinical implications, as this was observed in 88% of dogs with AE.


[Scintillation counting as an in vitro method for assessing the pretherapeutic effectiveness of planned tumor chemotherapy in patients with ovarian cancer].
In vitro testing methods to obtain information about the proliferation of the tumour, which we want to treat by chemotherapy, have been vindicated by the biological individuality of ovarian cancer cells. The determination of the incorporation rate of 3H-thymidine in cells of ovarian cancer by scintillation counting may be recommended as a prognostic factor in regard of success of chemotherapy in patients with this disease.


Effects of the placement of endosseous implants in vascularized bone grafts on bone union in beagle dogs.
Recently, reconstructive surgery with revascularized osteocutaneous flaps has been used to restore function in patients with bone defects caused by surgery for oral cancer. However, few basic studies have addressed problems such as the union of bone segments after osteotomy, the effects of dental implant placement on blood flow, and bone formation at the bone:implant interface in grafted bone. Nine adult beagle dogs were divided into three groups of three dogs each. Each group received osteotomized vascularized tibial grafts, osteotomized tibial grafts with implants (implants placed in contralateral limbs as control), or simple (non-vascularized) tibial grafts. The development of bone around the implants was studied by histological examination, contact micro-radiography (CMR), and fluorescent bone labeling. In the dogs receiving osteotomized vascularized tibial grafts, bone bridging was confirmed at both the medial and distal junctions of the bone segments after 4 weeks. Additional newly formed bone was observed after 8 weeks, and bone union at the surface of the segments was completed after 12 weeks. In contrast, bone formation was clearly delayed in dogs receiving simple (non-vascularized) tibial grafts. Histologically, no difference in bone union was evident between limbs with dental implants in tibial bone and control limbs without implants, suggesting that implant placement does not negatively affect revascularization. Fluorescent bone labeling technique confirmed high vascularity of the vascularized tibial bone grafts but not of the simple (non-vascularized) tibial bone grafts early after the procedure. Our results suggest that osseointegration occurred around dental implants placed at the same time as reconstruction with osteotomized vascularized bone grafts in this animal model.


Identification and association of ISSR markers for thermal stress in polyvoltine silkworm Bombyx mori.
Evaluation of genetic resources is an essential prerequisite for their effective utilization. In India, the tropical climate prevails in most of the sericultural belts, where temperature goes beyond the ambient during summer, adversely affecting the silkworm rearing. Although polyvoltine silkworms are poor in silk content, they are mostly tolerant to tropical conditions and diseases. With an aim to identify potential silkworm races/breeds specific to thermo-tolerance for their effective utilization in breeding programme, 15 selected polyvoltine silkworm races were studied for their thermo-tolerance behaviour. Their genomic DNA samples were analyzed for ISSR-PCR using 15 selected primers. The UPGMA analysis based on Nei and Li algorithm has clustered the 15 silkworm races into five groups and one isolate. ALSCAL-multidimensional scaling has not only supported the information generated by the dendrogram, but it has made the genetic distance among races more clear and substantiating their status in terms of thermal stress where pupation rate was taken as indicator. Further, discriminant function analysis (DFA) was done with three groups of silkworms classified for thermal stress viz. susceptible, moderately tolerant and tolerant. The canonical correlation value was estimated to be 0.987 (Wilk's lambda = 0.004; chi2 = 36.044, p < 0.05). DFA clearly discriminated the above three groups. Beta statistics with t value and its significance for the markers identified through stepwise multiple regression analysis (MRA) revealed a total of five bands (807(1300), 808(3000), 808(4000), 834(4000), and 834(3000)) showing correlation with pupation rate after thermal treatment. Out of them, marker 8083000 showed maximum and highly significant correlation (r = 0.757, p < 0.001, t = 4.182) with pupation rate among the silkworm races. The identified putative markers are being used to develop DNA marker to be used in evolving thermo-tolerant silkworm breeds using marker assisted selection programme.


Evaluating a nurse-led survivorship care package (SurvivorCare) for bowel cancer survivors: study protocol for a randomized controlled trial.
Colorectal cancer (CRC) is the most common cancer affecting both men and women in Australia. The illness and related treatments can cause distressing adverse effects, impact on emotional and psychological well-being, and adversely affect social, occupational and relationship functioning for many years after the end of treatment or, in fact, lifelong. Current models of follow-up fail to address the complex needs arising after treatment completion. Strategies to better prepare and support survivors are urgently required. We previously developed a nurse-led supportive care program (SurvivorCare) and tested it in a pilot study involving 10 CRC survivors. The intervention was found to be highly acceptable, appropriate, relevant and useful. This study is a multisite, randomised controlled trial, designed to assess the impact of the addition of the SurvivorCare intervention to usual post-treatment care, for people with potentially cured CRC. SurvivorCare comprises the provision of survivorship educational materials, a tailored survivorship care plan, an individually tailored nurse-led, face-to-face end of treatment consultation and three subsequent telephone calls. Eligible patients have completed treatment for potentially cured CRC. Other eligibility criteria include stage I to III disease, age greater than 18 years and adequate understanding of English. All consenting patients complete questionnaires at three time points over a six-month period (baseline, two and six months). Measures assess psychological distress, unmet needs and quality of life. This supportive care package has the potential to significantly reduce individual suffering, whilst reducing the burden of follow-up on acute cancer services through enhanced engagement with and utilisation of general practitioners and community based services. If the intervention is successful in achieving the expected health benefits, it could be disseminated readily. All training and supporting materials have been developed and standardised. Furthermore, the intervention could easily be adapted to other cancer or chronic disease settings. Australian New Zealand Clinical Trial Registry ACTRN12610000207011.


The stentless freestyle bioprosthesis: impact of age over 80 years on quality of life, perioperative, and mid-term outcome.
The steadily increasing life expectancy of the population in the Western World, together with the progress in noninvasive diagnostic methods and operating techniques lead to an increase in aortic valve surgery in elderly people. Is there an increased risk of adverse perioperative and mid-term outcome for octogenarians and do they benefit from aortic valve replacement (AVR) with stentless bioprostheses? Between 1996 and 2002, 503 patients older than 60 years underwent AVR with a stentless Freestyle bioprosthesis. Seventy-six of them were older than 80 years. The risk of operative mortality, perioperative complications, valve-related morbidity for octogenarians was determined by multivariate logistic regression. In general, risk-adjusted analyses did not reveal an increased risk of operative mortality (p = 0.4), postoperative atrial fibrillation (p = 0.2), prolonged ventilation (p = 0.5), prolonged stay in the intensive care unit (p = 0.3), or mid-term valve-related morbidity as prosthetic valve endocarditis (p = 0.2), reoperation (p = 0.4), bleeding events (p = 0.1), and stroke (p = 0.8) for octogenarians. Continuously increasing age was an independent risk factor for postoperative neurological complications (OR = 1.8 per 10 years, p = 0.04). Quality of life was equal to or better than the general population of the same age. Median survival time of octogenarians was 5.2 +/- 0.5 years. Except for postoperative neurological complications, octogenarians receiving stentless bioprostheses had no increased risk of adverse perioperative and mid-term outcome in comparison to younger patients. As quality of life and life expectancy after AVR with stentless valves were equal to the general population, AVR with stentless bioprostheses should not be withheld from octogenarians.


The bidirectional relationship of depression and diabetes: a systematic review.
Depression and diabetes are both serious chronic conditions common in Western cultures. These conditions impart a significant burden on the patients and society. Depression is often comorbid with chronic illness, and past research has found an increased prevalence of depressive symptoms in patients with Type 2 Diabetes Mellitus (T2DM). However, the exact nature and direction of this relationship are unknown. Depression is often thought to be a consequence of diabetes, perhaps due to the burden of chronic illness. Research has also suggested that depression may be a risk factor for development of diabetes, in part due to biochemical changes in depression and in part because of a reduction of health care behaviors in individuals with depression. This paper reviews the literature behind both lines of investigation and includes special diagnostic and clinical considerations for at risk populations. We discuss clinical implications, limitations of current research, and areas of interest for future research.


[Pulse oximetry screening of critical congenital heart defects in the neonatal period. The Spanish National Neonatal Society recommendation].
Due to its severity, as well as the consequences of a late diagnosis, critical congenital heart defects (CCHD) represent a challenging situation, making an early diagnosis necessary and ideally before symptoms appear when circulatory collapse or death of the newborn can occur. Due to this, a prenatal and very early postnatal diagnosis is very important. Prenatal ultrasound screening and physical examination of the newborn can miss a considerable number of CCHD cases. Pulse oximetry screening has been demonstrated to be an effective, non-invasive, inexpensive, and well accepted tool in the early diagnosis of CCHD. The Spanish National Society of Neonatology, through its Standards Committee, and based on the current evidence, recommend the implementation of pulse oximetry screening of CCHD in Spain, and then to offer the best therapy possible to these newborn infants.


Noninvasive continuous beat-to-beat radial artery pressure via TL-200 applanation tonometry.
The Tensys TL-200(®) noninvasive beat-to-beat blood pressure (BP) monitor displays continuous radial artery waveform as well as systolic, mean and diastolic BP from a pressure sensor directly over the radial artery at the wrist. It locates the site of maximal radial pulse signal, determines mean BP from maximal pulse waveform amplitude at optimal artery compression and then derives systolic and diastolic BP. We performed a cross-sectional study of TL-200 BP comparisons with contralateral invasive radial artery (A-Line) BP values in 19 subjects during an average 2.5 h of general anesthesia for a wide range of surgical procedures. Two hundred and fifty random sample pairs/patient resulted in 4,747 systolic, mean and diastolic BP pairs for analysis. A-Line BP ranged from 29 mm Hg diastolic to 211 mm Hg systolic, and heart rate varied between 38 and 210 beats/min. Bland-Altman analysis showed an average 2.3 mm Hg TL-200 versus A-Line systolic BP bias and limits of agreement (1.96 SD) were ± 15.3 mm Hg. Mean BP showed a 2.3 mm Hg TL-200 bias and ± 11.7 mm Hg limits of agreement, while diastolic BP showed a 1.7 mm Hg bias and ± 12.3 mm Hg limits of agreement. Coefficients of determination for TL-200 and A-Line BP regression were r² = 0.86 for systolic, r² = 0.86 for mean, and r² = 80 for diastolic BP, respectively, with no apparent change in correlation at low or high BP. Bland-Altman analysis suggested satisfactory agreement between TL-200 noninvasive beat-to-beat BP and invasive A-Line BP. Paired TL-200/A-Line BP comparisons showed a high coefficient of determination.


Persistent low bone mineral density in adolescent idiopathic scoliosis: A longitudinal study.
Since osteopenia has been reported to potentially associated with the progression of scoliosis, bone mineral density (BMD) might have some influences on adolescent idiopathic scoliosis (AIS). However, little is known about longitudinal BMD changes in AIS patients. This study aimed to investigate whether osteopenia in preoperative AIS patients persist at bone maturity, and to evaluate the association between BMD and AIS severity. We reviewed 61 AIS patients who underwent surgery when they were Risser grade 4 or below and less than 20 years old (16.6 ± 1.9 years), were followed until they were at least 18 years old and had a Risser grade of 5, and followed at least 2 years after the surgery (mean follow-up 4.9 ± 1.7 years). We evaluated radiographical parameters and proximal femur BMD before surgery and at the final follow-up. A BMD of less than the mean minus 1SD was considered as low BMD. Based on preoperative BMD, 37 patients were assigned to normal BMD (N) group (1.02 ± 0.08 g/cm2) and 24 patients to low BMD (L) group (0.82 ± 0.06 g/cm2). All patients in the N-group had normal BMD at the final follow-up. In the L group, 15 patients (62.5%) had low BMD at the final follow-up (L-L group; preoperative 0.79 ± 0.05 g/cm2 and final follow-up 0.78 ± 0.05 g/cm2). The mean preoperative Cobb angle was significantly larger in the L-L group (67.8 ± 11.2°) than in those with normal BMD at the final follow-up (L-N group, 55.6 ± 11.8°) or the N-N group (50.8 ± 7.6°). Preoperative BMD was significantly negative correlated with the preoperative Cobb angle. The age at surgery and mean preoperative BMI were similar in the L-N and L-L groups. Of AIS patients with low preoperative BMD, 62.5% still had low BMD after reaching bone maturity, and low BMD was associated with the severity of scoliosis.


Propofol increases contractility during alpha1a-adrenoreceptor activation in adult rat cardiomyocytes.
The objective of this study was to identify the extent to which propofol alters intracellular free Ca2+ concentration ([Ca2+]i), myofilament Ca sensitivity, and contraction of individual cardiomyocytes during activation of alpha1a adrenoreceptors and to determine the cellular mechanism of action. Freshly isolated ventricular myocytes were obtained from adult rat hearts. Myocyte shortening and [Ca2+]i were simultaneously monitored in individual cardiomyocytes exposed to phenylephrine after treatment with chloroethylclonidine (alpha1b-adrenoreceptor antagonist) and BMY 7378 (alpha1d-adrenoreceptor antagonist). Data are reported as mean +/- SD. Phenylephrine increased myocyte shortening by 124 +/- 9% (P = 0.002), whereas peak [Ca2+]i only increased by 8 +/- 3% (P = 0.110). Inhibition of phospholipase A2 and phospholipase C attenuated the phenylephrine-induced increase in shortening by 84 +/- 11% (P = 0.004) and 15 +/- 6% (P = 0.010), respectively. Inhibition of protein kinase C (PKC) and Rho kinase attenuated the phenylephrine-induced increase in shortening by 17 +/- 8% (P = 0.010) and 74 +/- 13% (P = 0.006), respectively. In the presence of phenylephrine, propofol increased shortening by 40 +/- 6% (P = 0.002), with no concomitant increase in [Ca2+]i. PKC inhibition prevented the propofol-induced increase in shortening. Selective inhibition of PKCalpha, PKCdelta, PKCepsilon, and PKCzeta reduced the propofol-induced increase in shortening by 12 +/- 5% (P = 0.011), 36 +/- 8% (P = 0.001), 32 +/- 9% (P = 0.007), and 19 +/- 5% (P = 0.008), respectively. Na+ - H+ exchange inhibition reduced the propofol-induced increase in shortening by 56 +/- 7% (P = 0.001). Activation of alpha1a adrenoreceptors increases cardiomyocyte shortening primarily via a phospholipase A2-dependent, Rho kinase-dependent increase in myofilament Ca2+ sensitivity. Propofol further increases myofilament Ca2+ sensitivity and shortening via a PKC-dependent pathway and an increase in Na+ - H+ exchange activity.


Diagnosing iron deficiency in a hospital population.
The iron status of four hundred and forty-seven hospital patients was studied in order to assess the efficiency of laboratory tests in diagnosing iron deficiency. One hundred and three patients (23%) were iron deficient on bone marrow examination. The laboratory tests had a low diagnostic efficiency, with either a low diagnostic rate or a high false positive rate. However, serum ferritin, despite a diagnostic rate of 25% did establish the diagnosis with near certainty, avoiding the need for invasive and costly investigations. Serum ferritin should be retained in the laboratory investigation of iron deficiency. Serum iron with iron binding capacity should be removed from the repertoir.


Development and function of cortical thymic epithelial cells.
The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCRαβ(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of β5t, a cTEC-specific subunit of the thymoproteasome.


Is the Pyriform Ligament Important for Alar Width Maintenance After Le Fort I Osteotomy?
To determine whether identification and incorporation of the pyriform ligament in the alar cinch results in decreased alar base widening compared with standard alar cinch techniques. This was a retrospective case series and the sample was composed of patients undergoing Le Fort I osteotomy. Intraoperatively, the pyriform ligament was identified and incorporated in the alar cinch suture. Greatest alar width (GAW) measured immediately after closure was compared with GAW measured at least 5 months postoperatively. The change in alar base width was compared with that reported in the literature using other alar cinch techniques. Two case examples are reported. The sample was composed of 15 patients (mean age, 27.1 yr; 27% female). The mean postoperative change in GAW was 1.0 ± 0.6 mm (2.59 ± 1.59%). Postoperative change in alar base width reported in the literature ranged from 0.5 to 10.8%. The pyriform ligament is easily identified during exposure of the maxilla and pyriform aperture and can be used to control widening of the alar base after Le Fort I osteotomy.


[Unusual tumor of the stomach].
Stomach melanomas are exceptional and often secondary to cutaneous tumors. Their symptomatology is not specific. We report the case of a 66-year-old woman, hospitalized with a three month history of epigastric pain and weight loss. Gastroscopy had revealed a polyp of the gastric mucosa. Histopathologic examination confirmed the diagnosis of a gastric infiltration by a melanoma. At exploration, there were lung, liver and bone metastasis and no cutaneous melanoma. The diagnosis of polymetastasis from a melanoma without primitive was kept. The patient died three months later.


Synergistic effect between two bacteriocin-like inhibitory substances produced by Lactobacilli Strains with inhibitory activity for Streptococcus agalactiae.
Group B streptococci (GBS) are bacterial species that colonize the vagina in pregnant women and as such may cause serious infections in neonates that passed through the birth channel. The objective of this work was to study the inhibitory activities produced by each bacteriocin-like inhibitory substance (BLIS) of Lactobacillus rhamnosus L60 and Lactobacillus fermentum L23, and the effects of the combined BLIS-es of these lactobacilli on GBS. The interactions between the BLIS-es were assessed by qualitative and quantitative methods on agar plates. The minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs) were determined by a modification of the broth microdilution and checkerboard methods, respectively. Antibiotic susceptibilities of all S. agalactiae strains were assayed and the results of these tests were evaluated for statistical significance. A 7.5% of GBS isolates were recovered from 760 pregnant women and 91% of those strains were susceptible to each BLIS produced by L. fermentum, L. rhamnosus, and also to a mixture of them. The comparisons among the BLIS-es showed statistically significant differences, with a combination of the BLIS-es from the two Lactobacillus species being better than the BLIS of each one alone (P < 0.05) as GBS growth inhibitors. Synergistic activities between the BLIS-es were found on 100% of susceptible GBS strains, MICs ranges of BLIS of L23 and L60 were 80-160 and 160-320 UA ml(-1), respectively. By the checkerboard method, the BLIS-es combination showed synergistic effect on all sensitive strains tested, with values of FICs ranging from 0.131 to 0.218. The BLIS-es produced by these lactobacilli of vaginal origin were able to inhibit S. agalactiae isolates. The results indicate that these strains may have probiotic potential for the control of GBS in women and may consequently prevent GBS infections in newborns.


Nursing Home COVID Relief Under QIP's Performance-Based Formula: Does Performance Actually Matter, and Should It?
The Quality Incentive Program (QIP) distributed US$2 billion to nursing homes (NHs) that met performance goals primarily related to their COVID-19 infection rates. We examine how QIP affected 15,331 NHs with different facility and community attributes, and the extent to which QIP payments per resident-week (QIP$) were associated with NHs' COVID-related attributes. We find that QIP$ was primarily determined by county (not facility) infection rates. QIP distributed US$2 billion to NHs for months in which they experienced virtually no COVID-19 cases; US$0 was distributed for months in which they experienced more than 300,000 cases. We find that QIP$ was larger for smaller, nonprofit NHs located in more rural and economically distressed communities. Regression analyses reveal that recipients of larger QIP$ maintained greater supplies of personal protective equipment, conducted more staff testing, and limited admissions of infected residents, and that greater staff testing and limited admissions are also associated with NHs' sustained success in receiving QIP payments. Policymakers should consider whether performance-based payment systems are optimal for addressing public health emergencies.


Endoscopic submucosal dissection or piecemeal endoscopic mucosal resection for large superficial colorectal lesions: A cost effectiveness study.
Endoscopic management is preferred to surgical management for large superficial colorectal lesions. However, the optimal endoscopic resection strategy (piecemeal endoscopic mucosal resection [pEMR] or endoscopic submucosal dissection [ESD]) is still debated from an economical point of view. To date, in France, there is no Health Insurance reimbursement rate for the hospital stays related to ESD. We searched to estimate the global cost of colorectal ESD and to define the most cost-effectiveness endoscopic strategy. A model was created to compare the cost-effectiveness of ESD and pEMR according to optical diagnosis (Japan NBI Expert Team [JNET], laterally spreading tumour [LST], CONECCT). We distinguished three groups from the same multicentre ESD cohort and compared the medical and economic outcomes: real-life ESD data (Universal-ESD or U-ESD) compared to modelled selective ESD (S-ESD JNET; S-ESD LST; S-ESD CONECCT) and exclusive pEMR strategies (Universal-EMR or U-EMR). The en-bloc, R0, and curative resection rates were 97.5%, 86.5%, and 82.6%, respectively in the real life French ESD cohort of 833 colorectal lesions. U-ESD was the least-expensive strategy, with a global cost of 2,858,048.17 €, i.e. 3,431.03 €/patient and was also the most effective strategy because it avoided 774 surgeries, which was more than any other strategy. It outperformed S-ESD CONNECT (global cost = 2,951,411.44 €, and 3,543.11 €/patient, 765 surgeries avoided, S-ESD LST (global cost = 3,055,951.53 €, and 3,668.61 €/patient, 749 surgeries avoided), and S-ESD JNET (global cost = 3,547,426.97 € and 4,258.62 €/patient, 704 surgeries avoided) and U-EMR (global cost = 4,060,547.62 € and 4,874.61 €/patient, 620 surgeries avoided). Even though a model which optimized pEMR results (0% technical failure, 0% primary surgery), U-EMR strategy remained the most expansive strategy and the one that avoided the least surgeries. ESD for all LSTs upper than 20 mm is more cost-effective than pEMR, and S-ESD.


Novel robot-assisted laparoscopic total extra-peritoneal repair with primary fascial closure plus pre-peritonea mesh for large groin defects.
Since the introduction of robot-assisted laparoscopic surgery, a variety of conventional laparoscopic procedures have been explored via this approach. In the robotic era, most of the reported robot-assisted laparoscopic hernia repairs were performed with the trans-abdominal pre-peritoneal approach. According to the evidence extrapolated from laparoscopic ventral hernia repair, simultaneous fascial defect closure and mesh repair can significantly decrease the risk of seroma formation and recurrence over those without fascial closure. Therefore, we describe our novel technique of robot-assisted total extra-peritoneal (TEP) repair with primary fascial closure and pre-peritoneal mesh and its preliminary clinical outcomes. We retrospectively reviewed our prospectively collected hernia database from October 2017 to July 2019, which included 26 consecutive patients with primary or recurrent groin hernias. Patients' baseline characteristics and perioperative outcomes were compared and analyzed. Perioperative factors included operative time, visual analog scale (VAS) score (0-100), hospital stay, perioperative complications, time to return to normal activity, and the modified Medical Outcome Study (MOS; item 3-12/36 items) score. All procedures were completed successfully without conversion to open or conventional laparoscopic surgery. The patients' age ranged from 28 to 74 years (median 57.5). The mean operative time was 115 minutes (range 95-172 min). There were no major procedure-related complications. Only four cases experienced asymptomatic seromas, which were detected by ultrasonography; and all resolved spontaneously within 6 weeks after the operation. The VAS and modified MOSs revealed quick recovery after robot-assisted endoscopic TEP repair. Robot-assisted endoscopic TEP repair combined with primary fascial closure and pre-peritoneal mesh is a safe and feasible technique for groin hernia repair.


Electroacupuncture for Gastrointestinal Function Recovery after Gynecological Surgery: A Systematic Review and Meta-Analysis.
Evidence for the efficacy and safety of electroacupuncture (EA) on gastrointestinal function recovery after gynecological surgery is unclear. This meta-analysis aimed to evaluate the effects of EA on recovery of postoperative gastrointestinal function for patients receiving gynecological surgery. Data sources: PubMed, Cochrane Central Register of Controlled Trials (CINAHL), Embase, China National Knowledge Infrastructure (CNKI), Weipu (CQVIP), and Wanfang databases were systematically searched from the inception dates to May 30, 2020, for relevant randomized controlled trials (RCTs). Study selection: RCTs that evaluated EA for postoperative gastrointestinal function directly related to gynecological surgery in adults aged 18 years or over. Data extraction and synthesis: paired reviewer independently extracted the data and assessed study quality. Standardized mean differences (SMD) were calculated as the effect measure from a random effects model. Main outcomes and measures: time to first flatus (TFF), time to bowel sounds recovery (TBS), and time to first defecation (TFD) were recorded as primary outcomes; postoperative nausea and vomiting (PONV), motilin (MTL), gastrin (GAS), pH value of gastric mucosa (pHi), gastric mucosal partial pressure of carbon dioxide (PgCO2), vasoactive intestinal peptide (VIP), and adverse event were reported as secondary outcomes. We included eighteen RCTs (1117 participants). Our findings suggested that compared to the control group (CG), electroacupuncture group (EG) showed significant effects on TFF (SMD = -0.98, 95% CI: [-1.28, -0.68], P < 0.00001, I 2 = 69%), TBS (SMD = -0.98, 95% CI: [-1.84, -0.12], P=0.03, I 2 = 92%), and TFD (SMD = -1.23, 95% CI: [-1.59, -0.88], P < 0.0001, I 2 = 0%). Moreover, the incidence of PONV at postoperative 6 h (OR = 0.42, 95% CI: [0.27, 0.64], P < 0.0001, I 2 = 0%) and 24 h (OR = 0.46, 95% CI: [0.32, 0.68], P < 0.0001, I 2 = 0%) was lower in the EG than that in the CG, whereas no significant difference in ratio of PONV at postoperative 48 h (OR = 0.55, 95% CI: [0.20, 1.51], P=0.25, I 2 = 0%) was detected between the two groups. Meanwhile, there was a significant effect in favor of EA on the level of MTL at postoperative 6 h (SMD = -0.93, 95% CI: [-1.36, -0.61], P < 0.0001, I 2 = 21%), while no significant effect was observed at postoperative 24 h (SMD = -0.43, 95% CI: [-0.89, 0.02], P=0.06, I 2 = 69%) in the EG when compared to the CG. Additionally, a large significant effect on decreasing PgCO2 was found in the EG in comparison to the CG, but no significant effect in favor of EA on GAS, VIP, or pHi was observed. It was reported that there was one participant with pain at the needling sites and bruising, and three participants withdrew because they were not intolerant to EA. EA could be a promising strategy for the prevention and treatment of gastrointestinal dysfunction after gynecological surgery, including shortening TFF and TFD, TBS, regulating MTL, and decreasing the ratio of PONV within postoperative 24h. The effects on MTL and PONV varied with different intervention points, and EA used at 30 min prior to surgery might be recommended. However, the evidence quality ranged from low to very low, and large-scale and high-quality RCTs were warranted.


A commentary revisiting the viral hypothesis of schizophrenia: Onset of a schizophreniform disorder subsequent to SARS CoV-2 infection.
The viral hypothesis for schizophrenia has persisted for decades, initially supported by observed increases in psychoses subsequent to the influenza pandemic of the early twentieth century, and then later by evidence of elevated viral antibody titres particularly in schizophrenia patient populations. Several research studies have also focused on maternal infections during the second trimester of pregnancy and their long-term effects on fetal brain development, ultimately leading to schizophrenia. No specific virus has been implicated although a handful have received increasing attention. The current pandemic spreading the SARS CoV-2 corona virus world-wide is now showing anecdotal evidence of psychoses newly developing post viral exposure, implicating neuronal inflammation in crucial areas of the brain that could initiate psychotic symptoms. Time will tell if epidemiological data will, similar to the 1918 influenza pandemic, show that schizophrenia spectrum disorders increase after serious viral infections.


A novel zinc finger protein-based amperometric biosensor for miRNA determination.
This paper reports a simple electrochemical strategy for the determination of microRNAs (miRNAs) using a commercial His-Tag-Zinc finger protein (His-Tag-ZFP) that binds preferably (but non-sequence specifically) RNA hybrids over ssRNAs, ssDNAs, and dsDNAs. The strategy involves the use of magnetic beads (His-Tag-Isolation-MBs) as solid support to capture the conjugate formed in homogenous solution between His-Tag-ZFP and the dsRNA homohybrid formed between the target miRNA (miR-21 selected as a model) and a biotinylated synthetic complementary RNA detector probe (b-RNA-Dp) further conjugated with a streptavidin-horseradish peroxidase (Strep-HRP) conjugate. The electrochemical detection is carried out by amperometry at disposable screen-printed carbon electrodes (SPCEs) (- 0.20 V vs Ag pseudo-reference electrode) upon magnetic capture of the resultant magnetic bioconjugates and H2O2 addition in the presence of hydroquinone (HQ). The as-prepared biosensor exhibits a dynamic concentration range from 3.0 to 100 nM and a detection limit (LOD) of 0.91 nM for miR-21 in just ~ 2 h. An acceptable discrimination was achieved between the target miRNA and other non-target nucleic acids (ssDNA, dsDNA, ssRNA, DNA-RNA, miR-122, miR-205, and single central- or terminal-base mismatched sequences). The biosensor was applied to the analysis of miR-21 from total RNA (RNAt) extracted from epithelial non-tumorigenic and adenocarcinoma breast cells without target amplification, pre-concentration, or reverse transcription steps. The versatility of the methodology due to the ZFP's non-sequence-specific binding behavior makes it easily extendable to determine any target RNA only by modifying the biotinylated detector probe.


Magnetic resonance metabolic imaging of glioma.
2-Hydroxyglutarate (2-HG) is a potential oncometabolite involved in gliomagenesis that has been identified as an aberrant product of isocitrate dehydrogenase (IDH)-mutated glial tumors. Recent genomics studies have shown that heterozygous mutation of IDH genes 1 and 2, present in up to 86% of grade II gliomas, is associated with a favorable outcome. Two reports in this issue describe both ex vivo and in vivo methods that could noninvasively detect the presence of 2-HG in glioma patients. This approach could have valuable implications for diagnosis, prognosis, and stratification of brain tumors, as well as for monitoring of treatment in glioma patients.


Activation of a diluted E. coli cell-free transcription-translation system within liposomes by hypertonic concentration.
We present a protocol for activating protein synthesis in liposomes encapsulating a diluted E. coli cell extract-based TX-TL (transcription-translation) system by hypertonic concentration. Protein expression is turned on in the liposome-encapsulated TX-TL system by simple treatment with a concentrated external solution. The expression of sfGFP is demonstrated here, but it can be applied to other proteins. This protocol can be applied to the development of artificial cells utilizing the switch-on mechanism to activate protein expression, responding to the outer environment. For complete details on the use and execution of this protocol, please refer to Akui et al. (2021).


Triad TMS of the human motor cortex.
Usually, cortical rhythmic activities are studied with local field potentials. To overcome small amplitude of EEGs easily disturbed by several factors, we developed a new method to study motor cortical rhythm using Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS). We, here, review triad-conditioning TMS technique for investigating the intrinsic rhythm of the human primary motor cortex (M1). MEP was recorded from the first dorsal interosseous muscle (FDI). TMS was applied over the M1 to study its frequency dependency. In the intervention condition, the subthreshold, same intensity three conditioning stimuli separated by a certain interval were given prior to the supra-threshold test stimulus. In the control condition, the test stimulus was given alone. MEPs were compared between the two conditions. In healthy volunteers, triad-conditioning stimulus (TCS) at an interval of 25 ms induced MEP facilitation, whereas the other intervals TCS induced no facilitation. This frequency dependent facilitation may reflect some intrinsic rhythm of M1 (25 ms, i.e. 40 Hz). In cortical myoclonus, the 40 ms TCS induced facilitation whereas 25 ms TCS induced no facilitation, which is consistent with abnormal rhythm of M1 at 25 Hz (40 ms interval) reported previously. In Parkinson's disease (PD), 25 ms TCS evoked no facilitation. Triad-conditioning TMS may enable us to investigate the intrinsic rhythmic activity of M1 and its abnormality.


Deferoxamine Attenuated the Upregulation of Lipocalin-2 Induced by Traumatic Brain Injury in Rats.
Intracranial hemorrhage is one of the most common consequences of traumatic brain injury (TBI). The release of iron from the breakdown of hemoglobin during intracerebral hematoma resolution results in an increase in perihematomal non-heme iron. Lipocalin 2 (LCN-2) is a siderophore-binding protein that mediates transferrin-independent iron transport. This study examined the effects of TBI (lateral fluid percussion) on LCN-2 expression in Sprague-Dawley rats. LCN-2 protein levels were markedly increased in the ipsilateral cortex and hippocampus after TBI, with the highest level at day 1. Most LCN-2-positive cells appeared to be astrocytes. Treatment with an iron chelator, deferoxamine (100 mg/kg, intramuscularly), attenuated the TBI-induced upregulation of LCN-2. In summary, TBI resulted in upregulation of LCN-2 and deferoxamine reduced TBI-induced LCN-2 increase, suggesting LCN-2 may have a role in iron-trafficking after TBI.


Click Nucleic Acid-DNA Binding Behavior: Dependence on Length, Sequence, and Ionic Strength.
Click nucleic acids (CNAs) are a new, low-cost class of xeno nucleic acid (XNA) oligonucleotides synthesized by an efficient and scalable thiol-ene polymerization. In this work, a thorough characterization of oligo(thymine) CNA-oligo(adenine) DNA ((dA)20) hybridization was performed to guide the future implementation of CNAs in applications that rely on sequence-specific interactions. Microscale thermophoresis provided a convenient platform to rapidly and systematically investigate the effects of several factors (i.e., sequence, length, and salt concentration) on the CNA-DNA dissociation constant (Kapp). Because CNAs have limited water solubility, all studies were performed in aqueous-DMSO mixtures. CNA-DNA hybrids between oligo(thymine) CNA (average length of 16 bases) and (dA)20 DNA have good stability despite the high organic content, a favorable attribute for many emerging applications of XNAs. In particular, the Kapp of CNA-DNA hybrids in 65 vol % DMSO with 10 mM sodium chloride (NaCl) was 0.74 ± 0.1 μM, whereas the Kapp for (dT)20-(dA)20 DNA-DNA was found to be 45 ± 2 μM in a buffer without DMSO but at the same NaCl concentration. CNA hybridized with DNA following Watson-Crick base pairing with excellent sequence specificity, discriminating even a single-base-pair mismatch, with Kapp values of 0.74 ± 0.1 and 3.7 ± 0.6 μM for complementary and single-base-pair mismatch sequences, respectively. As with dsDNA, increasing CNA length led to more stable hybrids as a result of increased base pairing, where Kapp decreased from 5.6 ± 0.8 to 0.27 ± 0.1 μM as the CNA average length increased from 7 to 21 bases. However, unlike DNA-DNA duplexes, which are largely unstable at low salt concentrations, the CNA-DNA stability does not depend on salt concentration, with Kapp remaining consistent between 1.0 and1.9 μM over a NaCl concentration range of 1.25-30 mM.


Temperature-sensitive Chinese hamster cell mutant with a defect in glycoprotein synthesis: accumulation of the EGF receptor in the endoplasmic reticulum and the role of the glucose-regulated protein GRP78.
A temperature-sensitive mutant of Chinese hamster fibroblasts with a defect in glycoprotein synthesis is investigated after transfection and amplification of the gene for the human EGF receptor. We demonstrate that at the nonpermissive temperature a partially glycosylated species of the receptor accumulates in the endoplasmic reticulum. The oligosaccharides present are the high mannose types, since they can be removed completely by treatment with endoglycosidase H. Pulse-chase experiments show that the abnormal species of the receptor cannot be chased to a form that is either resistant to endoglycosidase H, or altered in its mobility on SDS polyacrylamide gels. The abnormal species of the receptor appears within the first hour of a shift to the nonpermissive temperature, and no further changes are observed upon prolonged incubation of cells at 40 degrees C. However, after 3-4 hours immunoprecipitations of the receptor yield another protein, which has properties very similar, if not identical, to the glucose-regulated protein GRP78. The induction of this protein at 40 degrees C can be suppressed completely with an inhibitor of RNA synthesis, without any effect on the glycosylation defect, or on the accumulation of the EGF receptor in the endoplasmic reticulum.


Unexpected neonatal death caused by interrupted aortic arch, an uncommon congenital great vessel malformation: An autopsy case report.
A 21-day-old Japanese male infant became inactive and then collapsed unexpectedly. On autopsy, there was no connection between the ascending and descending thoracic aorta. The site of interruption was the aortic isthmus. The heart showed hypertrophy and exhibited intracardiac malformations, including subaortic valve stenosis resulting from posterior deviation of the ventricular outlet septum and ventricular septal defect. The cause of death was diagnosed as prolonged physiological closure of the ductus arteriosus complicated by interrupted aortic arch and followed by assumed ductal shock.


Electromyographic activity of rectus capitis posterior minor muscles associated with voluntary retraction of the head.
The functional role of rectus capitis posterior minor (RCPm) muscles is not well defined. To the best of our knowledge, electromyographic (EMG) data from RCPm muscles in humans have never been collected and analyzed. To test the null hypothesis that there will be no difference in normalized levels of EMG activity measured from RCPm muscles with the head in a neutral position and with the head in a retracted position. A repeated measures design intended to quantify normalized levels of EMG activity measured from RCPm muscles. Disposable 25-gauge, bipolar fine wire hooked electrodes were used to collect EMG data from both right and left RCPm muscles from 17 asymptomatic subjects. Data were collected while subjects performed five trials with the head maintained in a neutral position; performed three maximal voluntary isometric contraction efforts; performed four trials with the head maintained in a retracted position. Mixed effects beta regression models were used to analyze the data. Normalized EMG activity of RCPm muscles collected with the subject's head held in a retracted position was significantly higher (p<.0001) than normalized EMG activity collected with the subject's head held in a self-selected, neutral position. Rectus capitis posterior minor muscles are active when the head is held in a neutral position and show a significant increase in activity when the head is held in a retracted position.


Oxygen consumption in premature infants in an incubator of proven clinical efficacy.
Oxygen consumption was measured under carefully controlled conditions during non-REM sleep in 16 infants less than 1,500 g in a computer-controlled incubator and a skin servo-controlled incubator. Oxygen consumption was 7.16 +/- SE 0.35 ml/kg/min in the computer-controlled incubator and 6.84 +/- SE 0.37 ml/kg/min in the skin servo-controlled incubator. Oxygen consumption was similar in the two incubator systems.


A stereoselective alpha-fucosylation reaction using 1-hydroxy 2,3,4-tri-O-benzyl-L-fucose donor for the practical synthesis of selectin blocker.
A 1-hydroxy 2,3,4-tri-O-benzyl-L-fucose donor affords a high stereoselectivity of glycosylation in the presence of TMSOTf and is a very useful substrate for the preparation of an alpha-L-fucosyl dipeptide in a stereoselective manner. The donor will be a key component in the preparation of an attractively biological selectin blocker 1.


Suppression of trabecular meshwork phagocytosis by norepinephrine is associated with nocturnal increase in intraocular pressure in mice.
Intraocular pressure (IOP) is an important factor in glaucoma development, which involves aqueous humor (AH) dynamics, with inflow from the ciliary body and outflow through the trabecular meshwork (TM). IOP has a circadian rhythm entrained by sympathetic noradrenaline (NE) or adrenal glucocorticoids (GCs). Herein, we investigated the involvement of GC/NE in AH outflow. Pharmacological prevention of inflow/outflow in mice indicated a diurnal outflow increase, which was related to TM phagocytosis. NE showed a non-self-sustained inhibition in phagocytosis of immortalized human TM cells, but not GC. The pharmacological and reverse genetic approaches identified β1-adrenergic receptor (AR)-mediated exchange proteins directly activated by cyclic adenosine monophosphate (EPAC)-SHIP1 signal activation by ablation of phosphatidylinositol triphosphate, regulating phagocytic cup formation. Furthermore, we revealed the phagocytosis involvement in the β1-AR-EPAC-SHIP1-mediated nocturnal IOP rise in mice. These suggest that TM phagocytosis suppression by NE can regulate IOP rhythm through AH outflow. This discovery may aid glaucoma management.


Arteriographic evaluation of postsurgical stomach.
Visceral arteriography was performed in 35 adult patients who had undergone various types of gastric surgery. Nineteen of these patients had presented with gastrointestinal hemorrhage at different postoperative intervals (4 days-23 years). Arteriography showed the bleeding site in 14 (74%) and permitted its nonoperative control in 8 cases. Diffuse hemorrhage from the gastric pouch as well as localized bleeding from suture line, marginal or stress ulcers, and other sources were recognized. Arteriography was also crucial in the diagnosis of iatrogenic arteriovenous fistulas, telangiectasia in the anastomotic regions, inadvertently ligated arteries, and postoperative changes in the vascular architecture. Value and limitations of arteriography of the postsurgical stomach are presented together with a review of the pertinent literature.


Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration.
Neurodegeneration associated with amyloid β (Aβ) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and β1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Aβ-induced neurotoxicity independent of its capacity to promote Aβ generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Aβ-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Aβ and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Aβ generation but also antagonizing Aβ-induced neurotoxicity.


Isolation, structures and biological activities of medicinal glycoproteins from natural resources: A review.
In recent years, natural resources have proven to be tremendous sources of glycoproteins. As biological macromolecules, glycoproteins are essential to the growth and development of organisms, and have attracted increasing attention around the world. This review summarized and discussed the development of glycoproteins from natural resources, including isolation methods, purification processes, structural features and biological activities. Generally, the vast majority of glycoproteins can be isolated by hot water extraction followed by purification through gel filtration chromatography. Combined with component analysis, the physicochemical properties of glycoproteins are studied by using several spectroscopic techniques such as ultraviolet-visible (UV-visible), Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR). Moreover, natural glycoproteins possess various remarkable biological activities, including anti-tumor, anti-oxidant, anti-coagulant and anti-microbial activities. The content of this review will provide a theoretical basis for the research on related glycoproteins and give a perspective on the use of these medical resources.


Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy and prognosis.
To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all PBH < 0.05). We confirmed that T16362C was related to efficacy of GCs (PBH = 0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (PBH < 0.05). In the prognosis study, variants A4833G (PBH = 0.003) and G14569A (PBH = 9.744 × 10-4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (PBH < 0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (PBH = 0.001) and prognosis (PBH = 0.013). Moreover, mtDNA variant-environment interactions were observed. We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE.


Evaluation of post operative shoulder tip pain in low pressure versus standard pressure pneumoperitoneum during laparoscopic cholecystectomy.
Insufflation of carbon dioxide during laparoscopic cholecystectomy leads to postoperative shoulder tip pain. The origin of shoulder pain is commonly assumed to be due to overstretching of the diaphragmatic muscle fibres owing to a high carbon dioxide pressure. To study the frequency and intensity of post operative shoulder tip pain in laparoscopic cholecystectomy and compare low and standard pressure pneumoperitoneum during laparoscopic cholecystectomy with respect to post operative shoulder tip pain. Patients admitted in the department of surgery for elective cholecystectomy were enrolled in the study. The patients were randomly allocated to two groups (group A and group B). In group A (n = 50), low pressure pneumoperitoneum (8 mm Hg) and in group B (n = 50), standard pressure pneumoperitoneum (14 mm Hg) was generated during laparoscopic cholecystectomy. Postoperative shoulder tip pain was assessed at 4, 8 and 24 h after operation by the Visual Analogue Scale of Pain. 14 patients (28%) in group B complained of post operative shoulder tip pain as compared to only 5 patients (10%) in group A. The mean intensity of post operative shoulder tip pain assessed by visual analogue scoring scale at 4, 8 and 24 h was less in group A as compared to group B, although statistical significance was seen only at 4 h. Analgesic requirements and the mean length of post operative stay in the hospital were also less in group A as compared to group B. Low pressure laparoscopic cholecystectomy (LPLC) significantly decreases the frequency and intensity of postoperative shoulder tip pain. LPLC decreases the demand for postoperative analgesics, decreases postoperative hospital stay and hence improves the quality of life in the early stage of postoperative rehabilitation.


Responses of floccular Purkinje cells to sinusoidal vertical rotation and effects of muscimol infusion into the flocculus in alert cats.
To understand how the flocculus is involved in the integration process in the vertical VOR, we examined the responses of floccular Purkinje cells during whole-body rotation in many vertical and horizontal planes in alert cats. The great majority of cells that responded to pitch rotation received excitation from the contralateral posterior canal, whereas the minority received excitation from the anterior canal, either on the ipsilateral or contralateral side; 35% of these vertical canal responding cells received convergent inputs, either from the ipsilateral or contralateral horizontal canal. After infusion of a GABA agonist (muscimol) into the area where many posterior canal responding Purkinje cells were recorded, the downward VOR induced by nose-up pitch was selectively impaired at low stimulus frequencies, together with an impairment of gaze holding after downward saccades. These results indicate a crucial role for posterior canal responding floccular Purkinje cells in generating downward eye position signals. Since the flocculus inhibits VOR interneurons related to the anterior and horizontal canals but not the posterior canal (Ito, 1984), our results suggest the possibility that posterior canal responding floccular Purkinje cells may form a transfloccular inhibitory pathway to anterior canal related VOR interneurons. This pathway may facilitate the positive feedback effect in the vestibular commissural inhibitory pathway between the co-planar vertical canals for the posterior canal signal, and may thereby be specifically involved in integration in the vertical VOR.


Clinical utility of PSAD combined with PI-RADS category for the detection of clinically significant prostate cancer.
The goal of this study was to determine the predictive value of prostate-specific antigen density (PSAD) plus Prostate Imaging Reporting and Data System (PI-RADS) category for the detection of clinically significant prostate cancer. This retrospective study included 526 men without known prostate cancer (initial diagnosis group) and 133 men with prostate cancer grade group 1 (active surveillance group) who underwent magnetic resonance imaging-guided and/or systematic prostate biopsy procedures between August 2014 and October 2018. Prostate specific antigen (PSA), PSAD, and PI-RADS category were entered into logistic regression models for predicting clinically significant prostate cancer (grade group ≥2) at biopsy. Receiver operating characteristic curve analysis was performed to assess model accuracy. The area under the curve (AUC) increased when PSAD was combined with PI-RADS in the initial diagnosis group (difference in AUC = 0.031; 95% confidence interval: 0.012, 0.050; P = 0.002) but not in the active surveillance group (difference in AUC = 0.016; 95% confidence interval: -0.040, 0.071; P = 0.579). When a PSAD threshold of 0.15 was applied, the frequency of clinically significant prostate cancer in patients with a PI-RADS score of 3 or lower decreased from 9.8% to 5.6% in the initial diagnosis group and from 10.7% to 2.7% in the active surveillance group. The addition of PSAD improves the predictive performance of PI-RADS in men without known prostate cancer. A PSAD threshold of 0.15 can help to minimize the number of missed clinically significant prostate cancer cases in men with a PI-RADS score of 3 or lower who decide to defer biopsy.


Uterine rupture in Mekelle, northern Ethiopia, between 2009 and 2013.
To review cases of uterine rupture at a center in northern Ethiopia. In a retrospective chart review, data were assessed for cases of symptomatic uterine rupture treated at Ayder Referral Hospital in Mekelle between January 1, 2009, and December 31, 2013. In the 5-year study period, there were 5185 deliveries and 47 cases of uterine rupture, giving a rate of one case per 110 deliveries. All patients underwent laparotomy for suspected uterine rupture. Mean parity was 3.6 (range 0-8). The most common predisposing factors were cephalopelvic disproportion (35 [74%] patients), previous cesarean delivery (5 [11%)], and fetal malpresentation (4 [9%]). Hysterectomy was undertaken for 35 (74%) patients; the other 12 (26%) were treated conservatively by simple repair of the rupture. There were 44 (95%) stillbirths and 1 (2%) maternal death. Uterine rupture remains an important clinical problem in northern Ethiopia. Changes in the cultural preference for home delivery, better transport and referral systems, and improved obstetric training and hospital management of laboring women are needed.


Lost interest for existing compounds: New boosts.
Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.