A case of gastrointestinal bleeding due to right hepatic artery pseudoaneurysm following total remnant pancreatectomy: A case report.
Pseudoaneurysm is a serious complication after pancreatic surgery, which mainly depends on the presence of a preceding pancreatic fistula. Postpancreatectomy hemorrhage following total pancreatectomy is a rare complication due to the absence of a pancreatic fistula. Here we report an unusual case of massive gastrointestinal bleeding due to right hepatic artery (RHA) pseudoaneurysm following total remnant pancreatectomy. A 75-year-old man was diagnosed with intraductal papillary mucinous carcinoma recurrence following distal pancreatectomy and underwent total remnant pancreatectomy. After discharge, he was readmitted to our hospital with melena because of the diagnosis of gastrointestinal bleeding. Gastrointestinal endoscopy was performed to detect the origin of bleeding, but an obvious bleeding point could not be detected. Abdominal computed tomography demonstrated an expansive growth, which indicated RHA pseudoaneurysm. Emergency angiography revealed gastrointestinal bleeding into the jejunum from the ruptured RHA pseudoaneurysm. Transcatheter arterial embolization was performed; subsequently, bleeding was successfully stopped for a short duration. Because of improvements in his general condition, the patient was discharged. To date, very few cases have described postpancreatectomy hemorrhage following total remnant pancreatectomy. We suspect that the aneurysm ruptured into the jejunum, possibly because of the scarring and inflammation associated with his two complex surgeries. Pseudoaneurysm should be considered when the fragility of blood vessels is suspected, despite no history of anastomotic leak and intra-abdominal abscess. Our case also highlighted that detecting gastrointestinal bleeding is necessary to recognize sentinel bleeding if the origin of bleeding is undetectable.


The use of body surface temperatures in assessing thermal status of hutch-reared dairy calves in shaded and unshaded conditions.
The study was carried out in a Hungarian large-scale dairy farm during a 5-day period in hot August weather. Altogether 16 preweaning calves were chosen for the study. An agricultural mesh with 80% shielding was stretched over eight calf cages at 2 m from the ground to shield the cages in their entirety, while eight others were left unshaded. Ambient temperature and relative humidity were measured in 10 min intervals inside and outside one of the hutches in the shaded and unshaded groups during the total length of the study. The rectal temperature of the calves was measured by a digital thermometer every 4 h. Surface temperatures were measured on body parts, in the same intervals as rectal temperature with an infrared thermometer. Measuring sites included: the leg (metacarpus), muzzle, eye bulb, scapula, and ear. Statistical analyses were performed to assess the effects of shading on environmental and body temperatures and to also assess the strength of the association between core, skin and ambient temperatures; to estimate the temperature gradient between body shell and core; to compare the changes in heat dissipation capacity of the different body regions (as represented by temperatures of various sites) with increasing ambient temperature controlling for shaded or unshaded conditions; and to predict the risk of hyperthermia (rectal temperature not lower than 39.5°C) with the CART classification method. The average rectal temperatures suggest that the temperature conditions both in shaded and unshaded groups imposed a severe heat load on the calves. The temperature of the body shell, as represented by skin temperatures, shows a much more significant variation, similar to ambient temperature. As expected, areas that are closer to the core of the body (ear and eye) show less difference from rectal temperature and show a narrower range (lower variance), as more distal regions (leg, scapula) have a wider range. Body surface temperatures are more related to ambient temperature in calves than rectal temperature. The predictive value of infrared body surface temperatures for predicting heat stress or rectal temperature is low.


Golgi study of the isocortex in an insectivore: the common European mole (Talpa europaea).
In the common European mole (Talpa europaea) the isocortex is a six-layered structure representing about 50% of the total cerebral cortex. The internal granular layer is narrow in the occipital region, however, probably reflecting a poorly developed visual system in an animal adapted to life in a subterranean environment. Golgi impregnation of projection cells and most local-circuit neurons of layers III-VI suggests a relatively well-developed isocortex in this insectivore. The presence of extraverted neurons in the so-called accentuated layer II and the amount of local-circuit neurons with very long beaded dendrites, however, probably represents primitive characteristics of the isocortex in mammals.


Determination of the metabolic origins of the sulfur and 3'-nitrogen atoms in biotin of Escherichia coli by mass spectrometry.
Two steps in the biosynthesis of biotin in Escherichia coli, incorporation of the nitrogen atom of methionine into 7-keto-8-aminopelargonic acid and of the sulfur atom into dethiobiotin, were examined. Sulfur and nitrogen metabolism were monitored by gas chromatography-mass spectrometry of volatile derivatives of internal (protein-bound) amino acids and excreted biotin. We were able to show that internal cysteine and excreted biotin were labeled to the same extent with 34S from either of two exogenous sulfur sources, 34SO4(2)-or L-[sulfane-34S]thiocystine. Internal methionine was eliminated from consideration, while cysteine, or possibly a closely related intermediate, was implicated as providing the sulfur atom for biotin biosynthesis. Also, in experiments designed to follow the metabolism of the nitrogen atom of methionine, it was found that biotin excreted into the culture medium by this organism grown with 95 atom % [15N]methionine contained greater than 70 atom % excess 15N in one of the nitrogens over that obtained from cultures grown with methionine of natural abundance 15N. These results provide evidence for the direct transfer of the methionine nitrogen as the role of S-adenosylmethionine in the conversion of 7-keto-8-aminopelargonic acid to 7,8-diaminopelargonic acid.


[Characteristics and patterns of the human bone reactions to microgravity].
Hypothesized processes of changes found in spacecrew bones following 5 to 7 mo. orbital missions are reviewed. Selective osteopenia of trabecular bones in the lower skeleton is attributed to a greater weight loading at 1 g. Increased mineral content in the upper skeleton (dual energy X-ray adsoptiometry--DXA) and hypermineralization of the limbic spongious bone (computer tomography) appear to be secondary and reflect the body liquids redistribution headword including to the abdomen. The additional negative gradient of the lower skeleton mass during early readaptation (about 1.5 mo, after landing) can be explained by remodeling (resorption and bone formation) as a reaction to the "load return". Personal variability is probably a fingerprint of genetic determinism of bone mass and metabolic phenotype that may sometimes lead to an increased risk of fracture. The authors raise the discussion about practicality of the genetic osteopenia prediction for space flyers.


Knowledge utilization among experienced staff nurses.
The purpose of this descriptive exploratory study was to describe the processes staff nurses use to select and transfer new knowledge to practice. Eleven experienced staff nurses shared 29 examples in which gaining new knowledge resulted in changes in thinking or acting in a clinical situation. Findings indicated that knowledge utilization originated with the nurse who was active in selecting and using new knowledge. Nurses used multiple knowledge utilization processes primarily involving factual knowledge and instrumental utilization. Often, the decision to move knowledge to practice was based on comparison by similarity. There were no variations in utilization processes as nurses floated across units. Sources of new knowledge were primarily informal and unit based. Implications for staff development focus on developing unit-based resources and resource personnel, using innovative ways to introduce new knowledge on the unit, and providing time in formal classes for exchange of ideas on using new knowledge in practice.


Endoscopic Management of Paranasal Sinus Mucoceles: Meta-analysis of Visual Outcomes.
Objective Paranasal sinus mucoceles are benign cystic lesions originating from sinus mucosa that can impinge on adjacent orbital structures, causing ophthalmic sequelae such as decreased visual acuity. Definitive treatment requires surgery. We present the first meta-analysis quantifying the effect of preoperative visual function and time to surgery on postoperative visual acuity outcomes. Data Sources PubMed, Ovid, Embase, Web of Science, and the Cochrane Library. Methods Two independent authors systematically reviewed articles describing outcomes after endoscopic sinus surgery for paranasal sinus mucoceles presenting with visual loss. Available data from case reports and series were combined to analyze the associations among preoperative visual acuity, time to surgery, and postoperative outcomes. Results Eighty-five studies were included that provided data on 207 patients. The average presenting visual acuity was 1.57 logMAR (logarithm of the minimum angle of resolution), and the average postoperative visual acuity was 0.21 logMAR, with visual improvement in 71.5% of cases. Preoperative visual acuity ≥1.52 logMAR correlated with postoperative improvement >1 logMAR ( R = 0.4887, P < .0001). A correlation was found between a time to surgery <6 days and postoperative improvement ( R = 0.297, P < .0001). Receiver operator curve analysis of these thresholds demonstrated a moderately accurate prognostic ability (area under the curve: 75.1 for preoperative visual acuity and 73.1 for time to surgery). Conclusion Visual loss resulting from paranasal sinus mucoceles is potentially reversible in most cases, even those presenting with poor vision. When possible, surgery should be performed promptly after diagnosis, but emergency surgery does not appear to be necessary for vision restoration.


Influence of mother's educational level on food parenting practices and food habits of young children.
The main purpose of the present study is to examine whether differences in mothers' food parenting practices by educational level could explain differences in food consumption in Flemish preschool children. Three hundred and sixteen mothers of children aged 2.5-7 years, completed a self-administered questionnaire. Differences by educational level were found in children's and mothers' consumption frequencies of fruit, vegetables and soft drinks, and in the use of restrictions, verbal praise, negotiation, discouragement of sweets and restraining from negative modelling behaviour. Multiple logistic regression analyses revealed that mothers' consumption was an independent predictor for all four outcome variables; verbal praise was a significant predictor for children's vegetable consumption, permissiveness for regular consumption of soft drinks and sweets, and, using food as a reward for regular sweet consumption. Differences in children's food consumption by mothers' educational level were completely explained by mother's consumption and other food parenting practices for fruit and vegetables but not for soft drinks.


Improving the care of patients dying of heart failure.
Patients with heart failure have special palliative care needs, but palliative measures for treating the symptoms of end-stage heart failure have been largely ignored. A formal disease-management program for heart failure should include palliative care.


Pigmentation: selective photothermolysis or non-specific skin necrosis using different intense pulsed light systems?
This study considers end point tissue responses and side effects to determine whether 'square pulse' IPL is more or less effective than the traditional IPL. Supporting histological data and computational modelling results are provided. It provides guidance for IPL users unfamiliar with constant spectrum IPL devices and redirects attention to treatment end points. Twenty subjects of Fitzpatrick Skin Types I-III, presenting with various epidermal pigmented lesions, were treated 1-3 times with two different IPLs. Coupling gel was used and firm pressure was applied to exclude blood from the treatment area. Immediate and post-treatment side effects, degree of discomfort and end results at fourteen and thirty days were evaluated by professional observation, digital photography and a patient questionnaire. Both IPLs showed a mean clearance of over 80% after 1-3 treatments but the free discharge IPL demonstrated a greater side effect profile with a higher incidence of ulceration, crusting and erythema. Clinical observation and mathematical modelling suggests that the square pulse, partial discharge IPL system may provide the IPL operator with greater control over the coagulation of pigment and is therefore the more efficient device for effective pigment lightening with fewer side effects.


In-silico design, expression, and purification of novel chimeric Escherichia coli O157:H7 OmpA fused to LTB protein in Escherichia coli.
E. coli O157:H7, one of the major EHEC serotypes, is capable of developing bloody diarrhea, hemorrhagic colitis (HC), and fatal hemolytic uremic syndrome (HUS) and is accompanied by high annual economic loss worldwide. Due to the increased risk of HC and HUS development following antibiotic therapy, the prevention of infections caused by this pathogen is considered to be one of the most effective ways of avoiding the consequences of this infection. The main aim of the present study was to design, express, and purify a novel chimeric protein to develope human vaccine candidate against E. coli O157:H7 containing loop 2-4 of E. coli O157:H7, outer membrane protein A (OmpA), and B subunit of E. coli heat labile enterotoxin (LTB) which are connected by a flexible peptide linker. Several online databases and bioinformatics software were utilized to choose the peptide linker among 537 analyzed linkers, design the chimeric protein, and optimize the codon of the relative gene encoding this protein. Subsequently, the recombinant gene encoding OmpA-LTB was synthesized and cloned into pET-24a (+) expression vector and transferred to E. coli BL21(DE3) cells. The expression of OmpA-LTB chimeric protein was then carried out by induction of cultured E. coli Bl21 (DE3) cells with 1mM isopropyl-β-D-thiogalactopyranoside (IPTG). The purification of OmpA-LTB was then performed by nickel affinity chromatography. Expression and purification were analyzed by sodium dodecyl sulphate poly acrylamide gel electrophoresis. Moreover, the identity of the expressed protein was analyzed by western blotting. SDS-PAGE and western immunoblotting confirmed the successful expression of a 27 KDa recombinant protein after 24 hours at 37°C post-IPTG induction. OmpA-LTB was then successfully purified, using nickel affinity chromatography under denaturing conditions. The yield of purification was 12 mg per liter of culture media. Ultimately, we constructed the successful design and efficient expression and purification of OmpA-LTB divalent under the above-mentioned conditions.


A mechanobiological model of endothelial cell migration and proliferation.
How angiogenesis is regulated by local environmental cues is still not fully understood despite its importance to many regenerative events. Although mechanics is known to influence angiogenesis, the specific cellular mechanisms influenced by mechanical loading are poorly understood. This study adopts a lattice-based modelling approach to simulate endothelial cell (EC) migration and proliferation in order to explore how mechanical stretch regulates their behaviour. The approach enables the explicit modelling of ECs and, in particular, their migration/proliferation (specifically, rate and directionality) in response to such mechanical cues. The model was first used to simulate previously reported experiments of EC migration and proliferation in an unloaded environment. Next, three potential effects (increased cell migration, increased cell proliferation and biased cellular migration) of mechanical stretch on EC behaviour were simulated using the model and the observed changes in cell population characteristics were compared to experimental findings. Combinations of these three potential drivers were also investigated. The model demonstrates that only by incorporating all three changes in cellular physiology (increased EC migration, increased EC proliferation and biased EC migration in the direction perpendicular to the applied strain) in response to dynamic loading, it is possible to successfully predict experimental findings. This provides support for the underlying model hypotheses for how mechanics regulates EC behaviour.


Treatment of immune thrombocytopaenic purpura in childhood. A review of 146 patients.
Between 1969 and 1988, 146 children with immune thrombocytopaenic purpura (ITP) were seen in the outpatient clinic. The diagnosis was based upon an isolated thrombocytopaenia, without disseminated intravascular coagulation, splenomegaly or systemic disease and a normal bone marrow. Patients who required treatment (116/146) received either steroids (105/116) or IV gammaglobulins (IV-Ig) (11/116) as initial therapy. The long term outcome was similar in both groups. IV-Ig had the advantage to give a rapid increase in the platelet count without major side effects and to be very useful in chronic ITP either as maintenance therapy or as preparation for splenectomy.


Intersectoral and multisectoral approaches to enable recovery for people with severe mental illness in low- and middle-income countries: A scoping review.
The needs of people with severe mental illness are complex and require a range of services embedded in well-coordinated systems of care to enable recovery, promote well-being and optimise social integration. The concept of recovery is strongly rooted in the centrality of multi and intersectoral systems of care, and, while multi and -intersectoral dimensions of mental health systems have been highlighted in analyses focusing on high-income regions, little has been elaborated in terms of these approaches in the recovery of people with severe mental illness (SMI) in low- and middle-income countries (LMICs). The aim of this review was to identify and describe multi and intersectoral approaches underpinning community-based SMI recovery interventions in LMICs. A scoping review was carried out following the following steps: (1) Objectives for the review were developed and refined; (2) A systematic search of databases (EbscoHost, PubMed, Google Scholar) and previous reviews were undertaken from 2012 to 2022, where relevant papers were identified; (3) Papers with a focus on SMI and recovery, a specific description of an intervention, located in LMICs, with explicit linkages between sectors, and published in English, were selected for inclusion; (4) Data were extracted and charted and (5) Findings were analysed and reported thematically. Thirty-six papers were included for analysis, from 18 countries, including qualitative studies, trials, desktop and secondary data reviews and case studies. Examples of multi- and intersectoral action included collaboration between healthcare and community support systems, collaboration in providing supported housing and supportive community spaces for recovery, and linkages between biomedical and social spheres of care. Barriers included the dominance of mental health professions in delivering care, community-based stigmatising attitudes towards SMI. Multi- and intersectoral collaboration for SMI recovery requires investments in financing, education and coordination by a governing body.


On the metabolism of haloperidol.
1. p-Fluorobenzoyl-propionic acid, 4-(4-chlorophenyl)-4-hydroxy-piperidine, and reduced haloperidol were confirmed as metabolites of haloperidol. Their formation was catalysed by hepatic microsomes and was NADPH dependent. 2. The pyridinium metabolite of haloperidol (HP+) was identified. It is proposed that haloperidol first undergoes dehydration to form its 1,2,3,6-tetrahydropyridine analogue (HTP). HTP is then further metabolized to HP+, HTP N-oxide and its N-dealkylated product, 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP). HTPN-oxide was metabolized to CPTP and HTP. All these metabolites were confirmed by comparison with synthesized compounds using h.p.l.c. and h.p.l.c.-mass spectrometry. 3. Three unknown metabolites were present in microsomal metabolic incubations of haloperidol. One of them was tentatively characterized by h.p.l.c.-mass spectrometry as an oxygenated product of haloperidol, another appears to be the 2-pyridine analogue of haloperidol. The third metabolite was shown to be a neutral compound of unknown structure, which was not haloperidol N-oxide nor 4-hydroxy-4'-fluorobutyrophenone. In addition, HTP was metabolized to a further unknown product with a similar u.v. spectrum to that of HTP. 4. The identification of these metabolites led to the hypothesis that the metabolism of haloperidol is similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and may therefore produce motor neurone toxicity by a similar mechanism.


Drug-induced transmembrane lipid scrambling in erythrocytes and in liposomes requires the presence of polyanionic phospholipids.
The asymmetric transmembrane distribution of phospholipids between the two bilayer halves of erythrocyte can be modified upon addition of cationic amphiphilic drugs, such as chlorpromazine or verapamil. We studied this phenomenon in erythrocytes and in lipid vesicles using spin-labelled analogues of the endogenous phospholipids. The extent of the rapid disappearance of the analogues from the erythrocyte outer leaflet depended on the concentration of the drug. Up to 40% of spin-labelled sphingomyelin moved to the inner erythrocyte leaflet in 10 min in the presence of 1.5 mm chlorpromazine. Verapamil or vinblastine gave similar results. On the other hand, the inside-outside movement of the aminophospholipid analogues was less evident, and did not exceed 10%. This apparent discrepancy between inward and outward movements could result from the formation of an endovesicle which is known to occur upon drug addition at high concentration. A fraction of lipids would be trapped in the intravesicular leaflet, corresponding to the cell outer leaflet, and be inaccessible both from the cytoplasm and the extracellular medium. In cells submitted to a metabolic depletion of cellular ATP the intensity of the scrambling induced by the amphipaths was drastically lowered. We attribute this effect to the important reduction of the membrane content in phosphatidylinositol-4,5-bisphosphate (PIP2). The involvement of the latter lipid in triggering scrambling was partly confirmed by experiments carried out with artificial membranes. Indeed, in large unilamellar vesicles PIP2 is required in order to obtain a rapid redistribution of phospholipids between the two leaflets upon addition of drugs. However, the extent of phospholipid redistribution was limited to 15-20%. This redistribution was also induced when the vesicle membrane contained di-anionic phospholipids (phosphatidylinositol-4-monophosphate or diphosphatidylglycerol), but did not occur when it contained mono-anionic phospholipids (phosphatidylserine or phosphatidylinositol). Some drugs such as methochlorpromazine, active in artificial membranes, were ineffective in erythrocyte membranes, probably because they could not cross the membrane and reach PIP2 molecules at the cytoplasmic leaflet.


Asymmetric cyanomet valency hybrid hemoglobin, (alpha+CN-beta+CN-)(alpha beta): the issue of valency exchange.
A new framework for hemoglobin cooperativity was proposed by Ackers and colleagues on the basis of the hyper thermodynamic stability and deoxy (T) quaternary structure of one of diliganded deoxy-cyanomet hybrid hemoglobins, (alpha+CN-beta+CN-)(alpha beta), studied by hybridization of the equimolar mixture of deoxyhemoglobin and cyanomethemoglobin through a long (70-100 h) dimer exchange reaction [Daugherty et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 1110-1114]. Recently, we reported that the published hyperstability of (alpha+CN-beta+CN-)(alpha beta) is incorrect due to the occurrence of valency exchange between the heme sites of both parental hemoglobins during the long deoxy incubation [Shibayama et al. (1997) Biochemistry 36, 4375-4381]. We also noted a difficulty in maintaining both anaerobicity and excess free cyanide of the sample during the long incubation, which led to formation of cyanide-unbound aqometheme in the original deoxyhemoglobin resulting from the electron transfer to cyanometheme. This paper is a response to a recent argument against our work [Ackers et al. (1997) Biochemistry 36, 10822-10829]. Ackers et al. have claimed that no appreciable formation of aqomethemoglobin with their methods ensures their sample integrity, based on a supposition that our observed valency exchange may have occurred via aqometheme. In this paper, however, we demonstrate that appreciable (>27%) valency exchange really occurs between deoxy and cyanometheme sites during 72 h incubation under conditions where both anaerobicity and excess free cyanide of the sample solution are maintained by a continuous flow of humidified N2 with HCN. This confirms our view that previous experimental data on (alpha+CN-beta+CN-)(alpha beta) obtained by the long incubations should be subject to reexamination while our earlier estimation of a lower limit of free energy of (alpha+CN-beta+CN-)(alpha beta) (i.e., >/= -10.1 kcal/mol) by a rapid method (35 min) is still valid. We also suggest a possibility that the T quaternary structure of (alpha+CN-beta+CN-)(alpha beta) assigned by Ackers and colleagues using the long incubations is an artifact arising from the valency exchange. These results suggest that the putative mechanistic picture for hemoglobin cooperativity inferred from studies on deoxy-cyanomet hybrids is without foundation.


The long-term effects of pitavastatin on blood lipids and platelet activation markers in stroke patients: impact of the homocysteine level.
To examine the impact of the plasma homocysteine level on the anti-atherosclerotic effects of pitavastatin treatment, we retrospectively examined 59 patients who had a history of stroke and had been prescribed pitavastatin for the treatment of dyslipidemia at the Neurology department of Toho University Ohashi Medical Center Hospital. The patients were classified into two groups according to their homocysteine levels. Carotid artery plaque progression was determined before and after pitavastatin treatment. Plasma levels of high-sensitivity C-reactive protein, platelet molecular markers, and von Willebrand factor were measured. Pitavastatin treatment had beneficial effects on the lipid profiles of these patients and slowed atherosclerosis progression. These effects were observed in both the high and low homocysteine groups. Proactive lipid intervention using pitavastatin may inhibit the progression of atherosclerosis and contribute to secondary prevention of stroke in high-risk patients. We conclude that this statin could inhibit progression at any stage of disease and should therefore be proactively administered to these patient groups, regardless of disease severity.


An update on the referral pattern of patients with end-stage renal disease.
This article first describes the epidemiology and reasons of late referal to the nephrologist of patients suffering from end-stage renal disease (ESRD). Depending on the definition, between 25 and 50% of worldwide ESRD patients are referred very late. Second, the relation of late referral to the quality of pre-ESRD care, its impact on the selection of dialysis modality, on the time of start of dialysis and on the use of an adequate vascular access, are discussed. Finally, the economic aspects of late referral are described and ways to improve the referral pattern are proposed.


Physicochemical characteristics and in vitro digestibility of starches from colored quinoa (Chenopodium quinoa) varieties.
The quinoa flour processing is mostly subject to the properties of starch. Starches from four colored quinoa varieties, including white quinoa (QS-W), yellow quinoa (QS-Y), red (QS-R), and black (QS-B), were compared with respect to their physicochemical properties and in vitro digestibility. Results indicated that QS-B exhibited the highest content of amylose (8.14%) (p < 0.05). All starch samples exhibited as irregular sphere with a particle size less than 3 µm. Results of the FT-IR and X-ray showed that the short-range order of the four quinoa starches exhibited no significant difference; all starches showed a typical A-type diffractrometric pattern and was not affected by seed color, and QS-Y had the highest relative crystallinity (34.3%) (p < 0.05). In addition, QS-W reflected the highest solubility (6.32%) and QS-Y showed the highest swelling power (19.45 g/g) (p < 0.05). QS-Y also presented a higher ΔH value (11.46 J/g) (p < 0.05), while QS-R peak temperature and peak G' were the lowest. Besides, QS-B had the highest slow-digestible starch (SDS) and resistant starch (RS) content, while the lowest estimated glycemic index (eGI) value (p < 0.05). Also, there was a negative correlation between hydrolysis rates and amylose content of quinoa starch. PRACTICAL APPLICATION: Due to the low gelatinization temperature of quinoa starch, it can be used to both produce and improve instant and fast food products. Quinoa starch particles are small, and Pickering emulsions and additives have potential application values. Red quinoa contains easily digestible starch, which can be a good food choice for infants and the elderly, while white quinoa starch has less swelling power and can be used in noodle products. The results of this study can help to underpin the study of quinoa nonstarch components versus starch component.


Inhibition of Murine Pulmonary Microvascular Endothelial Cell Apoptosis Promotes Recovery of Barrier Function under Septic Conditions.
Sepsis is characterized by injury of the pulmonary microvasculature and the pulmonary microvascular endothelial cells (PMVEC), leading to barrier dysfunction and acute respiratory distress syndrome (ARDS). Our recent work identified a strong correlation between PMVEC apoptosis and microvascular leak in septic mice in vivo, but the specific role of apoptosis in septic PMVEC barrier dysfunction remains unclear. Thus, we hypothesize that PMVEC apoptosis is likely required for PMVEC barrier dysfunction under septic conditions in vitro. Septic stimulation (mixture of tumour necrosis factor α, interleukin 1β, and interferon γ [cytomix]) of isolated murine PMVEC resulted in a significant loss of barrier function as early as 4 h after stimulation, which persisted until 24 h. PMVEC apoptosis, as reflected by caspase activation, DNA fragmentation, and loss of membrane polarity, was first apparent at 8 h after cytomix. Pretreatment of PMVEC with the pan-caspase inhibitor Q-VD significantly decreased septic PMVEC apoptosis and was associated with reestablishment of PMVEC barrier function at 16 and 24 h after stimulation but had no effect on septic PMVEC barrier dysfunction over the first 8 h. Collectively, our data suggest that early septic murine PMVEC barrier dysfunction driven by proinflammatory cytokines is not mediated through apoptosis, but PMVEC apoptosis contributes to late septic PMVEC barrier dysfunction.


Multimodal Imaging in Diabetic Macular Edema.
Throughout ophthalmic history it has been shown that progress has gone hand in hand with technological breakthroughs. In the past, fluorescein angiography and fundus photographs were the most commonly used imaging modalities in the management of diabetic macular edema (DME). Today, despite the moderate correlation between macular thickness and functional outcomes, spectral domain optical coherence tomography (SD-OCT) has become the DME workhorse in clinical practice. Several SD-OCT biomarkers have been looked at including presence of epiretinal membrane, vitreomacular adhesion, disorganization of the inner retinal layers, central macular thickness, integrity of the ellipsoid layer, and subretinal fluid, among others. Emerging imaging modalities include fundus autofluorescence, macular pigment optical density, fluorescence lifetime imaging ophthalmoscopy, OCT angiography, and adaptive optics. Technological advances in imaging of the posterior segment of the eye have enabled ophthalmologists to develop hypotheses about pathological mechanisms of disease, monitor disease progression, and assess response to treatment. Spectral domain OCT is the most commonly performed imaging modality in the management of DME. However, reliable biomarkers have yet to be identified. Machine learning may provide treatment algorithms based on multimodal imaging.


Effect of diabetes mellitus on the regulation of enzyme secretion by isolated rat pancreatic acini.
The nature and mechanism of the pancreatic exocrine dysfunction in diabetes mellitus were evaluated in vitro using isolated pancreatic acini prepared from streptozotocin-induced diabetic rats. The content of amylase and ribonuclease in diabetic acini was approximately 0.5 and 50% of the normal content, respectively. Further, reduced amounts of both enzymes were secreted by diabetic acini in response to both cholecystokinin (CCK) and carbamylcholine. However, when enzyme secretion was normalized relative to initial acinar contents, both normal and diabetic acini released enzymes at a comparable maximal rate. The time course of the release of these enzymes, and newly synthesized protein were similar in both acini. In normal acini, the effect of CCK was maximal at a concentration of 100 pM; higher concentrations led to submaximal enzyme release. The dose-response curve in diabetic acini was similarly shaped, but shifted three-fold towards higher concentration. The mobilization of cellular Ca(2+) in response to CCK was also shifted. In contrast to these results with CCK, the dose-response curve to carbamylcholine was unaltered by diabetes. The observed effects were confirmed to be due to insulin deficiency and not due to direct toxic effect of streptozotocin on acinar cells or malnutrition. Streptozotocin had no acute effect on acini when measured 24 h after administration, and alloxan, another beta cell toxin, induced similar changes in acinar enzyme content and secretory response. Moreover, the administration of exogenous insulin to diabetic rats returned the content of pancreatic amylase and the secretory response to CCK towards normal. Starvation for 48 h, although inducing a significant weight loss, did not mimic the effects of diabetes. The present studies demonstrate two major abnormalities in pancreatic exocrine secretion in the diabetic rat: (a) the content of certain digestive enzymes is markedly altered, leading to an altered amount of zymogen secretion, (b) the sensitivity to CCK is selectively reduced, most likely related to a defect in receptor activated transmembrane signaling.


A fresh look at the vibrational and thermodynamic properties of liquids within the soft potential model.
Contrary to the case of solids and gases, where Debye theory and kinetic theory offer a good description for most of the physical properties, a complete theoretical understanding of the vibrational and thermodynamic properties of liquids is still missing. Liquids exhibit a vibrational density of states (VDOS) which does not obey Debye law, and a heat capacity which decreases monotonically with temperature, rather than growing as in solids. Despite many attempts, a simple, complete and widely accepted theoretical framework able to formally derive the aforementioned properties has not been found yet. Here, we revisit one of the theoretical proposals, and in particular we re-analyze the properties of liquids within the soft-potential model, originally formulated for glasses. We confirm that, at least at a qualitative level, many characteristic properties of liquids can be rationalized within this model. We discuss the validity of several phenomenological expressions proposed in the literature for the density of unstable modes, and in particular for its temperature and frequency dependence. We discuss the role of negative curvature regions and unstable modes as fundamental ingredients to have a linear in frequency VDOS. Finally, we compute the heat capacity within the soft potential model for liquids and we show that it decreases with temperature, in agreement with experimental and simulation data.


Ability of Platygaster demades (Hymenoptera: Platygastridae) to Parasitize Both Eggs and Larvae Makes it an Effective Natural Enemy of Dasineura mali (Diptera: Cecidomyiidae).
Dasineura mali Kieffer (Diptera: Cecidomyiidae) is an important pest of young apple trees in New Zealand and a serious quarantine pest in Asia, Australia, and western United States. Platygaster demades Walker (Hymenoptera: Platygastridae) is a parasitoid of D. mali. The developmental period of the parasitoid is longer than that of D. mail, suggesting a possible asynchrony between the two species in the field. Prior to the present study, this parasitoid was considered laying eggs only in the host eggs. Here we carried out experiments in the laboratory and field to determine whether P. demades also parasitized other stages of the host and explain the recently observed high parasitism rate and parasitoid-host synchronization in the field. We demonstrated for the first time that P. demades explored and accepted both eggs and first-instar larvae of D. mali as hosts. This feature widens the phenological window for parasitization, allowing the parasitoid to continue laying eggs after D. mali eggs hatch, and contributes to the high within- and between-generation parasitism rate and synchronization of the two species. Therefore, the difference in developmental period between the pest and its parasitoid cannot simply be considered evidence of asynchrony between the two. The consistent superparasitism rate and progeny sex ratio regardless of host stage at parasitization detected in the present study may be attributed to the fact that P. demades eggs do not hatch until the host larvae reach the third instar (mature) and thus all parasitoid larvae feed on the third-instar larvae with similar quantity and quality of nutrition. The higher parasitism rate in eggs than in larvae may be due to higher larval defense ability against attack by and lower attractiveness to the parasitoid.


Low-dimensional approximation searching strategy for transfer entropy from non-uniform embedding.
Transfer entropy from non-uniform embedding is a popular tool for the inference of causal relationships among dynamical subsystems. In this study we present an approach that makes use of low-dimensional conditional mutual information quantities to decompose the original high-dimensional conditional mutual information in the searching procedure of non-uniform embedding for significant variables at different lags. We perform a series of simulation experiments to assess the sensitivity and specificity of our proposed method to demonstrate its advantage compared to previous algorithms. The results provide concrete evidence that low-dimensional approximations can help to improve the statistical accuracy of transfer entropy in multivariate causality analysis and yield a better performance over other methods. The proposed method is especially efficient as the data length grows.


Mutational study of the rRNA in yeast mitochondria: functional importance of T1696 in the large rRNA gene.
Four intragenic suppressors of a mitochondrial mutation in the 21S rRNA gene have been characterized in S. cerevisiae. The determination of the nature of the nucleotide changes in the suppressor strains showed that a T at position 1696 in the large rRNA gene is essential for correct function of the mitoribosome. The importance of this specific nucleotide and the fact that this mitochondrial mutation can also be suppressed by a mutation in a nuclear gene are in good agreement with a rRNA-r protein interaction in this part of domain IV, which functional importance is demonstrated in vivo by our results.


Silicon vacancy color center photoluminescence enhancement in nanodiamond particles by isolated substitutional nitrogen on {100} surfaces.
Fluorescent nanodiamonds were produced by incorporation of silicon-vacancy (Si-V) defect centers in as-received diamonds of averaged size ∼255 nm using microwave plasma chemical vapor deposition. The potential for further enhancement of Si-V emission in nanodiamonds (NDs) is demonstrated through controlled nitrogen doping by adding varying amounts of N(2) in a H(2) + CH(4) feedgas mixture. Nitrogen doping promoted strong narrow-band (FWHM ∼ 10 nm) emission from the Si-V defects in NDs, as confirmed by room temperature photoluminescence. At low levels, isolated substitutional nitrogen in {100} growth sectors is believed to act as a donor to increase the population of optically active (Si-V)(-) at the expense of optically inactive Si-V defects, thus increasing the observed luminescence from this center. At higher levels, clustered nitrogen leads to deterioration of diamond quality with twinning and increased surface roughness primarily on {111} faces, leading to a quenching of the Si-V luminescence. Enhancement of the Si-V defect through controlled nitrogen doping offers a viable alternative to nitrogen-vacancy defects in biolabeling/sensing applications involving sub-10 nm diamonds for which luminescent activity and stability are reportedly poor.


Regulation of transient receptor potential cation channel subfamily V1 protein synthesis by the phosphoinositide 3-kinase/Akt pathway in colonic hypersensitivity.
The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor or vanilloid receptor 1 (VR1), is expressed in nociceptive neurons in the dorsal root ganglia (DRG) and participates in the transmission of pain. The present study investigated the underlying molecular mechanisms by which TRPV1 was regulated by nerve growth factor (NGF) signaling pathways in colonic hypersensitivity in response to colitis. We found that during colitis TRPV1 protein levels were significantly increased in specifically labeled colonic afferent neurons in both L1 and S1 DRGs. TRPV1 protein up-regulation in DRG was also enhanced by NGF treatment. We then found that TRPV1 protein up-regulation in DRG was regulated by activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway both in vivo and in vitro. Suppression of endogenous PI3K/Akt activity during colitis or NGF treatment with a specific PI3K inhibitor LY294002 reduced TRPV1 protein production in DRG neurons, and also reduced colitis-evoked TRPV1-mediated visceral hypersensitivity tested by hyper-responsiveness to colorectal distention (CRD) and von Frey filament stimulation of abdomen. Further studies showed that TRPV1 mRNA levels in the DRG were not regulated by either colitis or NGF. We then found that an up-regulation of the protein synthesis pathway was involved by which both colitis and NGF caused a PI3K-dependent increase in the phosphorylation level of eukaryotic translation initiation factor 4E-binding protein (4E-BP)1. These results suggest a novel mechanism in colonic hypersensitivity which involves PI3K/Akt-mediated TRPV1 protein, not mRNA, up-regulation in primary afferent neurons, likely through activation of the protein synthesis pathways.


Oral administration of D-alanine in monkeys robustly increases plasma and cerebrospinal fluid levels but experimental D-amino acid oxidase inhibitors had minimal effect.
Hypofunction of the N-methyl-d-aspartate (NMDA) receptor is thought to exacerbate psychosis in patients diagnosed with schizophrenia. Consistent with this hypothesis, D-alanine, a co-agonist at the glycine site of the NMDA receptor, was shown to improve positive and cognitive symptoms when used as add-on therapy for schizophrenia treatment. However, D-alanine had to be administered at high doses (~7 g) to observe clinical effects. One possible reason for the high dose is that D-alanine could be undergoing oxidation by D-amino acid oxidase (DAAO) before it reaches the brain. If this is the case, the dose could be reduced by co-administration of D-alanine with a DAAO inhibitor (DAAOi). Early studies with rodents showed that co-administration of D-alanine with 5-chloro-benzo[d]isoxazol-3-ol (CBIO), a prototype DAAOi, significantly enhanced the levels of extracellular D-alanine in the frontal cortex compared with D-alanine alone. Further, the use of CBIO reduced the dose of D-alanine needed to attenuate prepulse inhibition deficits induced by dizocilpine. The objective of the work reported herein was to confirm the hypothesis that DAAO inhibition can enhance D-alanine exposure in a species closer to humans: non-human primates. We report that while oral D-alanine administration to baboons (10 mg/kg) enhanced D-alanine plasma and CSF levels over 20-fold versus endogenous levels, addition of experimental DAAOi to the regimen exhibited a 2.2-fold enhancement in plasma and no measurable effect on CSF levels. The results provide caution regarding the utility of DAAO inhibition to increase D-amino acid levels as treatment for patients with schizophrenia.


Microcystic adnexal carcinoma. An immunohistochemical comparison with other cutaneous appendage tumors.
Since its initial description, microcystic adnexal carcinoma (MAC) of the skin has been controversial. In particular, it features keratin production of the type seen in some pilar neoplasms , and has been thought to pursue partial follicular differentiation. Diagnostically, MAC may be difficult to separate from desmoplastic trichoepithelioma (DTE) in superficial biopsy specimens. We studied 12 MACs, 22 malignant eccrine acrospiromas, 7 sudoriferous syringometaplasias, 6 syringomas, 5 DTEs, and 40 other benign pilar neoplasms immunohistochemically. Paraffin sections and antibodies to "hard" (pilar) keratins. epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Leu-M1, and S100 protein were employed. The MACs exhibited reactivity for hard keratin subclasses AE 13 and AE 14, EMA, CEA, and Leu-M1. Desmoplastic trichoepitheliomas expressed positivity for AE 14, EMA, and Leu-M1 focally, but lacked the other specified markers. Syringomas and malignant acrospiromas displayed EMA, CEA, and AE 14 reactivity, and 5 syringometaplastic lesions were AE 14-reactive. Benign pilar tumors aside from DTEs were reactive only for AE 13, AE 14, or both. These data indicate that MAC exhibits an immunophenotype that is a "hybrid" of those seen in pure sweat glandular and follicular neoplasms, and suggest that it may indeed show combined pilar and sudoriferous differentiation. Based on these results, it also appears that immunohistochemical analysis may be useful in the diagnostic separation of MAC and DTE.


Leaping eels electrify threats, supporting Humboldt's account of a battle with horses.
In March 1800, Alexander von Humboldt observed the extraordinary spectacle of native fisherman collecting electric eels (Electrophorus electricus) by "fishing with horses" [von Humboldt A (1807) Ann Phys 25:34-43]. The strategy was to herd horses into a pool containing electric eels, provoking the eels to attack by pressing themselves against the horses while discharging. Once the eels were exhausted, they could be safely collected. This legendary tale of South American adventures helped propel Humboldt to fame and has been recounted and illustrated in many publications, but subsequent investigators have been skeptical, and no similar eel behavior has been reported in more than 200 years. Here I report a defensive eel behavior that supports Humboldt's account. The behavior consists of an approach and leap out of the water during which the eel presses its chin against a threatening conductor while discharging high-voltage volleys. The effect is to short-circuit the electric organ through the threat, with increasing power diverted to the threat as the eel attains greater height during the leap. Measurement of voltages and current during the behavior, and assessment of the equivalent circuit, reveal the effectiveness of the behavior and the basis for its natural selection.


Adsorption of hydrogen on neutral and charged fullerene: experiment and theory.
Helium droplets are doped with fullerenes (either C60 or C70) and hydrogen (H2 or D2) and investigated by high-resolution mass spectrometry. In addition to pure helium and hydrogen cluster ions, hydrogen-fullerene complexes are observed upon electron ionization. The composition of the main ion series is (H2)(n)HC(m)(+) where m = 60 or 70. Another series of even-numbered ions, (H2)(n)C(m)(+), is slightly weaker in stark contrast to pure hydrogen cluster ions for which the even-numbered series (H2)(n)(+) is barely detectable. The ion series (H2)(n)HC(m)(+) and (H2)(n)C(m)(+) exhibit abrupt drops in ion abundance at n = 32 for C60 and 37 for C70, indicating formation of an energetically favorable commensurate phase, with each face of the fullerene ion being covered by one adsorbate molecule. However, the first solvation layer is not complete until a total of 49 H2 are adsorbed on C60(+); the corresponding value for C70(+) is 51. Surprisingly, these values do not exhibit a hydrogen-deuterium isotope effect even though the isotope effect for H2/D2 adsorbates on graphite exceeds 6%. We also observe doubly charged fullerene-deuterium clusters; they, too, exhibit abrupt drops in ion abundance at n = 32 and 37 for C60 and C70, respectively. The findings imply that the charge is localized on the fullerene, stabilizing the system against charge separation. Density functional calculations for C60-hydrogen complexes with up to five hydrogen atoms provide insight into the experimental findings and the structure of the ions. The binding energy of physisorbed H2 is 57 meV for H2C60(+) and (H2)2C60(+), and slightly above 70 meV for H2HC60(+) and (H2)2HC60(+). The lone hydrogen in the odd-numbered complexes is covalently bound atop a carbon atom but a large barrier of 1.69 eV impedes chemisorption of the H2 molecules. Calculations for neutral and doubly charged complexes are presented as well.


Mutation rates and mutational spectra in tumorigenic cell lines.
The rate and molecular nature of spontaneous mutations at the hgprt locus were examined in a series of tumorigenic and non-tumorigenic closely related Chinese hamster fibroblastic (CHEF) cell lines. Mutation rates of tumorigenic cells determined by fluctuation analysis were found to range from the low rate also seen in non-tumorigenic cells to values increased up to 25-fold. No simple correlation was found between elevated mutation rates and tumorigenic potential. The nature of the mutational event was examined in a set of 136 thioguanine resistant mutants selected from several tumorigenic and non-tumorigenic CHEF lines. Significantly different frequencies of point mutations were found compared with large partial or whole gene deletions in different cell lines. The clonal inheritance of specific mutational patterns as well as the high frequencies of large deletions were novel findings. Hypotheses to explain these results are discussed in relation to the known genomic instability of tumour cells. I am honoured by the opportunity to contribute to this collection of papers dedicated to Professor Guido Pontecorvo on the occasion of his eightieth birthday. For almost half of this time I have been privileged to enjoy his friendship, and to benefit from his influence at critical stages in my scientific development.


Shell cross-linked cylinders of polyisoprene-b-ferrocenyldimethylsilane: formation of magnetic ceramic replicas and microfluidic channel alignment and patterning.
Stable organometallic cylindrical nanostructures have been prepared by shell cross-linking of PI320-b-PFS53 wormlike micelles in hexane through metal-catalyzed hydrosilylation at 23 degrees C. The cross-linked structures permit the formation of cylindrical ceramic replicas containing size- and separation-tunable arrays of Fe nanoclusters. In addition, microfluidic alignment of the cross-linked cylinders was possible.


Systematic Review and Quality Evaluation of Pharmacoeconomic Studies on Traditional Chinese Medicines.
Objectives: This study was aimed to find and appraise the available published pharmacoeconomic research on Traditional Chinese Medicine (TCM), to identify related issues and make suggestions for improvement in future research. Methods: After developing a search strategy and establishing inclusion and exclusion criteria, pharmacoeconomic studies on TCM were sourced from seven Chinese and English databases from inception to April 2020. Basic information about the studies and key pharmacoeconomic items of each study were extracted. The quality of each study was evaluated by using the British Medical Journal economic submissions checklist for authors and peer reviewers, focusing on factors such as study design, research time horizon, sample size, perspective, and evaluation methods. Results: A total of 431 published pharmacoeconomic articles with 434 studies on topics including cost-effectiveness, cost-benefit, cost-minimization, cost-utility, or combination analyses were identified and included in this review. Of these, 424 were published in Chinese and 7 in English. These studies conducted economic evaluations of 264 Chinese patent medicines and 70 types of TCM prescriptions for 143 diseases, including those of the central nervous, cardiovascular, respiratory, gynecologyical, and other systems. The studied TCMs included blood-activating agents (such as Xuesaitong tablet, Fufant Danshen tablet, and Danhong Injection), blood circulation promoting agents (such as Shuxuetong injection, Rupixiao tablet, and Fufang Danshen injection), and other therapeutic agents. The overall quality score of the studies was 0.62 (range 0.38 to 0.85). The mean quality score of studies in English was 0.72, which was higher than that of studies in Chinese with 0.62. Conclusions: The quality of pharmacoeconomic studies on TCM was relatively, generally low. Major concerns included study design, inappropriate pharmacoeconomic evaluation, insufficient sample size, or non-scientific assessment. Enhanced methodological training and cooperation, the development of a targeted pharmacoeconomic evaluation guideline, and proposal of a reasonable health outcome index are warranted to improve quality of future studies.


Narratives to enhance smoking cessation interventions among African-American smokers, the ACCE project.
Low-income, African-American smokers are less likely to have resources to aid in quitting smoking. Narrative communication may provide an enhancement to traditional smoking cessation interventions like NRT, medications, or behavioral treatments for this audience. After extensive pilot testing of stories and personal experiences with smoking cessation from African-Americans from a low-income community, we conducted a randomized control trial using stories to augment routine inpatient treatment among African-Americans at an urban Southern hospital (N = 300). Differences in smoking cessation outcomes between the intervention (stories DVD + routine clinical treatment) and control (routine clinical treatment) arms were compared using self-report and carbon monoxide measurement at 6-months. Compared to control, individuals who viewed the intervention stories DVD reported greater intentions to quit. Although continuous quitting marginally favored the intervention, our main result did not reach statistical significance (p = 0.16). Narrative communication via storytelling to promote smoking cessation among African-Americans in the South is one method to communicate smoking cessation. Results suggest this may not be sufficient as a stand-alone augmentation of routine clinical treatment for continuous smoking cessation. Smoking cessation efforts need to continually assess different means of communicating to smokers about quitting. The ClinicalTrials.gov Identifier is NCT00101491. This trial was registered January 10, 2005.


Inhibition of AKT signaling by supercritical CO2 extract of mango ginger (Curcuma amada Roxb.) in human glioblastoma cells.
Mango ginger (Curcuma amada Roxb.) is a less-investigated herb for anticancer properties than other related Curcuma species. AKT (a serine/threonine protein kinase B, originally identified as an oncogene in the transforming retrovirus AKT8) plays a central role in the development and promotion of cancer. In this investigation, we have analyzed the effect of supercritical CO2 extract of mango ginger (CA) on the genetic pathways associated with AKT signaling in human glioblastoma cells. The inhibitory effect of supercritical CO2 extract of mango ginger (Curcuma amada) on AKT signaling was investigated in U-87MG glioblastoma cells. CA was highly cytotoxic to glioblastoma cell line (IC50=4.92±0.81 µg/mL) compared to mHypoE-N1 normal mouse hypothalamus cell line (IC50=40.57±0.06 µg/mL). CA inhibits AKT (protein Kinase B) and adenosine monophophate -activated protein kinase α (AMPKα) phosphorylation significantly in a dose-dependent manner. The cell migration which is necessary for invasion and metastasis was also inhibited by CA treatment, with about 43% reduction at 20 µg/mL concentration. Analysis of mRNA and protein expression of genes associated with apoptosis, cell proliferation and angiogenesis showed that CA modulates expression of genes associated with apoptosis (Bax, Bcl-2, Bcl-X, BNIP3, caspase-3, mutant p53 and p21), cell proliferation (Ki67) and angiogenesis vascular endothelial growth factor (VEGF). Additionally, heat shock protein 90 (HSP90) and AMPKα genes interacting with the AKT signaling pathway were also downregulated by CA treatment. These results indicate the molecular targets and mechanisms underlying the anticancer effect of CA in human glioblastoma cells.


Control of phosphate excretion in uremic man.
The present studies were performed in an effort to examine the characteristics of the control system governing phosphate excretion in uremic man. In a group of patients with glomerular filtration rates (GFR) ranging from normal to 2 ml/min, it was found that the lower the GFR the lower the fraction of filtered phosphate reabsorbed (TRP). On a fixed phosphate intake, phosphate excretion rate was the same in patients with GFRs ranging from 60 to 3 ml/min. When plasma phosphate concentrations were diminished to subnormal levels in hyperphosphatemic, hypocalcemic uremic patients, TRP values increased but did not return to normal. TRP failed to rise substantially when GFR, as well as plasma phosphate concentrations, were diminished. In patients with unilateral renal disease, TRP values were equal bilaterally, and values were substantially higher in the diseased kidneys than in patients with bilateral involvement. When plasma calcium concentrations were raised to normal for 2-3 wk in uremic patients in whom plasma phosphate concentrations had previously been lowered to subnormal levels, TRP values rose to an average value of 86%. Values remained in the normal range when phosphate concentrations were allowed to increase while normocalcemia was maintained. The data are interpreted to indicate that in advancing renal disease, the changing patterns of phosphate excretion are mediated by a control system in which parathyroid hormone serves as a major effector element. An increase in GFR per nephron, hyperphosphatemia, and intrinsic inability of the surviving nephrons to transport phosphate do not appear to be of primary importance in the progressive reduction in TRP.


Changes in nucleic acid and protein levels in atrophying skeletal muscle in cancer cachexia.
To investigate factors responsible for muscle loss in cachexia changes in nucleic acid and protein levels have been determined and compared with those induced by a tumour-produced cachectic factor, proteolysis-inducing factor (PIF). Mice were transplanted with the MAC16 tumour, while non-tumour bearing mice received PIF (1.5 mg/kg; i.v.) over a 24 h period. There was an exponential decrease in RNA and protein in gastrocnemius muscle with weight loss without an effect on the DNA content. Levels of myosin followed the decrease in total protein, while actin levels remained constant. There was also a significant loss of protein from soleus muscle and spleen, but not from heart, liver and kidney. PIF also produced a significant loss of RNA and protein in spleen and reduced the protein content of soleus muscle. This suggests that PIF may be responsible for changes in protein and RNA content of tissues with the development of cachexia.


Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain.
We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.


Sedation and analgesia in the pediatric intensive care unit.
Various clinical situations may arise in the PICU that necessitate the use of sedation, analgesia, or both. Although there is a large clinical experience with midazolam in the PICU population and it remains the most commonly used benzodiazepine in this setting, lorazepam may provide an effective alternative, with a longer half-life and more predictable pharmacokinetics without the concern of active metabolites. However, there are limited reports regarding its use in the PICU population, and concerns exist regarding the potential for toxicity related to its diluent, propylene glycol. Although the synthetic opioid fentanyl frequently is chosen for use in the PICU setting because of its hemodynamic stability, preliminary data suggest morphine may have a slower development of tolerance and may cause fewer withdrawal symptoms than fentanyl. Morphine's safety profile includes long-term follow-up studies that have demonstrated no adverse central nervous system developmental effects from its use in neonates and infants. In the critically ill infant at risk following surgery for congenital heart disease, clinical experience supports the use of the synthetic opioids, given their ability to modulate PVR and prevent pulmonary hypertensive crisis. Alternatives to the benzodiazepines and opioids include ketamine, pentobarbital, or dexmedetomidine. Ketamine may be useful for patients with hemodynamic instability or airway reactivity. There are limited reports regarding the use of pentobarbital in the PICU, with one study raising concerns of a high incidence of adverse effects associated with its use. Propofol has gained great favor in the adult population as a means of providing deep sedation while allowing for rapid awakening; however, its routine use is not recommended because of its potential association with "propofol infusion syndrome." As the pediatric experience increases, it appears that there will be a role for newer agents such as dexmedetomidine.


Manipulating liquid plugs in microchannel with controllable air vents.
An air venting element on microchannel, which can be controlled externally and automatically, was demonstrated for manipulating liquid plugs in microfluidic systems. The element's open and closed statuses correspond to the positioning and movement of a liquid plug in the microchannel. Positioning of multiple liquid plugs at an air venting element enabled the merging and mixing of the plugs. Besides these basic functions, other modes of liquid plug manipulations including plug partitioning, multiple plug mixing, and spacing adjustment between liquid plugs, were realized using combination of multiple elements. The structure, operation, and some functions of the element were demonstrated with a microfluidic chip application. The performances of the element including its failure modes, threshold flow rate, and structural optimization were also discussed.


Mixed-Probe Simulation and Probe-Derived Surface Topography Map Analysis for Ligand Binding Site Identification.
Membrane proteins represent a considerable fraction of pharmaceutical drug targets. A computational technique to identify ligand binding pockets in these proteins is therefore of great importance. We recently reported such a technique called pMD-membrane that utilizes small molecule probes to detect ligand binding sites and surface hotspots on membrane proteins based on probe-based molecular dynamics simulation. The current work extends pMD-membrane to a diverse set of small organic molecular species that can be used as cosolvents during simulation of membrane proteins. We also describe a projection technique for globally quantifying probe densities on the protein surface and introduce a technique to construct surface topography maps directly from the probe-binding propensity of surface residues. The map reveals surface patterns and geometric features that aid in filtering out high probe density hotspots lacking pocketlike characteristics. We demonstrate the applicability of the extended pMD-membrane and the new analysis tool by exploring the druggability of full-length G12D, G12V, and G13D oncogenic K-Ras mutants bound to a negatively charged lipid bilayer. Using data from 30 pMD-membrane runs conducted in the presence of a 2.8 M cosolvent made up of an equal proportion of seven small organic molecules, we show that our approach robustly identifies known allosteric ligand binding sites and other reactive regions on K-Ras. Our results also show that accessibility of some pockets is modulated by differential membrane interactions.


Exploring the Change of Host and Microorganism in Chronic Obstructive Pulmonary Disease Patients Based on Metagenomic and Metatranscriptomic Sequencing.
Chronic obstructive pulmonary disease (COPD) is a universal respiratory disease resulting from the complex interactions between genes and environmental conditions. The process of COPD is deteriorated by repeated episodes of exacerbations, which are the primary reason for COPD-related morbidity and mortality. Bacterial pathogens are commonly identified in patients' respiratory tracts both in the stable state and during acute exacerbations, with significant changes in the prevalence of airway bacteria occurring during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, the changes in microbial composition and host inflammatory responses will be necessary to investigate the mechanistic link between the airway microbiome and chronic pulmonary inflammation in COPD patients. We performed metatranscriptomic and metagenomic sequencing on sputum samples for twelve AECOPD patients before treatment and for four of them stable COPD (stabilization of AECOPD patients after treatment). Sequencing reads were classified by Kraken2, and the host gene expression was analyzed by Hisat2 and HTseq. The correlation between genes was obtained by the Spearman correlation coefficient. Mann-Whitney U-test was applied to identify microbes that exhibit significantly different distribution in two groups. At the phyla level, the top 5 dominant phyla were Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, and Fusobacteria. The proportion of dominant gates in metagenomic data was similar in metatranscriptomic data. There were significant differences in the abundance of specific microorganisms at the class level between the two methods. No significant difference between AECOPD and stable COPD was found. However, the different expression levels of 5 host genes were significantly increased in stable COPD and were involved in immune response and inflammatory pathways, which were associated with macrophages. Our study may provide a clue to investigate the mechanism of COPD and potential biomarkers in clinical diagnosis and treatment.


Uniaxial drawing and mechanical properties of poly[(R)-3-hydroxybutyrate]/poly(L-lactic acid) blends.
Blends of poly(L-lactic acid) (PLLA) with two kinds of poly[(R)-3-hydroxybutyrate] (PHB) having different molecular weights, commercial-grade bacterial PHB (bacterial-PHB) and ultrahigh molecular weight PHB (UHMW-PHB), were prepared by the solvent-casting method and uniaxially drawn at two drawing temperatures, around PHB's T(g) (2 degrees C) for PHB-rich blends and around PLLA's T(g) (60 degrees C) for PLLA-rich blends. Differential scanning calorimetry analysis showed that this system was immiscible over the entire composition range. Mechanical properties of all of the samples were improved in proportion to the draw ratio. Although PLLA domains in bacterial-PHB-rich blends remained almost unstretched during cold drawing, a good interfacial adhesion between two polymers and the reinforcing role of PLLA components led to enhanced mechanical properties proportionally to the PLLA content at the same draw ratio. On the contrary, in the case of UHMW-PHB-rich blends, the minor component PLLA was found to be also oriented by cold drawing in ice water due to an increase in the interfacial entanglements caused by the very long chain length of the matrix polymer. As a result, their mechanical properties were considerably improved with increasing PLLA content compared with the bacterial-PHB system. Scanning electron microscopy observations on the surface and cross-section revealed that a layered structure with uniformly oriented microporous in the interior was obtained by selectively removal of PLLA component after simple alkaline treatment.


[A Case of Autoimmune Acquired Factor XIII Deficiency Diagnosed from Recurrent Postoperative Bleeding].
The patient was a 79-year-old man with ureteroileal anastomotic stricture after a Bricker ileal conduit. Endourological treatment of stenosis was performed via percutaneous nephrostomy and ileal conduit. The patient experienced lower abdominal pain on the following day, and computed tomographic (CT) scan showed hematoma retention around the kidney and active bleeding from the renal artery branches. Transarterial embolisation (TAE) was performed and the bleeding was controlled. Two days later, there was a sudden progression of anemia and CT showed an increase in hematoma around the kidney. We subsequently performed nephrectomy for hemostasis. Five days later, the anemia progressed further. There was hematoma retention in the retroperitoneal cavity, and emergency laparotomy hemostasis was performed. Routine coagulation test results were normal. Heavy bleeding was observed several days after TAE and the possibility of coagulation factor XIII deficiency was considered. Factor XIII deficiency was confirmed by a low factor XIII activity level. The patient was given plasma-derived factor XIII. After receiving factor XIII replacement, factor XIII activity remained unchanged and the patient continued to bleed. Thereafter, a cross-mixing test was performed and the patient was diagnosed with autoimmune acquired factor XIII deficiency. Cortical steroids were administered to remove the factor XIII inhibitor. Steroid administration showed a rapid increase in factor XIII activity, and bleeding symptoms were no longer observed. In cases of serious bleeding of unknown cause with a normal coagulation profile, acquired factor XIII deficiency should be suspected and factor XIII activity measured.


The Efficacy of Bacillus thuringiensis spp. galleriae Against Rice Water Weevil (Coleoptera: Curculionidae) for Integrated Pest Management in California Rice.
Rice water weevil (Lissorhoptrus oryzophilus Kushel) is the most damaging insect pest of rice in the United States. Larval feeding on the roots stunt growth and reduce yield. Current pest management against the weevil in California relies heavily on pyrethroids that can be damaging to aquatic food webs. Examination of an environmentally friendly alternative biopesticide based on Bacillus thuringiensis spp. galleriae chemistry against rice water weevil larvae showed moderate levels of activity in pilot studies. We further examined the performance of different formulations of Bt.galleriae against the leading insecticide used in California rice, λ-cyhalothrin. The granular formulation performed as well as the λ-cyhalothrin in use in California in some of our greenhouse and field studies. This is the first reported use of B. thuringiensis spp. galleriae against rice water weevil.


Structure of an acidic phospholipase A(2) from the venom of Deinagkistrodon acutus in a new crystal form.
The three-dimensional structure of an acidic phospholipase A(2) purified from the venom of Deinagkistrodon acutus (Agkistrodon acutus) was determined in a new crystal form by molecular replacement at 0.28 nm resolution with a crystallographic R factor of 21.9% (R-free=25.7%) and reasonable stereochemistry. Being similar to the previous reported crystal form, a significant conformational adaptation of segment 14-23 at the dimer interface was observed. This segment was related to the "interface recognition site" (IRS). It was found that a positively charged residue at position 34 seems to be a common feature for most of hemolytic PLA(2)s belonging to group II. Structural comparison between the two crystal forms showed that NaCl had significant effects on the crystal packing, thus leading to dramatic changes of the unit cell parameters. In the new crystal form, MPD (2-methyl-2, 4-pentanediol) molecules exist in the hydrophobic channel of the enzyme.


The overcrowded emergency department: a comparison of staff perceptions.
To study perceptions of physicians and nursing staff about real-time demands and capacity of an emergency department (ED). To use ED data to calculate proposed demand ratios called Real-time Emergency Analysis of Demand Indicators (READI) scores. To compare the READI scores with ED staff perceptions of demand and capacity. This prospective study used a computerized clinical management system to provide data about ED demand and capacity. Physicians and staff charge nurses were surveyed about perceptions of ED demand and capacity. Results were compared with mathematical READI scores, which are proposed to objectively assess ED demand. Kappa scores were used to measure intrarater reliability between the physicians' and charge nurses' assessment of demand and between the staff assessments and the READI scores. Kappa scores of the perception of excess demand were as follows: between two physician groups, kappa = 0.392; between one physician group and charge nurses, kappa = 0.453; and between a second physician group and charge nurses, kappa = 0.243. Comparing respondents who indicated that demand had or had not exceeded capacity, one of the READI ratios, the Bed Ratio, showed a significant difference in mean, 0.245 (95% confidence interval = 0.153 to 0.336), between groups. Real-time data may be used to predict ED demand and resource needs. Subjective assessment of excess ED demand did not correlate between physician groups or between physicians and charge nurses. Although there was a trend toward predicting excess demand with one of the READI scores, these scores did not correlate to staff perceptions.


Temperature-Responsive Ionic Liquids: Fundamental Behaviors and Catalytic Applications.
Temperature-responsive ionic liquids (ILs), their fundanmental behaviors, and catalytic applications were introduced, especially the concepts of upper critical solution temperature (UCST) and lower critical solution temperature (LCST). It is described that, during a catalytic reaction, they form a homogeneous mixture with the reactants and products at reaction temperature but separate from them afterward at ambient conditions. It is shown that this behavior offers an effective alternative approach to overcome gas/liquid-solid interface mass transfer limitations in many catalytic transformations. It should be noted that IL-based thermomorphic systems are rarely elaborated until now, especially in the field of catalytic applications. The aim of this article is to provide a comprehensive review about thermomorphic mixtures of an IL with H2O and/or organic compounds. Special focus is laid on their temperature dependence concerning UCST and LCST behavior, including systems with conventional ILs, metal-containing ILs, polymerized ILs, as well as the thermomorphic behavior induced via host-guest complexation. A wide range of applications using thermoregulated IL systems in chemical catalytic reactions as well as enzymatic catalysis were also demonstrated in detail. The conclusion is drawn that, due to their highly attractive behavior, thermoregulated ILs have already and will find more applications, not only in catalysis but also in other areas.


Cadmium, lead, and thallium in smoke particulate from counterfeit cigarettes compared to authentic US brands.
Smoking remains the leading cause of preventable disease in the United States. Exposure to tobacco smoke leads to cancer, heart and lung disease, and addiction. The origin of the tobacco and cigarette manufacturing practices of counterfeit cigarettes are unknown. Because toxic metals are incorporated into the tobacco lamina during cultivation, the ambient metal content of the soil could produce significant differences in metal levels in both the tobacco and smoke of counterfeit cigarettes. We compared mainstream smoke cadmium, thallium, and lead deliveries from counterfeit and authentic brands. Mainstream smoke levels of all three metals were far greater for counterfeit than the authentic brands, in some cases by an order of magnitude. Significant differences still existed even after normalizing mainstream smoke metal levels with nicotine delivery; the counterfeits typically delivered much higher levels of all three analytes. Our findings, based on 21 different counterfeit samples, suggest that counterfeit cigarettes potentially result in a markedly greater exposure to toxic heavy metals than authentic brands, even after correcting for differences in nicotine intake. In view of the unknown health risks associated with inhaling higher levels of toxic metals, it is prudent to minimize exposure to toxic substances whenever possible.


[Impact on the risk of obesity due to interactions between fat mass- and obesity-associated gene rs9939609 variants and behavioral factors, in the Chinese school-aged children].
To investigate how the interactions between fat mass- and obesity-associated (FTO) gene rs9939609 variants and daily-life related behavioral factors would influence the risk of obesity among the Chinese school-aged children. 3503 school-aged children were selected from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) Study, and divided into obese children (n = 1229) and non-obese children (n = 2274). Venipuncture blood test, genotyping and questionnaire were performed. Five common factors including protein foods, tobacco & alcohol, vegetables & fruits, sedentary behavior and physical exercise in spare time were extracted with factor analysis methodology. Data from logistic regression analysis showed that taking the interaction of rs9939609 variant with protein foods as an example, the risk of interaction accounted for 19.16% when both factors existing simultaneously. Similarly, the interactions of this SNP with vegetables & fruits, sedentary behavior and physical exercise in spare time appeared to be 5.97%, 19.62% and 12.43% respectively; however there might not be interaction between tobacco, alcohol and the SNP in the Chinese children. Protein foods, vegetables & fruits, sedentary behavior and physical exercise might modify the effects of FTO rs9939609 variant on the risk of obesity in Chinese school-aged children. However, large-scale, prospective studies with detailed information on related behavioral factors would be ideal models for identifying the interactions between genes and environment.


The effect of residential environment satisfaction on depression in the elderly: Focusing on the mediating effect of stress.
This study aimed to determine the mediating effect of stress on the relationship between residential environment satisfaction and feelings of depression in the elderly. To achieve the purpose of the study, the researcher personally conducted interviews with 250 senior citizens residing in Jeollanam-do, South Korea, from October to November 2019. SPSS version 27.0 and Hayes' PROCESS ver. 4.0 were used for data analysis. As a result of testing the research hypothesis, a partial mediating effect of stress on the relationship between residential environment satisfaction and feelings of depression was confirmed. Based on these results, diverse practical and policy suggestions were recommended. First, a connection between barrier-free walking and public transportation linking elderly residences and major living facilities (transportation facilities, medical facilities, cultural facilities, social welfare facilities, parks, etc.) was suggested. Second, the application of a universal design was proposed when remodeling or building elderly residences. Third, policies promoting social participation of the elderly and providing assistance to increase the intimacy of their relationship with family members and neighbors are necessary to enable older adults to maintain their social relationships. Fourth, programs, such as educational schemes that provide older adults with a greater understating of stress, must be developed in parallel to facilitate stress self-management interventions. In future, it is necessary to include additional mediating or moderating variables to generalize these findings to the larger population.


311 disaster and mental health countermeasures.
On 11 March 2011, a devastating earthquake struck off the coast of Japan, causing blustering tsunami that swept over the northeast coast of the country. Many struggled to evacuate from their homes, schools, and workplaces as 8- to 9-m-tall tsunami rapidly reached the coast within half an hour after the earthquake (Emergency Disaster Response Headquarters). The officials reported a record-breaking magnitude of 9.0 Mw, which made this earthquake the most devastating earthquake in the Japan's history. It had not been long since the previous massive earthquake had hit Kobe in 1995, killing 6,434 people (Japan Meteorological Agency). The author presents the outline of the initial mental-health-care responses at various levels. It has focused on the comprehensive strategies and policies that were intended to cover all the affected areas but has not described the individual countermeasures and reactions in each prefecture and city. The psychological effects of the atomic plant accident in Fukushima has not been mentioned in detail, because the scope of the physiological effect of the accident has not been settled yet and the society is not necessarily ready to deal with the accident as a psychological matter rather than a sociopolitical one. A number of psychiatric professionals are deeply concerned with the psychological and prolonged impact of the accident, including those who are in the Fukushima prefecture and conducting heroic efforts to care for the residents.


The Influence of Component Rotational Malalignment on Early Clinical Outcomes in Total Knee Arthroplasty.
Background The most important cause of patient dissatisfaction following total knee arthroplasty (TKA) is pain. Component rotation is an important factor in the clinical success of TKA. This study aims to determine component rotational errors in patients with mobile- and fixed-bearing polyethylene inserts after TKA and also to evaluate the effect of possible malrotations on clinical outcomes. Methods Seventy-five knees from sixty-six patients who underwent TKA were evaluated retrospectively. The patients were divided into two groups according to whether they received a mobile-bearing polyethylene insert (group 1, n = 48) or a fixed-bearing polyethylene insert (group 2, n = 27). The Hospital for Special Surgery (HSS) score, the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the Lysholm Knee Scoring Scale, and the Oxford Knee Score were used for the clinical evaluation of the patients. The rotational state of the components was evaluated by computed tomography. Results The HSS, WOMAC, Lysholm, and Oxford clinical scores were not significant between the two groups (p > 0.05). The effect of femoral versus tibial component rotational deviation on clinical scores was not significant between the two groups (p > 0.05). Component rotational differences did not have a significant effect on the degree of knee flexion and extension between groups (p > 0.05). When the combined rotations of the components were compared with the clinical scores of function, no significant difference was detected between groups (p > 0.05). In addition, no significant difference between the operated sides of the patients and the combined component internal rotations was found (p > 0.05). Conclusion Although component rotation is an important factor in the clinical success of TKA, the current study did not find a clear association between the clinical results after TKA and the internal rotation of components. Component internal rotation alone is not an important predisposing factor for pain development after TKA. We believe that this may be attributed to the significant effects of patient expectation, which is often ignored, on clinical scores.


Lumbar epidural catheter insertion: the midline vs. the paramedian approach.
The purpose of this study was to compare the characteristics of epidural catheter insertion via the midline or the paramedian approach with regard to ease of catheter insertion, incidence of paraesthesias and efficacy of epidural block. In addition to the type of approach, the prognostic value of Patients characteristics variables with regard to the incidence of paraesthesias was assessed. Thirty patients scheduled for surgery under epidural anaesthesia were randomly assigned to one of two groups of 15 patients each. Epidural anaesthesia was performed via a midline or paramedian approach using loss of resistance to saline. Variables measured were: time needed to identify the epidural space, time needed for and ease of epidural catheter insertion and the incidence of paraesthesias. After completion of these observations, epidural anaesthesia was established with 150 mg ropivacaine 1%. Efficacy of the epidural block was assessed by the need for intraoperative analgesics and by the patient on a three-point scale (good/fair/poor). Quality of sensory blockade was adequate in both groups. Catheter insertion was significantly faster using the paramedian approach. The difference between the two approaches with regard to the incidence of paraesthesias was not significant, however, there was a trend towards more paraesthesias in the midline group. In the multivariate analysis, type of approach was an independent significant predictor of paraesthesias and we found a trend towards a higher incidence of paraesthesias in female patients. Catheter insertion was faster in the paramedian group and we found a trend towards a higher incidence of paraesthesias with the midline approach.


Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally-tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial.
Ranolazine has been previously shown to improve exercise capacity and symptoms in patients with severe chronic angina treated with standard doses of beta-blockers and calcium-channel blockers, without a significant effect on heart rate or blood pressure. The purpose of this study was to assess whether the benefit of ranolazine extends to the subgroup of angina patients treated with maximally-tolerated doses of beta-blockers or calcium blockers. In this post-hoc analysis, 258 patients from the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial were considered as treated with maximally-tolerated doses of beta-blockers or calcium-channel blockers (systolic blood pressure (SBP) ≤ 100 mm Hg, and/or a resting heart rate ≤ 60 beats per minute, and/or an ECG PR interval ≥ 200 msec). Change from baseline in total exercise duration after 12 weeks compared to placebo were 34.5 (95% CI 0.8; 68.1) sec (p = 0.045) with ranolazine (750/1000 mg bid) at trough drug levels and 46.3 (13.5; 79.1) (p = 0.006) at peak drug levels. The number of angina attacks per week compared to baseline were reduced compared to placebo (-2.3 ± 0.3 vs -0.9 ± 0.6 (p < 0.001)). The effects of ranolazine 750 mg bid and 1000 mg bid were similar and the beneficial effects of ranolazine in this subgroup of maximally-treated patients were consistent with those not on maximally-tolerated doses of the background therapy. Ranolazine is effective for the symptomatic treatment of patients with stable angina on background therapy with maximally-tolerated doses of first line anti-anginal therapies.


Effects of pH alteration on respiratory syncytial virus in human airway epithelial cells.
Respiratory syncytial virus (RSV) is a leading cause of respiratory distress and hospitalisation in the paediatric population. Low airway surface pH impairs antimicrobial host defence and worsens airway inflammation. Inhaled Optate safely raises airway surface pH in humans and raises intracellular pH in primary human airway epithelial cells (HAECs) in vitro. We aimed to determine whether raising intracellular pH with Optate would decrease infection and replication of RSV in primary HAECs. We cultured HAECs from healthy subjects in both air-liquid interface and submerged conditions. We infected HAECs with green fluorescent protein-labelled RSV (GFP-RSV; multiplicity of infection=1) and treated them with Optate or PBS control. We collected supernatant after a 4-h incubation and then every 24 h. We used fluorescence intensity, fluorescent particle counts, plaque assays, Western blots and ELISA to quantitate infection. In submerged culture, fluorescence intensity decreased in Optate-treated cells (48 h p=0.0174, 72 h p≤0.001). Similarly, Optate treatment resulted in decreased fluorescent particle count (48 h p=0.0178, 72 h p=0.0019) and plaque-forming units (48 h p=0.0011, 72 h p=0.0148) from cell culture supernatant. In differentiated HAECs cultured at ALI, Optate treatment decreased fluorescence intensity (p≤0.01), GFP via Western blot and ELISA (p<0.0001), and RSV-fusion protein via ELISA (p=0.001). Additionally, RSV infection decreased as Optate concentration increased in a dose-dependent manner (p<0.001). Optate inhibits RSV infection in primary HAECs in a dose-dependent manner. These findings suggest that Optate may have potential as an inhaled therapeutic for patients with RSV.


5-HT depletion, but not 5-HT1A antagonist, prevents the anxiolytic-like effect of citalopram in rat contextual conditioned fear stress model.
Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety. Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dl-p-chlorophenylalanine (PCPA), various subtype-selective serotonin (5-HT) receptor antagonists: the 5-HT1A receptor antagonist WAY 100635, the 5-HT2A receptor antagonist MDL 100907, the 5-HT2C receptor antagonist SB 242084, the 5-HT3 receptor antagonist tropisetron, the 5-HT4 receptor antagonist GR 125487, the 5-HT6 receptor antagonist SB 258585 or the 5-HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks. Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic-like effect of citalopram was prevented completely by pretreatment with the 5-HT-depleting agent PCPA, but not by the 5-HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype-selective 5-HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic-like effect of citalopram. The anxiolytic-like effect of citalopram in contextual CFS model depends on 5-HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic-like effect of citalopram.


[Clinical characteristics, pathology, and prognosis of children with diffuse endocapillary proliferative Henoch-Schönlein purpura nephritis].
To investigate the clinical characteristics, pathology, and prognosis of children with diffuse endocapillary proliferative Henoch-Schönlein purpura nephritis (DEP-HSPN). A retrospective analysis was performed on the clinical, pathological, and prognosis data of 44 children with DEP-HSPN and 765 children without DEP-HSPN. The children with DEP-HSPN were diagnosed by renal biopsy in Jiangxi Provincial Children's Hospital from January 2006 to December 2021. Among the 809 children with purpura nephritis, 44 (5.4%) had DEP-HSPN, with a mean age of (8±3) years, and there were 29 boys (65.9%) and 15 girls (34.1%). Compared with the non-DEP-HSPN group, the DEP-HSPN group had a significantly shorter time from onset to renal biopsy and a significantly higher proportion of children with respiratory infection or gross hematuria, and most children had nephrotic syndrome. The DEP-HSPN group had significantly higher levels of 24-hour urinary protein, urinary protein grading, microscopic hematuria grading, serum creatinine, and blood urea nitrogen and significantly lower levels of serum albumin and complement C3 (P<0.05). The DEP-HSPN group had a higher pathological grading, with predominant deposition of IgA in the mesangial area and capillary loops, and higher activity scores in the modified semi-quantitative scoring system (P<0.05). The Kaplan-Meier survival analysis showed that there was no significant difference in the renal complete remission rate between the two groups (P>0.05). Children with DEP-HSPN have a rapid onset, severe clinical manifestations and pathological grading, and high activity scores in the modified semi-quantitative scoring system. However, most of the children with DEP-HSPN have a good prognosis, with a comparable renal complete remission rate to the children without DEP-HSPN.


Chemical, dissolution stability and microscopic evaluation of suspensions of ibuprofen and sustained release ibuprofen-wax microspheres.
Chemical stability studies of suspensions of ibuprofen powder and ibuprofen-wax microspheres were performed using an accelerated stability protocol with a modified high performance liquid chromatography (HPLC) procedure. The variables considered were pH, suspending agents and temperature. The study showed little or no chemical degradation in the different suspending agents after storage for three months. Dissolution stability was examined in suspensions of ibuprofen microspheres made from an optimized formulation with 17% drug loading. The storage temperature were 23, 37 and 45 degrees C. Other variables for the dissolution stability studies were suspending agents, wax types, suspending medium pH and microsphere size. Suspensions of ceresine wax microspheres stored at 37 degrees C showed faster drug release than room temperature storage, but suspensions stored at 45 degrees C showed an opposite effect. Microspheres suspended in syrup and stored at 37 degrees C had faster dissolution rates than microspheres suspended in methylcellulose at the same temperature, possibly as a result of an interaction between the syrup and the microsphere constituents. Suspensions of microcrystalline wax microspheres had better dissolution stability than microspheres made from ceresine wax. Higher suspending medium pH resulted in faster release of drug from the suspended microspheres, but particle size did not significantly affect the dissolution stability.