Refined insights into the pain-depression association in chronic pain patients.
The relationship between chronic pain and depression is controversial and the data on association show strong variation. This study aimed to provide refined correlation and regression data on the basis of categorical and continuous measures. Cross-sectional assessment was based on standardized instruments that measure on a quasi-continuous scale, the Short Form-36, the Hospital Anxiety and Depression Scale, and the Multidimensional Pain Inventory. Correlations between depression and pain were determined by the instruments' scales, with and without correction for confounders, and within chronic pain subgroups using multivariate regression analysis. In 273 chronic pain patients participating in an inpatient pain rehabilitation program, the Multidimensional Pain Inventory pain severity scale and the Hospital Anxiety and Depression Scale showed maximum overall correlations of 0.27 to 0.29 (bivariate) and 0.30 (partial). The odds ratios for depression varied between 1.72 and 2.10 for different pain levels. Distinguishing 3 subtypes of pain patients, the pain-depression correlation was moderate in the "interpersonally distressed" subgroup (up to 0.57) (characterized by relatively low support, high punishing, low solicitous, and low distracting responses), weak in the "dysfunctional" subgroup (up to 0.26), and absent in the "adaptive copers/minimizers" subgroup (up to -0.09). The strengths of the pain-depression association and the "dose-response" relationship were both weak-weaker than to be expected if the hypothesis of a causal relationship were true. In the interpersonally distressed subgroup, the moderate association may have an impact on pain management, that is, pain could be treated by treatment of depression and vice versa.


Double-diffusive convection in Jeffery-Hamel flow.
In this paper, double-diffusive convection in flow of viscous fluid is investigated inside a horizontal channel. It has heated, inclined and rectangular plane walls. The upper wall has non-uniform temperature and variable species concentration. Note that the Jeffery-Hamel flow depends upon the radial component of velocity, whereas, the peripheral velocity is taken zero. However, the current simulation has been accomplished in view of new procedures and we dealt with two non-zero components of velocity. The problem has been described in a set of four PDEs and the relevant BCs, whereas, the whole set of BVP is taken in Cartesian Coordinates. A set of proper transformation is formed, which reduces the system of PDEs into a new system of ODEs. The system of ODEs is solved with the help of several methods in order to check the validity of the solution. An approximate analytical solution is provided for small values of inclination parameter. An accurate numerical solution of the modelled equations is also given. Moreover, skin friction, rate of the two diffusions are investigated for all different cases of assisting (opposing) and converging (diverging) flows. Thus, the current modelled problem perfectly describes the physical problems of real world in such special circumstances.


A set-theoretic definition of cell types with an algebraic structure on gene regulatory networks and application in annotation of RNA-seq data.
The emergence of single-cell RNA sequencing (RNA-seq) has radically changed the observation of cellular diversity. Although annotations of RNA-seq data require preserved properties among cells of an identity, annotations using conventional methods have not been able to capture universal characters of a cell type. Analysis of expression levels cannot be accurately annotated for cells because differences in transcription do not necessarily explain biological characteristics in terms of cellular functions and because the data themselves do not inform about the correct mapping between cell types and genes. Hence, in this study, we developed a new representation of cellular identities that can be compared over different datasets while preserving nontrivial biological semantics. To generalize the notion of cell types, we developed a new framework to manage cellular identities in terms of set theory. We provided further insights into cells by installing mathematical descriptions of cell biology. We also performed experiments that could correspond to practical applications in annotations of RNA-seq data.


Vitamin E/Coenzyme Q-Dependent "Free Radical Reductases": Redox Regulators in Ferroptosis.
Significance: Lipid peroxidation and its products, oxygenated polyunsaturated lipids, act as essential signals coordinating metabolism and physiology and can be deleterious to membranes when they accumulate in excessive amounts. Recent Advances: There is an emerging understanding that regulation of polyunsaturated fatty acid (PUFA) phospholipid peroxidation, particularly of PUFA-phosphatidylethanolamine, is important in a newly discovered type of regulated cell death, ferroptosis. Among the most recently described regulatory mechanisms is the ferroptosis suppressor protein, which controls the peroxidation process due to its ability to reduce coenzyme Q (CoQ). Critical Issues: In this study, we reviewed the most recent data in the context of the concept of free radical reductases formulated in the 1980-1990s and focused on enzymatic mechanisms of CoQ reduction in different membranes (e.g., mitochondrial, endoplasmic reticulum, and plasma membrane electron transporters) as well as TCA cycle components and cytosolic reductases capable of recycling the high antioxidant efficiency of the CoQ/vitamin E system. Future Directions: We highlight the importance of individual components of the free radical reductase network in regulating the ferroptotic program and defining the sensitivity/tolerance of cells to ferroptotic death. Complete deciphering of the interactive complexity of this system may be important for designing effective antiferroptotic modalities.


Selective molecularly imprinted polymer combined with restricted access material for in-tube SPME/UHPLC-MS/MS of parabens in breast milk samples.
A new molecularly imprinted polymer modified with restricted access material (a hydrophilic external layer), (MIP-RAM) was synthesized via polymerization in situ in an open fused silica capillary. This stationary phase was used as sorbent for in-tube solid phase microextraction (in-tube SPME) to determine parabens in breast milk samples by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Scanning electron micrographs (SEM) illustrate MIP surface modification after glycerol dimethacrylate (hydrophilic monomer) incorporation. The interaction between parabens and MIP-RAM was investigated by Fourier-transform infrared (FTIR) spectroscopy. The Scatchard plot for MIP-RAM presented two linear parts with different slopes, illustrating binding sites with high- and low-affinity. Endogenous compounds exclusion from the MIP-RAM capillary was demonstrated by in-tube SPME/LC-UV assays carried out with blank milk samples. The in-tube SPME/UHPLC-MS/MS method presented linear range from 10 ng mL(-1) (LLOQ) to 400 ng mL(-1) with coefficients of determination higher than 0.99, inter-assay precision with coefficient of variation (CV) values ranging from 2 to 15%, and inter-assay accuracy with relative standard deviation (RSD) values ranging from -1% to 19%. Analytical validation parameters attested that in-tube SPME/UHPLC-MS/MS is an appropriate method to determine parabens in human milk samples to assess human exposure to these compounds. Analysis of breast milk samples from lactating women demonstrated that the proposed method is effective.


Gene expression profiling and multiple myeloma.
Gene expression profiling is a powerful tool through which the biology of multiple myeloma can be dissected. We will describe in this chapter how early studies using this technology have provided meaningful insights into myeloma biology, have led to the identification of new therapeutic targets, and have identified powerful prognostic and pharmacogenomic markers. Specifically, we will demonstrate that gene expression profiling can be used to segregate myeloma patients into prognostic categories within which known IgH translocation signatures can be readily defined. We also show that expression signatures can identify patients with chromosome 13 deletion. Finally, we demonstrate that global gene expression signatures can be distilled to short lists of three genes or more which together impart clinical outcome information, which is significantly more powerful than any previously defined prognostic tool. Expression profiling has also led to the identification of a number of new therapeutic targets not only in myeloma cell survival but also in the pathogenesis of the osteolysis which is a hallmark of this disease.


Editorial Commentary: The Efficacy of Nonsteroidal Anti-inflammatory Drugs for Prophylaxis of Heterotopic Ossification in Hip Arthroscopy--Do We Treat Patients or X-rays?
A systematic review of 5 series comparing the incidence of heterotopic ossification after hip arthroscopy with and without nonsteroidal anti-inflammatory drug prophylaxis showed a statistically significant improvement with the use of prophylaxis.


Estimating ethnic admixture from pedigree data.
This paper introduces a likelihood method of estimating ethnic admixture that uses individuals, pedigrees, or a combination of individuals and pedigrees. For each founder of a pedigree, admixture proportions are calculated by conditioning on the pedigree-wide genotypes at all ancestry-informative markers. These estimates are then propagated down the pedigree to the nonfounders by a simple averaging process. The large-sample standard errors of the founders' proportions can be similarly transformed into standard errors for the admixture proportions of the descendants. These standard errors are smaller than the corresponding standard errors when each individual is treated independently. Both hard and soft information on a founder's ancestry can be accommodated in this scheme, which has been implemented in the genetic software package Mendel. The utility of the method is demonstrated on simulated data and a real data example involving Mexican families of mixed Amerindian and Spanish ancestry.


Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.
Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p < 0.05). WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.


Motoneuronal and motor axonal innervation in the rat hindlimb: a comparative study using horseradish peroxidase.
In order to validate the horseradish peroxidase (HRP) technique as a quantitative method for assessing neuronal pools, we compared counts of labeled motoneurons to numbers of corresponding motor axons. Rat spinal motoneurons were labeled by immersing in HRP either the L4 radicular nerve or the normal or deafferented nerve to the tibialis anterior muscle (TA). The technique slightly under-valued the L4 motoneuronal population estimated by counting ventral root motor fibres, while in deafferented TA, counts of labeled neurons closely reflected numbers of motor axons. Measurements of neuron and nerve fibre diameters revealed good correlations of alpha and gamma motor estimates at spinal cord and nerve levels. Values were considered representative because of the approximation obtained in HRP-estimates between control and deafferented animals, indicating no significant damage from the surgical deafferentation.


Quartz crystal microbalance sensor based on 11-mercaptoundecanoic acid self-assembly and amidated nano-titanium film for selective and ultrafast detection of phosphoproteins in food.
A novel quartz crystal microbalance (QCM) sensor for trace-phosphoprotein ultrafast detection was constructed based on the bridge interactions between the NH2-TiO2 sites enriched on Au-electrode and phosphate groups. Herein, 11-mercaptoundecanoic acid (MUA) modified by Au-S bond acted as carrier for immobilizing NH2-TiO2. Functionalized NH2-TiO2 to absorb phosphoproteins. Under the optimal conditions, the proposed sensor showed a linear frequency shift to the concentration of α-casein ranging from 1.0 × 10-3 to 1.0 mg mL-1 with a low detection limit of 5.3 × 10-6 mg mL-1 (S/N = 3), and the limit of quantitation was 0.001 mg mL-1. Compared with traditional Ti4+-IMAC/MOAC-system, the analysis process of NH2-TiO2/MUA/AuE-QCM sensor was simpler and faster which could complete within 5 min. Additionally, the constructed biosensor was successfully used for the non-fat milk and chicken egg white. This proposed sensor presents a great prospective strategy for the evaluation of the nutrition in different foods.


Team dynamics and clinician's experience influence decision-making during Upper-GI multidisciplinary team meetings: A multiple case study.
The probability of undergoing treatment with curative intent for esophagogastric cancer has been shown to vary considerately between hospitals of diagnosis. Little is known about the factors that attribute to this variation. Since clinical decision making (CDM) partially takes place during an MDTM, the aim of this qualitative study was to assess clinician's perspectives regarding facilitators and barriers associated with CDM during MDTM, and second, to identify factors associated with CDM during an MDTM that may potentially explain differences in hospital practice. A multiple case study design was conducted. The thematic content analysis of this qualitative study, focused on 16 MDTM observations, 30 semi-structured interviews with clinicians and seven focus groups with clinicians to complement the collected data. Interviews were transcribed ad verbatim and coded. Factors regarding team dynamics that were raised as aspects attributing to CDM were clinician's personal characteristics such as ambition and the intention to be innovative. Clinician's convictions regarding a certain treatment and its outcomes and previous experiences with treatment outcomes, and team dynamics within the MDTM influenced CDM. In addition, a continuum was illustrated. At one end of the continuum, teams tended to be more conservative, following the guidelines more strictly, versus the opposite in which hospitals tended towards a more invasive approach maximizing the probability of curation. This study contributes to the awareness that variation in team dynamics influences CDM during an MDTM.


Effect of a multiple freeze-thaw process on structural and foaming properties of individual egg white proteins.
In this study, major albumen proteins (ovalbumin, ovomucoid, ovotransferrin, lysozyme and ovomucin) were singly subjected to a multiple freeze-thaw process, and the resulting changes in structural characteristics and foamability were investigated. Structural changes of proteins occurred during the process, regarding by sulfhydryl-disulfide interchange and exposure of hydrophobic groups. The differential scanning calorimetry and scanning electron microscopy showed that these albumen proteins underwent denaturation, dissociation and possibly aggregation. Correspondingly, the foaming ability of albumen proteins improved after the freeze-thaw treatment, except for ovalbumin. The foaming ability of whole egg white was higher than that of each albumen protein, and improved after the multiple freeze-thaw process. This study extended knowledge of the relative contribution of each albumen protein to foaming properties of whole egg white during a freeze-thaw process, and suggested that a multiple freeze-thaw process is a promising technique for improving foaming properties of egg white proteins.


Precise Chip-to-Chip Reagent Transfer for Cross-Reactivity-Free Multiplex Sandwich Immunoassays.
Common multiplex sandwich immunoassays suffer from cross-reactivity due to the mixing of detection antibodies and the combinatorial, undesired interaction between all reagents and analytes. Here we present the snap chip to perform antibody colocalization microarrays that eliminates undesirable interactions by running an array of singleplex assays realized by sequestering detection antibodies in individual nanodroplets. When detecting proteins in biological fluids, the absence of cross-reactivity allows a higher level of multiplexing, reduced background, increased sensitivity, and ensures accurate and specific results. The use of the snap chip is illustrated by measuring highly related analytes such as proteins isoforms and phospho-proteins, both particularly prone to cross-reactivity, in a single experiment. The main steps of the protocol are preparation of sample, incubation on an assay slide harboring the microarrayed capture antibodies, transfer of the microarrayed detection antibodies on their cognate spots, and measurement of the assay results by fluorescence.


Pneumodissection: an alternative protective technique for the percutaneous cryoablation of small renal masses.
Percutaneous cryoablation is an emerging treatment option for the small renal mass. It poses a risk of thermal injury to adjacent tissues, limiting its application. We describe pneumodissection, a novel technique for preventing thermal injury during percutaneous cryoablation. The cases of 4 patients who underwent percutaneous renal cryoablation and pneumodissection were retrospectively reviewed. Pneumodissection mechanically separated four tumors from overlying bowel segments (mean distance 1.2 ± 0.4 cm), permitting successful cryoablation. There were no complications or recurrences with 7.5 months of follow-up. Pneumodissection is a feasible displacement technique that facilitates percutaneous cryoablation in at-risk patients. Further study is warranted.


Extracellular levels of ATP and acetylcholine during lithium-pilocarpine induced status epilepticus in rats.
Acetylcholine (ACh) and ATP are rapidly acting neurotransmitters with a putative role in epileptic seizures. In the present study we investigated extracellular concentrations of both neurotransmitters in parallel by microdialysis in rat hippocampus. We found that infusion of neostigmine increases, while calcium-free perfusion and infusion of tetrodotoxin (TTX) decreases, ACh levels. Calcium-free perfusion also decreased ATP levels which were, however, not affected by neostigmine or TTX. During status epilepticus, ACh levels were increased threefold but returned to baseline after the termination of seizures by diazepam. ATP levels were unchanged during status epilepticus but a several-fold increase was seen when AOPCP, an inhibitor of 5'-endonucleotidase, was infused. The results demonstrate an increase of ATP levels during epileptic seizures which, however, was not of neuronal origin.


Hand, Foot and Mouth Disease in West Bengal, India: A Preliminary Report on Clinicovirological Trend over 3 Successive Years (2013-2015).
Hand, foot, and mouth disease (HFMD), an enteroviral disease has emerged as a major emerging infection in India. This is caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) but can also be due to CVA4-10, CVA24, CVB2-5, and echovirus 18 (Echo18). Virological analysis of the cases of HFMD has been infrequently done in India. West Bengal is one of the worst affected states in India. To document the clinical and etiological aspect, the changing patterns and clinic-virological correlation. Method: a total of 62 samples of throat swab were collected from affected children over 3 successive years in Kolkata, West Bengal, India. Five cases had a previous history of HFMD during the last 1-5 years. Fever was usually of mild degree (highest 102°C). There was no apparent correlation between fever of >100°C and a positive test. There was no correlation of viral strain and clinical severity. A test positive for the Viral RNA was noted among 64.51% (40/62) cases. Multiple strains were characteristically present in each year. CVA6, EV71 were found in 2013, CVA6, EV71 in 2014, and CVA6, CVA16 in 2015. Presence of multiple strains explained the frequent occurrence of relapses. We expect this small study will serve as an important document for all future studies on HFMD.


Large-Scale Hf0.5 Zr0.5 O2 Membranes with Robust Ferroelectricity.
Hafnia-based compounds have considerable potential for use in nanoelectronics due to their compatibility with complementary metal-oxide-semiconductor devices and robust ferroelectricity at nanoscale sizes. However, the unexpected ferroelectricity in this class of compounds often remains elusive due to the polymorphic nature of hafnia, as well as the lack of suitable methods for the characterization of the mixed/complex phases in hafnia thin films. Herein, the preparation of centimeter-scale, crack-free, freestanding Hf0.5 Zr0.5 O2 (HZO) nanomembranes that are well suited for investigating the local crystallographic phases, orientations, and grain boundaries at both the microscopic and mesoscopic scales is reported. Atomic-level imaging of the plan-view crystallographic patterns shows that more than 80% of the grains are the ferroelectric orthorhombic phase, and that the mean equivalent diameter of these grains is about 12.1 nm, with values ranging from 4 to 50 nm. Moreover, the ferroelectric orthorhombic phase is stable in substrate-free HZO membranes, indicating that strain from the substrate is not responsible for maintaining the polar phase. It is also demonstrated that HZO capacitors prepared on flexible substrates are highly uniform, stable, and robust. These freestanding membranes provide a viable platform for the exploration of HZO polymorphic films with complex structures and pave the way to flexible nanoelectronics.


Optimisation of maintenance in delivery systems for cytostatic medicines.
The real-world application of maintenance in organisations brings together a number of maintenance policies in order to achieve the desired availability, efficiency and profitability. However, the literature mostly chooses a single maintenance policy, and so the decision process is not suited to the real conditions in the company to which it is applied. Our study takes a combination of maintenance policies as alternatives, and so conforms to the actual practice of maintenance in organisations. Furthermore, it introduces the possibility of including extra spare parts, or outsourcing maintenance policies. Although the selection of maintenance policies has been applied to many kinds of business and of machine, there is almost no instance of its application to hospitals, and it has never been applied to delivery systems for cytostatic drugs. The model uses the fuzzy Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS), which is recognised as being highly suitable for solving group decision-making problems in a fuzzy environment. Fuzzy set theory is also considered to be more proficient than crisp numbers for handling the ambiguity, imprecisions, data scarcity, and uncertainty inherent in decisions made by human beings. The judgements required were obtained from a decision group comprising the heads of facilities maintenance, maintenance of medical equipment, health and safety at work, environment, and programming-admission. The group also included care staff; specifically, the heads of the main clinical services, and the medical supervisors. The model includes original criteria, such as Quality of health care, which measures impact on care as a function of mean availability of each alternative. It also considers Impact on hospital management via the criteria: Working environment in the organisation and Impact on health care; the former criterion measures equality among care services in the hospital, while the latter assesses the effect on regional health cover. The model was built using real data obtained from a state hospital in Spain. The model can also be easily applied to other national and international healthcare organisations, providing weights specific to the criteria. These are produced by a decision group from each healthcare organisation and the alternatives are updated in accordance with what is considered important in each hospital. The results obtained from the model recommend changing the alternative that is currently in use, Corrective and Preventive Maintenance, to Corrective and Preventive Maintenance plus two spare hoods. This alternative would lead to an availability of 1 (the highest possible) in the systems for preparing personalised cytotoxic drugs, and so the quality of service is therefore very high. Additionally, it could offer services to all the users of the hospital, and also offer cover in the preparation of cytotoxic medicines to other hospitals in the catchment area. The results suggest the possibility that improvements to the support and logistical systems, which include maintenance, traditionally held to have no effect on quality of care, may be key to improving care quality, but also in reducing risk to patients, care and non-care staff, and the environment.


Understanding stakeholder power and influence gaps in a health care organization: an empirical study.
Scholars have vigorously debated the role of stakeholders since Freeman's 1984 landmark work. This article argues that an accurate assessment of relative power levels can enable stakeholders to accept their proper roles and responsibilities in planning and implementing strategy and enabling Top Management Teams to more fully integrate stakeholders' interest into the planning process.


TPA-induced neurite formation in a neuroblastoma cell line (SH-SY5Y) is associated with increased IGF-I receptor mRNA and binding.
The neuroblastoma cell line SH-SY5Y was cultured in the presence of TPA for three days. Increased neurite formation was noted as early as 24 hours after TPA was added. These changes were associated with an increase in IGF-I receptor binding as well as increased mRNA for the IGF-I receptor.


Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Systematic Review of Economic Evaluations.
Several studies have evaluated the economic evaluation of a group of medications known as novel oral anticoagulant drugs (NOACs) in recent years. The aim of this study is to review and systematically analyze the cost-utility studies results of warfarin compared with other NOAC drugs in atrial fibrillation patients. A systematic review was performed to identify all studies evaluating the NOAC medications in comparison with warfarin. For this purpose, PubMed, Cochrane Library, ISI Web of Science, and Scopus were searched from 2013 to 2022. Articles were independently screened with inclusion criteria, and full texts were reviewed. First, the Consolidated Health Economic Evaluation Reporting Standards checklist was used to evaluate the quality of the articles. Then, the costs and outcomes of the studies were analyzed, and findings were appraised critically. A total of 84 costs-per-quality-adjusted life-year (QALY) cases were extracted from the studies in which the share of rivaroxaban, edoxaban, apixaban, and dabigatran were 31%, 13%, 29%, and 27%, respectively. The median cost per QALY of rivaroxaban, edoxaban, apixaban, and dabigatran was 21 910$/QALY, 22 096$/QALY, 17 765$/QALY, and 24 161$/QALY, respectively. Subgroup analysis based on perspective showed that dabigatran had the highest incremental cost-effectiveness ratio (ICER) and edoxaban had the lowest ICER value. Edoxaban and apixaban had the highest and the lowest cost per QALY from an insurance perspective, respectively. Despite the differences and variations in the economic evaluation studies of NOAC drugs, these drugs have shown acceptable cost-effectiveness in developed and developing countries. Among NOAC drugs, apixaban has the lowest ICER and the highest cost-effectiveness.


Continuity and change in the development of category-based induction: The test case of diversity-based reasoning.
The present research examined the extent to which the cognitive mechanisms available to support inductive inference stay constant across development or undergo fundamental change. Four studies tested how children (ages 5-10) incorporate information about sample composition into their category-based generalizations. Children's use of sample composition varied across age and type of category. For familiar natural kinds, children ages 5-8 generalized similarly from diverse and non-diverse samples of evidence, whereas older children generalized more broadly from more diverse sets. In contrast, for novel categories, children of each age made broader generalizations from diverse than non-diverse samples. These studies provide the first clear evidence that young children are able to incorporate sample diversity into their inductive reasoning. These findings suggest developmental continuity in the cognitive mechanisms available for inductive inference, but developmental changes in the role that prior knowledge plays in shaping these processes.


A mitochondrial iron-responsive pathway regulated by DELE1.
The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.


Value of the 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. A pilot study.
The non-invasive diagnosis of endometriosis remains challenging. Recent data suggested that somatostatin might be involved in its pathogenesis. High sensitive visualization of somatostatin receptors expression is possible using PET-CT imaging after the administration of a 68Ga-labeled somatostatin analog (DOTATATE) that will bind to the somatostatin receptor sub-types 2 and 5. The aim of the present study was to assess the usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. This is a prospective, single center pilot study. A pre operative 68Ga-DOTATATE PET-CT was performed in all of the patients who presented with suspected endometriosis and who were scheduled for a laparoscopy. Surgical endometriosis staging and histopathological analysis, including somatostatin receptors SST1, 2 and 5 immunohistochemistry (IHC) of removed specimens, were confronted to the results of the 68Ga-DOTATATE PET-CT. 12 patients were included in this study. 68Ga-DOTATATE PET-CT performed pre operatively showed increased pathologic uptake in four patients with a deep infiltrating endometriosis (DIE) recto-vaginal lesion and in another patient with an adenomyoma. Expression of SST1, 2 and 5 receptors in surgical specimens was confirmed by IHC in these five lesions. Neither superficial peritoneal endometriosis, nor ovarian endometrioma were found to show an increased pathologic uptake on 68Ga-DOTATATE PET-CT. IHC analysis confirmed that SST1, 2, and 5 receptors were not present in these lesions. The results observed in this small size series of patients seem to confirm expression of somatostatin receptors only in recto-vaginal DIE and focal adenomyosis lesions. The usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of this entity is uncertain. Future research should concentrate on studying the role of somatostatin in the pathogenesis of DIE.


[Possible concentration-dependent mechanism of action exerted by epinephrine on giant neurons].
The results of an investigation carried out suggest that both the stimulating and inhibitory action of epinephrine on the neuronal activity are mediated by the adenylate-cyclase system. The reason of the effect of epinephrine depending on its concentration is, apparantly, the polyfunctionality of the "second mediator"--cAMP and the primordial existence in the cells of processes oppositely influencing its functional activity, whose intensity depends on the concentration of cAMP.


Characterization of electron transfer from water to plastocyanin catalyzed by resolved electron transfer complexes from chloroplasts.
The photoreduction of soluble plastocyanin in a homologous reconstituted system requires a resolved Photosystem II preparation and the cytochrome b6-f complex from spinach chloroplasts. Oxygen evolution is linked quantitatively to plastocyanin reduction in the reconstituted system, indicating that water is the electron donor for the photoreduction. The photoreduction is sensitive to inhibitors which specifically interact with the Photosystem II preparation [DCMU: 3-(3,4-dichlorophenyl)-1,1-dimethylurea] as well as those which interact with the cytochrome complex (DNP-INT: 2-iodo-6-isopropyl-3-methyl-2',4,4'-trinitrodiphenyl ether; and DBMIB: 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone). The plastocyanin requirement in the reconstituted system indicated a Km of 4.6 microM and a Vmax of 4.2 mumols plastocyanin reduced per nmol cytochrome f per h. Inhibition curves for DNP-INT and DBMIB show that both are effective inhibitors (50% inhibition at a ratio of inhibitor to cytochrome f of 1.0). The rate of reduction of plastocyanin was found to be stimulated by cations. This dependency was localized in the transfer of electrons from the Photosystem II preparation to the cytochrome complex. These results are considered in terms of organizational aspects of integral protein complexes in thylakoid membranes.


Elemental analysis with a full-field X-ray fluorescence microscope and a CCD photon-counting system.
The first result is presented of an X-ray fluorescence microscope with a Wolter mirror in combination with a CCD camera used as an energy-resolved two-dimensional detector in photon-counting mode. Two-dimensional elemental maps of metallic wires, such as Fe, Co, Ni and Cu, and inclusions of a synthesized diamond could be obtained with an energy resolution of 350 eV.


Epidemiology and treatment of proximal femoral fractures in the elderly U.S. population.
Proximal femoral fractures are a serious complication, especially for elderly patients. Detailed epidemiological analyzes provide a valuable resource for stakeholders in the health care system in order to foresee future development possibly influenceable by adaption of therapeutic procedures and prevention strategies. This work aimed at answering the following research questions: (1) What are the incidence rates of proximal femoral fractures in the elderly U.S. population? (2) What is the preferred treatment procedure for these fractures? Proximal femoral fractures occurred between January 1, 2009 and December 31, 2019 in patients ≥ 65 years were identified from the Medicare Physician Service Records Data Base. The 5% sample of Medicare beneficiaries, equivalent to the records from approximately 2.5 million enrollees formed the basis of this study. Fractures were grouped into head/neck, intertrochanteric, and subtrochanteric fractures. The overall incidence rate, age and sex specific incidence rates as well as incidence rate ratios were calculated. Common Procedural Terminology (CPT) codes were used to identify procedures and operations. In 2019, a total number of 7982 femoral head/neck fractures was recorded. In comparison to 9588 cases in 2009, the incidence substantially decreased by 26.6% from 666.7/100,000 inhabitants to 489.3/100,000 inhabitants (z = - 5.197, p < 0.001). Also, in intertrochanteric fractures, a significant decline in the incidence by 17.3% was evident over the years from 367.7/100,000 inhabitants in 2009 to 304.0 cases per 100,000 inhabitants in 2019 (z = - 2.454, p = 0.014). A similar picture was observable for subtrochanteric fractures, which decreased by 29.6% (51.0 cases per 100,000 to 35.9 cases per 100,000) over the time period (z = - 1.612, p = 0.107). Head/neck fractures were mainly treated with an arthroplasty (n = 36,301, 40.0%). The majority of intertrochanteric fractures and subtrochanteric fractures received treatment with an intramedullary device (n = 34,630, 65.5% and n = 5870, 77.1%, respectively). The analysis indicated that the incidence of all types of proximal femoral neck fractures decreased for the population of elderly patients in the U.S. within the last decade. Treatment of head and neck fractures was mainly conducted through arthroplasty, while intertrochanteric and subtrochanteric fractures predominantly received an intramedullary nailing.


Axonal growth in mesothelial chambers: effects of a proximal preconditioning lesion and/or predegeneration of the distal nerve stump.
Preformed, autologous mesothelial chambers were utilized to study axonal growth following selective predegeneration of the distal nerve stump and/or preconditioning of the proximal nerve stump. The left and/or right sciatic nerve of rats was exposed and transected in the thigh. Two weeks after transection, the left proximal nerve stump was cross-anastomosed with the right distal nerve stump by using a mesothelial chamber leaving a 15-mm gap between the two nerve stumps. Previous studies have shown that axonal overgrowth normally does not occur over this gap distance to the distal stump. Three months after cross-anastomosing, regeneration across the 15-mm gap was evaluated by muscle action potential recordings and light microscopical examination. In experiments in which a distal nerve stump was selectively degenerated and the proximal segment was freshly cut, axons had bridged the 15-mm gap in six of seven rats. When a proximal preconditioned nerve stump was matched with a freshly cut distal stump, axonal overgrowth occurred in only 4 of 10 experiments. In experiments including a proximal preconditioned nerve stump and a distal predegenerated stump, axons bridged the gap in 6 of 8 experiments. We concluded that a priming lesion, including manipulation with proximal and/or distal stump, enhances axonal growth in mesothelial chambers.


Anti-arcing loop and resectoscope.
A new modified cutting loop assembly and a modification of the resectoscope to prevent arcing between the bare wire loop and the distal end of the telescope are described.


IFN-gamma withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin alphavbeta3 signaling.
Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-gamma after immunotherapy. The relief of IFN-gamma stress led to the increase of alphavbeta3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through alphavbeta3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-gamma. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits alphavbeta3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-gamma and that targeting alphavbeta3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk.


Ultrasonic flow measurement and wall acoustic impedance effects.
An examination of the influence of wall acoustic impedance effects on sound propagation in flowing liquids confined by cylindrical walls is presented. Special focus is given to the importance of the wall acoustic impedance value for ultrasonic flow meter performance. The mathematical model presented allows any radially-dependent axial flow profile to be examined in the linear flow acoustics regime where fluid flow speed is much smaller than the fluid sound speed everywhere in the fluid medium.


Midterm follow-up results of a novel technique: Contralateral breast overlapped reconstruction after mastectomy for unilateral breast cancer.
The breasts of Oriental women are characterized by an obvious scar constitution and a relatively small mammary gland volume. Thus, plastic surgery, which is now popular in the West, is not suitable for most patients in China, and Chinese surgeons are searching for symmetrical plastic surgery options that are suitable for patients with breast tumors, unilateral breast implants and an obvious scar constitution. Between January 2016 and December 2019, 15 patients underwent contralateral breast overlapped reconstruction (COBOR) at the Affiliated Hospital of Putian University. We assessed their clinicopathological data, complications, cosmetic satisfaction and quality of life. The mean age was 41.6 years (range, 31-54 years), the average BMI was 24.36 kg/m2 (range, 20.3-28.4 kg/m2), the most common tumor location was the upper outer quadrant (n = 9), the mean preoperative tumor size was 21.11 mm (range, 7-42 mm), and 4 patients underwent neoadjuvant chemotherapy. The cancer grades and histological types were as follows: G3 nonspecial type (NST), 3 cases; G2 NST, 6 cases; G2 lobular carcinoma, 1 case; and ductal carcinoma in situ (DCIS), 5 cases. The nipple margin was negative in all of these cases. Among them, there was 1 case of poor wound healing caused by subcutaneous fat liquefaction around the incision. In another case, partial nipple necrosis occurred on the affected side due to an insufficient nipple blood supply after the operation and healed after debridement and dressing changes. There were no cases of tumor recurrence during the mean follow-up of 22.53 months (range, 11-47 months). The BREAST-Q scores showed that COBOR provided good patient satisfaction. For Oriental patients with small breasts, COBOR, which results in fewer scars, good symmetry and good satisfaction, is an effective and safe surgical method. However, larger studies with longer follow-up periods are needed to obtain more reliable postoperative results.


Albumin, copper, manganese and cobalt levels in children suffering from sickle cell anemia at Kasumbalesa, in Democratic Republic of Congo.
Sickle Cell Anemia (SCA) is characterized by high levels of oxidative stress markers and low levels of antioxidant capacity. Antioxidant defence mechanisms against the harmful effects of ROS requires cellular and extracellular enzymes. These enzymes requires micronutrient for complete activity. Information on micronutrients such as manganese, cobalt and copper in SCA population was poorly documented in the literature. Plasma copper, manganese, cobalt and albumin concentrations determined by atomic absorption spectrophotometry were compared between two groups of children: 76 with SCA (Hb-SS) and 76 without SCA (controls). This study was conducted in the Muhona Hospital of Kasumbalesa, which is situated in a rural and low in resources. The mean age was 10.0 years (SD = 5.4) in SCA children and 9.2 years (SD = 4.7) in the control group. The levels of cobalt, manganese, copper and albumin were not different between the two groups (p > 0.05). In our study, albumin, manganese, cobalt and copper values did not differ between SCA children in steady state and Hb-AA children. The lack of differences in plasma elemental concentrations between the two groups in context of increased demands in the SCA group, may represent adequate compensatory intake or elemental dyshomeostasis in the SCA group.


Bilateral semilunar perihilar opacities in a patient with pulmonary hypertension.
Pulmonary arterial aneurysm is a rare entity with a high mortality if left untreated. Pulmonary arterial hypertension is an important cause of PAAs although other infective and auto-immune causes must be excluded when an aneurysm is identified.


Source cancellation profiles of electroencephalography and magnetoencephalography.
Recorded electric potentials and magnetic fields due to cortical electrical activity have spatial spread even if their underlying brain sources are focal. Consequently, as a result of source cancellation, loss in signal amplitude and reduction in the effective signal-to-noise ratio can be expected when distributed sources are active simultaneously. Here we investigate the cancellation effects of EEG and MEG through the use of an anatomically correct forward model based on structural MRI acquired from 7 healthy adults. A boundary element model (BEM) with four compartments (brain, cerebrospinal fluid, skull and scalp) and highly accurate cortical meshes (~300,000 vertices) were generated. Distributed source activations were simulated using contiguous patches of active dipoles. To investigate cancellation effects in both EEG and MEG, quantitative indices were defined (source enhancement, cortical orientation disparity) and computed for varying values of the patch radius as well as for automatically parcellated gyri and sulci. Results were calculated for each cortical location, averaged over all subjects using a probabilistic atlas, and quantitatively compared between MEG and EEG. As expected, MEG sensors were found to be maximally sensitive to signals due to sources tangential to the scalp, and minimally sensitive to radial sources. Compared to EEG, however, MEG was found to be much more sensitive to signals generated antero-medially, notably in the anterior cingulate gyrus. Given that sources of activation cancel each other according to the orientation disparity of the cortex, this study provides useful methods and results for quantifying the effect of source orientation disparity upon source cancellation.


Modulation of pentylenetetrazol-induced seizures by prostaglandin E2 receptors.
There is evidence that prostaglandin E2 (PGE2) facilitates the seizures induced by pentylenetetrazol (PTZ), but the role of PGE2 receptors (EPs) in the development of seizures has not been evaluated to date. In the current study we investigated whether selective EP ligands alter PTZ-induced seizures in adult male Wistar rats by electrographic methods. Selective antagonists for EP1 (SC-19220, 10 nmol, i.c.v.), EP3 (L-826266, 1 nmol, i.c.v.) and EP4 (L-161982, 750 pmol, i.c.v.) receptors, and the selective EP2 agonist butaprost (100 pmol, i.c.v.) increased the latency for clonic and generalized tonic-clonic seizures induced by PTZ. These data constitute pharmacological evidence supporting a role for EPs in the seizures induced by PTZ. Although more studies are necessary to fully evaluate the anticonvulsant role these compounds and their use in the clinics, EP ligands may represent new targets for drug development for convulsive disorders.


Hydrocarbon ingestion: an unusual cause of multiple pulmonary pseudotumors.
I have reported a case of multiple pseudotumors seen on chest x-ray film after ingestion of roach killer in a suicide attempt. Hydrocarbon ingestion should be added to the list of causes of multiple pulmonary mass lesions.


Vestibular versus tail-pinch activation in cats with lateral hypothalamic lesions.
Mild tail-pinch induces eating in animals which are aphagic following lateral hypothalamic lesions. This study compares the specificity of the behavior produced by tail-pinch to that produced by vestibular stimulation in cats which are akinetic and aphagic following lateral hypothalamic lesions. In these cats, tail-pinch elicited licking and biting at food while vestibular stimulation preferentially elicited forward locomotion. These results suggest that such stimuli activate specific movement subsystems rather than producing general, nonspecific arousal.


Combined volar and dorsal plating for complex comminuted distal radial fractures.
To review outcomes of combined volar and dorsal locked plating for AO type-C3 complex comminuted distal radial fractures. Records of 24 patients aged 17 to 77 (mean, 53.3) years who underwent combined volar and dorsal locked plating for AO type-C3 distal radial fractures with volar and dorsal metaphyseal and intra-articular comminution were reviewed. 21 were closed fractures, and 3 were Gustilo-Anderson type-1 open fractures. Bone union, volar tilt, radial inclination, radial height, range of motion, grip strength, and any complications were assessed by a single hand surgeon. After a mean follow-up of 17 (range, 14-25) months, the mean palmar flexion was 49º (range, 30º-80º), dorsiflexion was 52º (range, 30º-80º), supination was 86º (range, 60º-90º), pronation was 77º (range, 30º-90º), radial deviation was 16º (range, 5º-30º), and ulnar deviation was 27º (range, 10º-50º). The mean grip strength of the injured hand was 69.2% of the uninjured side. The mean time to radiological union was 3.9 (range, 2.5-6.0) months; no patient had non-union. At the time of union, the mean volar tilt was 5º (-22º-14º), radial inclination was 18.6º (8º-28º), and radial height was 8.5 mm (5.0 mm-13.6 mm). One patient had collapse of the dorsal fragment resulting in a dorsal tilt of 22º and limited (30º) forearm pronation. The severity of dorsal metaphyseal comminution had not been recognised and bone grafting was not performed. The patient also had minor complications of little finger flexor tendon irritation and carpal tunnel syndrome. She underwent implant removal and carpal tunnel release at 8 months. One patient had implant-related extensor digitorum communis irritation. Another patient had non-specific chronic wrist pain, which was resolved at one year. No patient had infection, tendon rupture, or complex regional pain syndrome. Four patients underwent implant removal, including 2 who had no implant-related problems. Combined volar and dorsal plating enables early mobilisation and good outcome for certain complex comminuted distal radial fractures.


Gender and chronic stress effects on the neural retina of young and mid-aged Fischer-344 rats.
Young (5 months) and mid-aged (11 months) male and female Fischer rats were exposed to daily (5 days/week) chronic escapable foot-shock stress for 6 months. Following a subsequent 1-month rest period, by which time the animals were 12 and 18 months old, neural retinas were evaluated histopathologically and morphometrically. A significant reduction in the thickness of the retina occurred in the mid-aged, as compared to the young animals. A severe age-related loss in photoreceptor cells, particularly in the peripheral zones of the retina, occurred in a pattern resembling that described for aging humans. The effect of stress was to increase photoreceptor loss in a pattern resembling that of age-related cell loss. Stress-associated photoreceptor cell death was observed in males and females of both ages, but was more pronounced and statistically significant for mid-aged males (a five-fold increase in cell loss over females). The results demonstrated that exposure of rats to chronic escapable foot-shock stress exacerbates retinal changes commonly associated with aging and that the deleterious effects of chronic stress exposure were greater in the older age, male group.


White-light-emitting hydrogels with self-healing properties and adjustable emission colors.
White-light-emitting soft materials with self-healing properties show extensive applications in many fields. Herein, a novel self-healing hydrogel is successfully fabricated using oxidized dextran (Odex) and dithiodipropionate dihydrazide (TPH). Carbon dots (CDs), Riboflavin (Ri) and Rhodamine B (RhB) are incorporated into the gel matrix to produce white light emission through fluorescence resonance energy transfer (FRET) process, thus achieving excellent Commission Internationale de L'eclairage (CIE) coordinate value of (0.30, 0.33). The emission colors can be easily tuned via changing proportions of three emitters or the excitation wavelength. When the hydrogels are coated on an ultraviolet light-emitting diodes (UV LED), the hydrogel coating converts UV light to white light and repairs itself in 20 h while a hole is dug from it. Thanks to reversible exchanging reactions of acylhydrazone and disulfide bonds in hydrogel networks, the hydrogel coating exhibits perfect self-healing property in a wide range of pH (from 5 to 9 except for 7). The excellent emission and self-healing properties of hydrogels have great value in practical applications.


High sensitivity troponin T and I reflect mitral annular plane systolic excursion being assessed by cardiac magnetic resonance imaging.
This study aims to evaluate the association between high sensitivity troponins (hsTn) and mitral annular plane systolic excursion (MAPSE) in patients undergoing cardiac magnetic resonance imaging (cMRI). Patients undergoing cMRI were prospectively enrolled. Patients with right ventricular dysfunction (< 50%) were excluded. Blood samples for measurements of hsTn and amino-terminal pro-brain natriuretic peptide (NT-proBNP) were collected at the time of cMRI. 84 patients were included. Median left ventricular ejection fraction was 59% (IQR 51-64%). HsTn were correlated inversely with MAPSE within multivariable linear regression models (hsTnI: Beta - 0.19; T - 1.96; p = 0.05; hsTnT: Beta - 0.26; T - 3.26; p = 0.002). HsTn increased significantly according to decreasing stages of impaired MAPSE (p < 0.003). HsTn discriminated patients with impaired MAPSE < 11 mm (hsTnT: AUC = 0.67; p = 0.008; hsTnI: AUC = 0.64; p = 0.03) and < 8 mm (hsTnT: AUC = 0.79; p = 0.0001; hsTnI: AUC = 0.75; p = 0.001) and were still significantly associated in multivariable logistic regression models with impaired MAPSE < 11 mm (hsTnT: OR = 4.71; p = 0.002; hsTnI: OR = 4.22; p = 0.009). This study demonstrates that hsTn are able to reflect MAPSE being assessed by cMRI.


Discrete choice experiments: An overview on constructing D-optimal and near-optimal choice sets.
Discrete choice experiments (DCEs) are frequently used to estimate and forecast the behavior of an individual's choice. DCEs are based on stated preference; therefore, underlying experimental designs are required for this type of study. According to psychologists, DCE designs consist of a small number of choice sets with a limited size in the number of alternatives within a choice set to increase the response efficiency in the questionnaire. Even though algorithmic constructions (known as efficient designs) become quite common for practitioners, optimal designs (sometimes so-called orthogonal designs) continue to be used in choice experiment studies, particularly in the case that prior information about the extent of the population preference is not available. Various approaches have been developed to construct DCE designs with fewer choice sets. However, the question in many practitioners' minds is which techniques perform better (i.e. given small designs with high efficiency) in a given circumstance. In this paper and to address these concerns, we conducted an overview of the constructions of discrete choice experiments in the literature for models with only main effects. The various ways of constructing optimal and near-optimal designs were compared in terms of their ability to minimize the number of choice sets in the survey. Our findings shed light on the optimal sample sizes needed for efficient experimentation which then can help the researchers to design more effective experiments in this area.


A rare complication of pyogenic hepatic abscess after laparoscopic sleeve gastrectomy-case report and literature review emphasizing the role of imaging.
A pyogenic hepatic abscess is an uncommon complication after laparoscopic sleeve gastrectomy (LSG) that can develop secondary to an infected hematoma or a staple line leak due to bacterial seeding. Appropriate screening for and management of a pyogenic hepatic abscess are essential in patients with clinical suspicion for complications after LSG. Early diagnosis is essential as pyogenic hepatic abscess can be fatal if not treated early. Only five cases have been reported in the literature so far. We present a case of pyogenic hepatic abscess that occurred two weeks after LSG in a 46-year-old female without immunosuppressive conditions or early postoperative leak. The abscess was diagnosed by computed tomography (CT) and was successfully treated with antibiotics and CT-guided drainage.


Ethical issues in genetic screening for susceptibility to chronic lung disease.
The extent, severity, and irreversible nature of chronic lung disorders associated with occupation dictate careful review of any potentially mitigating measure. A genetic predisposition to lung injury is known to occur in the small percentage of individuals who are homozygous for alpha-1-antitrypsin (AAT) deficiency, a defect in the protein needed for inactivating proteolytic enzymes released after lung injury. It was found that the contribution of homozygous affected individuals to the total population at risk for chronic lung disease is too small (0.5% to 2.0%) to warrant screening. Screening could be justified if the more prevalent heterozygous AAT-deficient individuals were also at greater risk. A literature review demonstrated that up to 27.2% of persons of Spanish and 12.3% of Anglo-Saxon heritage but virtually no blacks or persons of Eastern origin are heterozygous for AAT alleles. Some heterozygous phenotypes are statistically overrepresented in hospitalized populations and among workers with impaired lung function, suggesting that they are statistically at slightly greater risk for developing lung disease than are homozygous normal individuals. These data suggest that a screen for AAT carriers would be marginally acceptable scientifically, but would pose ethical questions of discrimination and equity in use of disease-detecting resources. Review of ethical criteria for screening, particularly the availability of experimental therapies, increases the cogency and reinforces the acceptability of performing occupational tests for both homozygous and heterozygous AAT-deficient persons. Currently, programs directed at early detection of symptomatic workers coupled with reduction or elimination of offending agents are scientifically and ethically more warranted than full-scale genetic screening for AAT deficiency.


Nodal metastases in thyroid cancer: prognostic implications and management.
The significance of cervical lymph node metastases in differentiated thyroid cancer has been controversial and continues to evolve. Current staging systems consider nodal metastases to confer a poorer prognosis, particularly in older patients. Increasingly, the literature suggests that characteristics of the metastatic lymph nodes such as size and number are also prognostic. There is a growing trend toward less aggressive treatment of low-volume nodal disease. The aim of this review is to summarize the current literature and discuss prognostic and management implications of lymph node metastases in differentiated thyroid cancer.


Primary Follicular Lymphoma of the Gastrointestinal Tract: Case Report and Review.
Primary gastrointestinal follicular lymphoma (GI-FL) is considered a rare disease with fewer than 400 cases reported in the literature. It accounts for roughly 1-3 % of GI non-Hodgkins lymphomas (NHL). It originates in the GI tract and typically affects small bowel. The disease has an indolent course, and a prolonged survival can be expected in most cases. Due to its rarity, an optimal diagnostic work up and treatment plan has not been well established. Endoscopic evaluation of the entire gastrointestinal (GI) tract using esophagogastroduodenoscopy (EGD), wireless capsule endoscopy, double-balloon enteroscopy, colonoscopy, and whole body examination with fluorodeoxyglucose-positron emission tomography (FDG-PET) has been suggested to more accurately stage the disease and guide the treatment plan. Treatment options for GI follicular lymphoma include watch and wait strategy, surgery, chemotherapy, radiation, immuno-radiotherapy, or a combination of these modalities. In this article, we have summarized the existing information regarding clinical presentation, diagnostic evaluation, and treatment options for this rare entity after presenting a case of GI-FL who was diagnosed during an EGD for evaluation of belching, heartburn, and weight loss.


[Latest Progress of Intraoperative Pleural Lavage Cytology in Lung Cancer Surgery].
Intraoperative pleural lavage cytology is a diagnostic technique used to detect tumor cells and serve as a prognostic parameter for non-small cell lung cancer (NSCLC) patients. In the past several decades, many scholars have been dedicated to clarifying the relationships between positive intraoperative pleural lavage cytology results and postoperative survival as well as tumor recurrence and metastasis. However, the findings remained various due to the inhomogeneity of different research. It has been confirmed that a positive intraoperative pleural lavage cytology result is one of the risk factors for the prognosis of postoperative patients. This study reviewed the advances in research of intraoperative pleural lavage cytology in recent years from several aspects, including clinical significance, influencing factors and possible mechanisms. .


Individuals who sustain nonosteoporotic fractures continue to also sustain fragility fractures.
This retrospective case control study was done in order to investigate whether patients who sustain a "nonosteoporotic fracture" early in life also continue to sustain fragility fractures later in life. All patients who had been treated at the Department of Orthopedics in Malmö with a tibial shaft fracture from 1949 to 1963 (n = 767) or an ankle fracture from 1961 to 1965 (n = 786) were included in this study. At the time of follow-up in 1992, 231 of the patients who sustained a tibial shaft fracture and 260 of the patients who sustained an ankle fracture were still living in the city of Malmö. Objective registration was done of all subsequent fractures that these former patients had sustained. Comparison was done with corresponding data from double numbers of age- and sex-matched controls who at that time (1950s and 1960s) had no such fractures. At the time of the fracture as well as today, the controls were living in the area of Malmö. Individuals with earlier tibial or ankle fractures had an increased incidence of fractures generally classified as fragility fractures. There was no difference in this respect between men and women, nor whether the initial fracture had been diaphyseal or metaphyseal. We conclude that sustenance of fractures early in life may serve as a predictor for fragility fractures later in life.


Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)-S14297.
The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.


Rapid and multiplexed transcript analysis of microbial cultures using capillary electophoresis-detectable oligonucleotide probe pools.
A rapid assay for multiplex transcript analysis based on solution hybridization with pools of oligonucleotide probes was developed. In this assay called TRAC (transcript analysis with aid of affinity capture) the mRNAs to be studied are hybridized with gene-specific detection probe pools and biotinylated oligo(dT) and captured on streptavidin-coated magnetic particles. Unbound sample material and nonspecifically bound detection probes are removed and the target-specific probes are eluted and detected by capillary electrophoresis. Simultaneous treatment of 96 samples was automated using a magnetic bead particle processor. The assay enabled detection of in vitro transcribed RNA at the level of 30 amol (20 pg) and over a 300-fold linear range. Besides extracted RNA, crude cell lysates were directly used as samples. The assay was used for transcriptional analysis of selected mRNAs in the filamentous fungus Trichoderma reesei in two experimental conditions. TRAC analysis was highly reproducible, providing expression results that were consistent with conventional Northern blot analysis. The whole procedure starting from sample collecting can be carried out in 2 h, making this assay suitable for high-throughput analysis of a limited set of mRNAs e.g. in gene expression monitoring of production organism in microbial bioprocesses.


Parents and school children reported symptoms and treatment of allergic disease differently.
To examine the difference between children and their parents in reporting symptoms and treatment of allergic diseases within a longitudinal birth cohort. Information on symptoms and treatment of asthma, rhinitis, and eczema was obtained by questionnaire from 2,744 children (mean age: 12 years) and their parents. Differences between the responses were computed, and agreement assessed both absolutely and with kappa coefficient. On 12 of the 15 questions, children's and parents' reports differed significantly. Asthma-related issues appeared significantly more prevalent in the children's reports, although kappa values were fair to very good. For symptoms of allergic rhinitis, the prevalence pattern varied, and kappa values were moderate to good. Parents reported a higher prevalence of eczema-related issues, but the children reported a significantly higher prevalence of eczema itself. Kappa values ranged from moderate to good. Although reports of allergic symptoms and treatment by 12-year-old children and their parents were in moderate-to-good agreement, children reported more symptoms than their parents. Symptoms of allergic disease should be reported by children themselves, from the age of 11 years, whereas questions of prescribed pharmacological treatment could be answered either by the children or their parents.


Genetic variation of a fimbrial protein from Porphyromonas gingivalis and its distribution in patients with periodontal diseases.
Pg-II fim from various strains of Porphyromonas gingivalis was classified on the basis of each nucleotide sequence, while the distribution of Pg-II fim types in 141 subgingival plaque samples was analyzed using PCR assays. Pg-II fim was divided into two types as follows: strains OMZ409, HG405, 381, ATCC 33277 and BH18/10 (type 1) and strains OMZ314 and HW24D-1 (type 2). The presence of P. gingivalis was demonstrated in 2.8% of healthy subjects and 56.1% of patients with periodontal diseases, and Pg-II fim was detected in 91.8% of the P. gingivalis-positive subjects. We also analyzed the distribution of the Pg-II fim types among Pg-II fim-positive patients, with the following results: type 1 (38.2%), type 2 (56.4%) and types 1 and 2 (5.4%). These findings strongly suggest that P. gingivalis organisms possessing Pg-II fim type 2 was principally detected in patients with periodontal diseases.


Melatonin-induced augmentation of collagen deposition in cultures of fibroblasts and myofibroblasts is blocked by luzindole--a melatonin membrane receptors inhibitor.
Melatonin has been proven to have a regulatory influence on collagen accumulation in different types of wound. It was found to inhibit collagen accumulation in the superficial wound model but increase it in the myocardial infarction scar. The aim of the study is to determine the mechanism of melatonin action in the two wound types in rats. Cells were isolated from both the superficial wound (subcutaneously inserted polypropylene net) and myocardial infarction scar (induced by ligation of the left coronary artery) and were identified by electron microscopy. Long-shaped cells forming whirl-like structures in culture (mainly identified as fibroblasts) were isolated from the superficial wound model, while myofibroblasts growing in a formless manner were acquired from the infarcted heart scar. Melatonin (10(-7) M) increased collagen accumulation in both fibroblast and myofibroblast cultures. Luzindole (10(-6) M), the blocker of both MT1 and MT2 melatonin membrane receptors, inhibited the effect of melatonin on the two types of cells. Regardless of various healing potentials demonstrated by the tested cells (different cell composition, growth and organization), their response to melatonin was similar. Moreover, in the two investigated cultures, augmentation of the collagen content by melatonin was reversed by luzindole, which indicates the possibility of melatonin membrane receptor involvement in that process. The present results suggest that the increased melatonin-stimulated deposition of collagen observed in the infarcted heart of rats could be dependent on activation of the melatonin membrane receptors on scar myofibroblasts.


Outpatient experience of patients with GERD in the United States: analysis of the 1998-2001 National Ambulatory Medical Care Survey.
This study documents the number of ambulatory visits associated with gastroesophageal reflux disease (GERD) in the United States. Sample data from nearly 80,000 patients captured by the National Ambulatory Medical Care Survey (NAMCS; 1998-2001) were analyzed. Basic demographics of patients with GERD and factors associated with each visit were assessed. Approximately 38.53 million of 2.653 billion adult outpatient visits made in the United States during the study period were GERD-related. GERD-related visits increased by 46.5% from 1998 to 2001. Most GERD-related visits were by women (54.7%) with an average age of 56.0 years, compared with patients without GERD, who were even more likely to be women (62.2%) and younger (52.6 years). Patients with GERD were more likely to have multiple reasons (50.5%) and multiple diagnoses (79.3%) per medical visit versus non-GERD patients (37.6% and 48.4%, respectively). Utilization of data from the NAMCS reveals that GERD-related visits increased annually during the study period. Patients with GERD are more likely to see a physician if they have concomitant medical conditions, making GERD a condition that is very likely untreated in a high percentage of individuals.


Multi-Energy CT Applications: Problem-Solving in Emergency Radiology.
Multi-energy computed tomography is a technology that is being increasingly used in the emergency room (ER) setting and has many applications that can impact patient care, including virtual monoenergetic imaging and material-specific imaging. It is important for radiologists to understand this technology, and how it can be optimally used in the ER setting.


Application of adrenocorticotropic hormone in recurrent focal segmental glomerulosclerosis post-transplantation: A case report and literature review.
The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.


Vitamin D status in youth with type 1 and type 2 diabetes enrolled in the Pediatric Diabetes Consortium (PDC) is not worse than in youth without diabetes.
To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels. 25-hydroxy vitamin D (25OHD) levels were measured in 215 youth with T1D and 326 youth with T2D enrolled in the Pediatric Diabetes Consortium (PDC). These levels were compared with those of youth of the same age without diabetes from the 2005-2006 NHANES Survey. Vitamin D deficiency (<21 ng/mL) was present in 36% of PDC participants, and insufficiency (21-29 ng/mL) was present in an additional 34%. About 36% of age-matched youth in the NHANES Survey were vitamin D deficient and an additional 41% were insufficient. Deficiency or insufficiency varied by race/ethnicity, being highest in African-Americans (86%), intermediate in Hispanics (77%), and lowest in non-Hispanic whites (47%). Lower 25OHD levels were observed in African-American and Hispanic youth, during fall and winter, and at sites in the northern United States (all p-values < 0.001). Youth with T2D had significantly lower 25OHD levels than youth with T1D (p < 0.001), but this difference was largely eliminated after adjusting for race/ethnicity and socio-economic status. Vitamin D deficiency/insufficiency is present in a substantial proportion of youth with diabetes, particularly minorities, but the prevalence appears similar to that in youth without diabetes. Further studies are needed to examine whether youth with diabetes would benefit from vitamin D supplementation.


Streptavidin-exposed magnetic nanoparticles for lectin magnetic separation (LMS) of Staphylococcus aureus prior to three quantification strategies.
A lectin magnetic separation (LMS) method for Staphylococcus aureus (S. aureus) was developed with the aim to improve the efficiency of magnetic nanoparticles and to expand the scope of bacterial recognition. Poly(ethylene glycol) (PEG)-mediated magnetic nanoparticles modified with streptavidin (MNP-PEG-SA) were synthesized and then applied to a two-step LMS based on the use of wheat germ agglutinin (WGA). Three specific methods for S. aureus detection (suitable for different requirements including detection time and sensitivity) were designed. The new LMS has improved anchoring efficiency (compared to two-step LMS methods) and requires a reduced number of magnetic particles. The Baird-Parker (B-P) method can detect S. aureus with a detection limit of 3 × 100 CFU·mL-1 within 15 h; the polymerase chain reaction (PCR) method can be finished within 4 h, with the lowest detection limit (LOD) of 3 × 102 CFU·mL-1. The LOD of HRP-pig IgG-based colorimetric method is 3 × 105 CFU·mL-1, and the method only lasts for 2 h. If combined with specific detection methods, it meets different needs for rapid detection of S. aureus. Graphical abstractSchematic representation of lectin magnetic separation (LMS) based on biotin-wheat germ agglutinin (WGA) and poly (ethylene glycol) (PEG)-mediated streptavidin-modified magnetic nanoparticles (MNP-PEG-SA) and three different quantification strategies (including B-P culture assay, PCR assay, and colorimetric assay) for S. aureus.


HPLC method for analysis of a new 1,4-dihydropyridine: application to pharmacokinetic study in rabbit.
A high sensitive HPLC assay for plasma analysis of a new 1,4-dihydropyridine (nitrimidodipine) was developed to support the subsequent preclinical development of the compound. To 1 ml of rabbit plasma was added internal standard (3-(4-nitrooxy butyl)-5-ethyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridine dicarboxylate) and 0.5 ml of 1M HCl. The plasma was extracted using 5 ml ethyl acetate which evaporated under gentle stream of nitrogen. The residue was reconstituted in 200 microl mobile phase and 100 microl of aliquots were injected to HPLC system. Chromatographic separation was accomplished on octadecyl column (250 mm x 4.6mm) using a mobile phase consisting of acetonitrile-water (45:55, v/v). The method was sensitive to 2.5 ng/ml in plasma (LOD), acceptable within- and between day reproducibility and a linearity (r2>0.9957) over a concentration range from 5 to 400 ng/ml. The mean extraction efficacy was 90.6% and no interfering peaks of the blank plasma chromatograms were observed. By using the above procedure, a simple, sensitive and convenient HPLC assay for determination, stability evaluation and pharmacokinetic study of nitrimidodipine was developed.


Effectiveness of ertapenem for treatment of infections in children: An evidence mapping and meta-analysis.
To assess and summarize current evidence on the effectiveness and safety of ertapenem for treatment of childhood infections, in consideration of high infection prevalence in children and wide use of ertapenem. The following 8 databases were searched on 13th May 2021: Web of Science, Embase via Ovid SP, PubMed, The Cochrane Library (CENTRAL), Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP and Wanfang. The primary outcome was treatment success rate. Risk ratios (RRs) and 95% confidence interval (CI) were estimated using random-effect models. Subgroup analysis was conducted where heterogeneity was found. Fifteen studies (8 randomized controlled trials, 1 observational comparative study, and 6 before and after studies) involving 2,528 patients were included in the final review. Ertapenem had similar treatment success rates with β-lactam antibiotics [relative risk (RR) = 1.08, 95% CI: 0.99-1.19]. In a subgroup analysis, similar efficacy (RR = 1.08, 95% CI: 0.97-1.20) between ertapenem and other carbapenems. Compared with β-lactam antibiotics, ertapenem did not increase the risk of any adverse events (RR = 1.02, 95%CI: 0.71-1.48), drug-related diarrhea (all non-Asian children, RR = 0.62, 95%CI: 0.31-1.25), or injection site pain (all non-Asian children, RR = 1.66, 95%CI: 0.59-4.68). Subgroup analysis showed no obvious difference between ertapenem group and carbapenems or non-carbapenems group on risk of adverse events. Our findings suggest that ertapenem is effective and safe in treatment for children with infection. Further comparative real-world data is needed to supplement clinical evidence on the overall benefits of ertapenem in this population.


High signal in the adenohypophysis on T1-weighted images presumably due to manganese deposits in patients on long-term parenteral nutrition.
Hypermanganesaemia is reported in patients on long-term parenteral nutrition. Deposition of manganese, giving high signal on T1-weighted images, may involve the basal ganglia. MRI in nine patients (mean age 51 years, range 31-75 years) on long-term parenteral nutrition (mean duration 30 months, range 6-126 months), demonstrated high signal in the anterior pituitary gland on T1-weighted sagittal and coronal images. The gland appeared normal on T2-weighted images. Signal intensity in the basal ganglia on T1-weighted images was increased in all patients. Endocrine assessment showed no significant abnormality. Neurological examination showed a mild parkinsonian movement disorder in one patient. Hypermanganaesemia was present in all nine (1.3-2.8 micromol/l, mean 1.87 micromol/l). The high signal in the anterior pituitary gland was probably related to deposition of paramagnetic substances, especially manganese.


Low endometrial beta-catenin and cadherins expression patterns are predictive for primary infertility and recurrent pregnancy loss.
Inadequate uterine receptivity is responsible for two-third of implanting failures. Aim of the study was to investigate the role of epithelial adherence and tight-junction molecules expressed by human endometrium in predicting womens' fertility outcome. A total of 76 consecutive women, including 24 fertile (G1), 40 primary infertile (G2), and 12 recurrent pregnancy loss (RPL, G3) women, who underwent diagnostic hysteroscopy plus endometrial biopsy between 2005 and 2016 at the Gynecology Division of Sant'Andrea Hospital, Sapienza University of Rome, in Italy, were retrospectively identified and included into the study. Endometrial biopsies were assessed for the immunohistochemical expression of beta-catenin (β-catenin), E-cadherin and K-cadherin biomarkers. Expression profiles were compared between the three groups of patients and were correlated with patients' fertility outcome. In infertile patients there was a significant lower endometrial expression of β-catenin (p = .001), E-cadherin (p = .001) and K-cadherin (p = .002), compared to the fertile ones. Furthermore, β-catenin and E-cadherin intensity gradients of expression at glandular level were found totally reversed in infertile patients. Significant lower expression levels of K-catenin (p = .016) and E-cadherin (p < .0001) at glandular level were found in RPL patients. Results showed that the low endometrial expression of β-catenin, E-cadherin and K-cadherin were associated to fertility-related problems, such as primary intertility and RPL.


Interactive Voice Response Technology applied to sexual behavior self-reports: a comparison of three methods.
We tested the feasibility and performance of the Interactive Voice Response Technology (IVR) in the assessment of sexual behavior self-reports, relative to self-administered questionnaire (SAQ) and Timeline Followback (TLFB) methods. The sample consisted of 44 sexually active Hispanic students recruited at the University of Texas at El Paso who reported daily about sexual behaviors and substance use. Thirty-three participants (75%, 18 women, 15 men) were retained for at least 80 days of the 91-day IVR. At follow-up, sexual behaviors and substance use were assessed by questionnaire (summary) reports and by TLFB, referring to the same 3-month interval. ANOVAs with normalized variables indicated less reporting in the TLFB and over-reporting of substance use in the questionnaire relative to the daily IVR self-reports. Gender moderated the effects of assessment mode, which were observed among women only. HLM analyses indicated a significant decrease in self-reports over time, suggesting reactivity of self-monitoring via IVR on behavior.


Effect of influent nitrogen speciation on organic nitrogen occurrence in activated sludge process effluents.
The effect of influent nitrogen composition on organic nitrogen production in a sequencing batch reactor (SBR) activated sludge process was investigated. A laboratory-scale SBR was fed with three different type synthetic wastewaters with varying nitrogen compositions (phase I = nitriloacetic acid + ammonium [NH4-N], phase II = NH(4-)N, and phase III = amino acid mixture + NH(4-)N) was operated. The effluent contained approximately 1 to 2 mg N/L organic nitrogen, even though there was no organic nitrogen in influent. The effluent organic nitrogen increased to approximately 4 mg N/L when the influent composition was changed and then stabilized at <2 mg N/L. The maximum nitrifier growth rate constants (microN) were calculated as 0.91+/-0.10 to 1.14+/-0.08 day-1, 0.82 +/-0.13 day-1, and 0.89+/-0.08 day-1 at 20 degrees C for the three different influent compositions. The effluent colloidal organic nitrogen (CON) was negligible, suggesting that the effluent CON found in full-scale plants may be the result of influent-derived suspended matter.


Age-adjusted antitumoral therapy based on the demonstration of increased apoptosis as a mechanism underlying the reduced malignancy of tumors in the aged.
In view of the constant increase in the aged population, age-adjusted cancer therapy becomes an urgent target. Although cancer incidence rises with age, paradoxically, growth rate and metastasis often proceed at a slower rate in the aged. Determining the mechanism(s) underlying this reduced tumor progression in the old might have implications for a rational design of age-adjusted therapy. Thus far, decreased cell proliferation or immune response modifications were suggested as possible mechanisms. We show here that an increased tendency to apoptotic tumor cell death in the aged could constitute an additional mechanism. Based on this mechanism, we compared the therapeutic efficacy of two apoptosis inducers, hydrocortisone and adriamycin, on AKR lymphoma and B16 melanoma growth in young and old mice. Treatment with hydrocortisone acetate inhibited tumor growth practically only in old mice in the two tumor systems. Similar effects were obtained with adriamycin treatment of AKR lymphoma but opposite results were seen with B16 melanoma. We thus demonstrated, in three of the four tumor-therapeutic modality systems examined, an age-related antitumoral efficacy of two apoptosis-inducing agents, with tendency for a remarkably more pronounced effect in aged mice.


Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin.
Substance P (6.25-25 p-mole) produced dose-dependent flare and wheal responses when injected intradermally into the volar surface of the human forearm. The maximum flare response was obtained within the first 3 min of injection and declined thereafter. The wheal response reached a maximum after 12 min following the injection. Only those peptides having one or more basic residues in the N-terminal region were effective in producing a flare reaction. Eledoisin-related peptide and SP1-9 were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1-11 was twice as active. The N-terminal tetrapeptide, SP1-4 and eledoisin were inactive in the dose range tested. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin (2.0): [D-pro2, D-phe7, D-trp9]SP1-11 (1.1): SP1-11 (1.0): SP4-11 (0.4): SP1-9 (0.15): eledoisin-related peptide (0.08): eledoisin (0.06). The N-terminal tetrapeptide failed to produce a wheal response in the dose range tested. Substance P was approximately equi-active with poly-L-arginine in the production of wheal and flare and both of these agents were about 10 times more potent than histamine. Adenosine triphosphate (25-400 n-mole) produced dose-dependent wheal and flare responses and was 10,000 times less potent than substance P. Pre-treatment of the subjects with the H1 histamine antagonist, chlorpheniramine, (20 mg I.V.) reduced the wheal and flare responses to substance P. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine. The results are discussed in relation to the mechanism of the 'axon reflex' vasodilatation in skin. This is thought to involve mast cells in addition to substance P-containing primary afferent neurones.


Identification of parameters in systems biology.
We consider the inverse problem for the identification of the finite dimensional set of parameters for systems of nonlinear ordinary differential equations (ODEs) arising in systems biology. A numerical method which combines Bellman's quasilinearization with sensitivity analysis and Tikhonov's regularization is implemented. We apply the method to various biological models such as the classical Lotka-Volterra system, bistable switch model in genetic regulatory networks, gene regulation and repressilator models from synthetic biology. The numerical results and application to real data demonstrate the quadratic convergence.


Effects of stress on muscarinic mechanisms.
Hyperactivity of muscarinic mechanisms may be involved in the patho-physiology of depressive disorders and stress. The literature emphasizes the impact of stress on aminergic networks and muscarinic mechanisms are generally not accorded a significant role in the neurobiology of stress. However, experiments in man and animals indicate that acute and chronic stress activate central muscarinic mechanisms. The literature reporting these results is reviewed.


The Benefit of Postoperative Radiotherapy and Extending Neck Dissection in pT1-2 Oral Squamous Cell Carcinoma With a Single Ipsilateral Cervical Lymph Node Metastasis (pN1).
We compared postoperative radiotherapy (PORT) to surgery only (SO), and supraomohyoidal neck dissection (SOHND) to modified radical neck dissection (MRND) in patients with pT1-T2 squamous cell carcinomas of the oral cavity (OSCC) and a single cervical lymph node metastasis (pN1) in terms of overall survival (OS), oral cancer specific survival (OCSS), and regional recurrence-free survival (RRFS), in a prospective cohort study. We included patients with pT1-T2 pN1 OSCC with no distant metastasis and estimated the survival probabilities using the Kaplan-Meier method and calculated hazards ratios (HR) for PORT vs. SO and MRND vs. SOHND using adjusted Cox regression models. A total of 51 patients (26 SO vs. 25 PORT, 9 SOHND vs. 42 MRND) were evaluated. Patients who received PORT were more likely to be younger and healthier. OS at 5 years was 41% and 87% in the SO and PORT groups, respectively. OS at 5 years was 52% and 67% in the in the SOHND and MRND groups, respectively. Both OCSS and RRFS were improved by PORT. Extending neck dissection was not associated with improved OS (HR = 0.83). PORT is associated with preferable OS, OCSS, and RRFS in pT1-2 pN1 oral cancer and should be recommended regularly.


Fission and reconfiguration of bilobate comets as revealed by 67P/Churyumov-Gerasimenko.
The solid, central part of a comet--its nucleus--is subject to destructive processes, which cause nuclei to split at a rate of about 0.01 per year per comet. These destructive events are due to a range of possible thermophysical effects; however, the geophysical expressions of these effects are unknown. Separately, over two-thirds of comet nuclei that have been imaged at high resolution show bilobate shapes, including the nucleus of comet 67P/Churyumov-Gerasimenko (67P), visited by the Rosetta spacecraft. Analysis of the Rosetta observations suggests that 67P's components were brought together at low speed after their separate formation. Here, we study the structure and dynamics of 67P's nucleus. We find that sublimation torques have caused the nucleus to spin up in the past to form the large cracks observed on its neck. However, the chaotic evolution of its spin state has so far forestalled its splitting, although it should eventually reach a rapid enough spin rate to do so. Once this occurs, the separated components will be unable to escape each other; they will orbit each other for a time, ultimately undergoing a low-speed merger that will result in a new bilobate configuration. The components of four other imaged bilobate nuclei have volume ratios that are consistent with a similar reconfiguration cycle, pointing to such cycles as a fundamental process in the evolution of short-period comet nuclei. It has been shown that comets were not strong contributors to the so-called late heavy bombardment about 4 billion years ago. The reconfiguration process suggested here would preferentially decimate comet nuclei during migration to the inner solar system, perhaps explaining this lack of a substantial cometary flux.


Multiple Sclerosis: kFLC index values related to gender.
Multiple sclerosis (MS) is a chronic multifactorial inflammatory and neurodegenerative disease of the central nervous system (CNS). The identification of biomarkers with good diagnostic and prognostic power is of great importance for monitoring and treating MS patients. We analyzed serum and cerebrospinal fluid of 228 patients, with different neurological disorders and with MS to confirm our previous results and determine a possible gender difference of kFLC Index cut-off. We have obtained a kFLC Index cut-off of 12.5 (100% specificity and 90.4% sensitivity) and 11 (100% specificity and 97.5% sensitivity) for women and men with MS respectively. This study reinforces the importance that kFLC Index could have as a diagnostic aid to detect MS. Our data highlight a difference in the cut-off of the kFLC Index calculated by gender; male patients with a kFLC Index value greater than 11 are at higher risk to develop MS respect females having the same result.


Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy.
Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis, which correlate with recurrence after surgical treatment and poor prognosis. HCC may be an unusual cancer affected by continuous inflammation that can lead to consistent upregulation of transforming growth factor-beta (TGF-beta). Chronic inflammation shifts hepatocytic TGF-beta signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway. In this study, we investigated the functional roles of Smad3 and its phosphoisoforms in the progression of HCC. Tumor tissue microarrays of samples from 272 HCC patients who underwent curative surgical resection were used to detect the expression of Smad3, Smad4, pSmad3C (S423/425), pSmad3L (T179), pSmad3L (S204), and pSmad3L (S213). Disease-specific death was defined as 1) tumor occupying more than 80% of the liver, 2) portal venous tumor thrombus (PVTT) proximal to the second bifurcation, 3) obstructive jaundice due to tumor, 4) distant metastases, or 5) variceal hemorrhage with PVTT proximal to the first bifurcation. At the time of analysis, tumor recurrence was detected in 184 (67.6%) patients, and 96 (35.3%) had died of HCC. Nuclear and cytoplasmic localization of Smad3, and nuclear localization of Smad4 were observed in 18.0%, 9.9%, and 9.2% of HCCs, respectively. The rates of Smad3 phosphoisoform-immunoreactive HCC varied according to the location of phosphorylation: pSmad3C (S423/425) 8.1%, pSmad3L (T179) 2.6%, pSmad3L (S204) 2.2%, and pSmad3L (S213) 10.3%. Multivariate analyses revealed that pSmad3C (S423/425) (P=0.022) was an independent predictor of longer recurrence-free survival. pSmad3L (S213) (P=0.006), intrahepatic metastasis, multicentric occurrence, and liver cirrhosis were independent predictors of shorter recurrence-free survival. Cytoplasmic Smad3 (P=0.006), larger tumor size, and intrahepatic metastasis were independent predictors of shorter disease-specific survival. Only pSmad3L (S213) did not show an unfavorable influence on recurrence-free survival (P=0.331) on univariate analysis. pSmad3C (S423/425), pSmad3L (S213), and Smad3 may be predictors of prognosis in HCC patients after curative hepatectomy. pSmad3C (S423/425) and pSmad3L (S213) may be used as immunohistochemical biomarkers to identify patients with a high risk of recurrence.