Iron deficiency anemia in the emergency department: over-utilization of red blood cell transfusion and infrequent use of iron supplementation.
Three are no clinical practice guidelines that specifically address the management of patients with iron deficiency anemia (IDA) in the emergency department (ED). The goal of this study was to describe the characteristics of IDA patients who present to the ED, documentation of IDA by emergency physicians, utilization of iron supplementation, and the appropriateness of red blood cell (RBC) transfusions ordered in the ED. A retrospective medical chart review was performed of IDA patients who visited the ED of a large tertiary center over a three-month period. Appropriateness of RBC transfusion was determined using a novel algorithm developed by our institution. Over the study period, there was a 0.3% (49/14,394) prevalence of IDA in the ED. In thirty (30/49; 61%) patients, IDA was documented by an emergency physician. RBC transfusions were administered to 19 patients; 10 transfusions (53%) were appropriate, 3 (16%) were appropriate for indication, but more than the required number of units were ordered, and 6 (32%) were inappropriate. Of the patients discharged, one (1/25; 4%) patient received intravenous iron in the ED and 6 of the 11 patients (55%) that were not already taking oral iron received a prescription at discharge from the ED. This assessment demonstrated that management of IDA patients presenting to the ED may represent an important knowledge-to-practice gap. It revealed that RBC transfusion may be over-utilized and could be replaced by safer, lower-cost alternatives such as intravenous and oral iron. Guidelines for management of IDA in the ED may be necessary to achieve consistent IDA management and avoid inappropriate use of RBC transfusion.


Minimally invasive treatment of portal hypertension, abdominal aortic aneurysm, and colon cancer: a case report.
Surgical therapy in cirrhotic patients has high morbidity and mortality. Hepatic function and complexity of surgical procedures strongly influence postoperative results. We report the case of a cirrhotic patient with portal hypertension, abdominal aortic aneurysm (AAA), and right colon cancer. After neoadjuvant transjugular intrahepatic portosystemic shunt, we performed 1-stage endovascular aneurysm repair and laparoscopic right colectomy. Minimally invasive surgery allows the effective treatment of high-risk patients with severe comorbidities that some years ago would not have been operated on.


Production of soluble P-selectin by platelets and endothelial cells.
The distribution of a soluble form of a cell adhesion molecule, P-selectin, in human platelets and cultivated endothelial cells has been studied by enzyme-linked immunosorbent assay (ELISA). The concentration of soluble P-selectin in the blood plasma of healthy donors and patients with abnormal platelet count has also been determined. P-selectin was measured in the Triton X-100 lysate of platelets and endothelial cells (total P-selectin), in the 100,000g supernatant obtained after sedimentation of the membrane fraction from the homogenate of sonicated platelets and endothelial cells (intracellular soluble P-selectin), in the supernatant of activated and nonactivated platelets, and in the culture medium of endothelial cells. A soluble form of P-selectin which did not coprecipitate with the membrane fraction was detected in platelets and accounted for approximately 10% of the total P-selectin. Platelet activation by thrombin, ADP, or a thromboxane A2 analog resulted in the secretion of 30-50% of the intracellular soluble P-selectin. Measurements of P-selectin in endothelial cell culture revealed that endothelium from aorta contained about twofold more P-selectin than endothelium from umbilical vein. Intracellular soluble P-selectin was identified in both types of endothelial cells. In endothelial cells from the umbilical vein this form made up approximately 10% of the total P-selectin. Soluble P-selectin was also detected in the medium of cultivated endothelial cells, where its content correlated with the total cellular P-selectin. Concentration of P-selectin in blood plasma strongly correlated with the platelet count in the blood of healthy donors and patients with thrombocytosis and thrombocytopenia. These data indicate that platelets serve as one of the main source of plasma P-selectin. However, the presence of P-selectin in the plasma of patients with severe thrombocytopenia suggests that endothelium can also be involved in plasma P-selectin production. Thus, in vitro experiments as well as measurements of plasma P-selectin have shown that both platelets and endothelial cells can produce a soluble form of the protein. Platelet-derived soluble P-selectin and plasma P-selectin were shown to react with antibodies against the cytoplasmic domain of P-selectin. These data prove that at least part of soluble P-selectin is produced by synthesis employing special mRNA which lacks the sequence encoding the transmembrane domain, but not by the proteolytic shedding of the extracellular portion of membrane P-selectin.


Long-term exposure to air pollution and risk of venous thromboembolism in a large administrative cohort.
Venous thromboembolisms (VTE) are one of the most frequent cause among the cardiovascular diseases. Despite the association between long-term exposure to air pollution and cardiovascular outcomes have been widely explored in epidemiological literature, little is known about the air pollution related effects on VTE. We aimed to evaluate this association in a large administrative cohort in 15 years of follow-up. Air pollution exposure (NO2, PM10 and PM2.5) was derived by land use regression models obtained by the ESCAPE framework. Administrative health databases were used to identify VTE cases. To estimate the association between air pollutant exposures and risk of hospitalizations for VTE (in total and divided in deep vein thrombosis (DVT) and pulmonary embolism (PE)), we used Cox regression models, considering individual, environmental (noise and green areas), and contextual characteristics. Finally, we considered potential effect modification for individual covariates and previous comorbidities. We identified 1,954 prevalent cases at baseline and 20,304 cases during the follow-up period. We found positive associations between PM2.5 exposures and DVT, PE and VTE with hazard ratios (HRs) up to 1.082 (95% confidence intervals: 0.992, 1.181), 1.136 (0.994, 1.298) and 1.074 (0.996, 1.158) respectively for 10 μg/m3 increases. The association was stronger in younger subjects (< 70 years old compared to > 70 years old) and among those who had cancer. The effect of pollutants on PE and VTE hospitalizations, although marginally non-significant, should be interpreted as suggestive of a health effect that deserves attention in future studies.


ICMSF Methods Studies. XVI. Comparison of Salt Polymyxin Broth with Glucose Salt Teepol Broth for Enumerating Vibrio parahaemolyticus in Naturally Contaminated Samples.
Two media, glucose salt teepol broth (GSTB) and salt polymyxin broth (SPB), were compared for their efficacy in enumerating Vibrio parahaemolyticus in naturally contaminated samples using the most probable number (MPN) procedure. Eleven laboratories in four countries participated, six of them using two analysts. One hundred ninety-six of 335 samples were found to contain V. parahaemolyticus . Neither enrichment medium was superior, and both media appeared necessary to prevent false-negative results. There was a high (52.5%) percentage of MPN patterns that were improbable with respect to Poisson distribution in those MPN tubes that yielded V. parahaemolyticus . Suspect colonies that developed on thiosulfate citrate bile salts sucrose (TCBS) plates streaked from GSTB were confirmed (1,438/1,929 = 75%) about as frequently as when streaked from SPB (2,155/3,038 = 71%).


A macrophage relay for long-distance signaling during postembryonic tissue remodeling.
Macrophages have diverse functions in immunity as well as in development and homeostasis. We identified a function for these cells in long-distance communication during postembryonic tissue remodeling. Ablation of macrophages in zebrafish prevented melanophores from coalescing into adult pigment stripes. Melanophore organization depends on signals provided by cells of the yellow xanthophore lineage via airinemes, long filamentous projections with vesicles at their tips. We show that airineme extension from originating cells, as well as vesicle deposition on target cells, depend on interactions with macrophages. These findings identify a role for macrophages in relaying long-range signals between nonimmune cells. This signaling modality may function in the remodeling and homeostasis of other tissues during normal development and disease.


Interaction of bioactive compounds on capillary inner surfaces bearing a dense thermoresponsive polymer brush.
To confirm the modification of a dense thermoresponsive polymer brush on a silica surface by surface-initiated (SI) atom transfer radical polymerization (ATRP), poly(N-isopropylacrylamide) (PNIPAAm) was polymerized from a free ATRP initiator and an ATRP initiator immobilized silica particle (SiP) via ATRP under various initiator concentrations. The obtained PNIPAAm exhibited a well-controlled molecular weight and modification of the concentrated PNIPAAm brush on the SiP surface was confirmed. Based on the optimal ATRP conditions, the PNIPAAm- and poly(NIPAAm-co-butyl methacrylate [BMA]) (PIB)-grafted capillary lumen were prepared by SI-ATRP and used as capillary columns for micro high-performance liquid chromatography for the modulation of biomolecular interactions. The hydrophobic interactions of steroids on the thermoresponsive polymer brush grafted capillary lumens increased with increasing polymer length above the lower critical solution temperature for each polymer. In addition, an increase in the retention factor of steroids with the PIB-grafted capillary began at lower temperatures than that observed for the PNIPAAm-grafted capillary. Thus, the separation of steroids was achieved using a stepwise temperature gradient and was enhanced by modulating the aqueous eluent flow rate during thermoresponsive capillary chromatography. These results indicated that the chain lengths of the concentrated thermoresponsive polymer brushes on the capillary lumen have a crucial influence on the interaction and separation of bioactive compounds in an aqueous mobile phase.


Long non-coding RNA SNHG16 decreased SMAD4 to induce gemcitabine resistance in pancreatic cancer via EZH2-mediated epigenetic modification.
Gemcitabine resistance (GR) in pancreatic cancer (PC) results in poor patient outcomes. SMAD family member (Smad4) dysregulation is a significant role of GR in PC, and EZH2 is involved in Smad4 expression in tumor progression. Interestingly, lncRNA small nucleolar RNA host gene 16 (SNHG16) might interact with EZH2, indicating a potential pathway to overcome gemcitabine-resistant PC progression. We investigated the role of the SNHG16/EZH2/Smad4 pathway in gemcitabine-resistant PC cells (PANC-1/GR and SW1990/GR). First, we found that SNHG16 was upregulated both in wild-type PC cells and in gemcitabine-resistant PC cells. SNHG16 overexpression reduced gemcitabine cytotoxicity and apoptosis in PC cells. Meanwhile, SNHG16 upregulation caused p-Akt elevation and Smad4 reduction. However, SNHG16 silencing induced the opposite trend. Then, we found that EZH2 was enriched in SNHG16 based on RIP and RNA pulldown. In particular, SNHG16 overexpression promoted the interaction between EZH2 and the Smad4 promoter according to Chromatin immunoprecipitation-quantitative polymerase chain reaction. Finally, both EZH2 inhibition and Smad4 upregulation increased gemcitabine cytotoxicity and apoptosis in PC cells during SNHG16 overexpression. Moreover, both treatments decreased p-Akt and increased Smad4. Collectively, lncRNA SNHG16 decreased Smad4 to induce GR in PC via EZH2-mediated epigenetic modification.


Decellularized gastric matrix as a mesh for gastric perforation repair.
The development of novel materials with effective defect-repairing properties will help avoid subtotal gastrectomy in patients with large gastric perforations. We prepared perfused decellularized gastric matrix (PDGM) and analyzed its components, spatial structure, biomechanics, cytotoxicity, and histocompatibility to validate its efficacy in the repair of gastric perforation. PDGM retained large amounts of gastric extracellular matrix, while residual glandular cells and muscle fibers were not found. The spatial structure of the tissue was well preserved, while the DNA and glycosaminoglycan contents were significantly decreased compared with normal gastric tissue (p < .01). There was no obvious deformation of the spatial structure and tissue elasticity of PDGM after sterilization by Cobalt-60 irradiation. The PDGM had good histocompatibility. PDGM was then used to repair a rat gastric perforation model. Radiography of the upper gastrointestinal tract at 24 hr postoperatively revealed no contrast agent leakage. There was evidence of early fibroblast proliferation, which was complicated by capillary regeneration. The hyperplastic gastric gland was slightly disarranged after repair. Defects of the muscular layer also healed a little with the regeneration process. PDGM is a nontoxic biocompatible biological mesh that may be useful for repairing relatively large gastric defects.


Ethylene production by growing and senescing pear fruit cell suspensions in response to gibberellin.
A pear (Pyrus communis L. cv Passe Crassane) cell suspension was used as a model system to study the influence of gibberellin on processes related to fruit ripening. Growth of the cell cultures was inhibited and their loss of viability was accelerated when 0.5 millimolar gibberllic acid (GA(3)) was added to suspensions at two stages of cell development, namely, growth and quiescence. Cell respiration rate was unaffected up to 2 millimolar GA(3) but ethylene production, both basal and 1-aminocyclopropane-1-carboxylic acid-induced, was inhibited at all stages of cell development. However, the degree of inhibition decreased as the cell cultures aged. The site of ethylene inhibition by GA(3) appeared to be related to the ethylene-forming enzyme. The coincident acceleration of cell senescence and inhibition of ethylene production indicate that the pear cell suspension cannot serve as an analogous model for studying the mode of action of gibberellin in delaying ripening and senescence of fruits in its entirety, although certain specific effects might be relevant.


Olivine Dissolution in Simulated Lung and Gastric Fluid as an Analog to the Behavior of Lunar Particulate Matter Inside the Human Respiratory and Gastrointestinal Systems.
With the Artemis III mission scheduled to land humans on the Moon in 2025, work must be done to understand the hazards lunar dust inhalation would pose to humans. In this study, San Carlos olivine was used as an analog of lunar olivine, a common component of lunar dust. Olivine was dissolved in a flow-through apparatus in both simulated lung fluid and 0.1 M HCl (simulated gastric fluid) over a period of approximately 2 weeks at physiological temperature, 37°C. Effluent samples were collected periodically and analyzed for pH, iron, silicon, and magnesium ion concentrations. The dissolution rate data derived from our measurements allow us to estimate that an inhaled 1.0 μm diameter olivine particle would take approximately 24 years to dissolve in the human lungs and approximately 3 weeks to dissolve in gastric fluid. Results revealed that inhaled olivine particles may generate the toxic chemical, hydroxyl radical, for up to 5-6 days in lung fluid. Olivine dissolved in 0.1 M HCl for 2 weeks transformed to an amorphous silica-rich solid plus the ferric iron oxy-hydroxide ferrihydrite. Olivine dissolved in simulated lung fluid shows no detectable change in composition or crystallinity. Equilibrium thermodynamic models indicate that olivine in the human lungs can precipitate secondary minerals with fibrous crystal structures that have the potential to induce detrimental health effects similar to asbestos exposure. Our work indicates that inhaled lunar dust containing olivine can settle in the human lungs for years and could induce long-term potential health effects like that of silicosis.


Screening a Molecular Fragment Library to Modulate the PED/PEA15-Phospholipase D1 Interaction in Cellular Lysate Environments.
The overexpression of PED/PEA15, the phosphoprotein enriched in diabetes/phosphoprotein enriched in the astrocytes 15 protein (here referred simply to as PED), observed in some forms of type II diabetes, reduces the transport of insulin-stimulated glucose by binding to the phospholipase D1 (PLD1). The inhibition of the PED/PLD1 interaction was shown to restore basal glucose transport, indicating PED as a pharmacological target for the development of drugs capable of improving insulin sensitivity and glucose tolerance. We here report the identification and selection of PED ligands by means of NMR screening of a library of small organic molecules, NMR characterization of the PED/PLD1 interaction in lysates of cells expressing PLD1, and modulation of such interactions using BPH03, the best selected ligand. Overall, we complement the available literature data by providing detailed information on the structural determinants of the PED/PLD1 interaction in a cellular lysate environment and indicate BPH03 as a precious scaffold for the development of novel compounds that are able to modulate such interactions with possible therapeutic applications in type II diabetes.


Mice lacking GD3 synthase display morphological abnormalities in the sciatic nerve and neuronal disturbances during peripheral nerve regeneration.
The ganglioside 9-O-acetyl GD3 is overexpressed in peripheral nerves after lesioning, and its expression is correlated with axonal degeneration and regeneration in adult rodents. However, the biological roles of this ganglioside during the regenerative process are unclear. We used mice lacking GD3 synthase (Siat3a KO), an enzyme that converts GM3 to GD3, which can be further converted to 9-O-acetyl GD3. Morphological analyses of longitudinal and transverse sections of the sciatic nerve revealed significant differences in the transverse area and nerve thickness. The number of axons and the levels of myelin basic protein were significantly reduced in adult KO mice compared to wild-type (WT) mice. The G-ratio was increased in KO mice compared to WT mice based on quantification of thin transverse sections stained with toluidine blue. We found that neurite outgrowth was significantly reduced in the absence of GD3. However, addition of exogenous GD3 led to neurite growth after 3 days, similar to that in WT mice. To evaluate fiber regeneration after nerve lesioning, we compared the regenerated distance from the lesion site and found that this distance was one-fourth the length in KO mice compared to WT mice. KO mice in which GD3 was administered showed markedly improved regeneration compared to the control KO mice. In summary, we suggest that 9-O-acetyl GD3 plays biological roles in neuron-glia interactions, facilitating axonal growth and myelination induced by Schwann cells. Moreover, exogenous GD3 can be converted to 9-O-acetyl GD3 in mice lacking GD3 synthase, improving regeneration.


Auditory temporal integration in the normal-hearing and hearing-impaired cat.
Temporal integration functions obtained from human subjects with sensorineural hearing loss have shallower slopes than the functions obtained from normal-hearing subjects. The present investigation was designed to explore this relation in animals in order to compare normal-hearing cats and humans. Auditory temporal integration functions were measured for five cats before and after they were exposed to a 2-kHz tone at 110 dB SPL for 48 h. To measure the temporal integration functions, ten stimuli were used that had overall durations from 8.32 to 275 ms and that were configured either as single or multiple tone bursts of 6.25 kHz. Twelve thresholds for each stimulus were obtained from each animal before and after the sound exposure. Pre- and postexposure audiograms were also obtained and the mean permanent threshold shift at 6.25 kHz was 32.5 dB. Exponential and power function models were used to describe the data. The exponential model (with grand-mean data) yielded a pre-exposure time constant (tau) of 188 ms [mean absolute residual (MAR) of 1.5 dB] and a postexposure tau of 21 ms (MAR of 1.4 dB). For the power function model with grand-mean data, the pre-exposure slope was 6.6 dB per decade of duration (MAR of 1.4 dB) and a postexposure slope of 3.8 dB per decade of duration (MAR of 0.7 dB). The results indicated that the slope of the temporal integration function was less steep after sensorineural hearing loss of cochlear origin, and that the power function model was more effective in describing temporal integration data for the range of stimulus durations employed.(ABSTRACT TRUNCATED AT 250 WORDS)


Optimal embedding for shape indexing in medical image databases.
Fast retrieval using organ shapes is crucial in medical image databases since shape is a clinically prominent feature. In this paper, we propose that 2-D shapes in medical image databases can be indexed by embedding them into a vector space and using efficient vector space indexing. An optimal shape space embedding is proposed for this purpose. Experimental results of indexing vertebral shapes in the NHANES II database are presented. The results show that vector space indexing following embedding gives superior performance than metric indexing.


Management of acute otitis media by New Zealand general practitioners.
To determine the current management of acute otitis media by New Zealand general practitioners (GPs). A reply-paid questionnaire was sent to 2000 New Zealand GPs. The questions relate to management of a three year old child presenting with her first episode of acute otitis media. 95% of respondents reported they would usually or always use antibiotics. Amoxicillin was the antibiotic of choice, followed by amoxicillin/clavulanate. Cotrimoxazole was the antibiotic of choice in the case of allergy to amoxicillin. 82% of respondents recommended follow-up, with a broad range of follow-up times (24 hours to 12 weeks). Approximately half of practitioners considered 5-6 episodes of acute otitis media in a year as an appropriate threshold for referral for grommets. Most GPs had received an update on otitis media within the previous two years. There is considerable variation in the management of acute otitis media by New Zealand GPs. Use of a national guideline may result in a more standardised, rational approach to the treatment of acute otitis media.


Rapid increase in plasma IL-6 after hemorrhage, and posthemorrhage reduction of the IL-6 response to LPS, in conscious rats: interrelation with plasma corticosterone levels.
To study whether hemorrhage stimulates interleukin-6 (IL-6) production in conscious rats, 30% of the total blood was withdrawn over 3 min through an indwelling venous catheter and the shedblood was reinfused 1 h later. Plasma adrenocorticotropic hormone (ACTH), corticosterone and IL-6 concentration rapidly increased. Plasma ACTH levels peaked at 10 min and corticosterone and IL-6 peaked at 60 min; all started to decrease after reinfusion. In adrenalectomized (ADX) rats with or without a corticosterone pellet implant, there was an inverse relationship between IL-6 and corticosterone concentrations, greatest in ADX rats and lowest in ADX rats in which plasma corticosterone was elevated by crushing the implanted pellet. However, the ADX rats in which plasma corticosterone was maintained at normal or slightly elevated levels showed greater IL-6 responses to hemorrhage and elevated basal plasma IL-6 levels compared to sham-operated control rats. Twenty-four hours after hemorrhage/reinfusion, ACTH, corticosterone, and IL-6 responses to i.v. injection of lipopolysaccharide (LPS) were all reduced compared to the non-hemorrhaged animals, indicating that hemorrhage impaired general host defense. Although very high plasma corticosterone concentrations markedly suppressed the IL-6 response to LPS, in ADX rats in which plasma corticosterone was maintained at slightly higher levels than normal, the reduced IL-6 response to LPS in the posthemorrhage period was not reversed, but enhanced. Thus corticosterone has biphasic effects on the IL-6 response to hemorrhage and the response to LPS during the posthemorrhage period, which has important clinical implications with regard to the optimal dose of glucocorticoid for maintaining the host defense response.(ABSTRACT TRUNCATED AT 250 WORDS)


[Nuclear magnetic resonance in the Hallervorden-Spatz syndrome].
Two patients (mother and son) with Hallervorden-Spatz's syndrome were examined both via CT and Nuclear Magnetic Resonance (NMR), using different measuring modes. In the patient with progressing disease pathological findings were seen in the right and left putamen with CT and NMR. All examinations in the mother with a less progressive syndrome were without any result. Information obtained via NMR did not yield significantly more relevant data than computed tomography.


Cachexia assessment tools.
Cachexia is a common negative consequence of cancer and is often unrecognized. To assess cachexia, malnutrition assessment tools are used. This review discusses the advantages and disadvantages of the current malnutrition assessment tools and describes the requirements for a comprehensive cachexia assessment instrument and its implication for clinics and research. The historic definition of cachexia has been updated based on new understanding of mechanism and clinical concepts. Classification of cachectic patients includes novel domains and stages. Validated cachexia assessment tools based on the new classification are under development. Cachexia has an impact for patients and proxies. Due to a lack of formal cachexia assessment instrument, malnutrition assessment tools are in use. Future comprehensive cachexia assessment instruments will identify cachexia domains and stages and classify cachexia, the basis for better clinical treatment and research.


In-hospital outcomes of transesophageal versus intracardiac echocardiography guided left atrial appendage closure.
Transesophageal echocardiogram (TEE) is the preferred imaging modality to guide transcatheter left atrial appendage closure (LAAC). Intracardiac echocardiography (ICE) has evolved as a less invasive alternative to TEE. Several observational studies have shown similar success rates and perioperative complications between TEE and ICE for LAAC. We sought to examine the temporal trends and patient characteristics of TEE versus ICE use in LAAC using a national database. We also evaluated hospital outcomes including periprocedural complications, mortality, and length of hospital stay. This is a retrospective analysis of data from the National Readmission Database, collected from 2016 to 2018. The primary outcome was major adverse events (MAE) defined as in-hospital mortality, cardiac arrest, pericardial effusion with or without tamponade, pericardiocentesis or window pericardiocentesis and pericardial window, pericardial effusion and tamponade, and hemorrhage requiring transfusion. Trend analysis showed that TEE-guided LAAC increased from 96.6% in 2016 to 98.4% in 2018 (relative increase, 1.9%), while ICE-guided LAAC decreased from 3.4% to 1.6% during the same period (relative decrease, 53%, p for trend = 0.08). In the unmatched cohorts, the MAE was significantly lower in TEE-guided LAAC compared to ICE-guided LAAC (6.5% vs. 9.3%, p = 0.022). In the propensity score matching analysis, MAE remained significant (5.6% vs. 9.4%, p < 0.001). The incidence of pericardial effusion with or without tamponade remained significantly lower in the TEE group (2.3% vs. 5.8%, p < 0.001). Length of stay (3.4 vs. 1.9 days, p < 0.001) and hospitalization cost ($34,826 vs. $20,563, p < 0.001) remained significantly lower for TEE-guided LAAC. Compared to ICE, the incidence of MAE was significantly lower for TEE-guided LAAC, driven mainly by less pericardial effusion events. Large-scale randomized trials are needed to confirm the findings of the current and previous studies.


Transbilayer asymmetry of phospholipids in the plasma membrane regulates exocytotic release in mast cells.
To investigate the role of the asymmetric distribution of phospholipids of the plasma membrane in exocytosis, we examined the effects of disruption of this asymmetrical distribution of lipids on exocytotic release from mast cells (RBL-2H3). Lipid scramblase, which is activated by divalent cations and catalyzes the transbilayer movement of phospholipids, was overexpressed in mast cells. Exogenous lipid scramblase was expressed in the plasma membrane and the cytoplasm. Activation of scramblase by divalent cations disrupted the asymmetrical distribution of phospholipids in the plasma membrane. Exocytotic release induced by calcium ionophore and phorbol ester was significantly inhibited in the cells transfected with wild-type scramblase. This inhibition was observed with time lag of about 5 min. Furthermore, when the asymmetric distribution of lipids was disrupted before induction of exocytosis, the inhibition of exocytotic release was obvious from the beginning without time lag. These results suggest that the asymmetric distribution of phospholipids in the plasma membrane plays an essential role in fusion between secretory granules and the plasma membrane. This finding also demonstrates that the transbilayer asymmetry of phospholipids regulates exocytosis and gives a new insight into the significance of lipid asymmetry in the plasma membrane.


[Mother-infant Interactions with Very Low Birth Weight multiple newborns (< 1500 g). A comparison of mother-multiple and mother-single births].
Assisted reproductive techniques and fertility enhancing therapies have increased the rate of multiple births and, therefore, the risk of prematurity. Our hypothesis is that mothers of preterm multiples are less able to provide such enhancing interactions than mothers of preterm singletons, resulting in a developmental disadvantage for preterm twins and triplets. Of 77 very low birth weight preterms (VLBW) who were examined prospectively with their mothers in a longitudinal study, 35 were multiples and 42 were singletons. At a corrected age of three months the quality of the mother-infant interaction with multiples vs. singletons was examined. The Mannheim Rating System, a 40-item standardized observation instrument based on a 10 minute videotaped sequence of interaction, was used. The analyses showed several differences between mother-singleton and mother-multiple interactions. Mothers of multiples were less stimulating and reactive and showed less babytalk. Multiple infants were also less reactive than singletons. In mother-multiple dyads there were less verbal exchanges between mother and child. There are definite differences in mother-multiple compared to mother-singleton interactions, so that VLBW multiples may be at even greater risk for negative mother-infant interactions than singletons.


Endoscopy-assisted extraction of orbital and nasal foreign body.
Penetrating orbital injury with a foreign body is a complex problem that requires an interdisciplinary therapeutic approach. Conventionally, an external approach using either transconjuntival or transseptal entry is used by an ophthalmologist. However, there is a risk of damage to the optic nerve and orbital tissue using only the traditional approach. This study concerns a 36-year-old male who has an intra-orbital foreign body (OrbFB). Timely three-dimensional reconstruction computed tomography scan demonstrated an 8-cm-long intra-OrbFB adjacent to the optic nerve penetrating to the contralateral nasal cavity. Endoscopic inspection confirmed a chopstick fragment. Assisted by transnasal endoscopy, the chopstick penetrating from the orbit to the nasal cavity was smoothly removed. Nasal endoscopy is useful for an ophthalmologist in removing foreign body in the orbit.


Telomeres, aging, and cancer: the big picture.
The role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.


Viability and resilience of languages in competition.
We study the viability and resilience of languages, using a simple dynamical model of two languages in competition. Assuming that public action can modify the prestige of a language in order to avoid language extinction, we analyze two cases: (i) the prestige can only take two values, (ii) it can take any value but its change at each time step is bounded. In both cases, we determine the viability kernel, that is, the set of states for which there exists an action policy maintaining the coexistence of the two languages, and we define such policies. We also study the resilience of the languages and identify configurations from where the system can return to the viability kernel (finite resilience), or where one of the languages is lead to disappear (zero resilience). Within our current framework, the maintenance of a bilingual society is shown to be possible by introducing the prestige of a language as a control variable.


Advances in imaging approaches to fracture risk evaluation.
Fragility fractures are a growing problem worldwide, and current methods for diagnosing osteoporosis do not always identify individuals who require treatment to prevent a fracture and may misidentify those not a risk. Traditionally, fracture risk is assessed using dual-energy X-ray absorptiometry, which provides measurements of areal bone mineral density at sites prone to fracture. Recent advances in imaging show promise in adding new information that could improve the prediction of fracture risk in the clinic. As reviewed herein, advances in quantitative computed tomography (QCT) predict hip and vertebral body strength; high-resolution HR-peripheral QCT (HR-pQCT) and micromagnetic resonance imaging assess the microarchitecture of trabecular bone; quantitative ultrasound measures the modulus or tissue stiffness of cortical bone; and quantitative ultrashort echo-time MRI methods quantify the concentrations of bound water and pore water in cortical bone, which reflect a variety of mechanical properties of bone. Each of these technologies provides unique characteristics of bone and may improve fracture risk diagnoses and reduce prevalence of fractures by helping to guide treatment decisions.


Terminal Sugar Moiety Determines Immunomodulatory Properties of Poly(propyleneimine) Glycodendrimers.
Poly(propyleneimine) dendrimers fully surface-modified with disaccharide moieties (maltose, cellobiose, and lactose) designed to mimic natural lectin receptor ligands were tested for their bioactivity in two myeloid cell lines: THP-1 and HL-60. Depending on the sugar modification, we observed variable activation of NF-κB, AP-1, and NF-AT signaling pathways: lactose-coated dendrimers had the strongest impact on marker gene expression and most signaling events with the notable exception of NF-κB activation in THP-1 cells. The two cell lines showed an overall similar pattern of transcription factor and gene expression activation upon treatment with glycodendrimers, suggesting the involvement of galectin and C-type lectin receptor types. An important result of this action was the overexpression of CD40 and IL8 genes, potentially leading to an activated, proinflammatory phenotype in the monocyte/macrophage cell lineage. These pharmacodynamic characteristics of glycodendrimers need to be taken into account during their pharmaceutical applications both in drug delivery and direct immunomodulation.


Sequence and analysis of a swinepox virus homologue of the vaccinia virus major envelope protein P37 (F13L).
P37 (F13L gene product), the most abundant protein in the envelope of the extracellular virus form of the prototype poxvirus, vaccinia virus (VV), is a crucial player in the process leading to acquisition of the envelope, virus egress and transmission. We have cloned and sequenced a swinepox virus (SPV) gene homologous to VV F13L. The SPV gene product, termed P42, was 54% identical to P37, the VV F13L gene product, and, among the poxviruses, was most similar (73% identity) to the myxoma virus homologue. The SPV P42 gene contained late transcription signals and was expressed only at late times during infection. The protein was palmitylated, and showed an intracellular distribution similar to that of VV P37, both by immunofluorescence and by subcellular fractionation. As with VV P37, SPV P42 was incorporated in extracellular enveloped SPV particles, but was absent from the intracellular mature virus form. To check the ability of SPV P42 to function in the context of VV infection, we inserted the SPV gene into a VV deficient in P37, which is severely blocked in virus envelopment and cell-to-cell transmission. Despite correct expression of SPV P42, the resulting recombinant VV showed no rescue of extracellular virus formation or cell-to-cell virus spread. The lack of function of SPV P42 in the VV genetic background suggests that specific interactions between SPV P42 or VV P37 and other viral proteins is required to drive the envelopment process.


[Multilocular encapsulated intracerebral hematoma; a case report].
Encapsulated intracerebral hematomas mimicking a brain tumor have been reported as a rare occurrence. An additional case with a characteristic feature found on computed tomography (CT), and a clinical course is described. CT scans revealed a high density mass with peripheral low density in the brain. A hematoma was successfully removed and found to have a thick and multilobular fibrous capsule associated with cavernous hemangioma. Repeated hemorrhage due to vascular malformation was considered to have contributed to the formation of the capsule. Increasing awareness of the possibility of an encapsulated intracerebral hematoma as a clinical and pathological entity, would enable us to make a correct diagnosis and to select proper treatment. A thorough survey of occult vascular malformation is necessary in surgery.


Severe Uncompensated Metabolic Alkalosis due to Plasma Exchange in a Patient with Pulmonary-Renal Syndrome: A Clinician's Challenge.
Metabolic alkalosis secondary to citrate toxicity from plasma exchange is very uncommon in patients with normal renal function. In patients with advanced renal disease this can be a fatal event. We describe a case of middle-aged woman with Goodpasture's syndrome treated with plasma exchange who developed severe metabolic alkalosis. High citrate load in plasma exchange fluid is the underlying etiology. Citrate metabolism generates bicarbonate and once its level exceeds the excretory capacity of kidneys, the severe metabolic alkalosis ensues. Our patient presented with generalized weakness, fever, and oliguria and developed rapidly progressive renal failure. Patient had positive serology for antineutrophilic cytoplasmic antibodies myeloperoxidase (ANCA-MPO) and anti-glomerular basement membrane antibodies (anti-GBM). Renal biopsy showed diffuse necrotizing and crescentic glomerulonephritis with linear glomerular basement membrane staining. Patient did not respond to intravenous steroids. Plasma exchange was started with fresh frozen plasma but patient developed severe metabolic alkalosis. This metabolic alkalosis normalized with cessation of plasma exchange and initiation of low bicarbonate hemodialysis. ANCA-MPO and anti-GBM antibodies levels normalized within 2 weeks and remained undetectable at 3 months. Patient still required maintenance hemodialysis.


Clindamycin suppresses endotoxin released by ceftazidime-treated Escherichia coli O55:B5 and subsequent production of tumor necrosis factor alpha and interleukin-1 beta.
Treatment of septicemia caused by Escherichia coli with ceftazidime (CAZ) may be associated with the development of septic shock due to the release of bacterial lipopolysaccharide. We examined the suppressive effect of clindamycin (CLDM) on CAZ-induced release of endotoxin by cultured E. coli and the subsequent production of inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-1 beta [IL-1 beta]). E. coli ATCC 12014 was incubated in inactivated horse serum with or without CLDM for 1, 4, or 18 h, followed by the addition of CAZ and collection of the culture supernatant at 0, 1, and 2 h. The concentration of endotoxin in each sample was measured by a chromogenic Limulus test. Another portion of the culture supernatant was added to THP-1 cell culture and incubated for 4 h, and the concentrations of TNF-alpha and IL-1 beta in the supernatant were measured by an enzyme-linked immunosorbent assay. In the control group (no CLDM), CAZ administration resulted in significant increases in endotoxin, TNF-alpha, and IL-1 beta concentrations. Pretreatment of E. coli with CLDM for 4 or 18 h before the addition of CAZ significantly suppressed the concentrations of endotoxin, TNF-alpha, and IL-1 beta in a time-dependent manner. In addition, CAZ treatment transformed E. coli from rodshaped bacteria to filament-like structures, as determined by electron microscopy, while pretreatment with CLDM prevented these morphological changes. Our in vitro studies showed that CAZ-induced release of large quantities of endotoxin by E. coli could be suppressed by prior administration of CLDM.


Nerves Around the Shoulder: What the Radiologist Should Know?
Peripheral neuropathies of the shoulder are common and could be related to traumatic injury, shoulder surgery, infection or tumour but usually they result from an entrapment syndrome. Imaging plays an important role to detect the underlying causes, to assess the precise topography and the severity of nerve damage. The key points concerning the imaging of nerve entrapment syndrome are the knowledge of the particular topography of the injured nerve, and the morphology as well signal modifications of the corresponding muscles. Magnetic Resonance Imaging best shows these findings, although Ultrasounds and Computed Tomography sometimes allow the diagnosis of neuropathy.


Long-term follow-up of serum-interferon and its acid-stability in a group of homosexual men.
For a period of over two years 99 volunteer healthy homosexual men were examined periodically for the presence of interferon (IFN) in their serum. Thirty-nine subjects had either undetectable IFN levels in serum or IFN was detected only once in three to five samples tested. In another 45 subjects low IFN levels were detected throughout the study period. None of these subjects had or developed any disease symptoms. In the remaining 15 subjects high serum IFN levels were detected at their enrollment or during the study period. All these subjects started to manifest clinical symptoms compatible with AIDS. In six subjects the mean time elapsed between the first detection of serum IFN and disease symptoms was 6.5 months. In all subjects but one, the IFN was of type alpha. The acid-stability of serum IFN alpha decreased with time, and when its decrease was abrupt it was associated with a more rapid evolution of AIDS. Sera containing acid-labile IFN alpha can induce IFN alpha synthesis in normal lymphocyte cultures (LC), but do not influence IFN gamma synthesis in LC stimulated with phytohemagglutinin. LC stimulated with viral antigens in the presence of serum with acid-labile IFN alpha synthesized IFN with an increased sensitivity for acid treatment. The results confirm the prognostic value of serum IFN alpha in the development of AIDS, and suggest that the transition to acid-lability may be a gradual process.


Pharmacological study of the anococcygeus muscle of the dog.
1 The response of the dog anococcygeus muscle to field stimulation and to some drugs has been studied. The results are compared with those reported previously in the rat, cat and rabbit. 2 Field stimulation produced frequency-dependent contractions which were inhibited by guanethidine and phentolamine. When the tonus of the muscle was increased with guanethidine, field stimulation always produced frequency-dependent relaxation. The relaxation was not prevented by propranolol. 3 The muscle was contracted by noradrenaline, tyramine, acetylcholine, histamine (H1), 5-hydroxy-tryptamine, prostaglandin E2 and vasopressin. Phentolamine, atropine, promethazine (but not cimetidine) and methysergide inhibited the effect of the respective agonists. 4 After increasing the tonus of the muscle, it was relaxed by low concentrations of isoprenaline. The relaxation was antagonized by propranolol. 5 The response to adenosine triphosphate (ATP) was variable. In some preparations, it relaxed the muscle, in others it contracted the muscle prior to relaxation, in others still it only contracted the muscle. Indomethacin did not prevent ATP-induced contraction. 6 It is concluded that the anococcygeus of the dog, like that of rat, cat and rabbit, has an adrenergic motor innervation and an inhibitory innervation, the transmitter of which is not identified.


Maternal clinical diagnoses and hospital variation in the risk of cesarean delivery: analyses of a National US Hospital Discharge Database.
Cesarean delivery is the most common inpatient surgery in the United States, where 1.3 million cesarean sections occur annually, and rates vary widely by hospital. Identifying sources of variation in cesarean use is crucial to improving the consistency and quality of obstetric care. We used hospital discharge records to examine the extent to which variability in the likelihood of cesarean section across US hospitals was attributable to individual women's clinical diagnoses. Using data from the 2009 and 2010 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project--a 20% sample of US hospitals--we analyzed data for 1,475,457 births in 1,373 hospitals. We fitted multilevel logistic regression models (patients nested in hospitals). The outcome was cesarean (versus vaginal) delivery. Covariates included diagnosis of diabetes in pregnancy, hypertension in pregnancy, hemorrhage during pregnancy or placental complications, fetal distress, and fetal disproportion or obstructed labor; maternal age, race/ethnicity, and insurance status; and hospital size and location/teaching status. The cesarean section prevalence was 22.0% (95% confidence interval 22.0% to 22.1%) among women with no prior cesareans. In unadjusted models, the between-hospital variation in the individual risk of primary cesarean section was 0.14 (95% credible interval 0.12 to 0.15). The difference in the probability of having a cesarean delivery between hospitals was 25 percentage points. Hospital variability did not decrease after adjusting for patient diagnoses, socio-demographics, and hospital characteristics (0.16 [95% credible interval 0.14 to 0.18]). A limitation is that these data, while nationally representative, did not contain information on parity or gestational age. Variability across hospitals in the individual risk of cesarean section is not decreased by accounting for differences in maternal diagnoses. These findings highlight the need for more comprehensive or linked data including parity and gestational age as well as examination of other factors-such as hospital policies, practices, and culture--in determining cesarean section use. Please see later in the article for the Editors' Summary.


Consumption of alcoholic beverages and abdominal obesity: cross-sectional analysis of ELSA-Brasil.
The objective was to analyze the association between alcohol consumption and abdominal adiposity in adults. Cross-sectional study conducted at baseline data from ELSA-Brasil (2008- 2010). The sample consisted of 15,065 civil servants from six education and research institutions (35 to 74 years old, both sexes). To identify central adiposity by measuring waist circumference (WC) and waist-to-hip ratio (WHR), the cutoff points recommended by the World Health Organization were used. Poisson regression models adjusted for potentially confounding variables were tested. About 40% of the sample had elevated WC and WHR. The probability of having elevated WC was 5% and 3% higher in the most exposed group of beer consumption in men and women when compared to the reference group [PR= 1.05 (95% CI 1.02-1.08) and P R= 1.03 (95% CI 1.00-1.07)]. A higher probability of having a high WHR was also found among the highest beer consumers [PR = 1.03 (95% CI 1.00-1.07) in men and PR = 1.10 (95% CI 1.04-1.15) in women]. A greater number of doses/week of alcoholic drink increased the probability of occurrence of high WC and WHR, with the beer contribution being more important.


Evaluation of the body mass index in breast cancer prognosis in a cohort of small-stature overweight patients: multi-center study in China.
Overweight and obesity have become a major health issue in the past 30 years. Several studies have already shown that obesity is significantly associated with a higher risk of developing breast cancer. However, few studies have assessed the prognostic value of the body mass index (BMI) in Asian populations. The purpose of this study was to retrospectively analyze the impact of BMI on the prognosis of breast cancer in overweight, under 160 cm tall patients from southern China. We retrospectively analyzed data from 525 breast cancer patients diagnosed between 2003 to 2010 in a multi-center of China. After applying the exclusion criteria, 315 patients with complete data were retained. Their clinical and pathological characteristics were compared using the chi-square test. Survival analysis was performed with the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox regression to calculate hormone receptor status, HER-2 status, lymph node status, age, BMI and tumor size hazard ratio (HR), and 95% confidence intervals (95% CI). There was a strong correlation between BMI and age in the baseline feature analysis (P=0.001). After grouping the patients according to the molecular type of cancer, we found that in Luminal A and B, the BMI was related to age (P=0.002, P=0.010). The disease-free survival (DFS) and overall survival (OS) of patients with different BMI were not significantly different. This conclusion was also reached by pairwise comparison of subgroups. There was no significant difference in recurrence in patients from different BMI groups. We did not find a critical weight threshold associated with higher risk of recurrence. There were no statistically significant differences in treatment among the three BMI groups of overweight patients. We found that the BMI of Chinese breast cancer patients is related to age but not prognosis.


Immune Cell Number, Phenotype, and Function in the Elderly with Sepsis.
Sepsis is a form of life-threatening organ dysfunction caused by dysregulated host responses to an infection that can be partly attributed to immune dysfunction. Although sepsis affects patients of all ages, elderly individuals display increased susceptibility and mortality. This is partly due to immunosenescence, a decline in normal immune system function associated with physiological aging that affects almost all cell types in the innate and adaptive immune systems. In elderly patients with sepsis, these alterations in immune cells such as endothelial cells, neutrophils, monocytes, macrophages, natural killer cells, dendritic cells, T lymphocytes, and B lymphocytes, are largely responsible for their poor prognosis and increased mortality. Here, we review recent studies investigating the events affecting both innate and adaptive immune cells in elderly mice and patients with sepsis, including alterations in their number, phenotype, and function, to shed light on possible new therapeutic strategies.


Improved realism of hybrid mouse models may not be sufficient to generate reference dosimetric data.
Recent developments of hybrid realistic models, such as Moby (mouse) and Roby (rat) developed by Segars et al. ["Development of a 4-D digital mouse phantom for molecular imaging research," Mol. Imaging Biol. 6, 149-159 (2004)] have found several applications in preclinical experiments. Indeed, their improved realism and flexibility in terms of mass scaling represent an attractive option for absorbed dose calculations based on "representative" models. However, the range of radiations involved in small animal molecular imaging and radiotherapy is of the same order of magnitude as organs of interest dimensions. As a consequence, minor geometric variations between rodents may lead to major differences in absorbed dose calculations. This study aims at validating a voxel-based model for use in absorbed dose estimates with two Monte Carlo codes and at assessing the dosimetric impact of Moby-based models definition. The authors generated a 30 g-mouse phantom based on realistic hybrid model Moby (version 1). Dosimetric calculations (S-values, specific absorbed fraction) were performed with two Monte Carlo codes (MCNPX v2.7a and GATE v6.1) for (18)F, and a comparison with values published for Radiation Dose Assessment Resource realistic animal series was made. Several parameters such as material definition∕densities, fine suborgan segmentation for airways (trachea, lungs, remaining body), bones (ribs, spine, skull, remaining bones), heart (blood pool and myocardium), and stomach (wall and gastrointestinal content) were further studied, as well as nuclear data and spatial sampling. Most organ masses matched the reference model (Moby v1) within ± 6%, except lungs, thyroid, and bones for which differences could reach 29%. Comparison of S-values (especially self-S-values) was consistent with mass differences observed between the two models. The reciprocity theorem for source∕target pairs was satisfied within few percents for specific absorbed fractions (g(-1)). However, significant discrepancies, reaching 160%, were observed for mutual liver∕stomach∕spleen S-values and could not be directly related to mass variations. Nonetheless, differences between S-values calculated with MCNPX and GATE for our model remained in the order of a few percents, i.e., within statistical uncertainties. Besides, modifications of organ densities increased S-values up to a factor 50 for the lungs∕thyroid pair when upper airway was properly segmented out of the body. Specific material composition and densities for several bone types led to a 10% decrease of S-values from the bone source to several target organs. Moreover, relative differences up to 100% were observed for S(stomach wall⇐spleen) when improving spatial-sampling by a factor 3. This study demonstrated that comparison between two "similar" realistic digital mouse whole-body phantoms generated from the same software still led to very different S-values, even when total body and organ mass scaling were performed. Moreover, parameters such as organ segmentation, tissue material∕density, or spatial sampling should be defined and reported with great care to perform accurate small animal absorbed dose calculation based on "reference" models.


[A mechanism involved in augmentation of anti-tumor immunity by irradiation to the tumor: tumor irradiation promoted generation of CD4+helper T cells against a murine immunogenic tumor].
It has long been suggested but not generally accepted that anti-tumor immunity is enhanced by irradiation of the tumor. In this study, the mechanism involved in enhancing the effect of irradiation on tumor immunity was analyzed. 20 Gy of irradiation to a murine hepatoma, MH134, in the thigh muscle of syngeneic C3H/He mice, augmented the generation of cytotoxic T cells (CTL) in the spleen. It was assumed that radiation-damaged apoptotic tumor cells are readily phagocytosed by macrophages and that tumor specific transplantation antigen (TSTA) is presented as a complex with MHC class II antigen on macrophages to CD4+ T cells. To examine the hypothesis, that irradiated tumor cells induce CD4+ helper T cells required for the generation of CD8+ CTL, C3H/He mice were immunized with 2 x 10(7) MH134 cells which contained irradiated tumor cells (100 Gy, in vitro) at varying ratios. When irradiated tumor cells are contained at levels of 60-80%, the generation of helper T cells as well as CTL against the tumor was significantly enhanced. The findings obtained suggest that tumor irradiation enhances anti-tumor immunity by promoting the induction of antigen-specific helper T cells, which play a key role in anti-tumor immunity, i.e., either generating CTL or antibody-forming B cells depending on the activity of TH1 or TH2 subset cells.


Impact of training volume and experience on amateur Ironman triathlon performance.
To investigate the association between training volume, sleep time, signs and symptoms of excessive training (overtraining), and previous triathlon experience with overall and split race times in the Ironman distance triathlon. Ninety-nine triathletes (19 women and 80 men) answered an online survey containing questions about anthropometric characteristics (body mass and height), weekly training volume (hours per day and days per week), previous experience in Ironman distance triathlon race, and signs and symptoms of excessive training. Data of race times of all participants were collected by a single race (the Ironman Brazil 2019 - Florianópolis). All surveys were collected between 28 and 30 days before the race. The athlete was instructed to answer the questions according to what was happening in the week before completing the survey. Total race time did not differ among those who trained up to 14 h per week (11:28:46±01:54:30 h:min:sec), between 15 and 20 h per week (11:37:31±01:20:26 h:min:sec) or more than 20 h per week (11:30:18±01:31:28 h:min:sec) (p = 0.922). Total race time of the triathletes who presented (12:42:22±01:49:36 h:min:sec) or no (11:23:06±01:29:02 h:min:sec) unintentional body mass loss (p = 0.006), feeling (12:46:17±02:03:13 h:min:sec) or no (11:24:09±01:28:07 h:min:sec) of decreased performance (p = 0.009) or feeling (12:08:58±01:47:12 h:min:sec) or no (11:16:34±01:24:53 h:min:sec) loss of energy (p = 0.011) in the week prior to the race were significantly different. Triathletes who had a previous experience in Ironman races achieved a better performance (11:15:21±01:32:04 h:min:sec) than those without previous experience (12:06:38±01:32:10 h:min:sec) (p = 0.010). In summary, high volumes of training (more than 20 h per week), when performed forty days before a race, may not have a positive impact on performance compared to lower volumes of training (up to 14 h per week). However, athletes who had a previous experience in Ironman race presented better results in swimming splits and overall race time. Moreover, the presence of overtraining symptoms, such as unintentional loss of weight, sensation of fatigue and/or performance decrease impact negatively triathlon performance.


Relationship between changes in R-wave amplitude during left ventriculography and the seriousness of coronary heart disease.
Serious complications, such as myocardial infarction or death, may occur particularly in patients with severe coronary heart disease during coronary angiographies. Therefore, prediction of severe coronary heart disease before or during the initial steps of the procedure can provide a decrease in frequency of such complications. To predict the seriousness of coronary heart disease during left ventriculography, before, during, and after the application of contrast matter, electrocardiography (ECG) records were taken and R-wave amplitudes were measured. Lead DII was used for calculations. The patients were classified according to vessel lesions and were compared with the control group. Before and after left ventriculography, there was no significant difference between the groups with normal coronary arteries and one, two, or three vessel lesions. Although there was no significant difference obtained from the comparison of the control group and the groups with one-vessel and two-vessel lesions (9.7 mm, 9.2 mm, 10.1 mm, respectively, P > 0.05); there was statistical difference between the group with three-vessel lesions and the control group during left ventriculography (6.4 mm, 9.7 mm, respectively, P < 0.05). Nonionic contrast material was used in all procedures. The decrement of R-wave amplitude that is observed during left ventriculography can predict three-vessel disease, which is a more serious condition for the patients. These patients should be monitored more carefully during coronary angiographies.


[Behavior of external adjuvants in human skin. In vitro penetration of various polyethylene glycols].
Polyethylene glycols (PEG), which serve as vehicles or additives in salves, sometimes appear to cause contact allergies, depending on their molecular weight. Whether this can be determined quantitatively should be proven. To this end we investigated the penetrative behavior of various PEG (mol. wts. 400 to 4000) on intact and damaged (stripped) human skin in vitro. It is shown here that in the course of time liquid PEG (mol. wt. 400) makes the intact horny layer more permeable than solid PEG does. The concentrations found in the intact epidermal horny layer were clearly dependent on molecular weight, indicating that liquid PEG penetrates better than solid high-molecular PEG. If the horny layer is damaged - as is the case with most dermatitis patients - all PEGs penetrate the dermis and epidermis independent of molecular weight. The allergological consequences, in particular for epicutaneous testing, are discussed briefly.


Antimicrobial resistance profile of extended-spectrum beta-lactamases, adenosine-monophosphate-cyclic, and carbapenemase-producing Gram-negative bacteria isolated from domestic animals.
The production of beta-lactamase enzymes, such as extended-spectrum beta-lactamase (ESBL), adenosine-monophosphate-cyclic (AmpC), and Klebsiella pneumoniae carbapenemase (KPC), is one of the most important mechanisms of bacterial resistance to antimicrobials. Gram-negative bacteria show significant resistance due to various intrinsic and acquired factors. These intrinsic factors include low permeability of the outer membrane, various efflux systems, and the production of beta-lactamases, while acquired factors include chromosomal mutation and acquisition of resistance genes by horizontal transfer. Mobile elements such as plasmids, integrative conjugative elements, mobilizable islands, or transposable elements are involved in horizontal transfer. At present, the Gram-negative pathogens of most concern are Acinetobacter baumannii, Pseudomonas aeruginosa, and those belonging to the Enterobacteriaceae family (e.g., Escherichia coli, K. pneumoniae, and Proteus mirabilis). This study aimed to evaluate the profile of antimicrobial resistance and the production of the enzymes ESBL, AmpC, and KPC, in 21 gram-negative bacteria isolated from domestic animals treated at the University Veterinary Hospital (HVU) of the Federal University of Western Bahia (UFOB). The biological samples (21) were inoculated to brain heart infusion broth, blood agar, and MacConkey agar and incubated for 24-72 h at 37°C. Gram staining and identification through biochemical tests and matrix-associated laser desorption/ionization time-of-flight mass spectrometry were conducted. To evaluate the antimicrobial resistance profile, the disk diffusion method was used, and 25 antibiotics were employed. For the detection of ESBL, the disk approximation method was applied using chromogenic agar. The presence of KPC was observed using chromogenic agar and the Hodge test. For AmpC evaluation, the disk approximation method was used. The most isolated agent was E. coli (66.66%, 14/21), followed by K. pneumoniae and P. mirabilis (both 14.29%, 3/21), and then Pasteurella spp. (4.76%, 1/21). The bacterial isolates showed high levels of resistance against clindamycin, penicillin, imipenem, polymyxin, cefoxitin, gentamycin, cefotaxime, ceftazidime, cephalothin, ceftriaxone, ciprofloxacin, trimethoprim/sulfamethoxazole, chloramphenicol, and tetracycline. The best effectiveness rates were observed for cefepime, streptomycin, amoxicillin-clavulanate, aztreonam, nalidixic acid, tobramycin, levofloxacin, amikacin, and meropenem. All biological isolates showed multiple resistance to at least three of the antibiotics tested (3/25), and some showed resistance to 24 of the antibiotics tested (24/25). Among the 21 pathogens analyzed, 8 were ESBL producers (38.09%); of these, 6 were identified as E. coli (28.57%), and 2 were identified as K. pneumoniae (9.52%). Two strains of K. pneumoniae produced both ESBL and KPC. None of the isolates were producers of AmpC. The results found in the present work raise concern about the level of antimicrobial resistance among pathogens isolated from domestic animals in Brazil. The results highlight the need for the development and implementation of anti-resistance strategies to avoid the dissemination of multiresistant pathogens, including the prudent use of antimicrobials and the implementation of bacterial culture, antimicrobial sensitivity, and phenotypic tests for the detection of beta-lactamase enzymes in bacteria isolated from animals.


Resource Oriented Decision Making for Treatment of Metastatic Colorectal Cancer (mCRC) in a Lower-Middle Income Country: Egyptian Foundation of Medical Sciences (EFMS) Consensus Recommendations 2020.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second cause of cancer related mortality. Treatment options for patients with metastatic CRC (mCRC) expanded during the last two decades, with introduction of new chemotherapeutic and targeted agents. Egypt is a lower middle-income country; Egyptian health care system is fragmented with wide diversity in drug availability and reimbursement policies across different health care providing facilities. We report the results of consensus recommendations for treatment of patients with metastatic colorectal cancer developed by Egyptian Foundation of Medical Sciences (EFMS), aiming to harmonize clinical practice through structured expert consensus-based recommendations consistent with the national status. EFMS recommendations could be utilized in other countries with similar economic status. EFMS recommendations were developed using a modified Delphi process, with three rounds of voting till the final recommendations were approved. A non-systematic review of literature was conducted before generating the provisional statements. Content experts were asked to vote on some recommendations in two different resource groups (restricted resources and non-restricted resources). External review board of experts from a low income and lower-middle countries voted on the applicability of EFMS recommendations in their countries. The current recommendations highlighted the discrepancy in health care between restricted and non-restricted resources with expected survival loss and quality of life deterioration. Access to targeted agents in first line is very limited in governmental institutions, and no access to agents approved for third line in patients who failed oxaliplatin and irinotecan containing regimens for patients treated in restricted resource settings. Management of mCRC in developing countries is a challenge. The currently available resource-stratified guidelines developed by international cancer societies represent a valuable decision-making tool, adaptation to national status in each country based on healthcare system status is required.


Infliximab treatment in a patient with rheumatoid arthritis on hemodialysis.
We describe a 60-year-old woman with active rheumatoid arthritis (RA) and endstage renal disease secondary to hypertensive nephrosclerosis undergoing hemodialysis. She had tried multiple antirheumatic medications; however, their usefulness was limited due to toxic side effects or lack of efficacy. She was then treated with chimeric antitumor necrosis factor monoclonal antibody (infliximab), which resulted in immediate improvement in clinical and laboratory measures. After about 2 years of therapy, no side effects have been observed. This report expands the spectrum of infliximab to include RA patients with renal insufficiency.


[Analysis of gene mutations in Chinese patients with methylmalonic acidemia and homocysteinemia].
Methylmalonic acidemia complicated with homocysteinemia, cblC type, is the most common inborn error of cobalamin metabolism. The gene MMACHC (OMIM 277400) is located on chromosome 1p34.1 with four coding exons and a 5th non-coding exon. It encodes for a protein with 282 amino acid residues. So far, more than 40 mutations have been detected, in which 271dupA (R91KfsX14) is the hot spot of MMACHC gene. However, there have not been relevant reports in China. The present study aimed to identify the mutation types of MMACHC gene and analyze the genotype-phenotype correlations in Chinese patients. The diagnosis of this disease mainly depends on the measurement of C3 propionylcarnitine, C3/C0 (free carnitine) and C3/C2 (acetylcarnitine) in the blood by tandem mass spectrometry, the detection of methylmalonic acid in the urine by gas-chromatography mass spectrometry, the determination of total homocysteine in the serum, and the loading test of vitamin B12. The entire coding region of MMACHC gene was screened by polymerase chain reaction (PCR) combined with DNA direct sequencing in 28 Chinese patients. Genomic DNA was extracted using phenol-chloroform method from the peripheral blood leukocytes of each patient. PCR amplification products were checked by 1.8% agarose gel electrophoresis and were subsequently sequenced with both the forward and reverse primers. Mutational analyses were performed using normal human genomic MMACHC sequence as a reference (GenBank ID: 25974). In this study, ten mutations were identified in 27 of 28 Chinese patients. Most of them were located in exons 3 and 4 (91.3%). We detected four mutations reported, which were 609G>A (W203X), 217C>T (R73X), 271dupA (R91KfsX14), and 394C>T (R132X), and six novel mutations, which were 1A>G, 365A>T, 658_660delAAG, 301-3_327del 30, 567_568insT, and 625_626insT. The 609G>A (W203X) is the most common mutation, which was detected in 30 of 56 alleles (53.6%), including 10 homozygote mutations and 10 heterozygote mutations. In addition, three gene polymorphisms were detected, namely, -302T>G (rs3748643), -234A>G (rs3728644), and 321G>A (rs2275276). These mutations include missense mutations, nonsense mutations, duplication, deletions, and insertions. In this study, we found a part of gene mutations spectrum in Chinese patients with methylmalonic acidemia and homocysteinemia, in which the 609G>A (W203X) may be the hotspot mutation of MMACHC gene. This would be helpful in the prenatal diagnosis and gene screening programs of methylmalonic acidemia and homocystinemia.


Upgrading volatile fatty acids production through anaerobic co-fermentation of mushroom residue and sewage sludge: Performance evaluation and kinetic analysis.
Due to complex inherent structure of lignocellulosic biomass, inefficient hydrolysis and acidification limits fermentative volatile fatty acids (VFA) production of mushroom residues. Meanwhile, the mushroom residues present insufficient nutrient with a high C/N ratio. To solve this issue, anaerobic co-fermentation of cellulose-rich Oyster champost and sewage sludge was tested to enhance the VFA production, and the effect of proportion of mixed substrate was investigated in this study. The results indicated that the sewage sludge yielded higher VFAs than the Oyster champost in single-substrate fermentative system. The maximal VFA yield of 595 mgCOD/gVSadded was achieved when the proportion of sewage sludge increased to 50% in the mixed substrate. In the co-fermentation system, the optimal C/N ratio and features of mixed substrate contributed to the enhancement in hydrolysis and acidification in terms of organic solubilization and VFA production, respectively. But the co-fermentation could not increase VFA/SCOD ratio, probably due to the existence of refractory products such as humic-like and protein-like materials. Besides, this co-fermentation system had strong buffer capacity and it was not necessary to dose chemicals to control the system pH for stable VFA production. Acetate was the dominant VFA product in co-fermentation systems. A modified-Logistic model fitted co-fermentation of sludge and Oyster champost well, and presented a faster rate and higher efficiency of VFA production.


Antiepilepticus Effects of Tetrahedral Framework Nucleic Acid via Inhibition of Gliosis-Induced Downregulation of Glutamine Synthetase and Increased AMPAR Internalization in the Postsynaptic Membrane.
More than 15 million out of 70 million patients worldwide do not respond to available antiepilepticus drugs (AEDs). With the emergence of nanomedicine, nanomaterials are increasingly being used to treat many diseases. Here, we report that tetrahedral framework nucleic acid (tFNA), an assembled nucleic acid nanoparticle, showed an excellent ability to the cross blood-brain barrier (BBB) to inhibit M1 microglial activation and A1 reactive astrogliosis in the hippocampus of mice after status epilepticus. Furthermore, tFNA inhibited the downregulation of glutamine synthetase by alleviating oxidative stress in reactive astrocytes and subsequently reduced glutamate accumulation and glutamate-mediated neuronal hyperexcitability. Meanwhile, tFNA promotes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization in the postsynaptic membrane by regulating AMPAR endocytosis, which contributed to reduced calcium influx and ultimately reduced hyperexcitability and spontaneous epilepticus spike frequencies. These findings demonstrated tFNA as a potential AED and that nucleic acid material may be a new direction for the treatment of epilepsy.


HIPK3 Inhibition by Exosomal hsa-miR-101-3p Is Related to Metabolic Reprogramming in Colorectal Cancer.
Exosomes are extracellular vesicles secreted by most cells to deliver functional cargoes to recipient cells. MicroRNAs (miRNAs) constitute a significant part of exosomal contents. The ease of diffusion of exosomes renders them speedy and highly efficient vehicles to deliver functional molecules. Cancer cells secrete more exosomes than normal cells. Reports have showed that exosomal miRNAs of cancer cells facilitate cancer progression. Yet the complexity of cancer dictates that many more functional exosomal miRNAs remain to be discovered. In this study, we analyzed miRNA expression profiles of tissue and plasma exosome samples collected from 10 colorectal cancer (CRC) patients and 10 healthy individuals. We focused on hsa-miR-101-3p (101-3p), a profoundly up-regulated miRNA enriched in plasma exosomes of patients bearing CRC. We performed target analysis of 101-3p and pursued functional studies of this microRNA in two colorectal cancer cell lines, namely HCT116 and SW480. Our results indicated that inhibiting 101-3p slowed cell growth and retarded cell migration in vivo in two colorectal cancer cell lines. Target analysis showed that Homeodomain-interacting protein kinase (HIPK3) is a target of miR-101-3p. HCT116 and SW480 cells stably overexpressing HIPK3 showed increased level of phosphorylated FADD, as well as retarded cell growth, migration, and increased sensitivity to 5-FU. In-depth analysis revealed increased mitochondrial membrane potential upon HIPK3 overexpression along with increased production of reactive oxygen species, number of mitochondria, and expression of respiratory complexes. Measurements of glycolytic parameters and enzymes revealed decreased level of glycolysis upon HIPK3 overexpression in these two cell lines. Xenograft model further confirmed a profoundly improved potency of the synergistic treatment combining both 5-FU and 101-3p inhibitor compared to 5-FU alone. This study unraveled an oncogenic nature of the exosomal 101-3p and suggested a relationship between the 101-3p-HIPK3 axis and metabolic homeostasis in colorectal cancer. Expression level of 101-3p is positively correlated with glycolytic capacity in CRC and therefore 101-3p itself is an oncomiR. Combining 101-3p inhibitor with chemotherapeutic agents is an effective strategy against CRC.


A novel regulatory mechanism for Fgf18 signaling involving cysteine-rich FGF receptor (Cfr) and delta-like protein (Dlk).
Fibroblast growth factors (FGFs) transduce signals through FGF receptors (FGFRs) and have pleiotropic functions. Besides signal-transducing FGFRs, cysteine-rich FGF receptor (Cfr; Glg1) is also known to bind some FGFs, although its physiological functions remain unknown. In this study, we generated Cfr-deficient mice and found that some of them die perinatally, and show growth retardation, tail malformation and cleft palate. These phenotypes are strikingly similar to those of Fgf18-deficient mice, and we revealed interaction between Cfr and Fgf18 both genetically and physically, suggesting functional cooperation. Consistently, introduction of Cfr facilitated Fgf18-dependent proliferation of Ba/F3 cells expressing Fgfr3c. In addition, we uncovered binding between Cfr and delta-like protein (Dlk), and noticed that Cfr-deficient mice are also similar to Dlk-transgenic mice, indicating that Cfr and Dlk function in opposite ways. Interestingly, we also found that Dlk interrupts the binding between Cfr and Fgf18. Thus, the Fgf18 signaling pathway seems to be finely tuned by Cfr and Dlk for skeletal development. This study reveals a novel regulatory mechanism for Fgf18 signaling involving Cfr and Dlk.


Least activation path for protein folding: investigation of staphylococcal nuclease folding by stopped-flow circular dichroism.
Is the pathway of protein folding determined by the relative stability of folding intermediates, or by the relative height of the activation barriers leading to these intermediates? This is a fundamental question for resolving the Levinthal paradox, which stated that protein folding by a random search mechanism would require a time too long to be plausible. To answer this question, we have studied the guanidinium chloride (GdmCl)-induced folding/unfolding of staphylococcal nuclease [(SNase, formerly EC 126.96.36.199; now called microbial nuclease or endonuclease, EC 220.127.116.11] by stopped-flow circular dichroism (CD) and differential scanning microcalorimetry (DSC). The data show that while the equilibrium transition is a quasi-two-state process, kinetics in the 2-ms to 500-s time range are triphasic. Data support the sequential mechanism for SNase folding: U3 <--> U2 <--> U1 <--> N0, where U1, U2, and U3 are substates of the unfolded protein and N0 is the native state. Analysis of the relative population of the U1, U2, and U3 species in 2.0 M GdmCl gives delta-G values for the U3 --> U2 reaction of +0.1 kcal/mol and for the U2 --> U1 reaction of -0.49 kcal/mol. The delta-G value for the U1 --> N0 reaction is calculated to be -4.5 kcal/mol from DSC data. The activation energy, enthalpy, and entropy for each kinetic step are also determined. These results allow us to make the following four conclusions. (i) Although the U1, U2, and U3 states are nearly isoenergetic, no random walk occurs among them during the folding. The pathway of folding is unique and sequential. In other words, the relative stability of the folding intermediates does not dictate the folding pathway. Instead, the folding is a descent toward the global free-energy minimum of the native state via the least activation path in the vast energy landscape. Barrier avoidance leads the way, and barrier height limits the rate. Thus, the Levinthal paradox is not applicable to the protein-folding problem. (ii) The main folding reaction (U1 --> N0), in which the peptide chain acquires most of its free energy (via van der Waals' contacts, hydrogen bonding, and electrostatic interactions), is a highly concerted process. These energy-acquiring events take place in a single kinetic phase. (iii) U1 appears to be a compact unfolded species; the rate of conversion of U2 to U1 depends on the viscosity of solution. (iv) All four relaxation times reported here depend on GdmCl concentrations: it is likely that none involve the cis/trans isomerization of prolines. Finally, a mechanism is presented in which formation of sheet-like chain conformations and a hydrophobic condensation event precede the main-chain folding reaction.


Nanopharmaceuticals for wound healing - Lost in translation?
Today, many of the newly developed pharmaceuticals and medical devices take advantage of nanotechnology and with a rising incidence of chronic diseases such as diabetes and cardiovascular disease, the number of patients afflicted globally with non-healing wounds is growing. This has created a requirement for improved therapies and wound care. However, converting the strategies applied in early research into new products is still challenging. Many of them fail to comply with the market requirements. This review discusses the legal and scientific challenges in the design of nanomedicines for wound healing. Are they lost in translation or is there a new generation of therapeutics in the pipeline?


Cerebral oxygen metabolism in patients with early Parkinson's disease.
Decreased activity of the mitochondrial electron transport chain (ETC) has been implicated in the pathogenesis of Parkinson's disease (PD). This model would most likely predict a decrease in the rate of cerebral oxygen consumption (CMRO(2)). To test this hypothesis, we compared CMRO(2) and cerebral blood flow (CBF) PET scans from PD patients and healthy controls. Nine early-stage PD patients and 15 healthy age-matched controls underwent PET scans for quantitative mapping of CMRO(2) and CBF. Between-group differences were evaluated for absolute data and intensity-normalized values. No group differences were detected in regional magnitudes of CMRO(2) or CBF. Upon normalization using the reference cluster method, significant relative CMRO(2) decreases were evident in widespread prefrontal, parieto-occipital, and lateral temporal regions. Sensory-motor and subcortical regions, brainstem, and the cerebellum were spared. A similar pattern was evident in normalized CBF data, as described previously. While the data did not reveal substantially altered absolute CMRO(2) in brain of PD patients, employing data-driven intensity normalization revealed widespread relative CMRO(2) decreases in cerebral cortex. The detected pattern was very similar to that reported in earlier CBF and CMRglc studies of PD, and in the CBF images from the same subjects. Thus, the present results are consistent with the occurrence of parallel declines in CMRO(2), CBF, and CMRglc in spatially contiguous cortical regions in early PD, and support the hypothesis that ETC dysfunction could be a primary pathogenic mechanism in early PD.


Hypothalamic-pituitary-adrenal (HPA) axis response to exogenous corticotropin-releasing hormone (CRH) is attenuated in men with chronic insomnia.
Although insomnia is by far the most common sleep disorder, our understanding of its neurobiology is limited. Insomnia, particularly when associated with objective sleep disturbance, has been associated with activation of the hypothalamic-pituitary-adrenal axis. The objective of this experimental study was to compare the response of the hypothalamic-pituitary-adrenal axis to ovine corticotropin-releasing hormone, a stress test, in men with insomnia versus controls. Circulating adrenocorticotropic hormone and cortisol levels were assayed before (-30 min, -15 min), at (0 min) and after (+5 min, +15 min, +30 min, +60 min, +90 min, +120 min) exogenous ovine corticotropin-releasing hormone administration in 23 men (11 insomnia, 12 controls), who underwent four consecutive nights of in-lab polysomnography. Men with insomnia compared with controls demonstrated markedly and significantly shorter total sleep time (368.4 ± 8.99 min versus 411.61 ± 8.61 min; p < 0.01) and lower sleep efficiency (76.77 ± 1.80% versus 86.04 ± 1.72%; p < 0.01) on polysomnography, and showed decreased adrenocorticotropic hormone and cortisol levels after ovine corticotropin-releasing hormone administration. Adrenocorticotropic hormone levels at 15 min and 30 min were significantly lower in men with insomnia than in controls (p < 0.05). Similarly, the peak levels of cortisol at +60 min, and the total and net area under the curve levels of this hormone were significantly lower in men with insomnia than controls (all p < 0.01). Adrenocorticotropic hormone and cortisol response to ovine corticotropin-releasing hormone administration was attenuated in men with insomnia associated with objective sleep disturbance, suggesting that objectively defined insomnia subtypes have a disrupted hypothalamic-pituitary-adrenal axis function and highlight the need to develop treatments targeting the underlying hypothalamic-pituitary-adrenal axis dysregulation.


Landscape of Cyclin Pathway Genomic Alterations Across 5,356 Prostate Cancers: Implications for Targeted Therapeutics.
The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next-generation sequencing (315 genes, >500× coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (~27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.


[Effect of magnesium and selenium on the expression of matrix metalloproteinases-20 and kallikrein 4 in fluorosis mice].
To study the effect of magnesium/selenium on the expression of matrix metalloproteinases-20(MMP-20) and kallikrein 4(KLK4) during fluorosis in mice and to explore the formation mechanism of dental fluorosis. Eighty SPF male ICR mice were randomly divided into 8 groups according to body weight: control group, magnesium group, selenium group, magnesium-selenium group, fluoride group, magnesium-fluorine group, selenium-fluorine group and magnesium-selenium-fluorine group. Mice in control, magnesium, selenium and magnesium-selenium groups were fed double steamed water, and mice in the other four groups were feddouble steamed water with 50 mg/L F(-). Mice in control and fluoride groups were fed conventionally. Mice in magnesium and magnesium-fluorine groups were fed conventionally by adding MgSO4·7H2O 162.5 mg/kg. Mice in selenium and selenium-fluorine groups were fed conventionally by adding Na2SeO3·5H2O 2 mg/kg. Mice in magnesium-selenium and magnesium-selenium-fluorine groups were fed conventionally by adding MgSO4·7 H2O 162.5 mg/kg + Na2SeO3·5H2O 2 mg/kg. Incisor specimens were obtained after the mice were put into death when they were 42 days. The expressions of MMP-20 and KLK4 were observed by using immunohisto-chemicalstain. The meangray value of MMP-20 of fluoride group(133.1±10.3) was significantly higher than that of control group(116.8±10.0), magnesium group (113.6 ± 9.6), magnesium-selenium group(108.2 ± 15.2), magnesium-fluorine group(111.1 ± 8.1) and magnesium-selenium-fluorine group(108.2 ± 11.0), respectively(F=3.864, P<0.05). The mean gray value of MMP-20 of magnesium-selenium-fluorine group(108.2±11.0) was significantly lower than that of selenium group(125.4 ± 7.9), fluoride group (133.1 ± 10.3) and selenium-fluorine group(126.2 ± 2.8), respectively(F= 3.864, P<0.05). The mean gray value of KLK4 of magnesium-selenium group(117.2±11.7) was significantly lower than others(137.3±7.9 of control group, 144.2±7.7 of magnesium group, 138.9±13.3 of selenium group, 149.7 ± 12.4 of fluoride group, 148.9 ± 7.5 of magnesium-fluorine group, 140.6 ± 17.0 of selenium-fluorine group and 140.7 ± 7.3 of magnesium-selenium-fluorine group, F=3.668, P<0.05). In factorial analysis of fluorosis mice, magnesium had effect on the expression of MMP-20(F=42.613, P<0.05), selenium had effect on the expression of KLK4(F=6.649, P<0.05). The excessive fluoride could inhibit the expressions of MMP-20. The excessive fluoride hadno significant influence on the expression of KLK4. Magnesium and selenium had antagonistic effect on the dental fluorosis.


Vestibular Migraine.
To explore recent developments in vestibular migraine (VM). This review discusses the current diagnostic criteria for VM in the adult and pediatric populations, as proposed by the International Headache Society and Bárány Society. Recent VM studies confirm the prior findings and reveal new insights, including the wide range of vestibular symptoms, symptoms in the attack-free period, and triggers. Many patients experience persistent vestibular symptoms, even in the absence of acute attacks, which often significantly impact patients' quality of life. The syndrome of benign recurrent vertigo and its relationship to migraine, VM, and Meniere's disease is also discussed. There is a dearth of randomized controlled trials in VM treatment. Prospective and retrospective studies support the benefit of many migraine treatments are effective in VM, including neuromodulation, and calcitonin gene-related peptide monoclonal antibodies. VM affects almost 3% of the population, but remains under-diagnosed. Recent diagnostic criteria can help clinicians diagnose VM in adults and children.


Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study.
Few studies have quantified the relation between carotid plaques and stroke in asymptomatic patients, and limited data exist on the importance of location of plaques or the association with subtypes of cerebral infarction. We investigated the relationship between carotid plaques, measured at different locations, and risk of stroke and subtypes of cerebral infarction in a population-based study. Methods and Results- The study was based on the Rotterdam Study and included 4217 neurologically asymptomatic subjects aged 55 years or older. Presence of carotid plaques at 6 locations in the carotid arteries was assessed at baseline. Severity was categorized according to the number of affected sites. After a mean follow-up of 5.2 years, 160 strokes had occurred. Data were analyzed using Cox proportional hazards regression. Plaques increased the risk of stroke and cerebral infarction approximately 1.5-fold, irrespective of plaque location. Severe carotid plaques increased the risk of nonlacunar infarction in anterior (RR 3.2 [95% CI, 1.1 to 9.7]) but not in posterior circulation (RR 0.6 [95% CI, 0.1 to 4.9]). A >10-fold increased risk of lacunar infarction was found in subjects with severe plaques (RR 10.8 [95% CI, 1.7 to 69.7]). No clear difference in risk estimates was seen between ipsilateral and contralateral infarction. Carotid plaques increase the risk of stroke and cerebral infarction, irrespective of their location. Plaques increase the risk of infarctions in the anterior but not in the posterior circulation. It is likely that carotid plaques in neurologically asymptomatic subjects are both markers of generalized atherosclerosis and sources of thromboemboli.


Survival rate of frozen-thawed bovine IVM/IVF embryos in relation to post-thaw exposure time in two cryoprotectants.
The relationship between post-thaw exposure time in cryoprotectants and the viability of in vitro fertilized (IVF)-derived bovine embryos after culture was examined. Good- and excellent-quality Day 7 to Day 8 blastocysts and expanded blastocysts were frozen by the nonstepwise method using 1.6 M propylene glycol (PG) or ethylene glycol (EG) as the cryoprotectant. After the straws were thawed, the embryos were kept in the cryoprotectants for 1, 10, or 30 min. Then the embryos were placed directly into culture medium and washed three times, followed by coculture with cumulus cells. After 48 h of culture, there were no significant differences in survival rate among the various exposure times in PG (79-81%) and EG (71-75%). After 72 h of culture, there were no significant differences among the various exposure times in the fully expanded (PG 76-81%; EG 71-72%), hatching (PG 69-74%; EG 58-71%), and hatched blastocyst rates (PG 60-71%; EG 47-65%). Our findings suggest that different post-thaw exposure times up to 30 min using PG or EG as the cryoprotectant are not harmful to IVF bovine embryos.


Peroxidase-catalyzed generation of catechin oligomers that inhibit glucosyltransferase from Streptococcus sobrinus.
Oolong tea extract (OTE) and the purified polymeric polyphenols from OTE have been found to inhibit glucosyltransferase (GTase) of mutans streptococci. In view of the partial fermentation characteristic of oolong tea, we describe here an in vitro model reaction system to produce partially fermented products of D-(+)-catechin or green tea extract (GTE) using horseradish peroxidase. A dimeric catechin molecule was identified as dehydro-dicatechin A by instrumental analyses. The molecular size of some oligomeric catechins was estimated by the elution profile with HPLC. These catechin oligomers markedly inhibited GTase from Streptococcus sobrinus 6715. As the degree of polymerization of catechin or GTE increased, GTase was inhibited more effectively. These results suggest that polymeric polyphenols found in OTE are synthesized by partial fermentation due to oxidases/peroxidases present in tea leaves.


The physics behind the larger scale organization of DNA in eukaryotes.
In this paper, we discuss in detail the organization of chromatin during a cell cycle at several levels. We show that current experimental data on large-scale chromatin organization have not yet reached the level of precision to allow for detailed modeling. We speculate in some detail about the possible physics underlying the larger scale chromatin organization.


Endovascular Treatment of Posterior Cerebral Artery Trunk Aneurysm: The Status Quo and Dilemma.
The posterior cerebral artery (PCA) is an important artery that can be divided into four segments (P1-4): segments P1-2 are proximal segments, and segments P3-4 are distal segments. Various aneurysms can occur along the PCA trunk. True saccular aneurysms are rare, and most PCA trunk aneurysms are dissecting. Sometimes, the PCA trunk can give rise to flow-related aneurysms in association with high-flow arteriovenous shunt diseases or moyamoya disease and internal carotid artery occlusion. Some PCA trunk aneurysms require treatment, especially ruptured or large/giant aneurysms. Recently, endovascular treatment (EVT) has become the mainstream treatment for PCA trunk aneurysms, and it mainly involves reconstructive or deconstructive techniques. Traditional EVT includes selective coiling with/without stent or balloon assistance and parent artery occlusion (PAO). For proximal aneurysms, the PCA should be preserved. For distal aneurysms, PAO can be performed. However, during EVT, preservation of the PCA must naturally be the prime objective. Recently, flow-diverting stents have been used and are a revolutionary treatment for unruptured dissecting aneurysms of the PCA trunk. Despite the associated complications, EVT remains an effective method for treating PCA trunk aneurysms and can result in a good prognosis.


Innovations in knowledge transfer and continuity of care.
In summary, the transfer of continuity-of-care innovations to practice is a complex process. Knowledge transfer is complex in and of itself, and in the case of continuity-of-care innovations this complexity is compounded by the need to simultaneously target multiple sectors, settings, agencies, and providers. Although there are a number of knowledge transfer theories/models, their use in guiding implementation activities is not yet commonplace. If the health-care system and patients/clients are to benefit from continuity-of-care research, researchers and implementers will need to become better versed in the knowledge transfer literature, experiment with these frameworks when implementing innovations, and test their usefulness with different innovations in different contexts.


Don't Ignore That Chest Pain: Positionally Dependent Coronary Subclavian Steal Syndrome.
Coronary subclavian steal syndrome (CSSS) is a complication incurred after coronary artery bypass grafting (CABG), characterized by retrograde blood flow through the left internal mammary artery (LIMA) graft to the left subclavian artery (SCA) distal to a SCA stenosis, thereby compromising myocardial perfusion from the LIMA despite its patency. We present a 40-year-old female with a history of triple-vessel CABG who presented with crescendo angina, notably when elevating her arms above her head. Atypical angina related to arm activity following successful LIMA bypass should prompt angiography directed to the left SCA, as well as to the LIMA graft. Typically, cases of CSSS are claudication dependent and not positionally related. This suggests a two-pronged pathophysiological mechanism of both demand ischemia and mechanical obstruction, which is not well described in previous literature.