ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation.
Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply degraders of the matrix, but also play fundamental roles in modulating cellular behaviour through the proteolytic processing of specific substrates. Indeed, proteases can elicit both pro- and anti- tumorigenic effects depending on context. Using a heterocellular spheroid model of breast cancer progression, we demonstrate the repressive function of myoepithelial ADAMTS3, with its loss directing myoepithelial-led invasion of luminal cells through a physiologically relevant matrix. Degradomic analysis, using terminal amine isotopic labelling of substrates (TAILS), combined with functional assays, implicate ADAMTS3 as a mediator of fibronectin degradation. We show further that loss of ADAMTS3 enhances levels of fibronectin in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Our data highlight a tumour suppressive role for ADAMTS3 in early stage breast cancer, and contribute to the growing evidence that proteases can restrain cancer progression.


Transcranial cerebral oximetry related to transcranial Doppler after aneurysmal subarachnoid haemorrhage.
Noninvasive methods for detecting cerebral artery vasospasm, still a serious complication following aneurysmal subarachnoid haemorrhage, are of vital interest. Up-to-date transcranial Doppler ultrasound (TCD) has proved to be sensitive in detecting vasospasm in the middle cerebral artery, but has less accuracy for other cerebral arteries. Transcranial cerebral oximetry (TCCO) is a new non-invasive technique which may increase the reliability for detecting cerebral ischaemia. The purpose of the present study was to evaluate a putative correlation between TCCO and TCD. We examined the two hemispheres in 14 patients with the aim of evaluating a proposed correlation between TCD and TCCO. Analysis of all absolute values (maximum TCD mFV and minimum TCCO saturation, respectively) in all series indicate a correlation between TCCO and TCD, p < 0.01, r = -0.62. All patients with TCD mean flow velocity > 120 cm/s also presented TCCO saturation < 60%. Conversely, all patients with normal TCCO saturation (> or = 63%) presented normal or moderately increased TCD velocities. In clinical neurosurgical practice it is of great interest if a true correlation between TCD and TCCO exists. The present results support the assumption that TCCO may enhance the reliability for detecting cerebral ischaemia after aneurysmal subarachnoid haemorrhage.


Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.
Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.


Artifacts and essentialism.
Psychological essentialism is an intuitive folk belief positing that certain categories have a non-obvious inner "essence" that gives rise to observable features. Although this belief most commonly characterizes natural kind categories, I argue that psychological essentialism can also be extended in important ways to artifact concepts. Specifically, concepts of individual artifacts include the non-obvious feature of object history, which is evident when making judgments regarding authenticity and ownership. Classic examples include famous works of art (e.g., the Mona Lisa is authentic because of its provenance), but ordinary artifacts likewise receive value from their history (e.g., a worn and tattered blanket may have special value if it was one's childhood possession). Moreover, in some cases, object history may be thought to have causal effects on individual artifacts, much as an animal essence has causal effects. I review empirical support for these claims and consider the implications for both artifact concepts and essentialism. This perspective suggests that artifact concepts cannot be contained in a theoretical framework that focuses exclusively on similarity or even function. Furthermore, although there are significant differences between essentialism of natural kinds and essentialism of artifact individuals, the commonalities suggest that psychological essentialism may not derive from folk biology but instead may reflect more domain-general perspectives on the world.


Variable selection for model-based high-dimensional clustering and its application to microarray data.
Variable selection in high-dimensional clustering analysis is an important yet challenging problem. In this article, we propose two methods that simultaneously separate data points into similar clusters and select informative variables that contribute to the clustering. Our methods are in the framework of penalized model-based clustering. Unlike the classical L(1)-norm penalization, the penalty terms that we propose make use of the fact that parameters belonging to one variable should be treated as a natural "group." Numerical results indicate that the two new methods tend to remove noninformative variables more effectively and provide better clustering results than the L(1)-norm approach.


Dexmedetomidine alleviates vacuolization and necrosis in tubular epithelial cells induced by aortic cross-clamping.
Acute kidney injury (AKI) is one of the main causes of mortality in patients undergoing emergency surgery due to an abdominal aortic aneurysm. This study aimed to determine the potential nephroprotective characteristics of dexmedetomidine (DMD) for the establishment of a standard therapeutic method for AKI. Thirty Spraque Dawley rats were allocated to 4 groups: control, sham, ischemia-reperfusion, and ischemia/reperfusion (I/R)+dexmedatomidine. Necrotic tubules, degenerative Bowman's capsule and vascular congestion were observed in the I/R group. In addition, there was an increase in tissue malondialdehyde (MDA), interleukin (IL)-1 and IL-6 levels in tubular epithelial cells. In contrast, we observed decreased tubular necrosis, IL-1, IL-6 and MDA levels in the DMD treatment group. DMD has a nephroprotective effect against acute kidney injury resulting from I/R, which is related to aortic occlusion used in the treatment of ruptured abdominal aortic aneurysms.


Reciprocal effects of prolactin and thyroxine on the growth rate of rat pups from weaning to puberty.
Prolactin and thyroxine were added to the daily diet of rat pups from weaning to puberty (days 20--40). While prolactin significantly retarted the pups' growth, thyroxine stimulated growth and even compensated for the depression caused by prolactin. The significant retardation in the growth of the prolactin-treated pups around days 30--35 of age indicates that at that period they are extremely prolactin-dependent, thus confirming previous reports that exogenous prolactin inhibits its own endogenous secretion. On the other hand, the possible growth promotion caused by thyroxine is mild and does not initiate a feedback mechanism. This suggests that prolactin is indispensable for the normal development of the weaned, immature rat.


Disease severity impairs sleep quality in allergic rhinitis (The SOMNIAAR study).
Sleep is impaired in allergic rhinitis (AR) patients, with subsequent effects on daytime performance and health-related quality of life (QOL). Sleep quality in AR has rarely been considered through validated tools and consensus classifications. To evaluate sleep quality and daytime somnolence in AR patients, and to estimate its relationship to disease severity according to Allergic Rhinitis and Its Impact on Asthma (ARIA) conventional and modified classifications, as well as in terms of QOL and comorbidities. Allergic rhinitis adult patients were evaluated through a prospective, observational, multicentre survey in Spain. Symptoms were assessed using the Total Symptoms Score (TSS), specific QOL by the Rhinitis Quality of Life Questionnaire (RQLQ), sleep quality by Pittsburgh scale, and diurnal somnolence by a scale based on Epworth's, all recorded in a unique visit. A total of 2275 patients were included. According to ARIA criteria, 50.2% had persistent and 49.8% intermittent rhinitis, whereas 87.6% were classified as moderate-severe and 12.4% as mild; 52.8% had poor sleep quality, with a global median score for Pittsburgh scale of 6 (normal < 5) and 21.1% suffered from excessive diurnal somnolence. Correlation between Pittsburgh scale and RQLQ was moderate (r = 0.54). Among symptoms, nasal obstruction and concomitant asthma mainly, contributed to bad sleep quality. In a logistic regression model, moderate-severe rhinitis and nasal obstruction were all associated with a worse sleep quality. Sleep quality is altered in AR patients. Sleep quality was worse in moderate-severe, and particularly in severe AR. Nasal obstruction and RQLQ deterioration are associated with a poorer sleep quality. Sleep impairment is common in allergic rhinitis, particularly in more severe forms. Nasal obstruction and concomitant asthma should be considered as contributing factors. This is a large epidemiological survey of patients with allergic rhinitis showing a strong relationship between disease severity, as assessed by a consensus classification, and sleep impairment, as measured by a validated sleep quality tool.


The pathogenesis and therapy of multiple sclerosis is based upon the requirement of a combination of myelin antigens for autoimmune demyelination.
It is postulated that the pathogenesis of demyelination in multiple sclerosis (MS) might lie in the cooperative effect of a T cell response against one myelin antigen (e.g. myelin basic protein--MBP) and a B cell response against a second myelin component which may act as a hapten or a carrier for the primary antigen. The hypothesis is based upon recent experiments in guinea pigs in which the encephalitogenicity of MBP was enhanced by the myelin glycolipid, galactocerebroside. This pathogenetic mechanism might be analogous to antibody-dependent, cell-mediated demyelination. Based upon this assumption, therapeutic trials in MS should take into consideration the possibility that instead of MBP alone, MBP might be more effective in combination with a lipid hapten.


A simple method for locating methylated bases in DNA, as applied to detect asymmetric methylation by M.FokIA.
Class-IIS restriction enzymes, which cut the DNA outside their recognition sequence, could be used for locating the bases methylated by a DNA-modification methylase. This is possible because methylation of the class-IIS cut sites does not interfere with the cleavage. The method consists of (i) selection of a nucleotide sequence with appropriate overlap between the methylase recognition site and the class-IIS enzyme cut site, (ii) methylation using S-adenosylmethionine as [3H]methyl donor, (iii) cleavage of the methylated sequence with the class-IIS enzyme, (iv) separation of the cleavage products and identification of the 3H-labelled fragment. Using this simple and straightforward method, we have shown that M.FokIA is an adenine methylase and methylates asymmetrically one strand of the FokI recognition site, resulting in the (Formula: see text) sequence. In addition, it was observed that another class-IIS restriction enzyme, SfaNI, is completely inhibited by methylation of its recognition site, (Formula: see text), by M.FokIA.


Nucleometric study of anisonucleosis, diabetes and oxidative damage in liver biopsies of orthotopic liver transplant recipients with chronic hepatitis C virus infection.
Anisonucleosis is defined as a morphological manifestation of nuclear injury characterized by variation in the size of the cell nuclei. It has been described in variety of benign conditions and is most pronounced in dysplasia and malignancy. To better understand the pathogenesis of anisonucleosis in liver diseases, this study focused on hepatocyte anisonucleosis in biopsies of liver transplant recipients who developed recurrent chronic hepatitis C virus (HCV) infection. Post transplant surveillance liver biopsy specimens were evaluated employing light microscopy, immunohistochemistry, digital image analysis, and nucleometry for histopathological analyses, measurement of nuclear size, and quantification of tissue expression of oxidative marker 8-hydroxy-2'deoxyguanosine (8-OHdG). Our aim in this study was to determine whether there were any independent associations between hepatocyte anisonucleosis and various clinicopathological parameters. These features included patient age, body mass index, gender, race, donor age, live versus cadaveric donor status, history of diabetes mellitus, history of tacrolimus and cyclosporine therapy, duration post transplant and parameters of hepatitis activity index, fibrosis index, steatosis, and oxidative tissue damage in formalin fixed paraffin embedded (FFPE) liver biopsies as determined by immunohistochemistry using 8-OHdG, an indicator of hydroxyl radical mediated tissue damage. Our findings suggested that in liver transplant recipients with recurrent chronic HCV infection, hepatocyte anisonucleosis is more pronounced in individuals with diabetes mellitus (p = 0.0016), and among those who have heightened hepatic expression of the oxidative damage marker 8-OHdG (p = 0.0053). Further studies are necessary to determine whether anisonucleosis is an independent marker for diabetes or oxidative damage.


Regional Hospital Collaboration and Outcomes in Medicare Heart Failure Patients: See You in 7.
The objective of this study was to evaluate an interhospital collaborative approach to improve 7-day post-discharge follow-up (7dFU) rates and reduce 30-day readmissions in heart failure (HF) patients. Early post-discharge follow-up after HF hospitalization is associated with lower 30-day readmission rates. Observational analyses of Medicare HF patients discharged from 10 collaborating hospitals (CH) participating in the Southeast Michigan See You in 7 Collaborative were carried out. We compared pre-intervention (May 1, 2011 to April 30, 2012) and intervention (May 1, 2012 to April 30, 2013) 7dFU rates, unadjusted 30-day readmissions, risk-standardized 30-day readmissions (RSRR), and Medicare payments in CH and Michigan nonparticipating hospitals (NPH). 7dFU rates increased but remained low in both groups (CH: 31.1% to 34.4%; p < 0.001; NPH: 30.2% to 32.6%; p <0.001). During the intervention period, unadjusted readmissions decreased significantly in both groups (CH: 29.0% to 27.3%; p <0.001; NPH: 26.4% to 25.8%, p = 0.004); mean RSRR decreased more in CH than in NPH (CH: 31.1% to 28.5%; p < 0.001; NPH: 26.7% to 26.1%, p = 0.02; p = 0.015 for intergroup comparisons). Findings were similar when CH outcomes were matched 1:1 with similar NPH outcomes. Combined Medicare payments for inpatient and 30 days of post-discharge care decreased by $182 in CH and by $63 in NPH (per eligible HF discharge). See You in 7 Collaborative participation was associated with significantly lower 30-day readmissions and Medicare payments in HF patients. Increases in 7dFU were modest, but associated processes aimed at this goal may have improved the transition from inpatient to outpatient care. Regional hospital collaboration to share best practices could potentially reduce HF readmissions and associated costs.


A rare case of papillary fibroelastoma involving the tricuspid valve. A single center experience over a period of 22 years (1999-2021).
Papillary fibroelastoma (PFE) represents only 16% of the benign cardiac tumor and approximately 15% of these are located on the tricuspid valve. Over a period of 22 years (1999-2021) we observed 75 pts with cardiac tumors at our Center over 9650 pts operated on but only one case of a tricuspid valve PFE in a 69-year-old patient. Trans-thoracic echocardiography demonstrated a mobile mass (20 × 10 mm), adhering to the atrial side of the septal leaflet of the tricuspid valve of unknown origin. In consideration of the mobility of the mass and the consequent high embolic risk, surgical removal was made. The patient underwent surgery through a median sternotomy on CPBP. A 'gelatinous' mass adhering to the tricuspid leaflet was found and completely removed. The postoperative course was uneventful. The pathological diagnosis was PFE. PFEs of the tricuspid valve are rare entities being in most cases found incidentally. In our experience, the incidence of this tumor in this location is 1/10,000 cases of cardiac surgery. Although most patients are asymptomatic, surgical treatment is nevertheless recommended in consideration of the high embolic risk.


Protocol to differentiate glycosylphosphatidylinositol-anchored prion protein from pro-prion protein in cancer cells.
Defects of glycosylphosphatidylinositol (GPI)-anchor synthesis lead to the production of pro-proteins with altered functions. However, pro-protein-specific antibodies for functional analysis are lacking. Here, we present a protocol to differentiate GPI-anchored prion protein (PrP) from pro-PrP in cancer cells using a complementary approach applicable to other GPI-anchored proteins. We first describe steps for phosphatidylinositol-specific phospholipase C treatment and flow-cytometry-based detection. We then detail the carboxypeptidase Y (CPDY) assay including antibody immobilization, affinity purification, CPDY treatment, and western-blot-based detection. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).1.


Solid-pseudopapillary tumours of the pancreas: 14 years experience.
Solid-pseudopapillary tumour of the pancreas (SPTP) is a low-grade malignancy lesion that is distinct from other pancreatic tumours. Preoperative diagnosis is often inaccurate and treatment strategies remain controversial. The present study reviews the clinical features, diagnosis, treatment, and outcome of Asian patients with SPTP from a single institution. The medical records and images of patients who underwent surgery for SPTP between June 1990 and December 2003 were retrospectively reviewed. Study eligibility required that patients had undergone surgical resections and that the SPTP had been pathologically demonstrated. Twenty-eight patients with SPTP were identified. Eighteen patients (64.3%) reported the predominant symptom of 'vague abdominal pain', five patients (17.8%) had an apparent 'abdominal mass', and five patients (17.8%) without overt symptoms had masses that were discovered incidentally during screening. All patients underwent magnetic resonance (MR) imaging (n = 22) and/or computed tomography (n = 17), with a specificity of 90.9% and 76.4%, respectively. All masses were well-circumscribed, except for a tumour in one patient (3.6%), which adhered to the stomach wall and metastasized to the liver. Two patients (7.1%) underwent enucleation, while 25 patients (89.3%) received curative resection. The patient with the liver metastases underwent distal pancreatectomy and splenectomy with partial hepatectomy. The mean follow up was 66.9 months. No mortality occurred during follow up but the patient with the liver metastasis had progressive deterioration. Symptoms of SPTP are indistinct and preoperative diagnosis is often inaccurate. Magnetic resonance imaging improves SPTP diagnosis. In general, the prognosis of well-circumscribed SPTP is favourable after curative resection.


Amplified fluorescence detection of DNA based on catalyzed dynamic assembly and host-guest interaction between β-cyclodextrin polymer and pyrene.
The detection of nucleic acids is fundamental for studying their functions and for the development of biological studies and medical diagnostics. Herein, we report a new strategy for nucleic acid amplified detection by combining target-catalyzed dynamic assembly with host-guest interaction between β-cyclodextrin polymer (β-CDP) and pyrene. In this strategy, a metastable pyrene-labeled hairpin DNA probe (probe H1) and a metastable unlabeled hairpin DNA probe (probe H2) were elaborately designed as the assembly components, which were kinetically handicapped from cross-opening in the absence of target DNA. In this state, pyrene labled at the 5'-termini of single-stranded stem of probe H1 would be easily trapped into the hydrophobic cavity of β-CDP because of weak steric hindrance, leading to significant fluorescence enhancement. Once the dynamic assembly was catalyzed by target DNA, a hybridized DNA duplex H1-H2 would be created continuously. In this state, it is difficult for pyrene to enter the cavity of β-CDP due to steric hindrance and weak-binding interaction, leading to a weak fluorescent signal. Thus, target DNA could be detected by this simple mix-and-detect amplification method without the need of expensive and perishable protein enzymes. As low as 10 pM of the target DNA was detected by this assay, which was comparable to that of some reported enzyme-dependent amplification methods. Meanwhile, the proposed method was further successfully applied to detect DNA in cell lysate samples, showing great potential for target detection from complex fluids. In addition, as a novel transformation of dynamic DNA assembly technology into enzyme-free signal-amplification analytical application, the proposed strategy has shown great potential for applications in a wide range of fields, such as aptamer-based non-nucleic acid target sensing, biomedicine and bioimaging.


Effects of phase stability and processing on the mechanical properties of Ti-Nb based β Ti alloys.
The influence of β phase stability on mechanical properties, deformation behaviours and phase composition were investigated for a series of Ti-24Nb-3Zr-2Sn-xMo alloys in response to hot and cold rolling. For the hot rolled alloys, the phase composition and deformation behaviours were largely consistent with those predicted on the basis of a Bo-Md plot and the Ms estimates. The deformation mechanisms involve growth and/or reorientation of plate-like martensite and/or twins. However, these are largely restricted in the cold rolled alloys due to the effects of grain refinement and residual stress. The cold rolled alloys exhibit the highest strengthening in combination with more limited ductility, which increased with increasing β phase stability. The moderately stable alloy, B, with e/a around 4.18 and Moeq∼10wt% gave the greatest strengthening in response to cold rolling, which was related to intense localised grain refinement.


Stem cell transplantation for motor neuron disease: current approaches and future perspectives.
Motor neuron degeneration leading to muscle atrophy and death is a pathological hallmark of disorders, such as amyotrophic lateral sclerosis or spinal muscular atrophy. No effective treatment is available for these devastating diseases. At present, cell-based therapies targeting motor neuron replacement, support, or as a vehicle for the delivery of neuroprotective molecules are being investigated. Although many challenges and questions remain, the beneficial effects observed following transplantation therapy in animal models of motor neuron disease has sparked hope and a number of clinical trials. Here, we provide a comprehensive review of cell-based therapeutics for motor neuron disorders, with a particular emphasis on amyotrophic lateral sclerosis.


Global and local dispersion of ventricular repolarization: endocardial monophasic action potential mapping in swine and humans by using an electro-anatomical mapping system.
This article evaluates whether the global dispersion of ventricular repolarization (DVR) can be estimated from measurements between a few adjacent or remote sites. Monophasic action potentials (MAP) were recorded from 61 +/- 18 left (LV) or right ventricular (RV) sites in 10 pigs and 44 +/- 16 LV, or RV sites in 8 patients by using the CARTO mapping system. MAP duration (MAPd) and end-of-repolarization time were calculated at each site and 13 repolarization maps from pigs and 10 from patients were reconstructed. Global dispersions in MAPd and EOR over the LV or RV were compared with the adjacent DVR among 3 - 7 MAPs in areas > or = 0.7 and < or = 1 cm(2) and with the remote DVRs between 2 MAPs with the greatest activation time difference (remote DVR1) and between the apical and laterobasal LV or RV (remote DVR2). The adjacent dispersions in end-of-repolarization and MAPd were significantly smaller than the global ones, 13 +/- 3 and 12 +/- 3 ms vs. 44 +/- 9 and 42 +/- 12 ms in pigs and 13 +/- 7 and 14 +/- 8 ms vs. 72 +/- 24 and 66 +/- 22 ms in patients. The remote DVR1 (30 +/- 8 and 17 +/- 10 ms in pigs and 40 +/- 28 and 28 +/- 17 ms in patients) and remote DVR2 (16 +/- 7 and 11 +/- 10 ms in pigs and 35 +/- 24 and 21 +/- 21 ms in patients) were also significantly smaller than the global DVRs. In conclusion, global DVR is poorly estimated from MAP recordings from a few adjacent or remote sites, suggesting the importance of obtaining global information in evaluating DVR.


Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.
Cytochrome P450 4F2 (CYP4F2) enzyme is a member of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules such as arachidonic acid, tocopherols, and vitamin K. Several reports have demonstrated that the missense variant CYP4F2*3 (V433M) causes decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M in CYP4F2 at the atomic level has not yet been completely elucidated. In the current study, we evaluated the effect of the V433M substitution on CYP4F2 using 14 different bioinformatics tools. Further molecular dynamics (MD) simulations were performed to assess the impact of the V433M mutation on the CYP4F2 protein structure, stability, and dynamics. In addition, molecular docking was used to illustrate the effect of V433M on its interaction with vitamin K1. Based on our results, the CYP4F2*3 variant was a damaging amino acid substitution with a destabilizing nature. The simulation results showed that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means that it tends to change the overall structural conformation and flexibility of CYP4F2. The docking results showed that the CYP4F2*3 variant decreased the binding affinity between vitamin K1 and CYP4F2, which reduced the activity of CYP4F2*3 compared to native CYP4F2. This study determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and provided new information for understanding the structure-function relationship of CYP4F2 and other CYP4 enzymes. These findings will aid in the development of effective drugs and treatment options.


Temperature sensor based on an isopropanol-sealed photonic crystal fiber in-line interferometer with enhanced refractive index sensitivity.
We fabricate a simple, compact, and stable temperature sensor based on a liquid-sealed photonic crystal fiber (PCF) in-line nonpolarimetric modal interferometer. Different from other reported PCF devices, it does not need expensive polarimetric devices, and the liquid is sealed in one fiber. The device consists of a stub of isopropanol-filled PCF spliced between standard single-mode fibers. The temperature sensitivity (-166 pm/°C) increases over an order of magnitude compared with those of the previous sensors based on air-sealed PCF interferometers built via fusion splicing with the same mechanism. In addition, the refractive index sensitivity also increases. Higher temperature sensitivity can be realized by infiltrating some liquid having a higher thermo-optic coefficient into the microholes of the PCF.


Planning and execution of hand movements.
The presented approach focuses on the attempt to specify strategies of visually organizing sequences of different hand movements and the resulting fine-control of movement close to the target, since in skilled activities our ability to sequence a number of separate movements each having different spatiotemporal characteristics is of central importance. Sequences of different moves have been analysed here. After a gross distance covering part of the move, small correction movements are performed close to the target to reduce the position error. The length of the required correction movements and the corresponding positioning time increase with target distance. In order to investigate motor control strategies two different tasks, with and without time pressure, have been designed. Time pressure forces the subjects to finish the previous move and to prepare the next move simultaneously. Absolute, constant and variable errors revealed that under time pressure the subject changes the control strategy by increasing the constant and reducting the variable error.


Early presence of regulatory cells in transplanted rats rendered tolerant by donor-specific blood transfusion.
Mechanisms by which donor-specific blood transfusion (DSBT) promotes organ allograft acceptance are unclear. In a rat fully mismatched cardiac allograft model, we found that DSBT alone (without immunotherapy) induces the development of regulatory T cells (DSBT-Tregs) posttransplant, thereby shedding new light in the mechanisms of the transfusion effect. Compartments and timing of expansion, requirements, and phenotype of DSBT-Tregs are unknown. It is generally assumed that some time is necessary before Tregs develop. However, we show-by adoptive transfer from DSBT-tolerant into naive recipients: 1) the presence of DSBT-Tregs at 5 days posttransplant in spleen and lymph nodes; 2) their gradual expansion in these compartments; and 3) their presence in the graft 14 of 30 days posttransplant. DSBT-Tregs are donor specific and do not protect third-party allografts. Splenocytes from DSBT-treated nontransplanted recipients or from transplanted DSBT-untreated (rejecting) recipients do not transfer tolerance, indicating that both DSBT and graft are required for sufficient numbers of DSBT-Tregs to develop. Thymectomy (or splenectomy) before DSBT (not at transplantation) abrogate DSBT-Tregs generation and tolerance, showing that thymus (and spleen) are required for DSBT-Tregs generation (not for expansion/maintenance). In contrast with other Tregs models, DSBT-Tregs activity is not restricted to CD4(+)CD25(+) but to CD4(+)CD45RC(-) cells, whereas CD4(+)CD45RC(+) cells act as effector cells and accelerate rejection. In conclusion, DSBT alone induces-rapidly posttransplant-the development of alloantigen-specific Tregs in lymphoid tissues and in the graft. DSBT, graft, thymus, and spleen are required for DSBT-Tregs generation. DSBT-Tregs in this model are CD4(+)CD45RC(-) (identical to Tregs protecting from autoimmunity in rats).


A theoretical interpretation of the variations of some physical parameters within the [2Fe-2S] ferredoxin group.
A model is proposed to explain the variation of some physical parameters within the reduced [2Fe-2S] ferredoxin group. According to this model, the main effects result from a variable mixing of some d orbitals of the Fe2+ ion owing to rhombic distortion of the active site having the same geometrical character, but different in intensity, for each protein. Some peculiar experimental results such as the axial electron paramagnetic resonance spectra of adrenal ferredoxin and Pseudomonas putida ferredoxin and the electric field gradient tensor of P. putida ferredoxin are explained without assuming properties drastically different from those of the other ferredoxins, as had been suggested in the literature.


Pathogenesis of gallstones: implications for management.
How do gallstones form, and what can be done to reverse or prevent the process? Bile acid physiology and pathophysiology are reviewed, especially with respect to cholesterol stones, and bile acid treatment to dissolve them is discussed. Although less well understood, the pathogenesis of pigment (black or brown) stones may involve bilirubin or carbonate salts, or infection.


Recent advances in lignocellulosic biomass for biofuels and value-added bioproducts - A critical review.
Lignocellulosic biomass is a highly renewable, economical, and carbon-neutral feedstock containing sugar-rich moieties that can be processed to produce second-generation biofuels and bio-sourced compounds. However, due to their heterogeneous multi-scale structure, the lignocellulosic materials have major limitations to valorization and exhibit recalcitrance to saccharification or hydrolysis by enzymes. In this context, this review focuses on the latest methods available and state-of-the-art technologies in the pretreatment of lignocellulosic biomass, which aids the disintegration of the complex materials into monomeric units. In addition, this review deals with the genetic engineering techniques to develop advanced strategies for fermentation processes or microbial cell factories to generate desired products in native or modified hosts. Further, it also intends to bridge the gap in developing various economically feasible lignocellulosic products and chemicals using biorefining technologies.


Effects of UV-B radiation on near-surface zooplankton of puget sound.
An increase in incident solar ultraviolet irradiation, resulting from possible deterioration of the stratospheric ozone layer, would have important biological effects. Though the oceans are relatively opaque to UV radiation, compared to visible light, increases in incident UV may affect organisms living within the first few meters of the sea surface.Shrimp larvae, crab larvae, and euphausids were exposed to various low levels of simulated solar UV radiation (UV-B, 290-315 nm) under laboratory conditions. Comparisons between solar and artificial spectra were based on spectroradiometric measurements converted to erythemally effective irradiance. These zooplankton tolerated UV-B irradiance levels up to threshold levels with no significant reduction in survival or developmental rates compared to control organisms. Beyond the threshold levels, activity, development, and survival rapidly declined. The apparent UV thresholds are near present incident UV levels.Observed survival threshold levels for each experimental group were superimposed on seasonal solar incident UV levels at the experimental site. These threshold levels appeared to be exceeded by median ambient UV levels late in the season of surface occurrence of each species. UV increases resulting from ozone depletion may significantly shorten this season. Although the apparent impact would be lessened by the decrease in UV with depth, irreversible detrimental effects would probably occur before reported survival thresholds were exceeded.


Metabolic exit from naive pluripotency.
Spatiotemporally distinct pluripotent states captured in vitro provide an accessible way of modelling early human development. An intricate interplay between the metabolome and histone modifications is now shown to drive the metabolic switch from human naive to primed pluripotency, one of the earliest steps of embryogenesis.


Alternative Complement Pathway Signature Determines Immunosuppression and Resistance to Immunotherapy Plus Tyrosine Kinase Inhibitor Combinations in Renal Cell Carcinoma.
Latest guidelines recommended immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) combination as standard first-line therapy in renal cell carcinoma (RCC), with no predictive biomarker being applied. Complement system shapes tumor microenvironment, which may influence TKI+IO benefit. Two cohorts from our institute and 2 external cohorts were enrolled. RNA-sequencing was performed for each sample, and alternative complement pathway signature (ACPS) was defined by single sample gene set enrichment analysis. Immune infiltration and function were assessed by immunohistochemistry and flow cytometry. Under TKI+IO therapy, ACPS was elevated in non-responders (P<0.01), and high-ACPS predicted lower response rate and shorter progression-free survival (P=0.040). Moreover, TKI+IO, rather than TKI monotherapy, may benefit patients of low-ACPS combined with SETD2-wild type (HR=0.55, P<0.001). In RCC, ACPS was associated with increased tumor-infiltrating T cells (Spearman's ρ=0.50, P=0.001). However, in high-ACPS samples, CD8+ T cells revealed an exhausted phenotype with decreased GZMB (P<0.001) and increased PD1 (P=0.008) expression. Elevated PD1 expression in high-ACPS samples was confirmed by immunohistochemistry (P=0.046). Besides, macrophage infiltration was increased in high-ACPS samples (P=0.045), along with suppressive cytokines. Under TKI+IO, high-ACPS was linked to immunosuppression and treatment resistance. ACPS might be used as a biomarker for better treatment strategy between TKI+IO or TKI monotherapy.


Cathodal proteins from primitive (embryonic) red cells of amphibia. Isolation and characterization.
A group of abundant (15% of the soluble protein) nonhemoglobin proteins was isolated from the primitive (embryonic) red cells found in tadpoles, using the cationic properties of the proteins at pH 8.6 to separate them from hemoglobin and other red cell proteins. The cathodal proteins (CP) were resolved into five components, and the two most predominant proteins were separated and characterized. Purified CP-1b and CP-2 had an amino acid composition similar to that of unfractionated cathodal proteins and to each other, except for small variations in the lysine and half-cystine content. The molecular weight of the purified CP-1b and CP-2 was 13 to 14,000, determined by gel filtration chromatography and electrophoresis in the presence of sodium dodecyl sulfate. Cathodal proteins were immunologically related although there were quantitative differences in reactivity. The concentration of cathodal proteins in primitive (embryonic) red cells was 100 times that in definitive (adult) red cells coincided with the replacement of primitive red cells. The synthesis of the cathodal proteins appeared to continue throughout the life of the primitive red cells; when hemoglobin synthesis declined in primitive red cells, approximately half of the protein synthesized by the cells was cathodal protein. Although the function of the cathodal proteins is as yet unknown, the data suggest that the cathodal proteins are a unique characteristic of erythroid differentiation in early development.


Labeling of endotoxin lipopolysaccharide with technetium-99m pertechnetate.
Bacterial endotoxin treated with technetium-99m can be visualized in living animals by gamma camera imaging.


Effects of alpha-chymotrypsin on the outflow routes for aqueous humor.
The anterior chamber was perfused with alpha-chymotrypsin, 50 micrograms ml-1, in mock aqueous humor in cynomolgus monkeys. The enzyme caused a marked rise in outflow facility and had clear effects on the structure of the outflow routes for aqueous humor. The intertrabecular spaces in the iridocorneal chamber angle were wider than normal, the openings in the uveal and corneoscleral meshwork appeared enlarged, there was ballooning of the juxtacanalicular region and the inner wall of Schlemm's canal into the canal and also splitting of the inner wall of the canal. The trabecular cells appeared relaxed with most of the cell processes retracted, some broken. There were discontinuities in the cell membrane and blebs. Parts of the trabecular beams were denuded. Two days after the enzyme treatment the facility was in the normal range, no splits in the inner wall of Schlemm's canal we observed but many of the other changes in structure remained. The number of invaginations in the inner wall of Schlemm's canal was markedly reduced after 2-18 days. A second and third perfusion with alpha-chymotrypsin caused a rise in outflow facility similar to the first. Some morphological changes remained 163 days after enzyme treatment. Pilocarpine a few days after alpha-chymotrypsin treatment caused a marked increase in outflow facility. The results suggest that alpha-chymotrypsin affects the glycoproteins of the cell membrane and as a result causes disorganization of the cytoskeleton, loss of loose adhesions and breaks of cell processes. The rapid recovery of the resistance to outflow was probably due to healing of the splits in the inner wall of Schlemm's canal; a marked reduction in the number of cells with invaginations suggests that in addition there may have been a reduction in the number of transcellular pores in the inner wall of Schlemm's canal.


A machine learning classifier using 33 host immune response mRNAs accurately distinguishes viral and non-viral acute respiratory illnesses in nasal swab samples.
Viral acute respiratory illnesses (viral ARIs) contribute significantly to human morbidity and mortality worldwide, but their successful treatment requires timely diagnosis of viral etiology, which is complicated by overlap in clinical presentation with the non-viral ARIs. Multiple pandemics in the twenty-first century to date have further highlighted the unmet need for effective monitoring of clinically relevant emerging viruses. Recent studies have identified conserved host response to viral infections in the blood. We hypothesize that a similarly conserved host response in nasal samples can be utilized for diagnosis and to rule out viral infection in symptomatic patients when current diagnostic tests are negative. Using a multi-cohort analysis framework, we analyzed 1555 nasal samples across 10 independent cohorts dividing them into training and validation. Using six of the datasets for training, we identified 119 genes that are consistently differentially expressed in viral ARI patients (N = 236) compared to healthy controls (N = 146) and further down-selected 33 genes for classifier development. The resulting locked logistic regression-based classifier using the 33-mRNAs had AUC of 0.94 and 0.89 in the six training and four validation datasets, respectively. Furthermore, we found that although trained on healthy controls only, in the four validation datasets, the 33-mRNA classifier distinguished viral ARI from both healthy or non-viral ARI samples with > 80% specificity and sensitivity, irrespective of age, viral type, and viral load. Single-cell RNA-sequencing data showed that the 33-mRNA signature is dominated by macrophages and neutrophils in nasal samples. This proof-of-concept signature has potential to be adapted as a clinical point-of-care test ('RespVerity') to improve the diagnosis of viral ARIs.


Proton pump inhibitor use and hearing loss in patients with type 2 diabetes: Evidence from a hospital-based case-control study and a population-based cohort study.
This study aimed to investigate the association between proton pump inhibitor (PPI) use and risk of sensorineural hearing loss (SNHL) or tinnitus in patients with type 2 diabetes using hospital- and population-based data. For the case-control study using the Asan Biomedical Research Environment database, the characteristics between cases and sex-, age- and index-year-matched controls were compared by the chi-squared test. Conditional logistic regression was used to estimate the odds ratios (ORs). For the cohort study using the Korean National Health Insurance Service - National Sample Cohort, the hazard ratios (HRs) for SNHL or tinnitus associated with PPI use were analysed by the Cox proportional hazard regression model. The case-control study included 1379 cases and 5512 matched controls. After adjustment, PPI use was associated with an increased risk of SNHL or tinnitus (OR 1.61, 95% confidence interval [CI] 1.30-1.99). The ORs were higher for current or recent use of PPI and high average daily dose. In the cohort study including 17 233 pairs of PPI users and nonusers after propensity score matching, the risk of SNHL or tinnitus increased in PPI users compared with nonusers (HR 1.50, 95% CI 1.40-1.61). In the stratified analyses, risks remained significant and the magnitude of association was relatively high in those of younger age, patients without gastroesophageal reflux disease and patients not receiving histamine 2 receptor blockers. Our study suggests that PPI use is associated with an increased risk of SNHL or tinnitus. Given the widespread use of PPIs, the potential ototoxic effects of PPIs remain an important concern.


Bullous mycosis fungoides: report of a case complicated by Kaposi's varicelliform eruption.
Vesiculobullous eruptions in mycosis fungoides (MF) are extremely rare. Here, we report a case of a 62-year-old woman presenting with erythematous patches and plaques of 2 years in duration, who had recently developed vesicles on erythematous MF plaques. Histopathological examination showed intra-subepidermal blisters, and infiltration of the epidermis by atypical lymphoid cells, forming Pautrier's microabscesses. Negative immunofluorescence excluded autoimmune blistering diseases. Immunohistochemistry revealed a CD4⁺ T-cell phenotype and gene rearrangement study confirmed a clonal T-cell proliferation. Kaposi's varicelliform eruption (KVE) developed in the patient 1 week after initiation of systemic corticosteroids and immunotherapy. Cluster of vesicles and erosions arising on the pre-existing plaque and a positive immunofluorescence test for Herpes simplex virus and histopathological examination confirmed the diagnosis of cutaneous herpes infection. This is the first case report on bullous MF complicated by KVE in the published work.


How to accurately assess surfactant biodegradation-impact of sorption on the validity of results.
Surfactants not only are widely used in biotechnological processes but also constitute significant contaminants of the modern world. Among many reports, there is a shortage of works which summarize the issue of surfactant sorption to biomass in a way that would elucidate the biological factors for analysts and analytical factors for microbiologists. The main factor, which is not as obvious as one would expect, is associated with the susceptibility of analytical approaches to errors resulting from incorrect handling of biomass. In case of several publications reviewed in the framework of this study, it was not possible to establish whether the decrease of the analytical signal observed by the authors actually resulted from biodegradation of the surfactant. This review emphasizes the necessity to consider the possibility of surfactant sorption to microbial cells, which may result in significant detection errors as well as conceptual inconsistency. In addition, a reference study regarding representative surfactants (cationic, anionic and non-ionic) as well as yeast, Gram-negative, Gram-positive bacteria, and activated sludge was provided to highlight the possible errors which may arise from disregarding sorption processes when determining degradation of surfactants. This particularly applies to systems which include ionic surfactants and activated sludge as sorption may account for 90% of the observed depletion of the surfactant. Therefore, a systematic approach was proposed in order to improve the credibility of the obtained results. Finally, the need to employ additional procedures was highlighted which may be required in order to verify that the decrease of surfactant concentration results from biodegradation processes.


Sodium methoxide: a simple but highly efficient catalyst for the direct amidation of esters.
A simple NaOMe catalyst provides superior accessibility to a wide variety of functionalized amides including peptides through direct amination of esters in an atom-economical and environmentally benign way.


Epidemiology of Patellar Tendinopathy in Athletes and the General Population: A Systematic Review and Meta-analysis.
Patellar tendinopathy (PT) mainly affects athletes who use the tendon for repeated energy storage and release activities. It can have a striking impact on athletes' careers, although data on its real prevalence and incidence are sparse. Research efforts should start from the results of reliable and updated epidemiological research to help better understand the impact of PT and underpin preventative measures. To determine the prevalence and incidence of PT in athletes and the general population. Systematic review; Level of evidence, 3. A systematic review of the literature was performed on January 17, 2022, and conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Web of Science, and Wiley Cochrane Library databases were searched for epidemiological reports of any evidence level and clinical studies reporting data on the incidence or prevalence of PT for the 11,488 retrieved records. The primary endpoint was the prevalence and incidence of PT in sport-active patients. The secondary endpoints were PT prevalence and incidence in subgroups of athletes based on sex, age, sport type, and sport level played, as well as the same epidemiological measures in the general population. A total of 28 studies, with 28,171 participants, were selected and used for the qualitative and quantitative analysis. The general and athletes' populations reported an overall PT prevalence of 0.1% and 18.3%, respectively. In athletes, the prevalence of PT was 11.2% in women and 17% in men (P = .070). The prevalence of PT in athletes <18 years was 10.1%, while it was 21.3% in athletes ≥18 years (P = .004). The prevalence of PT was 6.1% in soccer players, 20.8% in basketball players, and 24.8% in volleyball players. Heterogeneous PT diagnostic approaches were observed. Higher prevalence values were found when PT diagnoses were made using patient-reported outcomes versus clinical evaluations (P = .004). This review demonstrated that PT is a common problem in the male and female sport-active populations. There are twice as many athletes aged ≥18 years than there are <18 years. Volleyball and basketball players are most affected by PT.


Effect of Pin Shape on Thermal History of Aluminum-Steel Friction Stir Welded Joint: Computational Fluid Dynamic Modeling and Validation.
This article studied the effects of pin angle on heat generation and temperature distribution during friction stir welding (FSW) of AA1100 aluminum alloy and St-14 low carbon steel. A validated computational fluid dynamics (CFD) model was implemented to simulate the FSW process. Scanning electron microscopy (SEM) was employed in order to investigate internal materials' flow. Simulation results revealed that the mechanical work on the joint line increased with the pin angle and larger stir zone forms. The simulation results show that in the angled pin tool, more than 26% of the total heat is produced by the pin. Meanwhile, in other cases, the total heat produced by the pin was near 15% of the total generated heat. The thermo-mechanical cycle in the steel zone increased, and consequently, mechanical interlock between base metals increased. The simulation output demonstrated that the frictional heat generation with a tool without a pin angle is higher than an angled pin. The calculation result also shows that the maximum heat was generated on the steel side.


Revitalizing miRNAs mediated agronomical advantageous traits improvement in rice.
One of the key enigmas in conventional and modern crop improvement programmes is how to introduce beneficial traits without any penalty impairment. Rice (Oryza sativa L.), among the essential staple food crops grown and utilized worldwide, needs to improve genotypes in multifaceted ways. With the global view to feed ten billion under the climatic perturbation, only a potent functional master regulator can withstand with hope for the next green revolution and food security. miRNAs are such, miniature, fine tuners for crop improvement and provide a value addition in emerging technologies, namely large-scale genotyping, phenotyping, genome editing, marker-assisted selection, and genomic selection, to make rice production feasible. There has been surplus research output generated since the last decade on miRNAs in rice, however, recent functional knowledge is limited to reaping the benefits for conventional and modern improvements in rice to avoid ambiguity and redundancy in the generated data. Here, we present the latest functional understanding of miRNAs in rice. In addition, their biogenesis, intra- and inter-kingdom signaling and communication, implication of amiRNAs, and consequences upon integration with CRISPR-Cas9. Further, highlights refer to the application of miRNAs for rice agronomical trait improvements, broadly classified into three functional domains. The majority of functionally established miRNAs are responsible for growth and development, followed by biotic and abiotic stresses. Tabular cataloguing reveals and highlights two multifaceted modules that were extensively studied. These belong to miRNA families 156 and 396, orchestrate multifarious aspects of advantageous agronomical traits. Moreover, updated and exhaustive functional aspects of different supplemental miRNA modules that would strengthen rice improvement are also being discussed.


Endometrial carcinoma: paraaortic dissemination.
The objective of our study was to identify pathologic factors predictive of tumor dissemination to paraaortic lymph nodes (LNs) in endometrial carcinoma. The identification of the risk factors may potentially facilitate selection of patients for radical surgery or radiotherapy directed to the paraaortic area (PAA). The study population was a cohort from 612 consecutive patients with endometrial cancer surgically managed at our institution over a 10-year period. Tumor dissemination to the PAA was identified by selecting those patients who had either paraaortic LNs positive for disease at the time of primary surgery or those who subsequently experienced paraaortic failure or both (n=41; the "PA mets" subgroup). Therefore, patients for whom no information was available about the status of paraaortic LNs but who had received adjuvant irradiation to the PAA and those for whom information was not available about sites of recurrent disease were excluded from the analysis, leaving 566 patients to compose the study population. On the basis of univariate analysis, numerous pathologic variables were significantly (P< or =0.01) associated with PA mets. However, logistic regression analysis identified only two independent factors predictive of PA mets: positive pelvic LNs (P<0.001, OR=5.00) and lymphovascular invasion (LVI) (P=0.01, OR=1.99). Notably, only 2% of patients with negative pelvic LNs had PA mets compared with 47% of those with positive pelvic LNs (P<0.001). When both pelvic LNs and LVI were negative, only 0.8% of the patients had PA mets compared with 31% of patients for whom at least one of the two variables was positive (P<0.001). Positive pelvic LNs and LVI identify a subgroup of high-risk patients (approximately one sixth of the overall population) who potentially may benefit from formal lymphadenectomy or adjuvant therapy or both directed to the PAA. Furthermore, with 47% of patients with positive pelvic LNs having PA mets, unstaged patients at risk for pelvic LN involvement should be considered candidates for both pelvic and paraaortic external beam radiotherapy or surgical restaging.


Polymeric nanostructures with pH-labile core for controlled drug release.
Efficient and stimuli-triggered controlled delivery of therapeutics is one of the important issues in modern advanced therapy. In the present work, a versatile route for the synthesis of core cross-linked polymeric nanostructures (CLPN) through thiol-acrylate Michael addition reaction via the formation of β-thiopropionate has been described. The acid groups of the poly(acrylic acid) block of poly(ethylene glycol)-b-poly(N-isopropylacrylamide)-b-poly(acrylic acid) triblock copolymer were reacted with 2-hydroxyethyl acrylate (HEA) to yield the corresponding acrylate-functionalized copolymer (P1). Following this, P1 was reacted with a thiol functionalized cross-linker (CL) resulting in the formation of core cross-linked polymeric nanoparticles through acrylate-thiol Michael reaction. The ability of these nanoparticles to encapsulate drug molecules inside their core and their effective release following a pH-triggered controlled degradation of the core were demonstrated. The temperature sensitive release behaviour of the system was also studied. The non-toxic nature of the precursor polymers and the core cross-linked polymeric nanoparticles was also established, that further substantiated their potential as carriers for controlled release of drugs.


Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass.
Ghrelin is an enteric peptide with strong orexigenic and adipogenic effects. Plasma ghrelin levels are decreased in obese subjects but increase after weight loss; this increase is not observed after Roux-en-Y gastric bypass (RYGB). Prospective and comparative data after adjustable silicone gastric banding (ASGB) have not been reported previously. Overnight fasting plasma ghrelin concentration was measured in morbidly obese subjects at baseline and 3, 6, 12, and 24 months after ASGB (n = 8) or RYGB (n = 5) and in nonoperated controls (n = 7). After RYGB, body weight (BW) decreased by 29.5 +/- 5.5 kg (mean +/- SE, p < 0.001), whereas plasma ghrelin failed to increase significantly (+167 +/- 119 pg/mL, not significant). In contrast, after ASGB, BW decreased less (by 22.8 +/- 5.9 kg; p < 0.001), and plasma ghrelin significantly increased by 377 +/- 201 pg/mL (p = 0.025). Neither BW nor plasma ghrelin changed in nonoperated controls. Plasma leptin decreased in both operated groups (similarly p < 0.05) but not in nonoperated controls. Plasma growth hormone and insulin-like growth factor 1 were not correlated with changes in plasma ghrelin concentrations. Plasma ghrelin levels failed to increase during substantial weight loss after RYGB, but did increase in response to lesser weight loss after ASGB. These findings suggest that the plasma ghrelin response after weight loss is impaired after exclusion of major parts of the stomach and the duodenum (RYGB), and the smaller long-term weight loss after ASGB compared with RYGB may be due, at least in part, to an absent increase in plasma ghrelin after RYGB.


Aminopeptidases in human retroplacental sera: purification and characterization of two enzymes.
Ten different maternal serum samples were analyzed for the hydrolysis of S-Bz-Cys-pNA (substrate for CAP) and Ala-pNA. The results showed clear differences in the activities in individual sera. Similar S-Bz-Cys-pNA hydrolysis activity was detected for all sera. However, Ala-pNA hydrolysis activity differed remarkably. Serum exhibiting low Ala-pNA hydrolysis activity contained only CAP, and that exhibiting high Ala-pNA hydrolyzing activity contained CAP and AAP. The two aminopeptidases were independently purified to a homogeneous state through the same purification procedures and some of their biochemical properties were compared. The enzymes were quite different with respect to molecular mass, the substrate specificities for some aminoacyl-pNA substrates, and the effects of inhibitors. Among various natural peptides tested for hydrolysis, the enzymes hydrolyzed Met-enkephalin most rapidly, but their modes of action were different. Furthermore, only CAP degraded oxytocin and AAP exhibited a high kinin-converting activity.


Incremental survival benefit with adherence to standardized heart failure core measures: a performance evaluation study of 2958 patients.
In 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) established four heart failure (HF) core measures to standardize and improve health care quality in the United States. Although adherence to these HF care processes may be improving, their collective impact on survival is not yet settled. JCAHO HF measures were implemented within a 20-hospital health care system. Eligible patients had a principal discharge diagnosis of HF. Metrics representing compliance with these measures were derived and their relationship with 1-year survival was examined using an adjusted Cox proportional hazards regression. A total of 2958 patients met study criteria. The average age was 73 years, 50% were male, and 9.9% were smokers. One-year survival benefits were seen in an item-by-item evaluation of HF measures for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (hazard ratio [HR] = 0.69), left ventricular function assessment (HR = 0.83), and patient education (HR = 0.79). When assessed collectively, improved survival was seen among patients eligible for two (HR = 0.53), three (HR = 0.36), or four HF measures (HR = 0.65). Further, we found a positive and incremental relationship between the degree of adherence and survival (P = .008). Adherence to JCAHO HF core measures is associated with improved 1-year survival after HF hospitalization. This validates these simple and effective performance measures and justifies efforts to implement them in all eligible patients with HF.


Origins, function, and regulation of the TOC-TIC general protein import machinery of plastids.
The evolution of chloroplasts from the original endosymbiont involved the transfer of thousands of genes from the ancestral bacterial genome to the host nucleus, thereby combining the two genetic systems to facilitate coordination of gene expression and achieve integration of host and organelle functions. A key element of successful endosymbiosis was the evolution of a unique protein import system to selectively and efficiently target nuclear-encoded proteins to their site of function within the chloroplast after synthesis in the cytoplasm. The chloroplast TOC-TIC (translocon at the outer chloroplast envelope-translocon at the inner chloroplast envelope) general protein import system is conserved across the plant kingdom, and is a system of hybrid origin, with core membrane transport components adapted from bacterial protein targeting systems, and additional components adapted from host genes to confer the specificity and directionality of import. In vascular plants, the TOC-TIC system has diversified to mediate the import of specific, functionally related classes of plastid proteins. This functional diversification occurred as the plastid family expanded to fulfill cell- and tissue-specific functions in terrestrial plants. In addition, there is growing evidence that direct regulation of TOC-TIC activities plays an essential role in the dynamic remodeling of the organelle proteome that is required to coordinate plastid biogenesis with developmental and physiological events.


DISC1 as a prognostic biomarker correlated with immune infiltrates in gastric cancer.
Multiple mental diseases could arise in people who have the disrupted in schizophrenia 1 (DISC1) gene. However, it was unknown how DISC1 might contribute to the development of tumors and immune responses. We extracted data from the Cancer Genome Atlas (TCGA) and TISIDB databases from stomach adenocarcinoma (STAD) patients, which revealed that DISC1 overexpression was closely associated with tumor histological type (mucinous vs. tubular, OR = 2.860, CI = 1.423-5.872, p = 0.004), as well as tumor stage and grade. Furthermore, the higher the DISC1 expression, the lower the overall 10-year survival rate. Patients with low DISC1 expression had a significantly longer progression-free interval (PFI) and disease-specific survival (DSS) than patients with high DISC1 expression. However, patients with higher DISC1 expression in the T3&T4, N0&N1 and M0 subgroups had poorer prognosis in terms of OS, DSS and PFI, as could be seen in the subgroup survival analysis. Public datasets were used to predict lncRNA-miRNA-DISC1 regulation. DISC1 was significantly up-regulated in GC(gastric cancer), and its expression levels showed a moderate to strong positive correlation with infiltration levels of effector memory T cells (Tem) and central memory T cells (Tcm), and a negative correlation was observed with Th17 cells and NK CD56bright cells. In addition, concomitant with the high expression of the DISC1 gene was a decrease in MHC-I (Major Histocompatibility Complex-I)expression and an increase in MHC-II expression, and altered chemokine expression. The upregulation of CXCL12 and CXCR4 expression could be caused by an increase in DISC1 expression. The above expression variability and correlation suggest a role for DISC1 in regulating tumor immunity in GC. These findings suggest that high expression of DISC1 could be an independent prognostic factor for GC.


Impact of Vitamin D Status in Chronic Liver Disease.
Vitamin D deficiency is extremely common in chronic liver disease (CLD) patients. Up to 93% of these patients have some degree of vitamin D insufficiency. Liver plays an important role in the metabolism and pleiotropic functions of vitamin D. Vitamin D deficiency has been associated with increased mortality, bacterial infections, portal hypertension complications, and fibrosis severity. We aimed to determine the impact of vitamin D level in CLD. One hundred fifty individuals consisting of 75 cirrhotic patients (cases) and 75 respective attendants (controls) were enrolled between July 2015 and July 2017. A detailed clinical and laboratory evaluation was done along with estimation of vitamin D level. Unpaired t-test and analysis of variance was used to compare difference in the level of continuous variables between different groups. Linear regression analysis was performed to analyze the correlation between vitamin D deficiency and severity of liver disease. The age of patients ranged from 18 years to 69 years with mean of 48.85 ± 13.6 years in the case group and 46.57 ± 17.24 years in the control group. Out of 75 CLD patients, vitamin D deficiency (<20 ng/dl) was found in 31 (41.4%) patients, out of which 14(18.7%) suffered from severe vitamin D deficiency (<10 ng/ml). On applying analysis of variance test, there was significant difference in vitamin D level and serum albumin and serum bilirubin (P < 0.05). On linear regression, vitamin D level showed significant negative correlation with Child-Pugh score (r = -0.7379, P < 0.0001) and Model For End-Stage Liver Disease score (r = -0.6671, P < 0.0001). Our study concluded that CLD is associated with a significantly low level of vitamin D, which was independent to patient's gender, body mass index, residence, and education level. The findings of our study suggest that awareness of serum vitamin D level in patients with CLD is important. Further studies are required to validate the importance of vitamin D levels and impact of vitamin D supplementation on CLD.


In vivo analysis of subchondral trabecular bone in patients with osteoarthritis of the knee using second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT).
Subchondral bone plays an important role in the pathological mechanisms of knee osteoarthritis (OA). High-resolution peripheral quantitative computed tomography (HR-pQCT) is an imaging modality allowing noninvasive microstructural analysis of human bone, and the second generation enables scanning of the knee. The purpose of this study was to perform in vivo analysis of subchondral trabecular bone in patients with medial knee OA, to elucidate features of bone microstructure in medial knee OA, and to investigate relationships between bone microstructure and both stage of disease and lower limb alignment. Subjects were 20 women, including both patients with medial knee OA (Kellgren-Lawrence (KL) grade 2, n = 5, KL grade 3, n = 7, and KL grade 4, n = 4; mean age: 63.0 years; body mass index (BMI): 23.8 kg/m2) and volunteers without knee OA (KL grade 1, n = 4, mean age: 66.0 years; BMI: 23.8 kg/m2). The proximal tibia (20-mm length) was scanned by second-generation HR-pQCT at a voxel size of 60.7 μm. A subchondral trabecular bone volume of 5 mm length was extracted from the medial and lateral plateaus. They were then divided into 4 regions: anterior, central, medial or lateral, and posterior. Finally, subchondral bone microstructure parameters were analyzed and compared, between each plateau and region. Relationships between microstructural parameters and disease stage (KL grade, minimum joint space width), and between those parameters and lower limb alignment (femorotibial angle: FTA, mechanical axis deviation: MAD) were also investigated. In the medial plateau, volumetric bone mineral density (vBMD), bone volume fraction (BV/TV), and trabecular thickness were significantly higher and structure model index (SMI) was significantly lower than in the lateral plateau, particularly in the anterior, central, and medial regions (p < .01 each). In the anterior region of the medial plateau, vBMD, BV/TV, and connectivity density showed strong positive correlations with KL grade, FTA, and MAD (r-range: 0.61 to 0.83), while trabecular separation and SMI exhibited strong negative correlations with KL grade, FTA, and MAD (r-range: -0.60 to -0.83). Higher bone volume, trabecular thickness, and a more plate-like structure were observed in the medial tibial plateau than in the lateral. Subchondral bone microstructure at the anterior region in the medial plateau showed strong relationships with KL grade and lower limb alignment. These results indicate that subchondral bone microstructure in this region may provide representative indices, particularly in medial knee OA. Although this study involved a specifically Asian cohort with a lower BMI distribution than other ethnic groups, the technique presented may be useful in studying the pathogenesis of OA or evaluating treatment effects.


Genome-wide identification and bioinformatics analysis of the WD40 transcription factor family and candidate gene screening for anthocyanin biosynthesis in Rhododendron simsii.
WD40 transcription factors (TFs) constitute a large gene family in eukaryotes, playing diverse roles in cellular processes. However, their functions in the major ornamental plant, Rhododendron simsii, remain poorly understood. In this study, we identified 258 WD40 proteins in the R. simsii genome, which exhibited an uneven distribution across chromosomes. Based on domain compositions and phylogenetic analysis, we classified these 258 RsWD40 proteins into 42 subfamilies and 47 clusters. Comparative genomic analysis suggested that the expansion of the WD40 gene family predates the divergence of green algae and higher plants, indicating an ancient origin. Furthermore, by analyzing the duplication patterns of RsWD40 genes, we found that transposed duplication played a major role in their expansion. Notably, the majority of RsWD40 gene duplication pairs underwent purifying selection during evolution. Synteny analysis identified significant orthologous gene pairs between R. simsii and Arabidopsis thaliana, Oryza sativa, Vitis vinifera, and Malus domestica. We also investigated potential candidate genes involved in anthocyanin biosynthesis during different flower development stages in R. simsii using RNA-seq data. Specifically, we identified 10 candidate genes during the bud stage and 7 candidate genes during the full bloom stage. GO enrichment analysis of these candidate genes revealed the potential involvement of the ubiquitination process in anthocyanin biosynthesis. Overall, our findings provide a valuable foundation for further investigation and functional analysis of WD40 genes, as well as research on the molecular mechanisms underlying anthocyanin biosynthesis in Rhododendron species.


The relationship between labor and route of delivery in the preterm infant.
The purpose of this prospective study was to evaluate the effects of the active phase of labor and route of delivery on the frequency of germinal layer/intraventricular hemorrhage in 89 infants with ultrasound-estimated fetal weights less than or equal to 1750 gm. Twenty-eight infants (31.5%) had germinal layer/intraventricular hemorrhage within 1 hour after birth and an additional 15 infants (17%) had germinal layer/intraventricular hemorrhage beyond 1 hour after birth. Infants with germinal layer/intraventricular hemorrhage had a significantly lower gestational age (p less than 0.003) and birth weight (p less than 0.007). Germinal layer/intraventricular hemorrhage within 1 hour after delivery was increased in the infants of women who experienced the active phase of labor regardless of the route of delivery. However, the incidence of germinal layer/intraventricular hemorrhage beyond 1 hour after delivery and the overall incidence were similar in the vaginal delivery and cesarean delivery groups. In addition, there was an increased incidence of progression to grades III and IV hemorrhage regardless of route of delivery in the infants whose mothers experienced the active phase of labor.


Rationale and design of phase II clinical trial of dual inhibition with ramucirumab and erlotinib in EGFR exon 19 deletion-positive treatment-naïve non-small cell lung cancer with high PD-L1 expression (SPIRAL-3D study).
Osimertinib is a standard treatment option for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, osimertinib monotherapy yields poor clinical outcomes in some patients, necessitating the development of novel treatment strategies. In addition, several studies have suggested that high programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) for osimertinib monotherapy in patients with advanced NSCLC harboring EGFR mutations. To evaluate the clinical efficacy of erlotinib plus ramucirumab for EGFR exon 19 deletion-positive treatment-naïve NSCLC with high PD-L1 expression. A single-arm, prospective, open-label, phase II study. Patients with treatment-naïve EGFR exon 19 deletion-positive NSCLC with high PD-L1 expression and a performance status of 0-2 will receive combination therapy with erlotinib plus ramucirumab until evidence of disease progression or development of unacceptable toxicity. High PD-L1 expression is defined as a tumor proportion score of 50% or higher, as determined by PD-L1 immunohistochemistry 22C3 pharmDx testing. The Kaplan-Meier method and the Brookmeyer and Crowley method with the arcsine square-root transformation will be used with PFS as the primary endpoint. The secondary endpoints include overall response rate, disease control rate, overall survival, and safety. A total of 25 patients will be enrolled. The study has been approved by the Clinical Research Review Board, Kyoto Prefectural University of Medicine, Kyoto, Japan, and written informed consent will be obtained from all patients. To the best of our knowledge, this is the first clinical trial to focus on PD-L1 expression in EGFR mutation-positive NSCLC. If the primary end point is met, combination therapy with erlotinib and ramucirumab could become a potential treatment option for this clinical population. This trial was registered with the Japan Registry for Clinical Trials on 12 January 2023 (jRCTs 051220149).


Load-bearing capacity of pressable lithium disilicates applied as ultra-thin occlusal veneers on molars.
The aim was to investigate the load bearing capacity of different pressable lithium disilicates cemented as occlusal veneers on molars. One control group and six test groups were formed consisting of 20 specimens each (n = 20). The six test groups differed in the utilizing pressable lithium disilicate to fabricate occlusal veneers. As a control group, "group Lis", the lithium disilicate with the highest reported flexural strength was used (initial LiSi Press, GC Europe; Leuven, Belgium / flexural strength: 508 MPa). The test groups consisted of other pressable lithium disilicates with lower flexural strength values: "Ema" (IPS e.max press), "Vit" (VITA Ambria), "Liv" (Livento Press), "Amb" (Amber Press), "Mas" (Amber Press Master) and "Ros" (Rosetta SP)". After the preparation of 140 extracted human molars, which included the removal of the central enamel, the specimens were scanned using a desktop scanner. With the aid of a design software, the occlusal veneers were designed in a standardized thickness of 0.5 mm. To fabricate the restorations, all tested materials were processed using heat-pressing technique. All restorations were adhesively cemented. Afterwards, the specimens underwent cyclic fatigue during an aging procedure in a chewing simulator (1'200'000 chewing-cycles, 49 N force, 5-55°C temperature changes). Subsequently, the specimens were statically loaded and the load which was necessary to fracture the specimen (Fmax) were measured. Differences between the groups were compared applying the Kruskal-Wallis (KW) test and the Wilcoxon-Mann-Whitney-Test (WMW: p < 0.05). The two-parameter Weibull distribution values were calculated. The fatigue resistance was 100% for the groups Lis, Vit, Liv, Amb, Mas and Ros, whereas the group Ema showed a fatigue resistance of 95%. The control group Lis showed median Fmax values of 2'328 N. The median Fmax values for the test groups ranged between 1'753 N (Vit) and 2'490 N (Ros). Statistically significant difference was observed among the groups Lis (control) and Vit (KW: p < 0.001). Weibull distribution presented the highest shape values for the group Ros (12.83) and the lowest values for the group Ema (4.71). Regarding their load-bearing capacity different pressable lithium disilicates can be recommended to fabricate ultra-thin occlusal veneers on molars when restoring occlusal tooth wear.


A general, positive ion mode ESI-MS approach for the analysis of singly charged inorganic and organic anions using a dicationic reagent.
Anion analysis continues to be of great importance to many scientific and technical fields. We propose here a general and sensitive method of detecting singly charged anions by ESI-MS and LC-ESI-MS as positive ions. This method utilizes a dicationic reagent to form a complex with the anion that retains an overall positive charge for analysis by MS. Nitrate, thiocyanate, perchlorate, perfluorooctanoic acid (PFOA), halogenated acetic acids, and various other inorganic and organic anions and are investigated. The use of tandem mass spectrometry to enhance the detection limits of some of the anions is demonstrated. Chaotropic anions provided the lowest detection limits, with PFOA detected at the hundreds of femtograms level. Indeed, this single approach provides the lowest reported detection limits for a variety of anions, especially PFOA, nitrate, monochloroacetic acid, dichloroacetic acid, and bromochloroacetic acid, among others. The integrated areas and signal-to-noise ratios for five ions during a chromatographic run in both the positive and negative ion modes are compared. The ability of this method to detect differences in related ions is shown for four arsenic species. Finally, a tap water sample is analyzed for the anions in this study using the dicationic reagent method.


Prediction of weight for height following intervention in three-year-old children with early histories of nonorganic failure to thrive.
The present study assessed the weight for height outcomes of 59 3-year-old children who had been hospitalized for nonorganic failure to thrive (NOFT) as infants (average age of 5 months) and received time-limited outreach intervention. Although the majority of children attained normal weight for height, nearly one-third demonstrated at least mild wasting. Type of outreach intervention did not affect weight for height at outcome. The predictive efficacy of a variable set which included characteristics of NOFT (age of onset and duration), velocity of weight gain subsequent to diagnosis and environmental characteristics (income and home stimulation) was tested. Shorter duration of NOFT prior to diagnosis and greater initial rate of weight gain following hospitalization predicted weight for height at 36 months. The findings underscore the need for close monitoring of physical growth and nutritional status of NOFT children following hospitalization as well as comprehensive assessment and treatment for children who continue to demonstrate nutritional deficits. Additional studies of factors which affect the prognosis of NOFT children are needed.


Pulmonary hypertension is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation for myelofibrosis.
Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative therapy for primary myelofibrosis (MF) as well as myelofibrosis secondary to other myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is a known complication of MF and may occur in up to 50% of such patients. PH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest) can eventually lead to right heart failure and may be associated with complications after alloHCT. We examined the association of PH with alloHCT outcome in patients with MF associated with MPN. Pre- and post-HCT echocardiograms were reviewed to estimate the peak pulmonary artery systolic pressure (PASP). Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 of 65 patients (57%) studied. With median follow-up of 35.0 months (range: 3.3-119.4) PH was significantly associated with inferior OS (58.9% vs. 88.8%, P = 0.025), primarily due to increased NRM (21.6% vs. 7.1%, P = 0.007). The majority of the deaths (8 of 14) in patients with PH occurred within 100 days after HCT. In patients with an available post-HCT echocardiogram (n = 33), the median PASP was 30 mmHg (range: 5.0-56.2); eight patients (24%) had persistent PH. Compared with pre-HCT values, PASP was significantly reduced after HCT (p < 0.001). We conclude that PH is associated with inferior survival due to the increased NRM in patients with MF undergoing alloHCT. PH appears at least partially reversible after successful alloHCT. PH should be considered a risk factor for early mortality after alloHCT and surveillance of pulmonary artery pressure in MF patients being considered for alloHCT may be useful.


Initial and extended inflammatory messages of the nongenomic signaling pathway of the TCDD-activated Ah receptor in U937 macrophages.
Using 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD) we have investigated the mechanisms through which the AhR elicits inflammation through the nongenomic pathway. This AhR signaling depends on the initial action of TCDD to rapidly increase the intracellular concentration of free Ca(2+), which subsequently activates cPLA2 and additional inflammatory markers (e.g. COX-2 mRNA expression) lasting up to 72h. Inhibition of cPLA2 activity resulted in attenuation of these inflammatory responses. We have hypothesized that specific protein kinases are responsible for further propagation of the initial transient nongenomic signaling into long-lasting cellular effects, and found protein kinase C (PKC) is activated at an early stage, followed by activation of cAMP-dependent protein kinase (PKA) at later stages. We clearly established in U937 macrophages cPLA2 activation is an essential initial step to activate the nongenomic inflammatory pathway of ligand-activated AhR. Furthermore, this pathway does not require the participation of ARNT, thus distinguishing itself from the classical genomic pathway.


Minimal biomass deposition in banded iron formations inferred from organic matter and clay relationships.
The cycling of iron and organic matter (OM) is thought to have been a major biogeochemical cycle in the early ferruginous oceans which contributed to the deposition of banded iron formations (BIF). However, BIF are deficient in OM, which is postulated to be the result of near-complete oxidation of OM during iron reduction. We test this idea by documenting the prevalence of OM in clays within BIF and clays in shales associated with BIF. We find in shales >80% of OM occurs in clays, but <1% occurs in clays within BIF. Instead, in BIF OM occurs with 13C-depleted carbonate and apatite, implying OM oxidation occurred. Conversely, BIF which possess primary clays would be expected to preserve OM in clays, yet this is not seen. This implies OM deposition in silicate-bearing BIF would have been minimal, this consequently stifled iron-cycling and primary productivity through the retention of nutrients in the sediments.


Rapid immunoelectrophoretic assay for detection of serum antibodies to Aspergillus fumigatus catalase in patients with pulmonary aspergillosis.
A rapid immunoelectrophoretic assay was developed to detect antibodies to Aspergillus fumigatus catalase. The method's diagnostic sensitivity for pulmonary aspergillosis was 88% (72-97%, 95% confidence limits) in 33 patients presenting with either aspergilloma or Aspergillus lung infiltrate. The diagnostic specificity was 94% (90-97%) as judged from 191 patients with other infiltrative lung diseases, including infections and neoplasia. None of the 185 healthy subjects had catalase antibodies. The highest titres (ranging up to 256) were found in aspergillosis patients with cavitary lesions. Catalase antibody titres increased in two patients with concomitant development of lung cavities and mycetomas. In patients with resected or stable Aspergillus lung disorders catalase antibody titres declined by less than one dilution step per year.


(S)-emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. 3rd communication: effect on postischemic cerebral blood flow and metabolism, and ischemic neuronal cell death.
The effect of (S)-emopamil ((2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride) treatment on postischemic cerebral blood flow and metabolism was investigated in nitrous oxide anesthetized, artificially ventilated rats. Forebrain ischemia was induced and maintained for 20 min by lowering arterial blood pressure to approximately 40 mmHg and clamping both carotid arteries. Local cerebral blood flow and glucose utilization were evaluated autoradiographically in 34 cerebral regions. In the cerebral blood flow studies intravenous infusion of 0.1 mg/(kg min) (S)-emopamil was begun 5 min after the end of ischemia. Local cerebral blood flow was determined 60 min later using [14C]iodoantipyrine. When the animals were treated with saline only, postischemic blood flow of 22 affected forebrain areas fell on average to 42 +/- 13% of nonischemic control. Treatment with (S)-emopamil increased perfusion of the same areas in a region-dependent fashion by an average of 54 +/- 19%, resulting in 63 +/- 17% of control values. The rise of blood flow in structures not directly affected by ischemia amounted to 52 +/- 27% (134 +/- 23% of control). In the studies on cerebral metabolism, the experimental animals received a total of 6 mg/kg (S)-emopamil by slow intravenous infusion before and during the ischemic episode. Determination of local cerebral glucose utilization was initiated after 50 min of postischemic recirculation using [14C]deoxyglucose. In the placebo-treated experimental group average glucose utilization of 14 forebrain areas was significantly lower (74 +/- 9% of control) than in the nonischemic control group.(ABSTRACT TRUNCATED AT 250 WORDS)


Increased HLA-DQ2-affinity of a synthetic gliadin peptide by acid-induced deamidation of glutamine residues.
Presentation of antigenic gliadin peptides by the HLA-DQ2 molecule is considered as a key event in celiac disease pathogenesis. Chemical deamidation of the side chains of glutamine residues might have a strong influence on gliadin peptide binding to the DQ2 molecule. Glutamine deamidation of A-gliadin peptide (45-56) under acidic conditions corresponding to the gastric environment was studied using RP-HPLC, Edman degradation, capillary electrophoresis and electrospray mass spectrometry. Deamidation resulted in peptides with increased DQ2-affinities as assessed in a cell-free binding assay.


Erikson's concept of inner space: a data-based reevaluation.
An analytical critique is presented of Erikson's theory that physical differences between the sexes produce differences in spatial organization, and of the experiment cited in support of that theory. Results of a new experiment are reported, which run counter to the original findings and suggest that the theory of "inner space" be reevaluated.


Downregulation of superoxide dismutase activity and gene expression in cultured rat brain astrocytes after incubation with vitamin C.
Reactive oxygen species have been linked with neuropathological changes in the central nervous system. Epidemiological studies supported the beneficial effect of supplementation of antioxidants. Superoxide dismutase (SOD) is an endogenous enzyme which can scavenge reactive oxygen species. This study investigated the effect of supplementation with ascorbic acid (vitamin C) on the changes of SOD in cultured neurological cells. Rat brain astrocytes (RBA-1 cells) were incubated with vitamin C and divided into four groups: a control group (without vitamin C) and three treatment groups with vitamin C at 40, 80, and 160 micromol/l. After short-term (2 days) and long-term (7 days) incubation, SOD activity, SOD mRNA level by Northern blotting, and SOD protein amounts by Western blotting were measured. After 2 days of incubation, vitamin C resulted in a decrease in the activity of SOD in a concentration-dependent manner (Mn-SOD from 14.8 +/- 1.2 to 13.2 +/- 0.5 U/mg protein and Cu/Zn-SOD from 64.8 +/- 1.2 to 51.7 +/- 0.9 U/mg protein; p < 0.05), and vitamin C also attenuated the Cu/Zn-SOD mRNA level from 100 to 86.3 +/- 6.7%; p < 0.01), whereas the protein amounts of these two SODs remained unchanged. After 7 days of incubation with vitamin C, the SOD activity of RBA-1 cells decreased significantly (Mn-SOD from 14.9 +/- 0.3 to 11.8 +/- 0.3 U/mg protein and Cu/Zn SOD from 61.8 +/- 1.8 to 54.6 +/- 0.9 U/mg protein; p < 0.01), and the mRNA level was also attenuated (Mn-SOD from 100 to 86.8 +/- 8.7% and Cu/Zn-SOD from 100 to 84.7 +/- 4.8%; p < 0.01). These results suggest that 2 and 7 days of incubation with relatively high concentrations of vitamin C may downregulate activity and gene expression of SOD in cultured RBA-1 cells.


The determination of microscopic ionization constants of a substituted piperazine using estimates from model compounds.
The microscopic ionization constants of 1-[3-(4-chlorophenyl) propyl] piperazine (I) were determined using piperazine (P) and 1,4-bis[3-(4-chlorophenyl)propyl] piperazine (II) as models for one of the ionizations. The macroscopic ionization constants for all three compounds were measured potentiometrically, and the micro constants of P and II, which are symmetrical molecules, were calculated from their macro constants. Only one micro constant of either P or II was suitable as a model for elucidating the micro constants of I.


Cumulation of N-acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function.
N-Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 microgram/ml 3 hr after a dose of procainamide which is well above the 3-hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 microgram/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 microgram/ml) and 38 days (0.9 microgram/ml) after procainamide was stopped, indicating a half-life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.


Quality of life of persons living with HIV and congruence with surrogate decision-makers.
Physicians and caregivers rate patient quality of life (QOL) lower than patients rate their own QOL. This study investigated discrepancies between self-assessments of patient QOL by adults with HIV and their surrogate decision-makers. We collected baseline data from 223 adult dyads in the FAmily-CEntered (FACE) Advance Care Planning (ACP) clinical trial, consisting of HIV positive patients and their chosen surrogates. Participants independently completed the Medical Outcome Study-HIV Survey (MOS-HIV) and the Palliative care Outcome Scale (POS). We used Wilcoxon Signed-Rank Test to assess differences in overall patient-surrogate means. We used Prevalence Adjusted Bias Adjusted Kappa (PABAK) statistics to assess dyadic agreement, with surrogate HIV status and cohabitation status as grouping variables. Patients were 56.1% male, 86.1% Black/African-American, aged 22-77 (mean = 50.83, SD = ± 12.33). Surrogates were 43.8% male, 84.1% Black/African-American, aged 18-82 (mean = 49.73, SD = ± 14.22). 46.2% of surrogates lived with the patient. 64.6% of surrogates reported negative HIV status. Surrogates were more likely to state patients were ill, p = 0.032. Among patient-surrogate dyads, most QOL assessments showed poor (0.00-0.39) or fair (0.40-0.59) agreement and agreement tended to be even poorer among patient-surrogate dyads where the surrogate had a shared HIV diagnosis. QOL discrepancies are said to arise from healthy surrogates overestimating the effects of chronic illness. In this novel assessment, many surrogates had a shared HIV diagnosis, without increased agreement. These findings highlight the challenge of accurately assessing patient QOL by surrogates, even when there is a shared HIV diagnosis. Improved communication is needed between patients and surrogates about the patients' representation of illness. National Clinical Trial Number: NCT01775436.


Comparing the predictions by NIR spectroscopy based multivariate models for distillation fractions of crude oils by F-test.
The whole range of distillation fractions in industrially relevant crude oil samples is predicted by using two multivariate models based on near-infrared (NIR) spectra. The first versions of the models as well as the respective model updates are considered, with the updates largely aimed at expanding the models. The prediction results are compared across all the fractions and F-test is used to critically compare the performance of the models and the effectiveness of the limited updates. The results suggest that both multivariate methods perform very comparably, and the updates do not lead to statistically significant changes, which differs from what one could conclude from the nominal prediction errors. The near-equivalency of the prediction accuracy of the updated models is additionally illustrated by perusing predictions of a number of batches from one sour and one sweet crude arriving at the refinery during a four month period.


Adduction of soluble proteins with malondialdehyde-acetaldehyde (MAA) induces antibody production and enhances T-cell proliferation.
The alcohol metabolites malondialdehyde and acetaldehyde can combine to form stable adducts (MAA) which are found in the livers of humans and rats after significant alcohol ingestion. While adducted proteins induce antibody responses in the absence of adjuvants, the mechanisms by which these responses occur are unknown. Thus, it was the purpose of these studies to investigate how MAA modification stimulates antibody and T-cell responses in the absence of adjuvants. Hen egg lysozyme (HEL) was modified with increasing levels of MAA and was used as an immunogen, and antibody and T-cell responses were determined. The role of scavenger receptors in the immunogenicity of MAA-adducted proteins was also investigated. Maximum antibody response was induced after immunization with 1.8 nM MAA/nM HEL, and was primarily an IgG1 response to HEL as determined by inhibition ELISAs. T-cell proliferative responses after immunization with HEL-MAA were solely to HEL. Immunization with a scavenger receptor ligand in conjunction with HEL-MAA increased the predominant IgG1 response and sharply decreased the IgG2a response by approximately 50%. Binding of HEL-MAA by splenocytes was determined by flow cytometry to be approximately 15% greater than HEL alone, showing a doubling of the geometric mean fluorescence. Also, most of the cells that bound HEL-MAA were class II positive, indicating that antigen-presenting cells can bind the MAA-adducted HEL, and potentially initiate immune responses. MAA modification of proteins induces antibody and T-cell proliferative responses in vivo. Initial studies suggest that these responses may be mediated by scavenger receptors that recognize MAA-adducted proteins. This suggests a mechanism by which proteins modified with oxidative products associated with chronic ethanol consumption may alter immune responses that may play an active role in the development and/or progression of alcoholic liver disease.