Phase 1 radioimmunotherapy study with lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma.
Patients with metastatic clear cell renal cell carcinoma (ccRCC) have a dismal prognosis. Therefore, new and less toxic treatments are needed. We determined the maximum tolerated dose (MTD) and potential therapeutic efficacy of multiple infusions of lutetium 177 ((177)Lu)-girentuximab (cG250) on various dose levels in a phase 1 trial in patients with progressive metastasized ccRCC. In this uncontrolled case series in 23 patients with progressive ccRCC metastases, cG250 accumulation was verified by diagnostic indium 111-cG250 imaging. Patients then received a high-activity dose of (177)Lu-cG250. Groups of three patients received (177)Lu-cG250, starting at a dose level of 1110 MBq/m(2)(177)Lu-cG250, with dose increments of 370 MBq/m(2) per group. In the absence of persistent toxicity, progressive disease, and accelerated blood clearance, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. Patients could receive a total of three treatment cycles. Determination of the MTD was the primary and therapeutic efficacy was the secondary outcome measurement of the study. The MTD was 2405 MBq/m(2) because higher doses resulted in dose-limiting myelotoxicity. Some patients received second (13 of 23 [56%]) and third (4 of 23 [17%]) treatment cycles. Most patients (17 of 23 [74%]) demonstrated stable disease 3 mo after the first treatment, and one patient showed a partial response that lasted for 9 mo. Mean growth of target tumor lesions was reduced from 40.4% (95% confidence interval [CI], ± 17.0) during the last 3 mo before study entry to 5.5% (95% CI, ± 5.3; p<0.001) at 3 mo after the first treatment cycle. No major nonhematologic side effects were observed. (177)Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m(2) (MTD). Radioimmunotherapy with (177)Lu-cG250 may stabilize previously progressive metastatic ccRCC.


Blocking Bacterial Naphthohydroquinone Oxidation and ADP-Ribosylation Improves Activity of Rifamycins against Mycobacterium abscessus.
Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against Mycobacterium tuberculosis. Here, we asked (i) why is rifabutin more active against M. abscessus than rifampicin, and (ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity? Comparative analysis of naphthoquinone- versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase ArrMab like rifampicin, preventing it from achieving the nanomolar activity that it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C-23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively resistant naphthoquinone core and C-25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.


Mental sociality and collective identity: a dialogical analysis of the Indian sense of self.
This chapter discusses the specific strengths of Dialogical Self Theory for the exploration and explanation of the phenomenon of society of the mind as it is expressed in various intricate, culturally specific discourse strategies among Indians. By focusing on a recent social movement to demonstrate the particularity of cultural processes, personal and collective meanings are explored through interviews of several citizens during a protest. The examples explain how a dramatic event can cause people to react, review, and reconstruct their internal positions related to collective reality.


Characteristics of histamine release from rat mast cells in relation to the valency of the stimulating ligand.
The relationship between the valency of a ligand and the subsequent characteristics of histamine release was investigated in rat peritoneal mast cells. The cells were passively sensitized to the DNP hapten and a series of DNP-human serum albumin conjugates of known valency were used to induce histamine release. The rate of release of histamine induced by these conjugates was independent of the DNP/HSA ratio when the ratio was between 71.3 and 7.2. Marked slowing of the release occurred as the ratio was reduced below 7.2. The rate of desensitization of the cells slowed as a continuous function as the DNP/HSA ratio was reduced. 45Calcium uptake measurements showed that the changes in histamine release were paralleled by changes in the membrane permeability to calcium. The rate of release of histamine from mast cells and the rate of desensitization of the cells are discussed in terms of the size of IgE receptor complexes on the cell membrane.


A double pass spectrometer for the far infrared.
A far ir spectrometer has been built which uses a double pass optical system to increase the spectral dispersion. Because of the energy limitations in this spectral range, this means of increasing the dispersion is an efficient way to improve the resolving power of a grating monochromator. The same optical system is also used to advantage in a lamellar grating interferometer where the increased dispersion improves the performance at higher frequencies. Consideration is also given to instrument errors and signal noise which can affect, and in some cases limit, the present performance of a far ir Fourier interferometer.


Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre-S- and S-encoded viral surface antigens.
The polymerase chain reaction was evaluated as a diagnostic tool in 72 chronic hepatitis B virus carriers. Hepatitis B virus DNA was detectable in the serum of HBsAg-positive virus carriers using aliquots as small as 100 al. The detection limit for cloned hepatitis B virus DNA was 100 ag. Primer pairs for different regions of the HBV genome resulted in different sensitivity. Detection of the amplified hepatitis B virus DNA by Southern blotting and subsequent scintillation counting or densitometry allowed a semiquantitative assay. Using several primer pairs in parallel for optimal detection, all HBeAg-positive HBsAg carriers, 80% of HBe antibody-positive symptomatic HBsAg carriers and 57% of asymptomatic HBe antibody-positive HBsAg carriers were found to have hepatitis B virus DNA in the serum. During antiviral therapy hepatitis B virus DNA disappeared by the polymerase chain reaction assay in patients who became HBeAg negative, but polymerase chain reaction detected a relapse earlier than did the conventional dot blot. Pre-S antigens were assayed in serum and liver samples from most chronic carriers by enzyme-linked immunosorbent assay and/or immunoblot. Although most viremic carriers were strongly positive for pre-S1 and pre-S2 antigens, some hepatitis B virus DNA-positive HBsAg carriers did not have detectable pre-S antigens, and vice versa. Our data show that assay of hepatitis B virus DNA in the serum by polymerase chain reaction is by far more proficient than by dot blot and that it cannot be replaced by serological assays of HBeAg or pre-S antigen.


Molecular correlates of hypothalamic development in songbird ontogeny in comparison with the telencephalon.
Development of the songbird brain provides an excellent experimental model for understanding the regulation of sex differences in ontogeny. Considering the regulatory role of the hypothalamus in endocrine, in particular reproductive, physiology, we measured the structural (volume) and molecular correlates of hypothalamic development during ontogeny of male and female zebra finches. We quantified by relative quantitative polymerase chain reaction (rqPCR) the expression of 14 genes related to thyroid and steroid hormones actions as well as 12 genes related to brain plasticity at four specific time points during ontogeny and compared these expression patterns with the expression of the same genes as detected by transcriptomics in the telencephalon. These two different methodological approaches detected specific changes with age and demonstrated that in a substantial number of cases changes observed in both brain regions are nearly identical. Other genes however had a tissue-specific developmental pattern. Sex differences or interactions of sex by age were detected in the expression of a subset of genes, more in hypothalamus than telencephalon. These results correlate with multiple known aspects of the developmental and reproductive physiology but also raise a number of new functional questions.


Scale-up of L-lactic acid production by mutant strain Rhizopus sp. MK-96-1196 from 0.003 m3 to 5 m3 in airlift bioreactors.
In order to study the feasibility of commercial-scale L-lactic acid production by Rhizopus sp. MK-96-1196 using large scale airlift bioreactors (ALBs), a scale-up study from 0.003 m3 to 5 m3 ALB was carried out using oxygen transfer rate (OTR) as the scale-up criterion. Enhanced L-lactic acid production was achieved at OTRs higher than 0.28 (g-O2/l/h) irrespective of the scale of the bioreactor in question: in the range of 0.003 m3 to 5 m3, more than 90 g/lL-lactic acid was produced with a yield of approximately 80%, based on the initial glucose concentration. In future research, we plan to design an ALB greater than 3000 m3 (working volume: 2000 m3) for further studies on the production of L-lactic acid in large quantities.


Determination of serum hepatitis B virus DNA in chronic HBsAg carriers: clinical significance and correlation with serological markers.
Hepatitis B virus infection is among the most devastating health problems in the world, including Turkey. In this cross-sectional study, we aimed to investigate the correlations between hepatitis B virus genomic load and various measures of the progression of chronic hepatitis B virus infection. A total of 354 chronic HBsAg carriers [126 inactive HBsAg carriers, 50 asymptomatic replicative carriers (immune tolerant patients), 90 chronic hepatitis B patients and 88 patients with liver cirrhosis] were enrolled into the study. Eligible patients included males and females, 14-62 years of age, with detectable serum HBsAg, HBeAg or anti-HBe in serum at the time of screening and for at least six months before study entry. Serum hepatitis B virus DNA was detected by liquid hybridization, and results under the level of 1 pg/ml were additionally confirmed by polymerase chain reaction. Of 354 patients, 118 (33%) were HBeAg-positive and 236 (67%) HBeAg-negative. Of HBeAg-negative patients, 126 (53%) had normal alanine aminotransferase, 31 (13%) had elevated alanine aminotransferase (chronic hepatitis B) and 79 (33%) had evidence of cirrhosis; corresponding figures in the HBeAg-positive patients were 50 (42%), 59 (50%) and 9 (8%). There is a significant correlation between transaminase values and histological liver damage, whereas no correlation was found between viral replication and liver damage. Hepatitis B virus DNA is an important and specific marker for ongoing hepatitis B virus related liver disease, but alanine aninotransferase was shown to be the best marker for liver inflammation and not hepatitis B virus viral load. Although these findings are not new, they are of some utility since they prevent unnecessary and cost-intensive viral load determinations in chronic HBsAg carriers.


Vaginal Urinary Calculi Formation Secondary to Vaginal Mesh Exposure with Urinary Incontinence.
Vaginal stones may form in the setting of mesh exposure with urinary incontinence. This report serves to help understand the presentation, evaluation, and management of vaginal urinary stones. A 68-year-old female presented with a vaginal calculus. She had a history of anterior and posterior polypropylene mesh placement for prolapse 7 years earlier and urinary incontinence. The stone was identified on a portion of exposed mesh and removed in office. Pathology confirmed urinary etiology. The exposed mesh resolved with topical estrogen. Cystourethroscopy excluded urinary fistula and bladder mesh erosion. When identified, a vaginal calculus should be removed and evaluated for composition. Cystourethroscopy should be performed to assess potential urinary tract fistulas and mesh erosion. Additional imaging should be considered.


18F-6-Fluoro-l-Dopa PET/CT Imaging of Congenital Hyperinsulinism.
Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. 18F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of 18F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.


Neuroleptic malignant syndrome induced by ziprasidone on the second day of treatment.
Neuroleptic malignant syndrome (NMS) is the rarest and most serious of the neuroleptic-induced movement disorders. We describe a case of neuroleptic malignant syndrome (NMS) associated with the use of ziprasidone. Although conventional neuroleptics are more frequently associated with NMS, atypical antipsychotic drugs like ziprasidone may also be a cause. The patient is a 24-year-old male with a history of schizophrenia who developed signs and symptoms of NMS after 2 days of treatment with an 80-mg/day dose of orally administrated ziprasidone. This case is the earliest (second day of treatment) NMS due to ziprasidone reported in the literature.


Partial Removal of Lipopolysaccharide from Thiobacillus ferrooxidans Affects Its Adhesion to Solids.
Conditions for the partial removal of lipopolysaccharide (LPS) from Thiobacillus ferrooxidans are described. Raising the pH of the solution containing the cells from pH 1.5 to pH 6.8 to 8.0 releases about 50% of the LPS without cell lysis. The release of LPS begins at pH 3.5, and it was not affected by EDTA concentration. Partial removal of LPS exposed higher amounts of a 40-kDa outer membrane protein in the bacteria, as detected by a dot immunoassay employing an antiserum against the T. ferrooxidans surface protein. This higher protein exposure and the reduced LPS content increased the hydrophobicity of the cell surface, as determined by an increased adhesion (50%) to hydrophobic sulfur prills and C-dodecanoic acid binding (2.5-fold) compared with control cells. In addition, adhesion of radioactively labeled microorganisms to a sulfide mineral was inhibited (40%) in the presence of previously added LPS. Our results suggest that not only LPS but also surface proteins probably play important roles in T. ferrooxidans adhesion to solid surfaces.


Poor sleep quality predicts decreased cognitive function independently of chronic mountain sickness score in young soldiers with polycythemia stationed in Tibet.
Little is known about the association between poor sleep and cognitive function in people with polycythemia at high altitude. The aim of this study was to survey the sleep quality of individuals with polycythemia at high altitude and determine its association with cognitive abilities. We surveyed 230 soldiers stationed in Tibet (all men; mean age 21-52±4.30 yr) at altitudes ranging from 3658 to 3996 m. All participants were given a blood tests for hemoglobin level and a questionnaire survey of cognitive function. Polycythemia was defined as excessive erythrocytosis (Hb≥21 g/dL in men or ≥19 g/dL in women). Poor sleepers were defined as having a global Pittsburgh Sleep Quality Index score (PSQI)>5. Cognitive abilities were determined by the Chinese revision of the Wechsler Adult Intelligence Scale and the Benton Visual Retention Test. Multiple linear regression analysis was used to determine the association between the PSQI and cognitive function. Logistic regression analysis was performed to determine the independent effect of sleep quality on cognitive function. The global PSQI score of enrolled participants was 8.14±3.79. Seventy-five (32.6%) soldiers were diagnosed with polycythemia. The proportion of poor sleepers was 1.45 times greater in those with polycythemia compared with those without polycythemia [95% (confidence interval) CI 1.82-2.56], and they had a statistically significant lower score for cognitive function. Multiple linear regression analysis showed that the global PSQI score was negatively associated with IQ (β=0.11, 95% CI -0.16 to -0.05) and digit symbol scores (β=0.66, 95% CI -0.86 to -0.44). Poor sleep quality was determined to be an independent predictor of impaired IQ [odds ratio (OR) 1.59, 95% CI 1.30-1.95] and digit symbol score (OR 1.18, 95% CI 1.07-1.31) in logistic regression analysis. The present study showed that for young soldiers with polycythemia at high altitude impaired subjective sleep quality was an independent predictor of decreased cognitive function, especially IQ and verbal short-term memory.


Mental Health Benefits of a Traditional Vegetative Biofeedback Therapy Online Program during the COVID-19 Lockdown: A Controlled Trial.
Mandatory lockdown resulting from a pandemic may be effective against the physical impact of the virus; however, the resulting mental strains can lead to the development of several mental disturbances. Taijiquan and Qigong are considered traditional vegetative biofeedback therapies that allow the practitioner to control the functions and processes of the body through specific movements or stances, breathing techniques, and meditative exercises. This study aims to understand if these techniques can be applied as an online distance therapeutic option to reduce the psychological impact of home confinement and social distancing. Sixty-four participants were recruited and allocated to three groups. The experienced and novice Taijiquan and Qigong participants' groups received the intervention for 8 weeks while the control group did not receive any intervention. The outcomes were psychological well-being and psychological distress levels and were assessed by the Mental Health Inventory and a written interview. The experienced Taijiquan and Qigong participants achieved significant improvements in psychological well-being and psychological distress. Novice Taijiquan and Qigong participants achieved a significant improvement in anxiety levels. Additionally, the control group showed a significant decrease in psychological well-being. This study suggests that this distance online program of Taijiquan and Qigong is feasible and may benefit the mental health of participants during a lockdown.


Nontraditional aspects of aldosterone physiology.
Aldosterone is the most important circulating mineralocorticoid. It is secreted by the zona glomerulosa of the adrenal gland and plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct, promoting sodium resorption and potassium excretion. The action of aldosterone on its classic target epithelia has been extensively studied, and many of the signaling events that mediate its effects have been described. Recently, there has been increased interest in aldosterone actions on the cardiovascular system, which are mediated through nonclassical actions. These include local tissue production, nongenomic actions, and effects on nonepithelial targets. In this review article, we focus on the effects of aldosterone in nonepithelial tissues that are mediated through MR, especially cardiovascular effects.


Processing of affective speech prosody is impaired in Asperger syndrome.
Many people with the diagnosis of Asperger syndrome (AS) show poorly developed skills in understanding emotional messages. The present study addressed discrimination of speech prosody in children with AS at neurophysiological level. Detection of affective prosody was investigated in one-word utterances as indexed by the N1 and the mismatch negativity (MMN) of auditory event-related potentials (ERPs). Data from fourteen boys with AS were compared with those for thirteen typically developed boys. These results suggest atypical neural responses to affective prosody in children with AS and their fathers, especially over the RH, and that this impairment can already be seen at low-level information processes. Our results provide evidence for familial patterns of abnormal auditory brain reactions to prosodic features of speech.


TCR v(beta) repertoire restriction and lack of CDR3 conservation implicate TCR-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas.
Thymic lymphoma development is a multistage process in which genetic and epigenetic events cooperate in the emergence of a malignant clone. The notion that signaling via TCR-ligand interactions plays a role in promoting the expansion of developing neoplastic clones is a matter of debate. To investigate this issue, we determined the TCR V(beta) repertoire of thymic lymphomas induced in AKR/J mice by either endogenous retroviruses or the carcinogen, N-methyl-N-nitrosourea (MNU). Both spontaneous and MNU-induced lymphomas displayed restricted V(beta) repertoires. However, whereas V(beta)6, V(beta)8 and V(beta)9 were expressed by a greater than expected frequency of MNU-induced lymphomas, V(beta)8, V(beta)7, V(beta)13 and V(beta)14 were over-represented on spontaneous lymphomas. The dissimilar TCR V(beta) profiles indicate that different endogenous ligands promote neoplastic clonal expansion in untreated and MNU-treated mice. Although the nature of these ligands is not clear, the lack of conservation in TCR beta chain CDR3 regions among lymphomas that express the same V(beta) segment suggests that endogenous superantigens (SAG), as opposed to conventional peptide ligands, are likely to be involved in the selection process. The biased representation of lymphomas expressing V(beta)6-, V(beta)7- and V(beta)9-containing TCRs that recognize endogenous SAG is consistent with this hypothesis. The finding that Bcl-2 is expressed at high levels in spontaneous and MNU-induced lymphomas suggests that preneoplastic thymocytes may be resistant to SAG-induced clonal deletion. A working model is presented in which preneoplastic clones expressing TCRs that recognize endogenous SAG are selectively expanded as a consequence of sustained TCR-mediated signaling.


Biogenesis of endoplasmic reticulum membrane in rat liver cells. II. Discharge of the nascent peptides of NADPH-cytochrome c reductase and cytochrome b5 on the cytoplasmic side of the endoplasmic reticulum membrane.
The direction of discharge of the nascent peptides of NADPH-cytochrome c reductase and cytochrome b5 from bound polyribosomes of rough microsomes was investigated in order to elucidate the mechanism of separation of these membrane proteins from secretory proteins, which are also synthesized by the same class of ribosomes of rough endoplasmic reticulum. The nascent peptides of NADPH-cytochrome c reductase and cytochrome b5 in intact rough microsomes were accessible to externally added 125I-Fab's against these proteins, and were susceptible to trypsin digestion, whereas the nascent peptides of serum albumin were not. The nascent peptides of these two microsomal proteins were released into the cytoplasm by puromycin treatment of intact rough microsomes, while the nascent peptides of serum albumin were retained in the microsomal lumen. These observations suggest that the nascent peptides of microsomal proteins, which are present on the cytoplasmic surface of the endoplasmic reticulum membrane, are exposed on the surface of microsomal vesicles, while those of secretory proteins are enclosed inside the vesicles. Therefore, the topographical separation of microsomal membrane proteins from secretory proteins is accomplished at the step of their synthesis by the bound polyribosomes of rough endoplasmic reticulum.


Quantitative evaluation of vascularity within cervical lymph nodes using Doppler ultrasound in patients with oral cancer: relation to lymph node size.
The aim of this study was to quantitatively evaluate the relationship between vascularity within lymph nodes and lymph node size on Doppler ultrasound images of patients with oral cancer. A total of 310 lymph nodes (86 metastatic, 224 benign) from 63 patients with oral cancer were classified into 4 groups according to their short axis diameters: Group 1, short axis diameters of 4-5 mm; Group 2, 6-7 mm; Group 3, 8-9 mm; and Group 4, ≥ 10 mm. Vascular and scattering indices of lymph nodes on Doppler ultrasound images were analysed quantitatively. The vascular index was defined as the ratio of blood flow area to the whole lymph node area and the scattering index was defined as the number of isolated blood flow signal units. For metastatic lymph nodes, the vascular index was highest in Group 1 and decreased as lymph node size increased. The vascular index of benign lymph nodes did not differ significantly among the four groups. The vascular index of metastatic lymph nodes was significantly higher than that of benign lymph nodes in Group 1. For metastatic lymph nodes, the scattering index increased as lymph node size increased and was significantly higher than that of benign lymph nodes in Groups 2-4. An increase in vascularity is a characteristic of Doppler ultrasound findings in small metastatic lymph nodes. As the metastatic lymph node size increases, blood flow signals become scattered, and the scattering index increases.


Effect of time-limited psychotherapy on patient dropout rates.
The authors conducted an archival study of 149 new clinic patients at a large community mental health center. The dropout rate for patients in brief psychotherapy in which the length of therapy was specified at the outset of treatment (time-limited psychotherapy) (32%) was about one-half the dropout rate for patients in brief (67%) and long-term (61%) individual psychotherapy. The difference in dropout rates could not be explained by patient demographic or diagnostic variables or by therapist characteristics measured in the study. The results suggest that setting a specific time limit on individual psychotherapy at the outset of treatment can reduce the patient dropout rate in a public mental health clinic.


Trail pheromone disruption of Argentine ant trail formation and foraging.
Trail pheromone disruption of invasive ants is a novel tactic that builds on the development of pheromone-based pest management in other insects. Argentine ant trail pheromone, (Z)-9-hexadecenal, was formulated as a micro-encapsulated sprayable particle and applied against Argentine ant populations in 400 m2 field plots in Hawai'i Volcanoes National Park. A widely dispersed point source strategy for trail pheromone disruption was used. Traffic rates of ants in bioassays of treated filter paper, protected from rainfall and sunlight, indicated the presence of behaviorally significant quantities of pheromone being released from the formulation for up to 59 days. The proportion of plots, under trade wind conditions (2–3 m s−1), with visible trails was reduced for up to 14 days following treatment, and the number of foraging ants at randomly placed tuna-bait cards was similarly reduced. The success of these trail pheromone disruption trials in a natural ecosystem highlights the potential of this method for control of invasive ant species in this and other environments.


The ethics of newborn resuscitation.
It is widely believed in neonatology and obstetrics that there are situations in which it is inappropriate to attempt newborn resuscitation, and other times when newborn resuscitation is obligatory despite parental refusal. In each case, an ethical justification for the decision needs to be identified. This essay is intended to provide guidance in deciding when resuscitation should be attempted, and in identifying ethical considerations that should be taken into account. It specifically addresses the issue of extreme prematurity, including an analysis of current recommendations, the data, relevant rights of patient and parents, and a discussion of the relative merits of withholding resuscitation vs providing resuscitation and possibly withdrawing intensive care later. In addition to extreme prematurity, the considerations presented are also relevant to a wider spectrum of newborn problems, including Trisomy 13, Trisomy 18, and severe congenital anomalies.


Resistance to Antibody-Drug Conjugates.
Antibody-drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs. Cancer Res; 78(9); 2159-65. ©2018 AACR.


A sea urchin Na(+)K(+)2Cl(-) cotransporter is involved in the maintenance of calcification-relevant cytoplasmic cords in Strongylocentrotus droebachiensis larvae.
The cellular mechanisms of calcification in sea urchin larvae are still not well understood. Primary mesenchyme cells within the larval body cavity form a syncytium to secrete CaCO3 spicules from intracellular amorphous CaCO3 (ACC) stores. We studied the role of Na(+)K(+)2Cl(-) cotransporter (NKCC) in intracellular ACC accumulation and larval spicule formation of Strongylocentrotus droebachiensis. First, we incubated growing larvae with three different loop diuretics (azosemide, bumetanide, and furosemide) and established concentration-response curves. All loop diuretics were able to inhibit calcification already at concentrations that specifically inhibit NKCC. Calcification was most effectively inhibited by azosemide (IC50=6.5 μM), while larval mortality and swimming ability were not negatively impacted by the treatment. The inhibition by bumetanide (IC50=26.4 μM) and furosemide (IC50=315.4 μM) resembled the pharmacological fingerprint of the mammalian NKCC1 isoform. We further examined the effect of azosemide on the maintenance of cytoplasmic cords and on the occurrence of calcification vesicles using fluorescent dyes (calcein, FM1-43). Fifty micromolars of azosemide inhibited the maintenance of cytoplasmic cords and resulted in increased calcein fluorescence within calcification vesicles. The expression of NKCC in S. droebachiensis was verified by PCR and Western blot with a specific NKCC antibody. In summary, the pharmacological profile of loop diuretics and their specific effects on calcification in sea urchin larvae suggest that they act by inhibition of NKCC via repression of cytoplasmic cord formation and maintenance.


Are chromosomal instabilities induced by exposure of cultured normal human cells to low- or high-LET radiation?
Radiation-induced genomic instability has been proposed as a very early, if not an initiating, step in radiation carcinogenesis. Numerous studies have established the occurrence of radiation-induced chromosomal instability in various cells of both human and rodent origin. In many of these studies, however, the cells were not "normal" initially, and in many cases they involved tumor-derived cell lines. The phenomenon clearly would be of even greater interest if it were shown to occur generally in cells that are normal at the outset, rather than cells that may have been "selected" because of a pre-existing susceptibility to induced instability. As a test of the generality of the phenomenon, we studied low-passage normal diploid human fibroblasts (AG1521A) to determine whether they are susceptible to the induction of chromosomal instability in the progeny of surviving cells after exposure in G(0) to low- and high-LET radiation. Cytogenetic assays for instability were performed on both mixed populations of cells and clones of cells surviving exposure. We found no evidence for the induction of such instability as a result of radiation exposure, though we observed a senescence-related chromosomal instability in the progeny of both irradiated and unirradiated cell populations.


Multifunctional one-dimensional polymeric nanostructures for drug delivery and biosensor applications.
Advances in nanotechnology in the last decades have paved the way for significant achievements in diagnosis and treatment of various diseases. Different types of functional nanostructures have been explored and utilized as tools for addressing the challenges in detection or treatment of diseases. In particular, one-dimensional nanostructures hold great promise in theranostic applications due to their increased surface area-to-volume ratios, which allow better targeting, increased loading capacity and improved sensitivity to biomolecules. Stable polymeric nanostructures that are stimuli-responsive, biocompatible and biodegradable are especially preferred for bioapplications. In this review, different synthesis techniques of polymeric one-dimensional nanostructures are explored and functionalization methods of these nanostructures for specific applications are explained. Biosensing and drug delibiovery applications of these nanostructures are presented in detail.


Ultra-low-dose dual-source CT coronary angiography with high pitch: diagnostic yield of a volumetric planning scan and effects on dose reduction and imaging strategy.
To evaluate the role of an ultra-low-dose dual-source CT coronary angiography (CTCA) scan with high pitch for delimiting the range of the subsequent standard CTCA scan. 30 patients with an indication for CTCA were prospectively examined using a two-scan dual-source CTCA protocol (2.0 × 64.0 × 0.6 mm; pitch, 3.4; rotation time of 280 ms; 100 kV): Scan 1 was acquired with one-fifth of the tube current suggested by the automatic exposure control software [CareDose 4D™ (Siemens Healthcare, Erlangen, Germany) using 100 kV and 370 mAs as a reference] with the scan length from the tracheal bifurcation to the diaphragmatic border. Scan 2 was acquired with standard tube current extending with reduced scan length based on Scan 1. Nine central coronary artery segments were analysed qualitatively on both scans. Scan 2 (105.1 ± 10.1 mm) was significantly shorter than Scan 1 (127.0 ± 8.7 mm). Image quality scores were significantly better for Scan 2. However, in 5 of 6 (83%) patients with stenotic coronary artery disease, a stenosis was already detected in Scan 1 and in 13 of 24 (54%) patients with non-stenotic coronary arteries, a stenosis was already excluded by Scan 1. Using Scan 2 as reference, the positive- and negative-predictive value of Scan 1 was 83% (5 of 6 patients) and 100% (13 of 13 patients), respectively. An ultra-low-dose CTCA planning scan enables a reliable scan length reduction of the following standard CTCA scan and allows for correct diagnosis in a substantial proportion of patients. Further dose reductions are possible owing to a change in the individual patient's imaging strategy as a prior ultra-low-dose CTCA scan may already rule out the presence of a stenosis or may lead to a direct transferal to an invasive catheter procedure.


Effects of Dietary Koumine on Growth Performance, Intestinal Morphology, Microbiota, and Intestinal Transcriptional Responses of Cyprinus carpio.
Gelsemium elegans Benth. (GEB) is a traditional medicinal plant in China, and acts as a growth promoter in pigs and goats. Koumine (KM) is the most abundant alkaloid in GEB and produces analgesic, anti-cancer, and immunomodulatory effects. KM can be used as an aquatic immune stimulant, but its growth-promoting effects and transcriptional mechanisms have not been investigated. Diets containing KM at 0, 0.2, 2, and 20 mg/kg were fed to Cyprinus carpio for 71 days to investigate its effects on growth performance, intestinal morphology, microflora, biochemical indicators, and transcriptional mechanisms. Cyprinus carpio fed with KM as the growth promoter, and the number of intestinal crypts and intestinal microbial populations were influenced by KM concentration. KM increased the abundance of colonies of Afipia, Phyllobacterium, Mesorhizobium, and Labrys, which were associated with compound decomposition and proliferation, and decreased the abundance of colonies of pathogenic bacteria Methylobacterium-Methylorubrum. A total of 376 differentially-expressed genes (DEGs) among the four experimental groups were enriched for transforming growth factor-β1 and small mother against decapentaplegic (TGF-β1/Smad), mitogen-activated protein kinase (MAPK), and janus kinases and signal transducers and activators of transcription (Jak/Stat) signaling pathways. In particular, tgfbr1, acvr1l, rreb-1, stat5b, smad4, cbp, and c-fos were up-regulated and positively correlated with KM dose. KM had a growth-promoting effect that was related to cell proliferation driven by the TGF-β1/Smad, MAPK, and Jak/Stat signaling pathways. KM at 0.2 mg/kg optimized the growth performance of C. carpio, while higher concentrations of KM (2 and 20 mg/kg) may induce apoptosis without significantly damaging the fish intestinal structure. Therefore, KM at low concentration has great potential for development as an aquatic growth promotion additive.


Looking beyond symptom relief: evolution of mucosal healing in inflammatory bowel disease.
The focus of effective management of inflammatory bowel disease, especially Crohn's disease, has shifted from short-term symptom control to long-term modification of disease course and complications. Intestinal healing has achieved prominence as a goal of therapy that influences long-term disease course. We review the natural history of inflammatory bowel disease, the markers of disease control that may reflect outcomes and the specific role of mucosal healing. We may aim at better mucosal healing by appropriate choice of therapy, appropriate combinations of therapy and intervening early in the disease course.


Transient neonatal hemolytic anemia due to the novel gamma globin gene mutation HBG2:C.290T>C, p.Leu97Pro (hemoglobin Wareham).
Unstable gamma globin variants can cause transient neonatal hemolytic anemia. We have identified a novel variant in a newborn who presented with jaundice and anemia requiring phototherapy and red blood cell transfusion. The patient was found to be heterozygous for the mutation HGB2:c.290T>C, p.Leu97Pro, which we have termed hemoglobin (Hb) Wareham. This substitution is expected to generate an unstable hemoglobin with increased oxygen affinity based on the homologous mutation previously described in the beta globin gene, which is termed as Hb Debrousse. The patient fully recovered by 9 months of age as expected with the transition from fetal to adult hemoglobin.


Pathophysiology of Drug-Induced Hyponatremia.
Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research.


Lemierre's syndrome.
This is a case report of Lemierre's syndrome in a 17-year-old male patient. Lemierre's disease consists of suppurative thrombophlebitis of the internal jugular vein (SIJVT) in the presence of oropharyngeal infection and can be complicated by septic pulmonary embolism. Other causes of SIJVT include deep neck infections and central venous catheterization. The disease usually results from Gram-negative anaerobic organisms such as Fusobacterium necrophorum.


Mixed Vaginitis in the Third Trimester of Pregnancy Is Associated With Adverse Pregnancy Outcomes: A Cross-Sectional Study.
Mixed vaginitis is a complex vaginal dysbiosis that differs from single vaginitis. Vaginitis in the third trimester may lead to adverse maternal and neonatal outcomes. The clinical characteristics, microbiological characteristics, and adverse pregnancy outcomes of mixed vaginitis in late pregnancy are worth studying. Therefore, this study investigated the clinical and microbiological characteristics of vaginitis and adverse pregnancy outcomes of patients with mixed vaginitis. We studied 1,674 women in late pregnancy who attended the Tianjin Medical University General Hospital from November, 2019 to October, 2021. We administered standardized questionnaires, performed vaginal examination and sampling plus microscope examinations, and assessed follow-up pregnancy outcomes. We cultured the vaginal discharge of the patients with mixed vaginitis to isolate pathogens and performed antimicrobial susceptibility tests of the isolated pathogens. For the patients with peripartum infection, we collected a sample to isolate pathogens. Among the 1,674 women, 66 (3.9%) had mixed vaginitis. The independent risk factor for mixed vaginitis in late pregnancy was a history of vaginitis during early and middle pregnancy (OR = 5.637, 95% CI: 3.314-9.580). The signs of vaginal erythema (63.6% vs. 42.0%), yellow discharge (81.8% vs. 59.6%), and malodor (31.8% vs. 18.8%) (P <0.05) were significantly higher in patients with mixed vaginitis than in patients with single vaginitis. Bacterial isolates of the vaginal secretions of patients with mixed bacterial vaginitis were mainly the pathogens of aerobic vaginitis and bacterial vaginosis, such as Gardnerella vaginalis, Streptococcus anginosus, and Staphylococcus epidermidis. Pathogen isolation of the vaginal secretions of patients with mixed fungus and bacteria vaginitis mainly included Candida albicans, followed by S. anginosus, Enterococcus faecalis, Staphylococcus hemolyticus, Staphylococcus aureus, Streptococcus agalactiae and Staphylococcus simulans. Women with mixed vaginitis had an increased incidence and risk of peripartum infections (6.1% vs. 1.4%, P <0.05; OR = 3.985, 95% CI:1.214-13.079). Escherichia coli is the main pathogen that causes peripartum infection. Mixed vaginitis in late pregnancy is characterized by a severe and complex phenotype, complex vaginal dysbiosis, and a long course of vaginal dysbiosis. This can lead to an increased incidence and risk of peripartum infection. Therefore, more attention should be paid to patients with mixed vaginitis in the third trimester of pregnancy.


Trapidil and other 5-triazolo-(1, 5-alpha)-pyrimidine derivatives as calcium channel blockers in 108CC5 cells.
The action of trapidil (RocornalR) and its derivatives AR 12-456 and AR 12-160 on the inward calcium current (ICa) was studied in mouse neuroblastoma x rat glioma hybrid cells of the line 108CC5 under voltage clamp conditions by means of a suction pipette method. A dissociation constant of the calcium channel-trapidil complex of 277 microM was estimated for the initial inhibition of ICa by trapidil. Half maximal block of ICa was produced by 80 +/- 20 microM AR 12-456 and 500 +/- 150 microM AR 12-160.


Chicken cells sense influenza A virus infection through MDA5 and CARDIF signaling involving LGP2.
Avian influenza viruses (AIV) raise worldwide veterinary and public health concerns due to their potential for zoonotic transmission. While infection with highly pathogenic AIV results in high mortality in chickens, this is not necessarily the case in wild birds and ducks. It is known that innate immune factors can contribute to the outcome of infection. In this context, retinoic acid-inducible gene I (RIG-I) is the main cytosolic pattern recognition receptor known for detecting influenza A virus infection in mammalian cells. Chickens, unlike ducks, lack RIG-I, yet chicken cells do produce type I interferon (IFN) in response to AIV infection. Consequently, we sought to identify the cytosolic recognition elements in chicken cells. Chicken mRNA encoding the putative chicken analogs of CARDIF and LGP2 (chCARDIF and chLGP2, respectively) were identified. HT7-tagged chCARDIF was observed to associate with mitochondria in chicken DF-1 fibroblasts. The exogenous expression of chCARDIF, as well as of the caspase activation and recruitment domains (CARDs) of the chicken melanoma differentiation-associated protein 5 (chMDA5), strongly activated the chicken IFN-β (chIFN-β) promoter. The silencing of chMDA5, chCARDIF, and chIRF3 reduced chIFN-β levels induced by AIV, indicating their involvement in AIV sensing. As with mammalian cells, chLGP2 had opposing effects. While overexpression decreased the activation of the chIFN-β promoter, the silencing of endogenous chLGP2 reduced chIFN-β induced by AIV. We finally demonstrate that the chMDA5 signaling pathway is inhibited by the viral nonstructural protein 1. In conclusion, chicken cells, including DF-1 fibroblasts and HD-11 macrophage-like cells, employ chMDA5 for sensing AIV.


Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast.
Infiltrating ductal mammary carcinomas are histologically graded according to their extent of differentiation. Well-differentiated, grade I, tumours have low proliferative activity, usually form tubules and exhibit little nuclear pleomorphism. Despite an apparently reassuring morphology, 10-15% of grade I ductal carcinomas metastasize, albeit after a prolonged period. Recent evidence supports the view that evolution to higher grade malignancies occurs rarely and that grade I tumours are biologically distinct from grade III tumours. We have examined a series of 148 grade I ductal carcinomas in order to ascertain whether information about the level of expression of cyclin D1, p27, p53, oestrogen receptor status (ER) or proliferative activity could be used to identify those patients with a poor outcome. The majority of tumours expressed high levels of cyclin D1, p27 and ER, low levels of p53 and had low Ki-67 expression and mitotic counts. Cyclin D1, p27 and ER expression were all significantly correlated with each other but not with p53 (cyclin D1 correlation with ER, p = 0.01; cyclin D1 correlation with p27 and ER correlation with p27 both p < 0.0001). Cyclin D1 and ER were also both correlated with Ki-67 (p = 0.01 and p < 0.0001) but not with mitotic count. Our results suggest that cyclin D1, ER and p27 are all markers of well-differentiated tumours and that their detection is related to proliferative activity in a manner reflecting their functional role within the normal cell cycle. However, none of the proteins or markers of proliferative activity were sensitive enough to predict which patients were likely to have a poor outcome.


Selective HDAC6 inhibitor TubA offers neuroprotection after intracerebral hemorrhage via inhibiting neuronal apoptosis.
A large body of evidence has demonstrated that neuronal apoptosis is involved in the pathological process of secondary brain injury following intracerebral hemorrhage (ICH). Additionally, our previous studies determined that the inhibition of HDAC6 activity by tubacin or specific shRNA can attenuate neuronal apoptosis in an oxygen-glucose deprivation reperfusion model. However, whether the pharmacological inhibition of HDAC6-attenuated neuronal apoptosis in ICH remains unclear. In this study, we used hemin-induced SH-SY5Y cells to simulate a hemorrhage state in vitro and adopted a collagenase-induced ICH rat model in vivo to assess the effect of the HDAC6 inhibition. We found a significant increase in HDAC6 during the early stages of ICH. As expected, the acetylated α-tubulin significantly decreased in correlation with the expression of HDAC6. Medium and high doses (25, 40 mg/kg) of TubA, a selective inhibitor of HDAC6, both reduced neurological impairments, histological impairments, and ipsilateral brain edema in vivo. TubA or HDAC6 siRNA both alleviated neuronal apoptosis in vivo and in vitro. Finally, HDAC6 inhibition increased the level of acetylated α-tubulin and Bcl-2 and lowered the expression of Bax and cleaved caspase-3 post-ICH. In general, these results suggested that the pharmacological inhibition of HDAC6 may act as a novel and promising therapeutic target for ICH therapy by up-regulating acetylated α-tubulin and reducing neuronal apoptosis.


Custom-Made 3D-Printed Implants for Anterior Column Reconstruction in the Upper Cervical Spine after Intralesional Extracapsular Excision-Report of 2 Cases and Literature Review.
The use of three-dimensional (3D)-printed custom-made implants is spreading in the orthopedics field for the reconstruction of bone losses or for joint replacement, thanks to their unparalleled versatility. In particular, this novel technology opens new perspectives to formulate custom-made fixation strategies for the upper cervical region, sacrum and pelvis, where reconstruction is challenging. We report and analyze the literature concerning upper cervical reconstruction with 3D-printed personalized implants after tumor surgery, and discuss two cases of patients where this technology was used to reconstruct the anterior column after extracapsular debulking of C2 recurrent chordoma at our institution.


Predicting the Adsorption of Amoxicillin and Ibuprofen on Chitosan and Graphene Oxide Materials: A Density Functional Theory Study.
The occurrence, persistence, and accumulation of antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) represent a new environmental problem due to their harmful effects on human and aquatic life. A suitable absorbent for a particular type of pollutant does not necessarily absorb other types of compounds, so knowing the compatibility between a particular pollutant and a potential absorbent before experimentation seems to be fundamental. In this work, the molecular interactions between some pharmaceuticals (amoxicillin, ibuprofen, and tetracycline derivatives) with two potential absorbers, chitosan and graphene oxide models (pyrene, GO-1, and coronene, GO-2), were studied using the ωB97X-D/6-311G(2d,p) level of theory. The energetic interaction order found was amoxicillin/chitosan > amoxicillin/GO-1 > amoxicillin/GO-2 > ibuprofen/chitosan > ibuprofen/GO-2 > ibuprofen/GO-1, the negative sign for the interaction energy in all complex formations confirms good compatibility, while the size of Eint between 24-34 kcal/mol indicates physisorption processes. Moreover, the free energies of complex formation were negative, confirming the spontaneity of the processes. The larger interaction of amoxicillin Gos, compared to ibuprofen Gos, is consistent with previously reported experimental results, demonstrating the exceptional predictability of these methods. The second-order perturbation theory analysis shows that the amoxicillin complexes are mainly driven by hydrogen bonds, while van der Waals interactions with chitosan and hydrophobic interactions with graphene oxides are modelled for the ibuprofen complexes. Energy decomposition analysis (EDA) shows that electrostatic energy is a major contributor to the stabilization energy in all cases. The results obtained in this work promote the use of graphene oxides and chitosan as potential adsorbents for the removal of these emerging pollutants from water.


Hindered fluorescence quenching in an insulated molecular wire.
A [3]rotaxane 2 within 1(2) consisting of an anionic phenylene ethynylene dumbbell 2(4-) threaded through two cationic cyclophanes 1(2+) has been prepared using aqueous Glaser coupling. Stern-Volmer analysis of the fluorescence quenching using three different electron-acceptors (methyl viologen 13(2+), dipropyl-4,4'-bipyridinium disulfonate 14 and anthraquinone-2,6-disulfonate 15(2-)) shows that the threaded cyclophanes inhibit electron-transfer from the excited state of the dumbbell by steric shielding, and by electrostatic shielding in the case of methyl viologen.


Ginger Extract and Fulvic Acid Foliar Applications as Novel Practical Approaches to Improve the Growth and Productivity of Damask Rose.
Plant biostimulants (BIOs) have been identified as among the best agricultural practices over the past few decades. Ginger extract (GE) and fulvic acid (FA) are a new family of multifunctional BIOs that positively affect development processes in plants. However, the underlying mechanisms that influence these development processes are still unknown. The objective of this study was to determine how GE and FA affect the plant growth and productivity in damask rose. Furthermore, the mechanisms of these BIOs that regulate the performance of this plant were investigated. Damask rose plants were foliar-sprayed with GE (5, 10 and 15 mg L-1) or FA (1, 3 and 5 g L-1), while control plants were sprayed with tap water. The results showed that GE or FA foliar applications enhanced plant height and branch number much more than the control; however, FA treatment was more effective than GE. Intriguingly, flower number, flower yield, relative water content, and total chlorophyll content were all improved by either GE or FA, paying attention to reducing the blind shoot number per plant. Relative to the control, foliar application with 15 mg L-1 GE or 3 mg L-1FA increased the flower number by 16.11% and 19.83% and the flower yield per hectare by 40.53% and 52.75%, respectively. Substantial enhancements in volatile oil content and oil yield were observed due to GE and FA treatments, especially with the highest concentrations of both BIOs. The treatments of GE and FA considerably improved the total soluble sugars, total phenolic content, total anthocyanin content, and total carotenoid content, more so with FA. Additionally, the contents of N, P, K, Mg, Fe, and Zn elements were also enhanced by applying either GE or FA, especially at higher levels of both BIOs. In sum, our findings illuminate the potential functions of exogenous application of GE and FA in improving the growth, flower yield, and volatile oil yield in damask rose through enhancing the phytochemical and nutrient profiles. Applications of GE and FA can, thus, be a promising approach for enhancing the productivity of damask rose.


Forgiveness and relationship satisfaction: mediating mechanisms.
Although the ability to forgive transgressions has been linked to overall relationship satisfaction, the mechanisms that mediate this association have not been established. We propose that the tendency to forgive a romantic partner increases relationship satisfaction via increased relational effort and decreased negative conflict. In two studies, we used structural equations modeling to examine these variables as potential mechanisms that drive this association. In Study 1 (N = 523) and Study 2 (N = 446) we found that these variables significantly mediated the association between forgiveness and relationship satisfaction. The findings were robust when examined concurrently and longitudinally, across multiple measures of forgiveness, and when accounting for baseline relationship satisfaction and interpersonal commitment. These two mechanisms parallel theorized positive and negative dimensions of forgiveness and the motivational transformation that is said to underlie forgiveness. Theoretical implications and implications for intervention are discussed.


Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and cervical cancer risk: a meta-analysis.
This meta-analysis aims to examine whether the genotype status of MspI and Ile462Val polymorphisms in Cytochrome-P450 1A1 (CYP1A1) is associated with cervical cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random effects models. Concerning MspI polymorphism, six studies were eligible (722 cases and 770 controls); four studies were eligible (350 cases and 519 controls) for Ile462Val. MspI polymorphism was associated with elevated cervical cancer risk (for heterozygous TC vs. TT carriers OR = 1.50, 95% CI: 0.93-2.42, random effects; for homozygous CC vs. TT carriers OR = 2.66, 95% CI: 1.14-6.19, random effects). Similarly, Ile462Val polymorphism was associated with elevated cervical cancer risk (for heterozygous Ile/Val vs. Ile/Ile carriers OR = 2.36, 95% CI: 1.10-5.08, random effects; for homozygous Val/Val vs. Ile/Ile carriers OR = 2.73, 95% CI: 1.21-6.15, fixed effects). The results were replicated upon Caucasian subjects, who represented the majority of existing data. The two examined CYP1A1 genotype polymorphisms seem to confer additional risk for cervical cancer. Accumulation of further data seems mandatory for future race-specific analyses and for the demonstration of CYP1A1-smoking interactions.


CMV and transplant-related coronary atherosclerosis: an immunohistochemical, in situ hybridization, and polymerase chain reaction in situ study.
Accelerated graft coronary atherosclerosis is the main obstacle to long-term survival in patients who have had a heart transplant. A possible involvement of the human cytomegalovirus (HCMV) in this type of coronary atherosclerosis has been postulated by many authors but has not been definitively demonstrated. In an attempt to clarify the role of HCMV infection in the pathogenesis of this complication, we looked for in situ antigens or DNA of HCMV in 30 coronary artery segments obtained at necropsy from patients who had undergone orthotopic cardiac transplantation at the São Paulo Heart Institute. We tried to correlate these HCMV markers with the presence of inflammation and/or atherosclerosis in histologic sections. The patients were grouped as follows: GI, less than 170 days of graft survival and absent/mild atherosclerosis; GII, more than 170 days of graft survival and absent/mild atherosclerosis; GIII, more than 170 days of graft survival and severe/moderate atherosclerosis (170 days was the shortest graft survival time associated with atherosclerosis). The search for HCMV genome and antigens in the coronary artery sections was performed using immunohistochemistry, in situ hybridization, and polymerase chain reaction in situ techniques. Immunohistochemistry and in situ hybridization revealed no evidence of HCMV in all 30 cases. Polymerase chain reaction in situ revealed scarce HCMV-positive lymphocytes in two cases (one each from GI and GIII) located in the adventitial layer. These findings preclude a direct role for the HCMV in the pathogenesis of accelerated graft coronary atherosclerosis. However, the possibility of an indirect effect of the virus, such as an immune-mediated inflammatory response by the host that increases the expression of histocompatibility antigens, leading to tissue injury, cannot be excluded.


Clonal Dissemination of OXA-370-Producing Klebsiella pneumoniae in Rio de Janeiro, Brazil.
Enzymes of the OXA-48 family have become some of the most important beta-lactamases in the world. A new OXA-48 variant (OXA-370) was first described for an Enterobacter hormaechei strain isolated in Rio Grande do Sul (southern region of Brazil) in 2013. Here we report detection of the blaOXA-370 gene in 24 isolates belonging to three Enterobacteriaceae species (22 Klebsiella pneumoniae isolates, 1 Enterobacter cloacae isolate, and 1 Enterobacter aerogenes isolate) collected from five hospitals in Rio de Janeiro, Brazil, in 2013 and 2014. The isolates showed a multidrug resistance profile, and 12.5% were resistant to polymyxin B. Besides blaOXA-370, no other carbapenemase genes were observed by PCR, whereas blaOXA-1 was found in all isolates and 22 isolates (91.6%) possessed blaCTX-M-15. Molecular typing of the K. pneumoniae isolates by pulsed-field gel electrophoresis (PFGE) showed the presence of two clonal groups, i.e., KpA (21 isolates) and KpB (1 isolate). KpA was characterized as sequence type 16 (ST16) and KpB as ST1041 by multilocus sequence typing (MLST). ST16 has been observed for KPC-producing K. pneumoniae in Rio de Janeiro. Plasmid analysis performed with six representative OXA-370-producing isolates showed plasmids harboring the blaOXA-370 gene in all strains, ranging from 25 kb to 150 kb. This study suggests that there is an urgent need to investigate the presence of OXA-370 and dissemination of the K. pneumoniae ST16 clone carrying this gene in Brazil.


Differential proteomics leads to identification of domain-specific epididymal sperm proteins.
The alteration in the protein signatures of the testicular sperm during its epididymal sojourn makes it functionally competent for successful fertilization. The present study was undertaken to identify the proteins acquired on its 2 domains, that is, the head and the flagellum, during the epididymal transit using a differential proteomics approach. Testicular sperm proteome was compared with cauda epididymal sperm proteome in rat. The protein spots exclusively present in the cauda epididymal sperm proteome were searched in the cauda sperm head proteome and the cauda sperm flagella proteome, and a total of 335 spots were found by alignment and auto-matching of the gels, of which 140 could be identified by mass spectrometry. Database search revealed that of these 9 proteins were novels. Gene Ontology annotation revealed that the identified proteins were distributed across different cellular components and were primarily involved in metabolic processes. The study also provides information on the localization of these proteins on the sperm domains, which indirectly gives a clue about its putative function. Validation of 3 proteins, namely MMSDH, NDUFS1, and UQCRC2, using antibodies very elegantly demonstrates that the strategy has been very effective. This comprehensive data of domain-specific epididymal sperm proteins will be useful in development of newer targets for posttesticular contraception and diagnostic markers for infertility.


Enhanced bioenergy and nutrients recovery from wastewater using hybrid anodes in microbial nutrient recovery system.
The combined microbial fuel cell-microbial nutrient recovery system has lately been thoroughly explored from an engineering standpoint. The relevance of microbial communities in this process, on the other hand, has been widely underestimated. A lab-scale microbial nutrients recovery system was created in this work, and the microbial community structure was further defined, to give a thorough insight into the important microbial groups in the present system. We reported for the first-time different hybrid anodes of activated carbon and chitosan that were used in the microbial nutrient recovery system for bioenergy production, and, for the removal of COD and recovery of nutrients present in the wastewater. The hybrid anodic materials were studied to adapt electrochemically active bacteria for the recovery of nutrients and energy generation from wastewater without the need for an external source of electricity. The potential of the created hybrid anodes in terms of nutrients recovery, chemical oxygen demand elimination, and energy generation from municipal wastewater was thoroughly examined and compared with each other under similar operating conditions. When the COD loading was 718 mg/L, a total COD removal of ~ 79.2% was achieved with a hybrid activated carbon and chitosan anode having an equal ratio after 10 days of the operation cycle. The maximum power density estimated for hybrid anode (~ 870 mWm-2) was found. Overall, this work reveals a schematic self-driven way for the collection and enrichment of nutrients (~ 72.9% phosphorus recovery and ~ 73% ammonium recovery) from municipal wastewater, as well as consistent voltage production throughout the operation.


[Restenosis after coronary angioplasty: pathomechanism and potential targets for therapeutic intervention. Focus on inflammation].
Percutaneous transluminal coronary angioplasty has become the most widely implemented method of heart revascularization. Despite many advances, such as application of bare metal stents, high-pressure inflation, and the recent invention of drug-eluting stents, restenosis remains the major limitation of invasive cardiology and is associated with a significant number or target lesion re-interventions. This review highlights contemporary concepts of the pathogenesis of coronary restenosis and potential targets for therapeutic intervention, with a special emphasis on the role of inflammation and distinctions in vessel re-narrowing patterns after balloon angioplasty and both bare metal and drug-eluting stenting.


Mass spectrometry in ionospheric research.
Mass spectrometry played a key role in the development of the understanding of the earth's ionosphere. Of primary importance was its use for in situ atmospheric measurements of the ion and neutral composition of the atmosphere. Mass spectrometry has also played an essential role in the laboratory measurement of critical ionospheric molecular processes. Examples of both are given.


A dynamically young and perturbed Milky Way disk.
The evolution of the Milky Way disk, which contains most of the stars in the Galaxy, is affected by several phenomena. For example, the bar and the spiral arms of the Milky Way induce radial migration of stars1 and can trap or scatter stars close to orbital resonances2. External perturbations from satellite galaxies can also have a role, causing dynamical heating of the Galaxy3, ring-like structures in the disk4 and correlations between different components of the stellar velocity5. These perturbations can also cause 'phase wrapping' signatures in the disk6-9, such as arched velocity structures in the motions of stars in the Galactic plane. Some manifestations of these dynamical processes have already been detected, including kinematic substructure in samples of nearby stars10-12, density asymmetries and velocities across the Galactic disk that differ from the axisymmetric and equilibrium expectations13, especially in the vertical direction11,14-16, and signatures of incomplete phase mixing in the disk7,12,17,18. Here we report an analysis of the motions of six million stars in the Milky Way disk. We show that the phase-space distribution contains different substructures with various morphologies, such as snail shells and ridges, when spatial and velocity coordinates are combined. We infer that the disk must have been perturbed between 300 million and 900 million years ago, consistent with estimates of the previous pericentric passage of the Sagittarius dwarf galaxy. Our findings show that the Galactic disk is dynamically young and that modelling it as time-independent and axisymmetric is incorrect.


Rapid Head Movements in Common Marmoset Monkeys.
Gaze shifts, the directing of the eyes to an approaching predator, preferred food source, or potential mate, have universal biological significance for the survival of a species. Our knowledge of gaze behavior is based primarily on visually triggered responses, whereas head orientation triggered by auditory stimuli remains poorly characterized. Common marmoset (Callithrix jacchus) is a diurnal, small-bodied (∼350 g), New World monkey species, known for its rich behavioral repertoires during social interactions. We used a lightweight head tracking system to measure marmosets' reflexive head orientations toward a natural stimulus presented from behind. We found that marmoset could rotate its head at angular velocities above 1,000°/s and maintained target accuracy for a wide range of rotation amplitudes (up to 250°). This unusual, saccadic head orienting behavior offers opportunities for understanding the many biological factors that have shaped the evolution of sensorimotor controls of gaze orientation by the primate brain.


Functional interaction of common gamma-chain and growth hormone receptor signaling apparatus.
We previously reported on an X-linked SCID (X-SCID) patient, who also had peripheral growth hormone (GH) hyporesponsiveness and abnormalities of the protein phosphorylation events following GH receptor (GHR) stimulation. In the present study, we examined a potential role of common cytokine receptor gamma-chain (gammac) in GHR signaling using EBV-transformed lymphocytes from healthy subjects and gammac-negative X-SCID patients. We demonstrated that the proliferative response to GH stimulation of the B cell lines of gammac-negative patients was impaired despite a comparable cellular expression of GHR molecules to controls. In patients, after GH stimulation, no phosphorylation of STAT5 was observed. In addition, the molecule localization through confocal microscopy revealed that in B cell lines of patients no nuclear translocation of STAT5b following GH stimulation occurred differently from controls. Biochemical analysis of the nuclear extracts of gammac-negative cell lines provided further evidence that the amount of STAT5b and its phosphorylated form did not increase following GH stimulation. In patients, cells reconstituted with wild-type gammac abnormal biochemical and functional events were restored resulting in nuclear translocation of STAT5. Confocal experiments revealed that GHR and gammac were colocalized on the cell membrane. Our study demonstrates the existence of a previously unappreciated relationship between GHR-signaling pathway and gammac, which is required for the activation of STAT5b in B cell lines. These data also confirm that growth failure in X-SCID is primarily related to the genetic alteration of the IL2RG gene.


Diagnostic Value of the Survivin Autoantibody in Four Types of Malignancies.
Tumor-associated antigen overexpression, which has been reported in many types of cancers, may trigger autoantibody secretion. The present study was designed to test whether levels of circulating autoantibodies to survivin protein-derived antigens is altered in liver, esophageal, breast, and lung cancers. Patients with liver (144), esophageal (159), breast (124), and lung cancers (267), and healthy volunteers (362) were recruited for the study, and serum samples were collected for ELISA autoantibody analysis. Compared with the control group, survivin autoantibody levels were significantly higher in serum from patients with breast cancer and lung cancer, but were significantly lower in serum from patients with liver cancer (p < 0.05). In stage I and II lung cancer, the best-fit areas under the receiver operating characteristic curve was 0.731 (standard error [SE] = 0.023; 95% confidence interval [CI] 0.687-0.776) and the sensitivity, with 90% specificity, was 23.7%. Analysis across four types of malignancies revealed that the survivin autoantibody had good specificity and sensitivity in lung cancer. Circulating autoantibodies to survivin could be a potential biomarker for the early lung cancer diagnosis.


Value of magnetic resonance diffusion combined with perfusion imaging techniques for diagnosing potentially malignant breast lesions.
Lesions of breast imaging reporting and data system (BI-RADS) 4 at mammography vary from benign to malignant, leading to difficulties for clinicians to distinguish between them. The specificity of magnetic resonance imaging (MRI) in detecting breast is relatively low, leading to many false-positive results and high rates of re-examination or biopsy. Diffusion-weighted imaging (DWI), combined with perfusion-weighted imaging (PWI), might help to distinguish between benign and malignant BI-RADS 4 breast lesions at mammography. To evaluate the value of DWI and PWI in diagnosing BI-RADS 4 breast lesions. This is a retrospective study which included patients who underwent breast MRI between May 2017 and May 2019 in the hospital. The lesions were divided into benign and malignant groups according to the classification of histopathological results. The diagnostic efficacy of DWI and PWI were analyzed respectively and combinedly. The 95 lesions were divided according to histopathological diagnosis, with 46 benign and 49 malignant. The main statistical methods used included the Student t-test, the Mann-Whitney U-test, the chi-square test or Fisher's exact test. The mean apparent diffusion coefficient (ADC) values in the parenchyma and lesion area of the normal mammary gland were 1.82 ± 0.22 × 10-3 mm2/s and 1.24 ± 0.16 × 10-3 mm2/s, respectively (P = 0.021). The mean ADC value of the malignant group was 1.09 ± 0.23 × 10-3 mm2/s, which was lower than that of the benign group (1.42 ± 0.68 × 10-3 mm2/s) (P = 0.016). The volume transfer constant (Ktrans) and rate constant (Kep) values were higher in malignant lesions than in benign ones (all P < 0.001), but there were no significant statistical differences regarding volume fraction (Ve) (P = 0.866). The sensitivity and specificity of PWI combined with DWI (91.7% and 89.3%, respectively) were higher than that of PWI or DWI alone. The accuracy of PWI combined with DWI in predicting pathological results was significantly higher than that predicted by PWI or DWI alone. DWI, combined with PWI, might possibly distinguish between benign and malignant BI-RADS 4 breast lesions at mammography.


Thomas Willis, a pioneer in translational research in anatomy (on the 350th anniversary of Cerebri anatome).
The year 2014 marked the 350th anniversary of the publication in London of Cerebri anatome, a ground-breaking work of neuroscience heavily influenced by the political and cultural context of Baroque Europe and mid-17th century England. This article aims to review the work of the English physician and anatomist Thomas Willis, specifically with regard to the contents of his Cerebri anatome. Willis's academic and professional career was influenced by the turbulent period of the English Civil War during which he studied medicine. Willis went from chemistry to dissection arguably because of his need to justify the body-brain-soul relationship. As a result, he became a fellow of a select club of eminent experimentalists, and afterward was a Fellow of the Royal Society. Later on, he went to London, leaving the academic life to dedicate himself fully to the profession of medicine. As a physician, Willis did not base his practice on aphorisms but on a 'bench to bedside' approach to medicine, while studying neuroanatomy--covering embryology, comparative anatomy and pathological anatomy--as a basis for the comprehension of neurological pathology. He developed innovative anatomical methods for the preservation and dissection of the brain, injection of coloured substances and illustration of his findings. In Cerebri anatome, Willis recognized the cerebral cortex as the substrate of cognition. He also claimed that the painful stimuli came from the meninges, but not from the brain itself. He explained for the first time the pathological and functional meaning of the brain's circular arterial anastomosis, which is named after him. He also specified some features of the cranial origin of the sympathetic nerves and coined the term 'neurologie'. Cerebri anatome marked the transition between the mediaeval and modern notions of brain function, and thus it is considered a cornerstone of clinical and comparative anatomy of the nervous system. The new contributions and methods employed by Willis justify his place as a father of neurology and a pioneer of translational research.


NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver.
We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE). Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system. NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver. By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.


Intrinsic Triple Order in A-site Columnar-Ordered Quadruple Perovskites: Proof of Concept.
There is an emerging topic in the science of perovskite materials: A-site columnar-ordered A2 A'A''B4 O12 quadruple perovskites, which have an intrinsic triple order at the A sites. However, in many examples reported so far, A' and A'' cations are the same, and the intrinsic triple order is hidden. Here, we investigate structural properties of Dy2 CuMnMn4 O12 (1) and Ho2 MnGaMn4 O12 (2) by neutron and X-ray powder diffraction and prove the triple order at the A sites. The cation distributions determined are [Ho2 ]A [Mn]A' [Ga0.66 Mn0.34 ]A'' [Mn3.66 Ga0.34 ]B O12 and [Dy2 ]A [Cu0.73 Mn0.27 ]A' [Mn0.80 Dy0.20 ]A'' [Mn1.89 Cu0.11 ]B1 [Mn2 ]B2 O12 . There are clear signatures of Jahn-Teller distortions in 1 and 2, and the orbital pattern is combined with an original type of charge ordering in 1. Columnar-ordered quadruple perovskites represent a new playground to study complex interactions between different electronic degrees of freedom. No long-range magnetic order was found in 2 by neutron diffraction, and its magnetic properties in low fields are dominated by an impurity with negative magnetization or magnetization reversal. On the other hand, 1 shows three magnetic transitions at 21, 125, and 160 K.


Dynamical memristive neural networks and associative self-learning architectures using biomimetic devices.
While there is an abundance of research on neural networks that are "inspired" by the brain, few mimic the critical temporal compute features that allow the brain to efficiently perform complex computations. Even fewer methods emulate the heterogeneity of learning produced by biological neurons. Memory devices, such as memristors, are also investigated for their potential to implement neuronal functions in electronic hardware. However, memristors in computing architectures typically operate as non-volatile memories, either as storage or as the weights in a multiply-and-accumulate function that requires direct access to manipulate memristance via a costly learning algorithm. Hence, the integration of memristors into architectures as time-dependent computational units is studied, starting with the development of a compact and versatile mathematical model that is capable of emulating flux-linkage controlled analog (FLCA) memristors and their unique temporal characteristics. The proposed model, which is validated against experimental FLCA LixNbO2 intercalation devices, is used to create memristive circuits that mimic neuronal behavior such as desensitization, paired-pulse facilitation, and spike-timing-dependent plasticity. The model is used to demonstrate building blocks of biomimetic learning via dynamical memristive circuits that implement biomimetic learning rules in a self-training neural network, with dynamical memristive weights that are capable of associative lifelong learning. Successful training of the dynamical memristive neural network to perform image classification of handwritten digits is shown, including lifelong learning by having the dynamical memristive network relearn different characters in succession. An analog computing architecture that learns to associate input-to-input correlations is also introduced, with examples demonstrating image classification and pattern recognition without convolution. The biomimetic functions shown in this paper result from fully ion-driven memristive circuits devoid of integrating capacitors and thus are instructive for exploiting the immense potential of memristive technology for neuromorphic computation in hardware and allowing a common architecture to be applied to a wide range of learning rules, including STDP, magnitude, frequency, and pulse shape among others, to enable an inorganic implementation of the complex heterogeneity of biological neural systems.


Research development on graphitic carbon nitride and enhanced catalytic activity on ammonium perchlorate.
Recently, graphitic carbon nitride (g-C3N4) has attracted considerable attention due to its attractive features including excellent electrochemical performance, suitable band gap, nontoxicity, and high mechanical and thermal stability. Such unique advantages endow it with promising applications in batteries, photocatalysts, photodegradation, and so on. In particular, it has been applied to catalyze the thermal decomposition of ammonium perchlorate (AP) and has shown excellent performance. In this review, the structure, preparation methods and exfoliation strategies of g-C3N4 are comprehensively introduced. Furthermore, the enhanced catalytic mechanism for the thermal decomposition of AP is discussed in detail, and a future research direction is also proposed.


Oral Clonidine Premedication Attenuates Hemodynamic Responses of Ketamine during Total Intravenous Anesthesia.
The most commonly used drug for total intravenous anesthesia (TIVA) is ketamine which results in cardiovascular stimulation. The primary aim of this study was to assess the effect of oral clonidine premedication on attenuating the hemodynamic responses following ketamine administration. This was a prospective, observational, comparative study conducted in a tertiary care institution. A total of 40 female patients aged 18-55 years who were posted for elective short gynecological procedures under TIVA were recruited for this study. Group A patients were given oral clonidine 150 μg 60 min before proposed surgical procedure, whereas Group B patients received a placebo tablet. Before induction, all patients received glycopyrrolate 0.2 mg, midazolam 2 mg, and fentanyl 2 μg/kg intravenously. Anesthesia was induced with ketamine 1.5 mg/kg body weight intravenously over 2-3 min. The hemodynamics after premedication and induction were assessed. To test the statistical significance or difference between the mean change from the basal value at various time points, student's t-test was applied. At 20, 30, 40, 50, and 60 min postpremedication and after induction at 1, 3, 5, 10, 15, 20, and 30 min, Group B showed significantly higher heart rate. Systolic and diastolic blood pressures showed a significant decrease in Group A after induction up to 30 min. Nearly 6.7% of the patients in Group B had emergence delirium with none in Group A, which was not statistically significant. Oral premedication with clonidine 150 μg, administered 60 min before the conduct of TIVA, attenuated hemodynamic responses of intravenous ketamine.


Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice.
Theiler's murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3+ T cells, CD45R+ B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3+ regulatory T cells and arginase-1+ macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.


Increased myocardial ischemia after food is not explained by endothelial dysfunction.
Recent studies suggest that a high-fat meal can impair endothelial function. The aim of this study was to determine whether greater myocardial ischemia after either a low-fat or a high-fat meal is associated with an increase in brachial artery endothelial dysfunction. Twenty subjects with coronary artery disease and > or =1-mm ST-segment depression during exercise were studied. In a randomized, double-blind, crossover design, ST-segment changes during treadmill exercise and brachial artery diameter and flow-mediated dilation were measured before and 3 hours after a low-fat milkshake meal or the same meal supplemented with 64 grams of cooked fat. After the low-fat but not the high-fat meal, resting brachial artery diameter decreased (before meal 4.72 +/-0.50 mm, after low fat meal 4.62 +/-0.49 mm, P =.001; after high fat meal 4.70 +/-0.51 mm, not significant). High-flow brachial artery diameter was similar before (4.81 +/- 0.48 mm) and after the low-fat (4.82 +/- 0.48 mm) and high-fat (4.84 +/- 0.48 mm) meals (P >.05 for all). Brachial artery flow-mediated dilation was not impaired after either meal. Exercise duration decreased more after the low-fat meal (mean change 39 seconds, 95% CI -14 to -63 seconds, P =.004) than after the high-fat meal (-7 seconds, 95% CI +19 to -34 seconds, not significant). ST-segment depression during equivalent exercise was greater after compared with before both meals (before meals 1.03 +/- 0.69 mm, after low fat 1.27 +/- 0.80 mm, P =.03; after high fat 1.24 +/- 0.74 mm, P =.04). Increased myocardial ischemia after food is caused by mechanisms other than endothelial dysfunction and by meal components other than cooked fat.


Perioperative myocardial ischaemia, heart rate and arrhythmia in patients undergoing thoracotomy: an observational study.
We have studied myocardial ischaemia, heart rate and arrhythmia in 82 patients undergoing elective thoracotomy. Myocardial ischaemia was detected using a microprocessor-based surveillance system programmed to record leads V2 and V5. Patients were monitored on the day before and for up to 72 h after surgery. The total monitoring time was 5158 h. The incidence of silent myocardial ischaemia before operation was 11% (nine of 82). This increased to 24% (20 of 82) after operation. Postoperative myocardial ischaemia was associated with preoperative myocardial ischaemia in six patients. Before operation, the mean duration of myocardial ischaemia was 0.31 min per hour of monitoring. After operation, this increased to 1.36 min per hour of monitoring (P < 0.05). For the whole population, mean heart rate before operation was 74 beat min-1 and increased to 84 beat min-1 after operation (P < 0.01). Patients with ischaemia had a mean heart rate of 92.8 beat min-1 after operation compared with those with no ischaemia whose mean heart rate was unchanged at 81.8 beat min-1 (P < 0.05). The incidence of atrial tachyarrhythmia increased from one patient before operation to 12 patients after operation (P < 0.01). Atrial tachyarrhythmia was not associated with postoperative myocardial ischaemia. Nine patients had an adverse operative outcome; two had non-fatal myocardial infarction and seven died. Postoperative myocardial ischaemia was associated with adverse outcomes (P < 0.05).


Predictive index for optimizing empiric treatment of gram-negative bacteremia.
In a survey of 296 episodes of gram-negative bacteremia in 286 patients (aged 13-99 years), four clinical variables were found to predict both significantly and independently the subsequent isolation of a multiresistant strain; hospital acquisition of the infection, antibiotic treatment before the bacteremic episode, endotracheal intubation, and thermal trauma as the cause of hospitalization. These variables were combined in an index that served to classify the patients into four groups with an increasing prevalence of multiresistant strains, Pseudomonas isolates, and isolates resistant to each of the antibiotic drugs in common use. For example, the percentage of isolates susceptible to cefuroxime in the four groups were 79%, 56%, 34% and 25%, and to gentamicin, 89%, 79%, 46%, and 33% (P less than .001 for both comparisons). The performance of the index was validated in a second group of 144 episodes of gram-negative bacteremia. The index kept its discriminative power. Compared with the prescriptions of the attending physicians, the index could probably have improved empiric antibiotic treatment in 24% of patients.


The prevalence and associated factors of burnout among undergraduates in a university.
The study aimed to evaluate the prevalence and possible factors associated with burnout (BO) among undergraduates in a university setting in Dali.This cross-sectional study involved students enrolled in different specialties. The method of stratified random sampling was used to conduct the investigation. The questionnaire included Maslach Burnout Inventory and the influencing factors. The data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL). The quantitative data were compared using t tests or ANOVA. Multiple linear regression was used to assess the relationship between BO risk and relevant influencing factors.The prevalence of study BO was 38.1%. Significant differences of the mean scores on BO and low personal efficacy were observed between men and women, with women obtaining a higher score (t = -2.588, P = .010; t = -2.929, P = .003; respectively). The scores of overall BO, emotional exhaustion (EE), and cynicism were low, whereas that of professional efficacy was higher for students with excellent marks (P = .000). Students majoring in liberal arts obtained low scores of overall BO, EE, and cynicism. Nevertheless, their score for professional efficacy was higher than those from other specializations (P < .05). Total BO, as the dependent variable, revealed that 3 predictors (social factors, school factors, and interpersonal communication) accounted for 30.8% of the variance (R2 = 0.308). A regression analysis of EE as the dependent variable identified that 2 variables (social and school factors) explained 45.8% of the variance (R2 = 0.458).BO among undergraduates is present in a university setting in Dali. A variety of factors including social factors, school factors, and interpersonal communication can influence the prevalence of BO. Therefore, society should strengthen employment and further understand psychology; schools and families must pay attention to the psychological development of college students.


Au nanostructure fabrication by pulsed laser deposition in open air: Influence of the deposition geometry.
We present a fast and flexible method for the fabrication of Au nanocolumns. Au nanostructures were produced by pulsed laser deposition in air at atmospheric pressure. No impurities or Au compounds were detected in the resulting samples. The nanoparticles and nanoaggregates produced in the ablated plasma at atmospheric pressure led to the formation of chain-like nanostructures on the substrate. The dependence of the surface morphology of the samples on the deposition geometry used in the experimental set up was studied. Nanocolumns of different size and density were produced by varying the angle between the plasma plume and the substrate. The electrical, optical, and hydrophobic properties of the samples were studied and discussed in relation to their morphology. All of the nanostructures were conductive, with conductivity increasing with the accumulation of ablated material on the substrate. The modification of the electrical properties of the nanostructures was demonstrated by irradiation by infrared light. The Au nanostructures fabricated by the proposed technology are difficult to prepare by other methods, which makes the simple implementation and realization in ambient conditions presented in this work more ideal for industrial applications.


Popliteal artery pseudoaneurysms in patients affected by osteochondroma.
Although exostosis or osteochondroma is a common bone tumor, associated vascular complications are rare. Clinical and radiological diagnoses are sometimes challenging, and there is no codification for surgical management. We report two cases of popliteal arterial pseudoaneurysms due to osteochondroma of the distal femur. A review of the current literature about case series and case reports of patients affected by arterial pseudoaneurysm complicating osteochondroma was also performed.


Massive proteinuria in light chain disease.
A 33-year-old man with overall renal function in the lower normal range had daily excretion in the urine of between 31 and 70 gm of protein composed entirely of free monoclonal K light chains. K light chains were also present in the serum. Serum protein electrophoresis and findings on bone marrow and lymph node biopsy were diagnostic of light chain disease. Amyloid was absent from renal tissue. General clinical improvement and almost total disappearance of protein from the urine followed treatment with phenylalanine mustard.


THE THREE DS OF PCR-BASED GENOMIC ANALYSIS OF PHYTOBACTERIA: Diversity, Detection, and Disease Diagnosis.
The advent of molecular biology in general and the polymerase chain reaction in particular have greatly facilitated genomic analyses of microorganisms, provide enhanced capability to characterize and classify strains, and facilitate research to assess the genetic diversity of populations. The diversity of large populations can be assessed in a relatively efficient manner using rep-PCR-, AFLP-, and AP-PCR/RAPD-based genomic fingerprinting methods, especially when combined with computer-assisted pattern analysis. Genetic diversity maps provide a framework to understand the taxonomy, population structure, and dynamics of phytobacteria and provide a high-resolution framework to devise sensitive, specific, and rapid methods for pathogen detection, plant disease diagnosis, as well as management of disease risk. A variety of PCR-based fingerprinting protocols such as rDNA-based PCR, ITS-PCR, ARDRA, T-RFLPs, and tRNA-PCR have been devised, and numerous innovative approaches using specific primers have been adopted to enhance both the detection and identification of phytobacteria. PCR-based protocols, combined with computer-based analysis, have provided novel fundamental knowledge of the ecology and population dynamics of bacterial pathogens, and present exciting new opportunities for basic and applied studies in plant pathology.


CLINICAL MANAGEMENT OF FAMILIES WITH HEREDITARY COLORECTAL CANCER SYNDROMES.
Hereditary colorectal cancer syndromes can be associated with a lifetime risk of CRC of >70% in the absence of specialized surveillance. Diagnosing a genetic predisposition to cancer allows clinicians to tailor cancer prevention strategies for patients and families at highest risk. Once a genetic syndrome has been identified in a family, communication with family members, timely implementation of screening tests and/or surgeries, and psychosocial support are all instrumental for effective cancer prevention.Molecular screening of tumors, computerized risk assessment models, and genetic testing can help clinicians identify individuals at risk for hereditary cancer syndromes. This review discusses some of the complexities involved in the diagnosis and management of families with hereditary CRC syndromes and provides strategies for coordinating clinical care.