Circular bioeconomy: Life cycle assessment of scaled-up cascading production from orange peel waste under current and future electricity mixes.
Orange peel waste (OPW) is present in large quantities both locally and globally, which makes them feasible input into the circular bioeconomy. However, due to their antimicrobial and anti-nutritional activity, they are problematic biomass, and proper waste management is yet to be determined. This life cycle assessment (LCA) quantifies the environmental performance of biorefinery producing limonene, citric acid, and animal feed from OPW generated from juice factories. Only previously assessed sustainable technologies were considered (cold press, microwave extraction, solid-state fermentation). The life cycle inventories were refined by a scale-up procedure to reflect industrial production at i) 0.5 t, ii) 100 t, and iii) 1000 t of OPW weekly. The data were translated per functional unit of 1 tonne OPW. Three electricity mixes and both attributional (average) and consequential (marginal) inventories were compared. Results showed that the environmental performance, in particular for climate change, was essentially dependent upon the electricity input, with 4388 CO2 eq for current electricity mix, 2404 CO2 eq using renewable, and 594 CO2 eq using electricity from wind. Business-as-usual scenarios for OPW (incineration and animal feed) showed better performance in most scenarios, representing -150 CO2 eq (animal feed) and -135 CO2 eq (incineration) in the climate change. Lower impacts are reached due to avoided impacts of fossil fuel use and conventional feed cultivation. Renewable energy had better environmental performance than the current electricity mix, except for eutrophication, due to digestate spreading associated with biogas use, calling for mitigation action. Our results suggest that stopping the biorefinery processes immediately after the recovery of limonene via solvent-free microwave extraction process, with subsequent use of the dried OPW as animal feed, is the most environmentally performant option. This represents a feasible strategy for the circular bioeconomy and is in line with the updated food waste hierarchy.


Identifying and assessing the multiple effects of informal environmental regulation on carbon emissions in China.
Against the backdrop of the global carbon peak and carbon neutrality goals, the role of informal environmental regulation, epitomized by public engagement, is assuming an increasingly pivotal position within the realm of environmental management. By contrast, amidst the prevailing landscape dominated by formal environmental regulation (command-and-control and market-driven approaches), the environmental effects of informal environmental regulation on carbon emissions have received scant attention. Consequently, we examine the net, nonlinear, and mediation effects of informal environmental regulation on carbon emissions using panel data from 30 provinces in China, from 2003 to 2019. We find that informal environmental regulation has a significant effect on regional carbon emission reduction, especially in the eastern cities, pilot cities, and cities with long-term governor's tenure. Its U-shaped effect is confirmed by changes in environmental decentralization. The key points remain valid after the robustness test and the endogenous processing. The mechanism analysis shows that informal environmental regulation can reduce carbon emissions in the dual channels by improving industrial structure transition and renewable energy substitution. Therefore, this study assesses the management effectiveness of informal environmental regulation and determines the underlying mechanism between it and regional carbon emission reduction to provide a reference and an empirical basis for other countries regarding environmental improvement.


Evaluation and comparison of the mitochondrial and developmental toxicity of three strobilurins in zebrafish embryo/larvae.
Strobilurin fungicides have been frequently detected in aquatic environments and can induce mitochondrial toxicity to non-target aquatic organisms. However, the derived toxicity and subsequent mechanisms related to their adverse effects are not fully elucidated. In the present study, we compared the mitochondrial and developmental toxicity of azoxystrobin, pyraclostrobin, and trifloxystrobin using zebrafish embryo/larvae. The results showed that all three strobilurins inhibited mitochondrial and non-mitochondrial respiration (the potency is pyraclostrobin ≈ trifloxystrobin > azoxystrobin). Behavioral changes indicated that sublethal doses of pyraclostrobin and azoxystrobin caused hyperactivity of zebrafish larvae in dark cycles, whereas trifloxystrobin resulted in hypoactivity of zebrafish larvae. In addition, pyraclostrobin exposure impaired the inflation of swim bladder, and caused down-regulation of annexin A5 (anxa5) mRNA levels, and up-regulated transcript levels of pre-B-cell leukemia homeobox 1a (pbx1a); conversely, azoxystrobin and trifloxystrobin did not cause detectable effects with swim bladder inflation. Molecular docking results indicated that azoxystrobin had higher interacting potency with iodotyrosine deiodinase (IYD), prolactin receptor (PRLR), antagonistic conformation of thyroid hormone receptor β (TRβ) and glucocorticoid receptor (GR) compared to pyraclostrobin and trifloxystrobin; pyraclostrobin and azoxystrobin were more likely to interact with the antagonistic conformation of TRβ and GR, respectively. These results may partially explain the different effects observed in behavior and swim bladder inflation, and also point to potential endocrine disruption induced by these strobilurins. Taken together, our study revealed that all three strobilurins alter mitochondrial bioenergetics and cause developmental toxicity. However, the toxic phenotypes and underlying mechanisms of each chemical may differ, and this requires further investigation. Pyraclostrobin showed higher mitochondrial toxicity at lethal doses and higher developmental toxicity at sublethal doses compared to the two other strobilurins tested. These results provide novel information for toxicological study as well as risk assessment of strobilurin fungicides.


Enhanced glucose homeostasis in BHE/cdb rats with mutated ATP synthase.
The BHE/cdb rat has a mutation in adenosine triphosphate (ATP) synthase that impairs insulin secretion. However, male BHE/cdb rats have normal circulating glucose and enhanced glucose tolerance. The aim of the current study was to identify mechanisms of enhanced glucose tolerance. The respiratory exchange ratio was increased, indicating increased oxidation of carbohydrate in BHE/cdb rats, consistent with increases in liver pyruvate dehydrogenase activity and muscle citrate synthase activity. Liver also exhibited diminished phosphoenol pyruvate carboxykinase content, which correlated with a decreased counter-regulatory response in the insulin tolerance test. Signaling via Akt or AMP-dependent kinase pathways in the liver could not account for lower blood glucose. We conclude that chronically low insulin secretion leads to adaption in glucose metabolism primarily in liver to maintain euglycemia.


Encephalitis with antibodies against the GABAB receptor: seizures as the most common presentation at admission.
Autoimmune encephalitis associated with antibodies against gamma-aminobutyric-acid B receptor (GABABR) has not been described in detail in Chinese patients. Patients with anti-GABABR encephalitis treated between January 2013 and December 2015 were analyzed in terms of clinical characteristics, laboratory findings, tumor presence, autoantibody patterns, treatment response and outcomes. Eleven patients were identified (male, N = 8; female, N = 3), with the median age of 51 years. All patients presented with seizures (N = 11; 100%), and they were given anti-epileptic drugs and first-line immunotherapy to address the disease. Seizures always accompanied by limbic manifestations (N = 10; 90.9%). Extralimbic manifestations were present in 4 patients (N = 4; 36.4%). MRI Brain abnormality with increased medio-temporal lobe T2/FLAIR signal were present in 2 patients (N = 2; 18.2%), and epileptiform epileptiform activity on electroencephalography were observed in 2 patients (N = 2; 18.2%). Small-cell lung cancer was histologically confirmed in 3 patients (N = 3; 27.3%). Seven patients showed good outcomes (mRS 1-2; N = 7; 63.6%), one patient showed poor neurological status with minimal changes (mRS 4; N = 1; 9.1%), and three patients died during follow-up (mRS = 6; N = 3; 27.3%). Outcomes were correlated with age-of-onset, and were worse among older patients (P = 0.0112). Anti-GABABR encephalitis is a potentially treatable disorder involving seizures as the most predominant presentation at admission. It should be considered as a possible diagnosis in middle-aged and older patients with refractory new-onset epilepsy.


Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial.
For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.


Biomarker responses in fish exposed to sediments from northern Taihu Lake.
Our study investigated multiple biomarker responses of goldfish exposed to sediments collected from northern Taihu Lake. The activities of acetylcholinesterase, 7-ethoxyresorufin-O-deethylase, glutathione-S-transferase and superoxide dismutase did not differ significantly from controls following exposure to sediment from the center of the lake. However, sediment collected from the northern bays did significantly alter enzymatic activities. An integrated biomarker response (IBR) was calculated and used to evaluate the impact of pollutants from different stations. The results indicated that Mashan in Meiliang Bay and Xiaogongshan in Gong Bay were the most stressful places for fish. Sediment polychlorinated biphenyl and polybrominated diphenyl ether concentrations were associated with IBR variation.


Evaluation of multi-attribute auditory discrimination in dyslexia with the mismatch negativity.
Dyslexia is associated with impairments in the phonological system or with more general auditory dysfunctions. We determined the discrimination of 5 sound contrasts (pitch, duration, intensity, location, and the presence of a gap) in dyslexia with the mismatch negativity (MMN). We compared MMNs of 9 adult dyslexic and 11 control subjects with a new 5-deviant paradigm which enables one to assess the discrimination of each of these features in 15 min. Also, a control oddball condition with pitch and duration deviants was included. In the new paradigm, all deviant stimuli are presented in the same stimulus block so that the standard stimuli, of which there are 50%, alternate with the deviant stimuli. In the 5-deviant paradigm, a diminished pitch-MMN and an enhanced location-MMN were found in dyslexic individuals. Furthermore, pitch and duration MMNs in this and in the oddball paradigms suggested that smaller MMNs are elicited in the new than oddball paradigm in dyslexic subjects. Pitch discrimination is impaired in dyslexia. However, location discrimination, not addressed previously with MMN, is enhanced. Furthermore, dyslexic subjects are more impaired in detecting changes in sound streams with than without variation. In dyslexia research, the new 5-deviant MMN paradigm is feasible and even more sensitive than the traditional oddball paradigm.


Sulfated glycosaminoglycans in Alzheimer's disease.
Using the sulfated alcian blue and alcian blue-MgCl2 techniques for demonstrating sulfated glycosaminoglycans (GAGs), we have shown sulfated GAGs to be associated with the amyloidotic lesions of Alzheimer's disease, the neuritic plaques, the neurofibrillary tangle, and the congophilic angiopathy. To determine how specific these findings are to Alzheimer's disease, other neurologic disorders with neurofibrillary tangles and filamentous inclusions were examined. These included progressive supranuclear palsy, Pick's disease, subacute sclerosing panencephalitis, and postencephalitic parkinsonism. Sulfated GAGs were not demonstrated in the neurofibrillary tangles or filamentous structures in any of these disorders. The relationship of GAGs to the pathology of Alzheimer's disease is discussed as is their possible importance in determining the characteristic morphology of the amyloidotic lesion.


Mode of initiation of cell infection with sludge-associated poliovirus.
Association with sludge solids did not allow poliovirus to enter cells other than through the normal receptor-mediated route. This implies that the infectivities of sludge-encapsulated virions are masked until their exposure permits binding to cell surface receptors.


Complex open elbow fracture Gustilo-Anderson type IIIB treated with the primary elbow arthroplasty: A case report.
Total elbow arthroplasty as a treatment option for open elbow fracture is relatively rare described. We reported a 39 years old polytrauma patient with complex open elbow fracture (Gustilo-Anderson type IIIB). The patient presented with large soft tissues defect on dorsal part of the left elbow, ulnar palsy due to the irreparable loss of the ulnar nerve, distal triceps loss due to the complete loss of the olecranon, loss of both humeral condyles with collateral ligaments and complex elbow instability. Only few similar cases have been published. Reconstructive surgery included repetitive radical debridement, irrigation, vacuum assisted closure system therapy, external fixation, coverage of the soft tissue defect with fascia-cutaneous flap from the forearm. Four months after the injury, total elbow arthroplasty with autologous bone graft (from the proximal radius) inserted in the ulnar component, was performed. At 3 years postoperatively, the patient is able to perform an active flexion from 0° to 110° with full prono-supination. Only passive extension is allowed. The ulnar neuropathy is persistent. Patient has no signs of infection or loosening of the prosthesis.


ceRA: an RH allele variant producing a new rare blood.
Antibodies against RH antigens are clinically significant. Some rare RH phenotypes, for example, RH:-46 (R(N)), RH:-18 (Hr(s)-), RH:-34 (Hr(b)-), and homozygous partial RH5 (e), are found exclusively in black persons of African descent. Quantitative and qualitative RHCE variants require characterization because the presence of these alleles can lead to difficulties when transfusion is needed. Here a new RH5 variant (ceRA) in an Indian patient is described and investigated by serology (agglutination and flow cytometry analysis) and molecular and immunoblot analysis. Red blood cells (RBCs), typed as RH:-1,-2, -3,4,w5, expressed a very depressed RH5 antigen, with no expression of the RH19 (h) high-frequency antigen. Molecular analysis revealed a new Rhce allele (homozygous state), hereafter called ceRA. This new allele exhibited a G48C mutation in exon 1 and a G538C mutation in exon 4, predicting, respectively, a Trp16Cys substitution and a Gly180Arg substitution, both in the intramembranous domain of the Rhce polypeptide. Immunoblot analysis showed that this defect results in a dramatic loss of the amount of RHCE polypeptides within the RBC membrane. No reactivity was evidenced with most of anti-RH5, in agglutination as well as in flow cytometry techniques. Both serologic results and localization of the Gly180Arg substitution emphasize the risk of anti-RH5 alloimmunization for patients expressing this new allele ceRA at the homozygous state. These results point out the importance of obtaining blood donations for the frozen rare blood bank in case future transfusion is needed.


Integral-valued polynomials over sets of algebraic integers of bounded degree.
Let K be a number field of degree n with ring of integers [Formula: see text]. By means of a criterion of Gilmer for polynomially dense subsets of the ring of integers of a number field, we show that, if [Formula: see text] maps every element of [Formula: see text] of degree n to an algebraic integer, then [Formula: see text] is integral-valued over [Formula: see text], that is, [Formula: see text]. A similar property holds if we consider the set of all algebraic integers of degree n and a polynomial [Formula: see text]: if [Formula: see text] is integral over [Formula: see text] for every algebraic integer α of degree n, then [Formula: see text] is integral over [Formula: see text] for every algebraic integer β of degree smaller than n. This second result is established by proving that the integral closure of the ring of polynomials in [Formula: see text] which are integer-valued over the set of matrices [Formula: see text] is equal to the ring of integral-valued polynomials over the set of algebraic integers of degree equal to n.


Determination of Rare Earth Elements in multi-year high-resolution Arctic aerosol record by double focusing Inductively Coupled Plasma Mass Spectrometry with desolvation nebulizer inlet system.
An inductively coupled plasma sector field mass spectrometer (ICP-SFMS) was used to develop an analytical method for the fast determination of Na, Al, Sc, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Y, Mo, Cd, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Pb in Arctic size-segregated aerosol samples (PM10), after microwave acidic digestion. The ICP-SFMS was coupled with a microflow nebulizer and a desolvation system for the sample introduction, which reduced the isobaric interferences due to oxides and the required volume of sample solutions, compared to the usual nebulization chamber methods. With its very low limit of detection, and taking into account the level of blanks, this method allowed the quantification of many metals in very low concentration. Particular attention was given to Rare Earth Elements (REEs - La to Lu). The efficiency in the extraction of REEs was proved to be acceptable, with recoveries over 83% obtained with a Certified Reference Material (AMiS 0356). The analytical method was then applied to particulate matter samples, collected at ground level in Ny Ålesund (Svalbard Islands, Norway), during spring and summer, from 2010 to 2015, with daily resolution and using a low-volume device. Thus, for the first time, a large atmospheric concentrations dataset of metals in Arctic particulate matter at high temporal resolution is presented. On the basis of differences in LREE/HREE ratio and Ce and Eu anomalies in spring and summer samples, basic information to distinguish local and long-range transported dust were achieved.


Regional myocardial nitrogen-13 glutamate uptake in patients with coronary artery disease: inverse post-stress relation to thallium-201 uptake in ischemia.
The purpose of the present study was to evaluate the clinical significance of myocardial scintigraphy with nitrogen-13 (N-13) glutamate as a marker of myocardial metabolism. Within 2 weeks after cardiac catheterization, 25 patients with single vessel left anterior descending coronary artery disease underwent thallium-201 imaging (5 min and 3 h after injection) and N-13 glutamate scintigraphy (10 min after injection). Radionuclide studies were performed in the 30 degrees left anterior oblique projection after symptom-limited bicycle exercise, and regional tracer uptake was quantified by computer-assisted placement of regions of interest within the regions of myocardial activity. Poststenotic tracer uptake in the perfusion bed of the left anterior descending coronary artery (septum) was then normalized to the tracer uptake in the nondiseased left circumflex territory (posterolateral segments = 100%). In 14 patients with a history of previous myocardial infarction (Subgroup A), deficient poststenotic N-13 uptake correlated closely with thallium-201 uptake in both initial (r = 0.82, p less than 0.001) and redistribution (r = 0.74, p less than 0.01) scintigrams. By contrast, in 11 patients with no previous myocardial infarction and normal left ventricular function at rest (Subgroup B), initial uptake of both tracers was inverse: poststenotic N-13 glutamate uptake increased with decreasing thallium-201 uptake during exercise-induced ischemia (r = -0.64, p less than 0.05) and was closely correlated with the percent thallium-201 redistribution (r = 0.74, p less than 0.01). Thus, augmented accumulation of N-13 glutamate in reversibly ischemic (that is, viable) myocardium, and decreased uptake in myocardial scar tissue suggest the clinical usefulness of this metabolic tracer in the differentiation between viable (metabolically active) and irreversibly damaged myocardium.


Colon Adenocarcinoma Associated with Synchronous Extramural Gastrointestinal Stromal Tumor (GIST) of the Ileum.
GISTs are mesenchymal tumors representing approximately 1% of all gastrointestinal neoplasia. Their concurrence with colorectal cancers is rare. We present a case of coexistence of colon adenocarcinoma and GIST of the ileum in a 68-year-old white woman. The coexistence of mesenchymal and epithelial neoplasia is very challenging; further research is needed to clarify the role of oncogenic mutations and signalling pathways in carcinogenesis of neoplasia of various histiogenic origins.


Utility of age, creatinine, and ejection fraction score in patients with type B aortic dissection undergoing thoracic endovascular aortic repair.
Older age, renal and cardiac dysfunction are predictors of poor outcome in aortic dissection. The aim of this study was to evaluate the association of the age, creatinine and ejection fraction (ACEF) score with adverse events in patients with type B aortic dissection (TBAD) undergoing thoracic endovascular aortic repair (TEVAR). The study enrolled 605 patients from January 2010 to July 2015, who were classified into three groups according to the tertiles of ACEF score: Tertile 1 (≤0.77, n = 204), Tertile 2 (0.77-0.96, n = 205) and Tertile 3 (>0.96, n = 196). The association between ACEF, AGEF (age, glomerular filtration rate and ejection fraction) and the updated version of the ACEF (ACEF II) score with adverse events was analyzed. After a median 3.4 years follow-up, 63 (10.4%) patients died. Multivariable analysis revealed that ACEF score was independently associated with long-term mortality (adjusted hazard ratio = 3.54; 95% confidence interval, 2.09-6.01; p < 0.001). ACEF, AGEF and ACEF II score had similar predictive ability for both in-hospital and long-term death. The in-hospital mortality (1.5% vs. 1.0% vs. 6.6%, p = 0.001) were significantly higher in Tertile 3. In addition, cumulative long-term mortality in Tertile 3 was significantly higher than that in Tertile 1 and 2 (Log-Rank = 23.74; p < 0.001). ACEF score could be served as an useful and relatively simple tool for pre-TEVAR risk stratification in TBAD patients.


Insights into generalization of the rate-limiting steps of the dehalogenation by LinB and DhaA: A computational approach.
LinB and DhaA are well-known haloalkane dehalogenases (HLDs) capable of converting a plethora of halogenated alkanes, also those considered persistent pollutants. The dehalogenation reaction that these two enzymes catalyze has been studied to determine its rate-limiting step (rls) for the last two decades now. As a result, it has been determined that HLDs can show different rate-limiting steps for individual substrates, and at this point we do not have a basis for any generalization in this matter. Therefore, in this work we aimed at gaining insights into the enzymatic dehalogenation of selected dibromo- and bromochloro-ethanes and propanes by LinB and DhaA using computational approach to determine whether defined structural similarities of the substrates result in a unified mechanism and the same rls. By predicting halogen binding isotope effects (BIEs) as well as computing interaction energy for each HLD-ligand complex the nature of the protein-ligand interactions has been characterized. Furthermore, C and Br kinetic isotope effects (KIEs) as well as the minimum free energy paths (MFEPs) were computed to investigate the chemical reaction for the selected systems. Accuracy of the approach and robustness of the computational predictions were validated by measuring KIEs on the selected reactions. Overall results strongly indicate that any generalization with respect to the enzymatic process involving various ligands in the case of DhaA is impossible, even if the considered ligands are structurally very similar as those analyzed in the present study. Moreover, even small structural differences such as changing of one of the (non-leaving) halogen substituents may lead to significant changes in the enzymatic process and result in a different rls in the case of LinB. It has also been demonstrated that KIEs themselves cannot be used as rls indicators in the reactions catalyzed by the studied HLDs.


Acid secretion by isolated canine gastric mucosa.
1. An isolated gastric mucosal preparation from the dog stomach which is capable of acid secretion is described. Average values for normal resting potential difference (p.d.) was 49 +/- 2 mV (mucosal side negative with respect to the serosal side), short-circuit current (Isc) was 172 +/- 4 muA and resistance (R) was 285 +/- 6 omega.cm2. Low rates of spontaneous acid secretion (0-0.58 muequiv/cm2.hr) were present initially but following short-circuiting of the tissue these values decreased to low levels (less than 0.1 muequiv/cm2.hr) within an hour. 2. Histamine in doses exceeding 10(-6)M stimulated acid secretion, increased Isc and decreased R. Concentrations ranging from 10(-5) to 8 X 10(-4)M produced maximal secretion. The maximal secretory rate achieved was 4.24 +/- 0.35 muequiv/cm2.hr. 3. Pentagastrin (10(-8)M) and acetylcholine (10(-6)--10(-5)M) also stimulated acid secretion with a lower maximal secretion as compared to histamine stimulation. These concentrations of pentagastrin and acetylcholine did not alter histamine stimulated acid secretion. Higher concentrations of pentagastrin (10(-6)M) and acetylcholine (10(-4) M) reversibly inhibited acid secretion of histamine stimulated mucosa. 4. These results demonstrate that there are many similarities between in vitro and in vivo findings on the dog stomach, indicating the great potential of the in vitro dog gastric mucosa for studies on the mechanism of action and interaction of gastric secretagogues.


Appealing for efficient, well organized clinical trials on COVID-19.
The rapid emergence of clinical trials on COVID-19 stimulated a wave of discussion in scientific community. It is important to understand the characteristics of the ongoing or pending interventional clinical trials on COVID-19. We reviewed the characteristics of interventional trials from Chinese Clinical Trial Registration (ChiCTR) and ClinicalTrials.gov. A total of 171 COVID-19-related interventional trials were identified on Feb 22, 2020. These trials are classified into 4 categories based on treatment modalities, including chemical drugs (CDs), biological therapies (BTs), traditional Chinese medicine (TCM) treatments and other therapies. Our analysis focused on the issues of stage, design, randomization, blinding, primary endpoints (PEs) definition and sample size of these trials. Although most trials use parallel-arm design (88.3%) and randomization (77.2%), blinding is applied in only 25 trials (14.6%). More than half of the trials planned to recruit ≤100 patients, indicating a possibility of insufficient statistical power. About one third of trials will recruit severe and critically ill patients. More trials on traditional Chinese medical treatment use 2 or more PEs than those on CDs or biological treatments (57.6%, 39.4% and 40.5%, respectively). We found some studies with potential defects including unreasonable design, inappropriate PE and small sample size. Clinical trials on COVID-19 should be designed based on scientific rules, ethics and benefits for patients.


The significance of cutaneous metastasis from visceral tumors diagnosed by fine-needle aspiration biopsy.
Cutaneous metastases from various visceral organs were studied in 43 patients. The morphologic diagnosis in each case was established by fine-needle aspiration cytodiagnosis. There were 28 males and 15 females, with median ages of 62 and 61 yr, respectively. The most common primary tumor in men was carcinoma of the lung (35%), followed by malignant melanoma (21%) and carcinoma of the oropharynx (14%). In women, the most frequent primary cancers were carcinoma of the colon (59%) and lung (20%). Metastatic cutaneous lesions were more frequent in the back (23%), upper extremities (21%), and scalp (12%). Median survival from onset of cutaneous metastasis was shortest in primary lung cancer at 3 mo followed by colon at 5 mo and oropharynx at 5.5 mo. Our study confirms that cutaneous metastasis represents a terminal manifestation of the disease due to either hematogenous or lymphatic spread. This study also reiterates the clinical usefulness of needle aspiration biopsy as an alternative diagnostic tool in establishing the presence of cutaneous metastasis.


The Effect of Gender and APOE ɛ4 Status on Brain Amyloid-β Deposition in Different Age Groups of Mild Cognitively Impaired Individuals: A PET-CT Study.
Gender, APOE ɛ4 status and age have different effects on brain amyloid deposition in patients with mild cognitively impaired (MCI). To investigate the effect of gender×APOE ɛ4 status interaction on Aβ deposition in the brains of individuals with MCI in different age groups by PET scanning. 204 individuals with MCI were classified into younger or older groups based on whether they were under or over 65 years of age. APOE genotyping, structural MRI, amyloid PET scans, and neuropsychological tests were performed. The effect of gender×APOE ɛ4 status interaction on Aβ deposition was assessed in different age groups. APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the whole group. Females with MCI had more amyloid deposition in the medial temporal lobe than males in the whole cohort and younger group. Older individuals with MCI had higher amyloid deposition than younger individuals. In stratified analysis by age, female APOE ɛ4 carriers had significantly increased amyloid deposition compared to their male counterparts only in the medial temporal lobe in the younger group. Amyloid deposition was increased in female APOE ɛ4 carriers compared to noncarriers in the younger group, whereas higher amyloid deposition was observed in male APOE ɛ4 carriers in the older group. Women in the younger group with MCI who were APOE ɛ4 carriers had more amyloid deposition in the brain, while men in the older group with MCI who were APOE ɛ4 carriers had higher amyloid deposition.


Tranexamic acid and aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic acid or aprotinin.
Antifibrinolytics are widely used in cardiac surgery to reduce bleeding. Allogeneic blood transfusion, even in primary cardiac operations with low blood loss, is still high. In the present study we evaluated the impact of tranexamic acid compared to aprotinin on the transfusion incidence in cardiac surgical patients with low risk of bleeding. This prospective, randomized, double-blind study included 220 patients undergoing primary coronary artery revascularization (coronary artery bypass grafting [CABG]) or aortic valve replacement (AVR). Randomized in blocks of 20, patients received either tranexamic acid (approximately 6 g) or full-dose aprotinin (approximately 5-6 x 10(6) Kallikrein Inhibiting Units). Transfusion was guided by a strict transfusion algorithm. Molecular markers of hemostasis were determined to assess differences in the mode of action of the two drugs. Primary end-points were the incidence of allogeneic red cell transfusion and 24-h postoperative blood loss. Data were analyzed according to the intention-to-treat principle and compared using the chi(2) and Mann-Whitney U-test. Two-hundred-twenty patients were enrolled (CABG: 134, AVR: 86). In the aprotinin Group 47% of patients received allogeneic blood during the hospital stay as compared to 61% in the tranexamic acid group (P = 0.036). Aprotinin conferred a 23% reduction in allogeneic transfusion risk (RR 0.77, 95% CI 0.53-0.88). Overall, no significant difference in postoperative bleeding was observed, although 24-h blood loss was reduced in aprotinin-treated CABG patients (500, 350-750 mL vs 650, 475-875 mL (median, 25th-75th percentile); P = 0.039). Despite the lower transfusion rate, the hemoglobin concentration on the first postoperative day was higher in the aprotinin group (11.3, 9.9-12.1 vs 10.6, 9.9-11.6 mg/dL; P = 0.023). The fibrinolytic activity at the end of operation determined by D-Dimer was comparable in both groups. (0.15, 0.11-0.17 mg/L [aprotinin] versus 0.18, 0.12-0.24 mg/L [tranexamic acid]). The activated partial thromboplastin time was prolonged up to 4 h postoperatively in the aprotinin group, while the heparin requirement was reduced: 19% of the patients in the aprotinin group and 45% in the tranexamic acid group received at least one additional bolus heparin during cardiopulmonary bypass (P < 0.001). Troponin T levels postoperatively and on postoperative day 1 were significantly higher in the tranexamic acid group (P = 0.017). No differences in renal, cardiac, or mortality outcomes were observed. Considering the rate of transfusion of red blood cells, tranexamic acid was slightly inferior in patients undergoing CABG, but there was no difference in patients receiving AVR. Tranexamic acid seems to be less effective in operations with increased bleeding such as CABG. Clinical benefit depends on specific patient and institution characteristics (ClinicalTrials.gov NCT00396760).


Reflection: a flawed strategy for the nursing profession.
The meaning and process of reflection and reflective practice appear to be currently accepted and institutionalized within the nursing profession. This paper, through use of a literature review, attempts to question the value that is consequently placed on this strategy and argues that on closer examination, reflection has no clear or universal definition, an uncertain framework for implementation, and is of unproven benefit to the professional practice of nurses. Given this evidence, the author concludes that reflection is a fundamentally flawed strategy that must be of limited benefit to the nursing profession.


Butterflies and Ribbons: Supporting Families Experiencing Perinatal Loss in Multiple Gestation.
Introduction: In neonatology, multiple pregnancies are common. Unfortunately, it is not rare for one baby to die. Communication with parents in these circumstances has been demonstrated to be sub-optimal. Methods: Two educational programs were evaluated with pre- and post-course surveys, questionnaires administered to participants, and audits. Results: In the online Butterfly project (UK; n = 734 participants), all participants reported that the training exceeded or met their expectations, 97% reported they learned new skills, and 48% had already applied them. Participants expressed gratitude in their open-ended answers: "I feel a lot more confident in supporting parents in this situation". In the Ribbon project (workshop for neonatal clinicians, Quebec; n = 242), 97% were satisfied with the training and reported feeling more comfortable caring for bereaved parents. Knowledge improved pre-post training. Audits revealed that 100% of cases were identified on the incubator and the baby's/babies' admission card, all changed rooms after the death of their co-twin/triplet, and all had the name of their co-twin/triplet on the discharge summary. All clinicians (55) knew what the ribbon symbol meant when asked during surprise audits at the bedside. Conclusion: Different educational strategies to optimize communication with families after the perinatal loss of a co-twin are appreciated and have a positive impact.


Combination of alpha-stat strategy and hemodilution exacerbates neurologic injury in a survival piglet model with deep hypothermic circulatory arrest.
The optimal pH strategy and hematocrit during cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA) remain controversial. We studied the interaction of pH strategy and hematocrit and their combined impact on cerebral oxygenation and neurological outcome in a survival piglet model including monitoring by near-infrared spectroscopy (NIRS). Thirty-six piglets (9.2+/-1.1 kg) underwent DHCA under varying conditions with continuous monitoring by NIRS (pH-stat or alpha-stat strategy, hematocrit 20% or 30%, DHCA time 60, 80, or 100 minutes). Neurological recovery was evaluated daily. The brain was fixed in situ on postoperative day 4 and a histological score (HS) for neurological injury was assessed. Oxygenated hemoglobin (HbO2) and total hemoglobin signals detected by NIRS were significantly lower with alpha-stat strategy during cooling (p < 0.001), suggesting insufficient cerebral blood supply and oxygenation. HbO2 declined to a plateau (nadir) during DHCA. Time to nadir was significantly shorter in lower hematocrit groups (p < 0.01). Significantly delayed neurologic recovery was seen with alpha-stat strategy compared with pH-stat (p < 0.05). The alpha-stat group had a worse histological score compared with those assigned to pH-stat (p < 0.001). Neurologic impairment was estimated to be over 10 times more likely for animals randomized to alpha-stat compared with pH-stat strategy (odds ratio = 10.7, 95% confidence interval = 3.8 to 25.2). Combination of alpha-stat strategy and lower hematocrit exacerbates neurological injury after DHCA. The mechanism of injury is inadequate cerebral oxygenation during cooling and a longer plateau period of minimal O2 extraction during DHCA.


Chylous ascites as the main manifestation of left ventricular dysfunction: a case report.
Ascites is one of the most common complications of liver diseases, even though in 15% of the cases it is related to extrahepatic diseases; 3% are of cardiac nature and they appear associated with signs and symptoms of heart failure. A 70 year old man was admitted with more than one year history of abdominal distension and a weight gain of 10 kilograms. He is asymptomatic and walks 2000-3000 meters a day without angor or dyspnea. The physical examination shows moderate abdominal distension, with no hepatosplenomegaly or edema, and there is mild jugular vein distension. The studies performed (complete laboratory work up, paracentesis, liver biopsy, echocardiogram, intrahepatic pressure measurements, etc.) showed a chylous ascites related to portal hypertension, and left ventricular dysfunction was the only probable cause found. Asymptomatic heart dysfunction can mimic liver disease and should be kept in mind as a cause of chylous ascites.


The role of point of care testing for patients with acute pharyngitis.
There is no consensus favoring a particular strategy for evaluating patients with pharyngitis. To compare a clinical decision aid and a rapid office-based point of care (POC) test with routine culture for group A beta-hemolytic streptococcus (GAS). Prospective observational study. Among 179 patients enrolled, 150 were eligible and 148 had POC testing and cultures initially performed. An encounter form included eligibility criteria, clinical information based upon the Centor rule, and treatment provided. Sensitivity and specificity of POC test compared to routine culture for GAS. Thirty-eight patients (25.7%) had a positive GAS culture. The POC test was 92.1% sensitive (95% confidence interval [CI] 80% to 98%) and 100% specific (95% CI 97% to 100%). Although the Centor rule did not adequately discriminate among symptomatic patients with or without GAS (receiver operating curve area 0.63), the 3 patients with a false-negative POC test had a Centor score of less than 2. Among patients with a negative POC test, 26% initially received antibiotics. For patients with a Centor score of > or =2, a POC test was highly sensitive for GAS. Future studies should confirm these results and assess whether implementation of POC testing as part of a local practice guideline can decrease variability in testing and treatment.


Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A.
Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously. To evaluate further longer-term data including patients' perceptions at study completion. Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up-titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg. Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre-emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered 'improved' for bleeding severity and time until bleeding stops, except 1 answering 'slightly improved'. Most patients answered 'improved' or 'slightly improved'' for daily life and feelings; in particular, all patients except 1 answered 'improved' or 'slightly improved' for anxiety. Long-term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients' daily lives and feelings, regardless of inhibitor status.


Plasma fibrinogen and troponin I in acute coronary syndrome and stable angina.
We aimed to determine whether there is a stratification among patients with different stages of coronary artery disease with respect to plasma fibrinogen levels, and to assess diagnostic value of plasma fibrinogen in comparison to troponin I in patients with acute coronary syndrome. Fifty-one consecutive patients presenting to our department with acute coronary syndrome within the last 24 h and 52 patients with stable angina with no episode of unstable disease within the last month were analysed. Forty-nine patients with acute coronary syndrome in which both troponin I and fibrinogen levels were present were further evaluated. Blood was collected on admission for routine laboratory tests. Statistical analysis was done using Student's t-test, Pearson correlation and chi-square test, P<0.05 being considered statistically significant. Plasma fibrinogen levels (g/l) were significantly higher in patients presenting with unstable than with stable angina (3.87+/-1.2 vs. 3.26+/-0.65 P=0.002). We have found significant correlation between fibrinogen and troponin I levels in unstable patients (r=0.43, P=0.0015). In patients with acute coronary syndrome an increased inflammation and cardiac injury seem to coexist and correlate. These results seem to confirm the role of this acute phase protein in the pathophysiology of acute coronary syndrome.


The synaptic significance of metoclopramide induced dyskinetic-dystonic head and neck movements in pregnancy.
Two young, pregnant women presenting dyskinetic-dystonic crises limited to head and neck (HNDD) due to metoclopramide (MP) were observed. Evidence has been brought for the specific extrapyramidal effect of dyskinetic-dystonic head and neck movements induced by MP in young females. The synaptic action of MP differs from that of the generally accepted dopamine receptor blocking neuroleptics such as the phenothiazines. Concomittant quasi opposing neuroleptic and nonneuroleptic like effects of this drug can not support the mechanism of dopamine receptor blockade as the explanation of the synaptic effect. The concept of "dopamine receptor imbalance" may explain the synaptic action of the metoclopramide.


PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases. We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib. Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation. Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach.


[Effect of Yufeining on induced sputum interleukin-8 in patients with chronic obstructive pulmonary disease at the stable phase].
To evaluate the effect of Yufeining, a traditional Chinese medicine, on induced sputum interleukin-8 (IL-8) in patients with chronic obstructive pulmonary disease (COPD) at the stable phase. Thirty-six patients with COPD were divided into trial group (18 cases) and control group (18 cases) randomly. The trial group was treated with Yufeining pills taken orally for half a year; the control group was not given any medicine. Routine lung function was recorded before and after treatment. Total cell count (TCC), differential cell counts (DCCs) and IL-8 in induced sputum were determined at the baseline and 6 months later. The indices of lung function improved significantly after 6 months' treatment in trial group (P < 0.05); TCC and absolute neutrophil count decreased significantly compared with baseline in the trial group (P < 0.05); Sputum IL-8 concentration dropped significantly after 6 months' treatment, from a mean of 5.216 +/- 2.914 microg/L to 4.222 +/- 2.140 microg/L (P < 0.05). There were insignificant changes in the parameters in the control group between baseline and 6 months later. Yufeining could improve lung function, decrease sputum TCC, absolute neutrophil count and IL-8 concentration, and relieve airway inflammation in patients with COPD in the stable phase.


Transarterial fiducial marker implantation for CyberKnife radiotherapy to treat pancreatic cancer: an experience with 14 cases.
The purpose of this study was to evaluate the safety and feasibility of transarterial fiducial marker implantation for CyberKnife radiotherapy to treat locally advanced pancreatic cancer. Fifteen pancreatic cancer patients were enrolled for transarterial marker implantation. Embolization platinum coils were implanted as a fiducial marker within 20 mm of the cancer edge, and preferably within 3 mm. The technical success of the implantation was defined as implantation of at least one fiducial marker within 20 mm of the target tumor. Irradiation was performed using the CyberKnife system. For 14 of 15 patients, transarterial implantation was successfully performed, and for 13 of 14 patients, the tracking marker was implanted within 3 mm of the cancer. Tracking instability was observed in two patients, but irradiation was accomplished in all 14 patients. No major complications caused by the implantation procedure were observed. The median overall survival after irradiation was 13.8 months, and the 1- and 2-years survival rates were 62.9% and 32.3%, respectively. Transarterial fiducial marker implantation for pancreatic cancer can be safely performed for tracking, and it will be a valuable alternative approach to percutaneous fiducial marker implantation.


The angiotensin AT1 receptor antagonist, losartan, induces barrel rotation in the rat.
Intracerebroventricular injections of [Arg8]vasopressin (500 ng/rat) or endothelin-1 (70 ng/rat) into the right lateral ventricle induced rotation along the long axis of the body (barrel rotation) in rats. Losartan (10-200 microg/rat), an angiotensin AT1 receptor antagonist, also evoked barrel rotation, which was not inhibited by vasopressin and endothelin receptor antagonists. However, barrel rotation was not observed after injections of high doses of another angiotensin II receptor antagonist, [Sar1,Ile8]angiotensin II (100 microg/rat), or after angiotensin II (10 microg/rat). The results indicate that losartan does evoke barrel rotation which may be not mediated via vasopressin and endothelin receptors.


[Degenerative valvular and left ventricle structural changes in echocardiography in patients with rheumatoid arthritis].
The disproportion between absence of clinical manifestations of circulatory system involvement and serious lesions in the heart found on post mortem examinations, more frequently diagnosed congestive circulatory failure and also higher mortality rate of patients with rheumatoid arthritis (RA), encouraged the authors to study the subject. Echocardiographic assessment of the effect of rheumatoid process on the heart in patients with RA without clinically overt features of heart disease. The study was conducted in 50 patients with RA diagnosed on the basis of the American College of Rheumatology (ACR) criteria and in 50 persons matched with the patients with respect to age, gender, body area and body mass index, heart rate and arterial pressure. Persons with manifestations and/or history of cardiovascular diseases were excluded from the study. The authors found that: in rheumatoid arthritis, the involvement of the heart by the pathological process is manifested as degenerative changes of valve leaflets, and these lesions correlate with interventricular septum thickness and the mass and mass index of the left ventricle.


Evolution of L-phenylalanine biosynthesis in rRNA homology group I of Pseudomonas.
Group I pseudomonads exhibit diversity for L-phenylalanine biosynthesis that is a basis for separation of two subgroups. Subgroup Ib (fluorescent species such as Pseudomonas aeruginosa, P. fluorescens, or P. putida) possesses an unregulated overflow pathway to L-phenylalanine, together with a second, regulated pathway. Subgroup Ia (non-fluorescent species such as P. stutzeri, P. mendocina, or P. alcaligenes) possess only the regulated pathway to L-phenylalanine. Thus, subgroup Ia species lack an unregulated isozyme of chorismate mutase and arogenate dehydratase, enzymes which are thought to divert chorismate to L-phenylalanine under conditions of high carbon input into aromatic biosynthesis. A priori the overflow pathway could have been either lost in subgroup Ia or gained in subgroup Ib. Since Group V pseudomonads (mainly Xanthomonas) are known to branch off from the Group I lineage at a deeper phylogenetic level than the point of divergence for subgroups Ia and Ib, the presence of the overflow pathway in Group V pseudomonads reveals that the overflow pathway must have been lost in the evolution of subgroup Ia. All Group I species possess a bifunctional protein (P-protein) which catalyzes both chorismate mutase and prephenate dehydratase reactions. In subgroup Ia species this highly conserved protein must be the sole source of prephenate to be used for tyrosine biosynthesis. Thus, the channeling action of the P-protein whereby chorismate is committed towards L-phenylalanine formation can be negated by selective feedback inhibition exerted by L-phenylalanine upon the prephenate dehydratase component of the P-protein. Diversion of prephenate molecules under the latter conditions towards L-tyrosine comprises a channel-shuttle mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)


A Black Phosphorus-Graphite Composite Anode for Li-/Na-/K-Ion Batteries.
Black phosphorus (BP) is a desirable anode material for alkali metal ion storage owing to its high electronic/ionic conductivity and theoretical capacity. In-depth understanding of the redox reactions between BP and the alkali metal ions is key to reveal the potential and limitations of BP, and thus to guide the design of BP-based composites for high-performance alkali metal ion batteries. Comparative studies of the electrochemical reactions of Li+ , Na+ , and K+ with BP were performed. Ex situ X-ray absorption near-edge spectroscopy combined with theoretical calculation reveal the lowest utilization of BP for K+ storage than for Na+ and Li+ , which is ascribed to the highest formation energy and the lowest ion diffusion coefficient of the final potassiation product K3 P, compared with Li3 P and Na3 P. As a result, restricting the formation of K3 P by limiting the discharge voltage achieves a gravimetric capacity of 1300 mAh g-1 which retains at 600 mAh g-1 after 50 cycles at 0.25 A g-1 .


The effect of donor age on the in vitro life span of cultured human arterial smooth-muscle cells.
The number of population doublings of cultured human arterial smooth-muscle cells decreased as a function of donor age (0.5 to 82 years). Cells from older donors also showed longer latent periods for outgrowth from explants. These results extend other comparable observations with human skin fibroblasts to another cell type, and may have relevance to the pathogenesis of atherosclerosis with aging in vivo.


Brief overview of the mounting evidence that atherosclerosis is both preventable and reversible.
The major life-threatening events in advanced atherosclerosis are precipitated by the plaque. Thrombosis in the muscular arteries and rupture of the large elastic arteries usually follows rupture of the plaque's fibrous cap. The smooth muscle cell (SMC) participates in many aspects of the atherosclerotic process: lipid uptake, synthesis of plaque components, and cell proliferation. The latter is a particularly significant aspect of the disease. High serum cholesterol levels stimulate proliferation of arterial medial cells; low-density lipoproteins (LDL) from hyperlipidemic plaques induce ingress and storage of cholesterol ester. These effects are inhibited by high-density lipoproteins (HDL). Endothelial injury may be an important part of the pathogenesis of some atherosclerotic plaques because powerful growth factors actively stimulate SMC proliferation, even when other risk factors are absent. Utilization of animal models of atherosclerosis, especially nonhuman primate models, has led to great progress in understanding this disease process. In controlled feeding experiments, severe atherosclerosis has been produced in rhesus monkeys by means of a high fat, high cholesterol diet. Animals then placed on a low fat, low cholesterol diet, or given cholestyramine, or a combination of these two approaches, showed a remarkable decrease in the size of their atherosclerotic plaques. Many epidemiologic studies, as well as more recent prospective intervention studies involving bile acid sequestrants, indicate by imaging techniques that plaque regression takes place in humans.


Comparison of the Wright ataxiameter and the Kistler force platform in the measurement of sway.
A comparison has been made between two methods of measuring body sway during quiet standing. In the first method a Wright ataxiameter was used to measure the trunk movement in the anteroposterior direction; whilst in the second method a Kistler force platform was used to monitor the locus of the resultant ground reaction force. The good correlation between the two sets of data has resulted in a regression equation to convert one set into the equivalent other set. This equation should be useful while comparing the sway data from various research centres.


Biological function of calcium-sensing receptor (CAS) and its coupling calcium signaling in plants.
The calcium-sensing receptor (CAS), as a chloroplast thylakoid membrane protein, is involved in the process of external Ca2+-induced cytosolic Ca2+ increase in plants. However, the underlying mechanism regulating this process is lacking. Furthermore, recent evidence suggests that CAS may perform additional roles in plants. Here, we provided an update covering the multiple roles of CAS in stomatal movement regulation and Ca2+ signaling in plants. We also analyzed the possible phosphorylation mechanism of CAS by light and discuss the role of CAS in abiotic stress (drought, salt stress) and biotic stresses (plant immune signaling). Finally, we proposed a perspective for future experiments that are required to fill gaps in our understanding of the biological function of CAS in plants.


Changes in posterior corneal elevation after laser in situ keratomileusis enhancement.
To evaluate changes in posterior corneal elevation using the Pentacam topographer (Oculus) in patients having laser in situ keratomileusis (LASIK) enhancement. Private practice, Chevy Chase, Maryland, USA. The Pentacam device was used to evaluate the changes in posterior corneal elevation above the best-fit sphere before LASIK enhancement and after LASIK enhancement in 24 eyes. The change in posterior corneal elevation in eyes for which pre-primary LASIK data were available was also evaluated. After LASIK enhancement, the mean change in posterior corneal elevation was 5 microm. The mean posterior corneal elevation was 12 +/- 7 microm before LASIK enhancement and 16 +/- 6 microm after enhancement; the difference was statistically significant (P = .004). In eyes for which pre-primary LASIK data were available, the mean change in posterior corneal elevation after primary LASIK was 2 microm. The mean posterior corneal elevation was 11 +/- 5 microm before LASIK enhancement and 11 +/- 7 microm after enhancement. There was a statistically significant difference in posterior corneal elevation between before LASIK enhancement and after LASIK enhancement. However, the change in posterior corneal elevation was much smaller than previously reported values and below the sensitivity of the Pentacam topographer.


Serial Observations of Muscle and Fat Mass as Prognostic Factors for Deceased Donor Liver Transplantation.
Muscle depletion in patients undergoing liver transplantation affects the recipients' prognosis and therefore cannot be overlooked. We aimed to evaluate whether changes in muscle and fat mass during the preoperative period are associated with prognosis after deceased donor liver transplantation (DDLT). This study included 72 patients who underwent DDLT and serial computed tomography (CT) scans. Skeletal muscle index (SMI) and fat mass index (FMI) were calculated using the muscle and fat area in CT performed 1 year prior to surgery (1 yr Pre-LT), just before surgery (Pre-LT), and after transplantation (Post-LT). Simple aspects of serial changes in muscle and fat mass were analyzed during three measurement time points. The rate of preoperative changes in body composition parameters were calculated (preoperative ΔSMI [%] = [SMI at Pre-LT - SMI at 1 yr Pre-LT] / SMI at Pre-LT × 100; preoperative ΔFMI [%] = [FMI at Pre-LT - FMI at 1 yr Pre-LT] / FMI at Pre-LT × 100) and assessed for correlation with patient survival. SMI significantly decreased during the preoperative period (mean preoperative ΔSMI, -13.04%, p < 0.001). In the multivariable analysis, preoperative ΔSMI (p = 0.016) and model for end-stage liver disease score (p = 0.011) were independent prognostic factors for overall survival. The mean survival time for patients with a threshold decrease in the preoperative ΔSMI (≤ -30%) was significantly shorter than for other patients (p = 0.007). Preoperative ΔFMI was not a prognostic factor but FMI increased during the postoperative period (p = 0.009) in all patients. A large reduction in preoperative SMI was significantly associated with reduced survival after DDLT. Therefore, changes in muscle mass during the preoperative period can be considered as a prognostic factor for survival after DDLT.


Transciptome analysis reveals flavonoid biosynthesis regulation and simple sequence repeats in yam (Dioscorea alata L.) tubers.
Yam (Dioscorea alata L.) is an important tuber crop and purple pigmented elite cultivar has recently become popular because of associated health benefits. Identifying candidate genes responsible for flavonoid biosynthesis pathway (FBP) will facilitate understanding the molecular mechanism of controlling pigment formation in yam tubers. Here, we used Illumina sequencing to characterize the transcriptome of tubers from elite purple-flesh cultivar (DP) and conventional white-flesh cultivar (DW) of yam. In this process, we also designed high quality molecular markers to assist molecular breeding for tuber trait improvement. A total of 125,123 unigenes were identified from the DP and DW cDNA libraries, of which about 49.5% (60,020 unigenes) were annotated by BLASTX analysis using the publicly available protein database. These unigenes were further annotated functionally and subject to biochemical pathway analysis. 511 genes were identified to be more than 2-fold (FDR < 0.05) differentially expressed between the two yam cultivars, of which 288 genes were up-regulated and 223 genes were down-regulated in the DP tubers. Transcriptome analysis detected 61 unigenes encoding multiple well-known enzymes in the FBP. Furthermore, the unigenes encoding chalcone isomerase (CHS), flavanone 3-hydroxylase (F3H), flavonoid 3'-monooxygenase (F3'H), dihydroflavonol 4-reductase (DFR), leucoanthocyanidin dioxygenase (LDOX), and flavonol 3-O-glucosyltransferase (UF3GT) were found to be significantly up-regulated in the DP, implying that these genes were potentially associated with tuber color formation in this elite cultivar. The expression of these genes was further confirmed by qRT-PCR. Finally, 11,793 SSRs were successfully identified with these unigenes and 6,082 SSR markers were developed using Primer 3. This study provides the first comprehensive transcriptomic dataset for yam tubers, which will significantly contribute to genomic research of this and other related species. Some key genes associated with purple-flesh trait were successfully identified, thus providing valuable information about molecular process of regulating pigment accumulation in elite yam tubers. In the future, this information might be directly used to genetically manipulate the conventional white-fleshed tuber cultivars to enable them to produce purple flesh. In addition, our SSR marker sets will facilitate identification of QTLs for various tuber traits in yam breeding programs.


Acute and chronic effects of MDMA on molecular mechanisms implicated in memory formation in rat hippocampus: surface expression of CaMKII and NMDA receptor subunits.
Acute 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") treatment induces learning deficits in different animal models. In a passive avoidance learning task in rats, previous studies suggested a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) and N-methyl-D-aspartate (NMDA) receptors in the acute learning impairment. As cognitive deficits by "ecstasy" in humans have been only reported in frequent recreational users, we examined whether a repeated MDMA treatment could induce in rats lasting molecular changes related to memory consolidation of passive avoidance. In rats with a pronounced 5-HT depletion by MDMA, the effect of another drug challenge was also examined. The surface expression in the hippocampus of NMDA receptor subunits, the scaffolding postsynaptic density protein PSD-95, phosphorylated CaMKII and protein phosphatase 1 (PP1) was measured. In rats repeatedly treated with MDMA (10 mg/kg) twice daily for 4 consecutive days, hippocampal 5-HT levels were markedly reduced 1 week later. At this time, neither learning performance was affected nor changes in membrane levels of NMDA receptor subunits, PSD-95, CaMKII and PP1 were found. In these rats, however, another drug challenge produced a rapid reduction in PSD-95 immunoreactivity and prevented the learning-specific increase in the NMDA receptor NR1 subunit and phosphorylated CaMKII. The results show no lasting change in learning-associated molecular events after a neurotoxic MDMA treatment. This drug only produces transient effects on early molecular events involved in memory consolidation, which do not appear to depend on endogenous 5-HT levels.


Target therapy in elderly breast cancer patients.
Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients.


Molecular detection of Nocardia: development and application of a real-time PCR assay in sputum and bronchoalveolar lavage fluid samples.
The diagnosis of pulmonary nocardiosis remains challenging. Rapid detection of Nocardia is of primary importance for early diagnosis and precise treatment of nocardiosis. In this study, our objective was to develop and validate a new TaqMan real-time PCR (qPCR) assay for rapidly detecting Nocardia spp. in respiratory samples. Based on published sequence data, primers in a conserved region of the 16S rRNA gene and a probe within that region that was specific for Nocardia were designed. The distinction effect of the qPCR assay was assessed between Nocardia and other respiratory-associated bacteria. Furthermore, the specificity and sensitivity of the assay were evaluated in respiratory clinical samples (n = 205), compared to the results of 16S rRNA gene amplicon sequencing and clinical diagnosis. The qPCR assay exhibited high specificity, sensitivity, repeatability, and reproducibility. The limit of detection of standard plasmid DNA was 3 × 102 copies/mL. Additionally, the qPCR assay was applied to the direct detection of 205 clinical respiratory samples. The specificity and sensitivity of the qPCR were all 100% compared to 16S rRNA gene amplicon sequencing, as well as 98.4% and 100% compared to clinical diagnosis respectively. The qPCR yielded results within 3 h of sample processing, compared to several days for culture, significantly reducing turnaround time. The results suggest that the new qPCR assay developed in this study provides reliable and rapid detection of Nocardia spp. in the respiratory tracts and is expected to reduce the time required for diagnosing and treating nocardiosis.


Exploring the sensitivity in jellyfish locomotion under variations in scale, frequency, and duty cycle.
Jellyfish have been called one of the most energy-efficient animals in the world due to the ease in which they move through their fluid environment, by product of their bell kinematics coupled with their morphological, muscular, material properties. We investigated jellyfish locomotion by conducting in silico comparative studies and explored swimming performance across different fluid scales (i.e., Reynolds Number), bell contraction frequencies, and contraction phase kinematics (duty cycle) for a jellyfish with a fineness ratio of 1 (ratio of bell height to bell diameter). To study these relationships, an open source implementation of the immersed boundary method was used (IB2d) to solve the fully coupled fluid-structure interaction problem of a flexible jellyfish bell in a viscous fluid. Thorough 2D parameter subspace explorations illustrated optimal parameter combinations in which give rise to enhanced swimming performance. All performance metrics indicated a higher sensitivity to bell actuation frequency than fluid scale or duty cycle, via Sobol sensitivity analysis, on a higher performance parameter subspace. Moreover, Pareto-like fronts were identified in the overall performance space involving the cost of transport and forward swimming speed. Patterns emerged within these performance spaces when highlighting different parameter regions, which complemented the global sensitivity results. Lastly, an open source computational model for jellyfish locomotion is offered to the science community that can be used as a starting place for future numerical experimentation.


SARS-CoV-2-associated organs failure and inflammation: a focus on the role of cellular and viral microRNAs.
SARS-CoV-2 has been responsible for the recent pandemic all over the world, which has caused many complications. One of the hallmarks of SARS-CoV-2 infection is an induced immune dysregulation, in some cases resulting in cytokine storm syndrome, acute respiratory distress syndrome and many organs such as lungs, brain, and heart that are affected during the SARS-CoV-2 infection. Several physiological parameters are altered as a result of infection and cytokine storm. Among them, microRNAs (miRNAs) might reflect this poor condition since they play a significant role in immune cellular performance including inflammatory responses. Both host and viral-encoded miRNAs are crucial for the successful infection of SARS-CoV-2. For instance, dysregulation of miRNAs that modulate multiple genes expressed in COVID-19 patients with comorbidities (e.g., type 2 diabetes, and cerebrovascular disorders) could affect the severity of the disease. Therefore, altered expression levels of circulating miRNAs might be helpful to diagnose this illness and forecast whether a COVID-19 patient could develop a severe state of the disease. Moreover, a number of miRNAs could inhibit the expression of proteins, such as ACE2, TMPRSS2, spike, and Nsp12, involved in the life cycle of SARS-CoV-2. Accordingly, miRNAs represent potential biomarkers and therapeutic targets for this devastating viral disease. In the current study, we investigated modifications in miRNA expression and their influence on COVID-19 disease recovery, which may be employed as a therapy strategy to minimize COVID-19-related disorders.


Exhaust and non-exhaust contributions from road transport to PM10 at a Southern European traffic site.
It is a well - established fact that road traffic is one of the main contributors to ambient levels of airborne particulate matter (APM). This study was carried out at a traffic site in which the PM10 levels are monitored all year round. A trend analysis of these levels revealed that over a decade there was no discernible trend, with the PM10 concentrations normally hovering around the EU limit values. In 2018, one of these limit values was exceeded. The contribution of traffic at the site was therefore investigated through a chemical speciation of 209 PM10 samples collected throughout this year. The speciation data were used in a source apportionment exercise in which the output of the PMF model was further refined using the lesser-known, constraint weighted non - negative matrix factorization (CW - NMF) model. This technique enabled the isolation of two factors clearly related to traffic, which were labelled as "exhaust contribution" (responsible for 3.4% of the PM10), "tire/brake wear contribution" (contributing 17% of the PM10). Additionally, a factor including both traffic resuspended dust and crustal material was also isolated and labelled "road dust/crustal" factor. The two contributors to the factor jointly contribute 18% to the PM10 and the contribution of the traffic resuspended dust was estimated at 7.3%. The traffic resuspended component of this factor together with the "tire/brake wear contribution" jointly make up the non-exhaust contribution of traffic - derived dust. Consonant with what has been known for quite some time, the exhaust fraction is the minor component of traffic PM10. It is therefore, clear that policies aimed at controlling traffic derived PM10 pollution at the receptor will have a minimal effect unless the non - exhaust emissions are adequately controlled.


Interferon inhibits preferentially the synthesis of proteins associated with growth stimulation of Swiss 3T3 mouse fibroblasts.
The putative role of inhibition of protein synthesis within the antiproliferative effect of interferon was analyzed in serum-stimulated Swiss 3T3 mouse fibroblasts. We observed an apparent coupling between protein-synthesis inhibition during G1 and a delayed entry into the S-phase. To reveal any specificity in the protein-synthesis inhibition, we measured the amounts of synthesis of 56 major individual proteins, by using isotope double-labelling and two-dimensional gel electrophoresis. Interferon inhibited preferentially the synthesis of proteins which were increased after serum stimulation, whereas proteins synthesized in constant or decreased amounts after serum stimulation were significantly more resistant. The effects of interferon were also compared to those of 5,6-dichloro-1-beta-ribofuranosylbenzimidazole (DRB), an inhibitor of transcription. All interferon-sensitive proteins studied were inhibited by DRB treatment, but in addition DRB also inhibited several proteins which were completely resistant to interferon. We conclude that interferon primarily inhibits protein synthesis originating from a subset of newly transcribed messenger RNAs. The mechanism(s) for inhibition of protein synthesis and the possible relationship to the antiproliferative and antiviral effects of interferon are discussed.


Enhanced activity of anticancer drugs in murine tumours by co-administration with 3-amino-pyrrolidine-2,5-dione-N-mustard derivative.
(R,S)3-(N,N-[bis-(2-chloroethyl)]-amino)-1-(2'-methoxyphenyl)- pyrrolidine-2,5-dione hydrochloride (I) has shown antitumor activity against P388 and L1210 leukaemias and Sarcoma 180 (ascites). The effect of (I), when co-administered with anticancer drugs, was studied in these murine tumours. Although co-administration of (I) with methotrexate showed a significant increase of the activity against P388 and L1210 leukaemias and Sarcoma 180 (ascites), co-administration of (I) with 5-fluorouracil, mitomycin C, adriamycin or vincristine did not exhibit any enhancing, synergistic or additive effect in the activity of these drugs.


Integration of a maxillary model into facial surface stereophotogrammetry.
Three-dimensional (3D) integration of a maxillary model into a facial model has only been possible by a complex procedure using face bow transfer after taking impressions of certain maxillary and facial parts. In this study, we aimed to develop a method for integrating a scanned maxillary model into a scan-realized facial model. A total of 19 patients with the medical indication for cone-beam computed tomography (CBCT) and orthodontic treatment were included in this study. Facial and maxillary scans were also taken. The construction of the integrated surface model required 10 steps. This integration procedure was evaluated by taking ten 3D dentofacial linear segment measurements in the integrated scan and the CBCT. These results were analyzed using descriptive statistics. All measurements demonstrated good intra-individual reliability. We observed almost perfect congruence between integrated scan and CBCT in vertical distances, while the sagittal measurements revealed more, yet clinically acceptable, deviations possibly caused by different error sources in either of the two methods. This new method is suitable for generating 3D integrated surface-scan models which can be used for growth and therapy control studies in orthodontics and other disciplines in the dentofacial fields. Since this method does not require ionizing radiation, it is highly recommendable as an application for children and adolescent patients.


Manganese enhanced MRI detects mossy fiber sprouting rather than neurodegeneration, gliosis or seizure-activity in the epileptic rat hippocampus.
We tested a hypothesis that manganese enhanced magnetic resonance imaging (MEMRI) after systemic injection of MnCl(2) could detect axonal sprouting in the hippocampus following kainate (KA) induced status epilepticus (SE). MEMRI was performed at 3 h, 25 h, 4 days, and 2 months post-SE. To assess the contribution of various cellular alterations that occur in parallel with sprouting to the MEMRI signal, we sacrificed animals for histology at 4 days and 2 months post-SE. Neurodegeneration was assessed from thionin and Fluoro-Jade B stained preparations, astrogliosis from GFAP (glial fibrillary acidic protein) and microgliosis from Ox-42 immunostained preparations. Sprouting of granule cells axons (mossy fibers) in the dentate gyrus was analyzed from Timm stained sections. Occurrence of spontaneous epileptic seizures was analyzed at 2 months post-SE using continuous video-EEG monitoring. Integrity of the blood-brain barrier (BBB) was studied using Gd-enhanced MRI. We found abnormal MEMRI hyperintensity in the CA1 and the dentate gyrus at 2 months post-SE but not at earlier time points. Based on histologic analysis of individual animals with MEMRI hyperintensity, hippocampal MEMRI changes could be attributed to increasing axonal density rather than to neurodegeneration, astrogliosis, or microgliosis. Moreover, MEMRI contrast was not affected by seizure activity, and we could not detect any leakage of the BBB that could have explained the observed MEMRI hyperintensity. Present data show that systemic MEMRI can reveal axonal sprouting, and thus, can potentially serve as a marker for neuroplasticity in preclinical studies.


NF-κB and STAT3 inhibition as a therapeutic strategy in psoriasis: in vitro and in vivo effects of BTH.
Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) is a simple and interesting synthetic derivative of petrosaspongiolide M, a natural compound isolated from a sea sponge with demonstrated potent anti-inflammatory activity through inhibition of the NF-κB signaling pathway. In the present study, we report the in vitro and in vivo pharmacological effect of BTH on some parameters related to the innate and adaptive response in the pathogenesis of psoriasis. BTH inhibited the release of some of the key psoriatic cytokines such as tumor necrosis factor α, IL-8, IL-6, and CCL27 through the downregulation of NF-κB in normal human keratinocytes. Moreover, it impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. These results were confirmed in vivo in two murine models of psoriasis: the epidermal hyperplasia induced by 12-O-tetradecanoylphorbol-13-acetate and the imiquimod-induced skin inflammation model. In both cases, topical administration of BTH prevented skin infiltration and hyperplasia through suppression of NF-κB and STAT3 phosphorylation. Our results confirm the pivotal role of both transcriptional factors in skin inflammation, as occurs in psoriasis, and highlight the potential of small molecules as therapeutic agents for the treatment of this skin disease, with BTH being a potential candidate for future drug research.


Genetic association of hypertension and several other metabolic disorders with Bell's palsy.
Background: Effects of hypertension, type 2 diabetes and obesity on Bell's palsy risk remains unclear. The aim of the study was to explore whether hypertension and these metabolic disorders promoted Bell's palsy at the genetic level. Methods: Genetic variants from genome-wide association studies for hypertension, type 2 diabetes, body mass index and several lipid metabolites were adopted as instrumental variables. Two-sample Mendelian randomization including IVW and MR-Egger was used to measure the genetic relationship between the exposures and Bell's palsy. Sensitivity analyses (i.e., Cochran's Q test, MR-Egger intercept test, "leave-one-SNP-out" analysis and funnel plot) were carried out to assess heterogeneity and horizontal pleiotropy. All statistical analyses were performed using R software. Results: Hypertension was significantly associated with the increased risk of Bell's palsy (IVW: OR = 2.291, 95%CI = 1.025-5.122, p = 0.043; MR-Egger: OR = 16.445, 95%CI = 1.377-196.414, p = 0.029). Increased level of LDL cholesterol might upexpectedly decrease the risk of the disease (IVW: OR = 0.805, 95%CI = 0.649-0.998, p = 0.048; MR-Egger: OR = 0.784, 95%CI = 0.573-1.074, p = 0.132). In addition, type 2 diabetes, body mass index and other lipid metabolites were not related to the risk of Bell's palsy. No heterogeneity and horizontal pleiotropy had been found. Conclusion: Hypertension might be a risk factor for Bell's palsy at the genetic level, and LDL cholesterol might reduce the risk of the disease. These findings (especially for LDL cholesterol) need to be validated by further studies.


[Treatment of erectile dysfunction by implantation of domestic made three-piece inflatable penile prosthesis, a retrospective study of 29 cases].
To evaluate the effect of implantation of domestic made three-piece inflatable penile prosthesis on erectile dysfunction (ED). Domestic made three-piece inflatable penile prosthesis were implanted through an incision at the border of penis and scrotum on 29 patients with ED refractory to non-operative treatment, among which 23 being with neurogenic ED, including 18 paraplegia cases and 5 cases of traumatic injury of nervi erigentes; 4 cases with ED caused by arteriovenous fistula; I case with ED caused by fibrosis of corpus cavernosum, and 1 case with ED caused by Klinefelter's syndrome. Follow-up was conducted for 3 - 36 months to survey the clinical effect. Operation was successfully performed upon all 29 patients. Follow-up after operation lasted 3 - 36 months, 18 months on average. Fluid exudation of penile prosthesis and localized infection occurred in 1 patient and mechanic complication occurred in 2 patients. Maintained sexual intercourse rate was 28/29. 3 ED patients with primary arteriovenous fistula made their spouses pregnant after treatment. With excellent covertness and at low cost, implantation of domestic made three-piece inflatable penile prosthesis is effective and well accepted by ED patients.


Thoracic splenosis mimicking thoracic schwannoma: case report and review of the literature.
Thoracic splenosis is a rare entity. It occurs sometime after splenic and diaphragmatic injury, and it is rarely symptomatic. We report a case of left upper thoracic paraspinal splenosis 25 years after a thoracoabdominal penetrating trauma that required a splenectomy. The pathology was suspected on a routine chest x-ray and it mimicked a schwannoma on magnetic resonance imaging. Less than 40 cases of thoracic splenosis were described in the literature, but few were misinterpreted as schwannoma. Alertness to the possibility of thoracic splenosis can lead to confirmation of the diagnosis with technetium Tc 99m-tagged red blood cell radionuclide scanning based on a previous history of traumatic splenectomy.


Insulin/IGF-1 hybrid receptors: implications for the dominant-negative phenotype in syndromes of insulin resistance.
Classical insulin and IGF-1 receptors are alpha 2 beta 2 heterotetrameric complexes synthesized from two identical alpha beta half-receptor precursors. Recent data strongly suggests, however, that nonidentical alpha beta half-receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and in vitro. This review focuses primarily on two types of hybrid receptors. The first type is an insulin/IGF-1 hybrid receptor generated by the association of an alpha beta insulin half-receptor with an alpha beta IGF-1 half-receptor. The second type is one formed from a wildtype (kinase-active) insulin or IGF-1 alpha beta half-receptor and a mutant (kinase-inactive) insulin alpha beta half-receptor. Although the functional properties of insulin/IGF-1 hybrid receptors have not yet been completely defined, wildtype/mutant hybrid receptors are essentially substrate kinase inactive. These data indicate that the mutant alpha beta half-receptor exerts a transdominant inhibition upon the wildtype alpha beta half-receptor within the alpha 2 beta 2 holoreceptor complex. This defect in substrate kinase activity may contribute to the molecular defect underlying some syndromes of severe insulin resistance and diabetes. Heterozygous individuals expressing both wildtype and mutant tyrosine kinase-defective insulin receptor precursors demonstrate varying degrees of insulin resistance and diabetes. In addition, cell lines which express both endogenous wildtype and transfected kinase-defective insulin receptors display markedly decreased insulin and IGF-1 sensitivity and responsiveness. Formation of hybrid receptors which results in premature termination of insulin signal transduction may be one mechanism underlying the observation that kinase-inactive receptors inhibit the function of native receptors.


Ultra-high sensitivity of the non-immunological affinity of graphene oxide-peptide-based surface plasmon resonance biosensors to detect human chorionic gonadotropin.
Specific peptide aptamers can be used in place of expensive antibody proteins, and they are gaining increasing importance as sensing probes due to their potential in the development of non-immunological assays with high sensitivity, affinity and specificity for human chorionic gonadotropin (hCG) protein. We combined graphene oxide (GO) sheets with a specific peptide aptamer to create a novel, simple and label-free tool to detect abnormalities at an early stage of pregnancy, a GO-peptide-based surface plasmon resonance (SPR) biosensor. This is the first binding interface experiment to successfully demonstrate binding specificity in kinetic analysis biomechanics in peptide aptamers and GO sheets. In addition to the improved affinity offered by the high compatibility with the target hCG protein, the major advantage of GO-peptide-based SPR sensors was their reduced nonspecific adsorption and enhanced sensitivity. The calculation of total electric field intensity (ΔE) in the GO-based sensing interfaces was significantly enhanced by up to 1.2 times that of a conventional SPR chip. The GO-peptide-based chip (1mM) had a high affinity (KA) of 6.37×1012M-1, limit of detection of 0.065nM and ultra-high sensitivity of 16 times that of a conventional SPR chip. The sensitivity of the slope ratio of the low concentration hCG protein assay in linear regression analysis was GO-peptide (1mM): GO-peptide (0.1mM): conventional chip (8-mercaptooctanoic acid)-peptide (0.1mM)=8.6: 3.3: 1. In summary, the excellent binding affinity, low detection limit, high sensitivity, good stability and specificity suggest the potential of this GO-peptide-based SPR chip detection method in clinical application. The development of real-time whole blood analytic and diagnostic tools to detect abnormalities at an early stage of pregnancy is a promising technique for future clinical application.


Efficacy of an Educational Intervention for Improving the Hydration Status of Female Collegiate Indoor-Sport Athletes.
Research focusing on improving hydration status and knowledge in female indoor-sport athletes is limited. Investigators have demonstrated that hydration education is an optimal tool for improving the hydration status of athletes. To assess the hydration status and fluid intake of collegiate female indoor-sport athletes before and after a 1-time educational intervention. Controlled laboratory study. Collegiate women's volleyball and basketball practices. A total of 25 female collegiate volleyball and basketball athletes (age = 21 ± 1 years, height = 173.5 ± 8.7 cm, weight = 72.1 ± 10.0 kg) were assessed during 6 days of practices. Participants' hydration status and habits were monitored for 3 practice days before they underwent a hydration educational intervention. Postintervention, participants were observed for 3 more practice days. Change in body mass, fluid consumed, urine specific gravity (Usg), urine color (Ucol), and sweat rate were recorded for 6 practice days. Participants completed a hydration-knowledge questionnaire before and after the intervention. Three-day mean Usg and Ucol were considered euhydrated prepractice (Usg = 1.015 ± 0.006, Ucol = 4 ± 1) and remained euhydrated postpractice (Usg = 1.019 ± 0.005, Ucol = 5 ± 2) during the preintervention period. Decreased prepractice Ucol (P < .01) and increased hydration knowledge (P < .01) were present postintervention. Basketball athletes had greater body mass losses from prepractice to postpractice than did volleyball athletes (P < .001). Overall increases were evident when we compared prepractice and postpractice measures of Usg and Ucol in the preintervention (P < .001 and P = .001, respectively) and postintervention (P = .001 and P < .001) period, respectively. No correlation was found between hydration knowledge and physiological indices of hydration and fluid intake. Overall, female collegiate indoor-sport athletes were hydrated and knowledgeable on hydration. However, our variable findings indicated that further research on these athletes is needed; clinically, attention should be given to the individual needs of each athlete. More examination will demonstrate whether a 1-time educational intervention may be an effective tool for improving hydration status in this population.


Increases in groundwater arsenic concentrations and risk under decadal groundwater withdrawal in the lower reaches of the Yellow River basin, Henan Province, China.
The spatiotemporal variability in groundwater arsenic concentrations following extensive groundwater extractions over decades was rarely studied on a large scale. To fill this gap, variations in groundwater arsenic concentrations in the North Henan Plain in China from 2010 to 2020 were investigated. The possibility of high-arsenic groundwater (>10 μg/L) was higher than 40% in aquifers within a distance of 100 m from paleochannels. This may be due to the fact that deposits in paleochannels were rich in organic matter and suitable for arsenic enrichment. Following groundwater withdrawal over ten years from 2010 to 2020, nearly half of groundwater samples (44%) were elevated in groundwater arsenic concentrations, and the proportion of high arsenic groundwater increased from 24% in 2010 to 26% in 2020. These may be related to enhanced Fe(III) oxide reduction under decadal groundwater withdrawal. However, around 56% groundwater samples were decreases in arsenic concentrations because of increased NO3- levels in these samples in 2020. Furthermore, extensive groundwater withdrawal decreased groundwater tables averagely by 4.6 m from 2010 to 2020, which induced the intrusion of high-arsenic groundwater from shallow aquifers into deeper ones. More importantly, the long-term groundwater pumping has perturbed groundwater flow dynamics and redistributed high-arsenic groundwater in the plain, leading to 18% more areas and 33.8% more residents being potentially at risk. This study suggests that the threat of groundwater overexploitation may be much more severe than previously expected.


Prolixicin: a novel antimicrobial peptide isolated from Rhodnius prolixus with differential activity against bacteria and Trypanosoma cruzi.
We identified and characterized the activity of prolixicin, a novel antimicrobial peptide (AMP) isolated from the hemipteran insect, Rhodnius prolixus. Sequence analysis reveals one region of prolixicin that may be related to the diptericin/attacin family of AMPs. Prolixicin is an 11-kDa peptide containing a putative 21 amino acid signal peptide, two putative phosphorylation sites and no glycosylation sites. It is produced by both adult fat body and midgut tissues in response to bacterial infection of the haemolymph or the midgut. Unlike most insect antibacterial peptides, the prolixicin gene does not seem to be regulated by NF-κB binding sites, but its promoter region contains several GATA sites. Recombinant prolixicin has strong activity against the Gram-negative bacterium Escherichia coli and differential activity against several Gram-negative and Gram-positive bacteria. No significant toxicity was demonstrated against Trypanosoma cruzi, the human parasite transmitted by R. prolixus.


In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis.
Studies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death.


[In vitro effects of hexavalent and tetravalent tellurium on immune functions].
The "in vitro" immune effects of K2TeO3xH2O (Te IV) and K2TeO4x2H2O (Te VI) on peripheral blood mononuclear cells (PBMC) was determined. Te(IV) inhibited PBMC proliferation and IFN-gamma, IL-5 and TNF-alpha release from PBMC more than Te (VI).


Localization and subcellular distribution of N-copine in mouse brain.
N-Copine is a novel protein with two C2 domains. Its expression is brain specific and up-regulated by neuronal activity such as kainate stimulation and tetanus stimulation evoking hippocampal CA1 long-term potentiation. We examined the localization and subcellular distribution of N-copine in mouse brain. In situ hybridization analysis showed that N-copine mRNA was expressed exclusively in neurons of the hippocampus and in the main and accessory olfactory bulb, where various forms of synaptic plasticity and memory formation are known to occur. In immunohistochemical analyses, N-copine was detected mainly in the cell bodies and dendrites in the neurons, whereas presynaptic proteins such as synaptotagmin I and rab3A were detected in the regions where axons pass through. In fractionation experiments of brain homogenate, N-copine was associated with the membrane fraction in the presence of Ca2+ but not in its absence. As a GST-fusion protein with the second C2 domain of N-copine showed Ca2+-dependent binding to phosphatidylserine, this domain was considered to be responsible for the Ca2+-dependent association of N-copine with the membrane. Thus, N-copine may have a role as a Ca2+ sensor in postsynaptic events, in contrast to the known roles of "double C2 domain-containing proteins," including synaptotagmin I, in presynaptic events.