Activity-dependent upregulation of presynaptic kainate receptors at immature CA3-CA1 synapses.
Presynaptic kainate-type glutamate receptors (KARs) regulate glutamate release probability and short-term plasticity in various areas of the brain. Here we show that long-term depression (LTD) in the area CA1 of neonatal rodent hippocampus is associated with an upregulation of tonic inhibitory KAR activity, which contributes to synaptic depression and causes a pronounced increase in short-term facilitation of transmission. This increased KAR function was mediated by high-affinity receptors and required activation of NMDA receptors, nitric oxide (NO) synthetase, and postsynaptic calcium signaling. In contrast, KAR activity was irreversibly downregulated in response to induction of long-term potentiation in a manner that depended on activation of the TrkB-receptor of BDNF. Both tonic KAR activity and its plasticity were restricted to early stages of synapse development and were lost in parallel with maturation of the network due to ongoing BDNF-TrkB signaling. These data show that presynaptic KARs are targets for activity-dependent modulation via diffusible messengers NO and BDNF, which enhance and depress tonic KAR activity at immature synapses, respectively. The plasticity of presynaptic KARs in the developing network allows nascent synapses to shape their response to incoming activity. In particular, upregulation of KAR function after LTD allows the synapse to preferentially pass high-frequency afferent activity. This can provide a potential rescue from synapse elimination by uncorrelated activity and also increase the computational dynamics of the developing CA3-CA1 circuitry.


Properties and function of lysyl oxidase.
Lysyl oxidase catalyzes the oxidation of peptidyl lysine to alpha-aminoadipic-delta-semialdehyde, the precursor to the covalent crosslinkages that stabilize fibers of elastin and collagen. This enzyme contains both copper and a carbonyl cofactor consistent with an o-quinone. The proposed mechanism of action is derived from available kinetic and chemical data and also can account for mechanism-based inhibition of the enzyme by specific monoamines and diamines. Recent evidence for biosynthetic precursors and for the regulation of lysyl oxidase in fibrotic and malignant diseases is discussed.


Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date.
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.


[Exploring efficacy of Chinese medicine injection for promoting blood circulation and removing blood stasis in treatment of acute cerebral infarction based on two complex network analysis methods].
This study aims to explore the efficacy of Chinese medicine injections( CMIs) for promoting blood circulation and removing blood stasis for acute cerebral infarction from the perspectives of clinical medication and mechanism of action based on two complex network analysis methods. Firstly,the current 13 kinds of CMIs for acute cerebral infarction were obtained from 2019 List of medicines for national basic medical insurance,industrial injury insurance and maternity insurance with the method of network Meta-analysis. Secondly,with the use of network pharmacology,the mechanisms of top 2 CMIs with the highest therapeutic effect for acute cerebral infarction were explored from two levels including core target and network function enrichment. The result of network Meta-analysis showed Mailuoning Injection was superior to Danhong Injection in terms of total effectiveness rate for neurological deficit score and NIHSS score. The network pharmacology results showed that Mailuoning Injection had more core targets,interaction networks,enriched biological functions and more signaling pathways than Danhong Injection for cerebral infarction. Both two CMIs can play a role in treating cerebral infarction through core targets such as TP53 and NOS3,biological processes such as fibrinolysis,nitric oxide biosynthesis,nitric oxide-mediated signal transduction,negative regulation of apoptosis in endothelial cells and apoptosis process,as well as the signaling pathways such as PI3 K-Akt signaling pathway,HIF-1 signaling pathway and cell apoptosis signaling pathways. The results of pharmacological studies explained their differences in clinical efficacy to a certain extent. A research strategy based on curative effect should be advocated in efficacy evaluation of traditional Chinese medicine,where comparative research on clinical efficacy can be conducted firstly,and then mechanism research based on outstanding effective drugs to better provide references and basis for selection of similar competitive drugs for one disease in the clinical practice.


Adherence to the TQIP Palliative Care Guidelines Among Patients With Serious Illness at a Level I Trauma Center in the US.
The American College of Surgeons Trauma Quality Improvement Program (TQIP) guidelines encourage trauma service clinicians to deliver palliative care in parallel with life-sustaining treatment and recommend goals of care (GOC) discussions within 72 hours of admission for patients with serious illness. To measure adherence to TQIP guidelines-recommended GOC discussions for trauma patients with serious illness, treated at a level I trauma center in the US. This retrospective cohort study included 674 adults admitted to a trauma service center for 3 or more days between December 2019 and June 2020. The medical records of 486 patients who met the criteria for serious illness using a consensus definition adapted to the National Trauma Data Bank were reviewed for the presence of a GOC discussion. Patients were divided into 2 cohorts based on admission before or after the guidelines were incorporated into the institutional practice guidelines on March 1, 2020. The primary outcomes were GOC completion within 72 hours of admission and during the overall hospitalization. Patient and clinical factors associated with GOC completion were assessed. Other palliative care processes measured included palliative care consultation, prior advance care planning document, and do-not-resuscitate code status. Additional end-of-life processes (ie, comfort care and inpatient hospice) were measured in a subset with inpatient mortality. Of 674 patients meeting the review criteria, 486 (72.1%) met at least 1 definition of serious illness (mean [SD] age, 60.9 [21.3] years; mean [SD] Injury Severity Score, 16.9 [12.3]). Of these patients, 328 (67.5%) were male and 266 (54.7%) were White. Among the seriously ill patients, 92 (18.9%) had evidence of GOC completion within 72 hours of admission and 124 (25.5%) during the overall hospitalization. No differences were observed between patients admitted before and after institutional guideline publication in GOC completion within 72 hours (19.0% [47 of 248 patients] vs 18.9% [45 of 238]; P = .99) or during the overall hospitalization (26.2% [65 of 248 patients] vs 24.8% [59 of 238]; P = .72). After adjusting for age, GOC completion was found to be associated with the presence of mechanical ventilation (odds ratio [OR], 6.42; 95% CI, 3.49-11.81) and meeting multiple serious illness criteria (OR, 4.07; 95% CI, 2.25-7.38). The findings of this cohort study suggest that, despite the presence of national guidelines, GOC discussions for patients with serious illness were documented infrequently. This study suggests a need for system-level interventions to ensure best practices and may inform strategies to measure and improve trauma service quality in palliative care.


[Inhaled nitric oxide therapy].
Inhaled nitric oxide (NO) therapy is a measure to improve pulmonary hypertension and ventilation-perfusion inequality by administering NO gas. Basic studies suggest that low concentrations of inhaled NO decreases the increased pulmonary capillary pressure, depresses the increased permeability of pulmonary vasculature, inhibits the increased agglutination and adhesion of leucocytes to the lungs, depresses the increased agglutination and adhesion of platelets, and decreases the hypertensive remodeling of pulmonary vasculature. In the emergency and critical care settings, quite a lot of life-threatening patients with the exacerbation of pulmonary hypertension and/or hypoxemia by trauma, surgery and infections are admitted for treatment. In this paper, we discuss the present status of inhaled NO therapy from the point of view of an emergency and critical care physician.


"These Issues Aren't Separate": The Relationship Among Being Indigenous, Motherhood, and the Criminal Justice System.
In using an approach encompassing intersectionality and interconnectedness, we highlight how the experiences of Indigenous mothers and mother figures in contact with the law are a result of various historical and contemporary events. We highlight a need for a wholistic approach to eliminate the overrepresentation of Indigenous Peoples, including parents, in the criminal justice system. There is a lack of research and discussion on Indigenous women and their experience with the justice system and by using an Indigenous lens, we can explore the establishment of culturally safe resources and care wherein gender inclusivity is prioritized. Our team of researchers and advocates intends for this article to contribute and spark dialogue on Indigenous Peoples, particularly mothers and mother figures and their interactions with the justice system. Although this article mainly focuses on federal programs and policies in Canada, insights on the barriers to care can be applied into policy and practice across multiple settler states.


The flavonoid Kaempferol suppresses the graft-versus-host reaction by inhibiting type 1 cytokine production and CD8+ T cell engraftment.
We have here examined the immunoregulatory effects of a natural flavonoid, Kaempferol, on T cells. Kaempferol suppressed IFN-gamma and IL-2 production but not that of IL-4 by T cells and shifted the Th1/Th2 balance into the Th2 phenotype. In C57BL/6 anti-BDF1 MLC, Kaempferol inhibited the development and expansion of type 1 effector CD8+ T cells and diminished allospecific CTL activity. Based on these in vitro results, we evaluated the effects of Kaempferol treatment on the development of C57BL/6-into-BDF1 acute graft-versus-host disease (GVHD). Brief administration of Kaempferol led to early recovery from body weight loss, increased survival, and reduced tissue injury in the liver and large intestine. Kaempferol treatment activated Th2 cells and the engraftment of donor cells and also diminished GVHD-associated antihost CTL activity. Thus, our study indicates that Kaempferol has the capacity to modulate the Th1/Th2 balance and could be useful for the treatment of cell-mediated immune diseases, such as acute GVHD.


Structure-activity relationship and elucidation of the determinant factor(s) responsible for the mechanism-based inactivation of cytochrome P450 2B6 by substituted phenyl diaziridines.
It has been demonstrated previously that several 3-trifluoromethyl-3-(4-alkoxyphenyl)diaziridines inhibit the 7-ethoxy-4-(trifluoroethyl)coumarin (7-EFC) O-deethylation activity of P450 2B6 in a mechanism-based manner. In contrast, 3-trifluoromethyl-3-(4-methylthio)phenyl)diaziridine did not have any effect on the activity of P450 2B6. It is interesting that both the alkoxy and the thiophenyl compounds were metabolized by P450 2B6. In this report, the structure-activity relationships for the mechanism-based inactivation of cytochrome P450 2B6 by a series of aryl diaziridines were investigated. Three diaziridines that did not contain a 4-alkoxy-substituent on their phenyl ring, namely, 3-trifluoromethyl-3-(3-methoxyphenyl)diaziridine, 3-trifluoromethyl-3-phenyl diaziridine, and 3-trifluoromethyl-3-(4-chlorophenyl)diaziridine had no effect on the P450 2B6 7-EFC activity. Another analog that did not contain a diaziridine substructure, 3-trifluoromethyl-3-(4-methoxyphenyl)ethanone, also had no effect on the activity of P450 2B6. Glutathione ethyl ester adducts of the phenyldiaziridine reactive intermediates were isolated from reaction mixtures of the inactivated samples and analyzed by liquid chromatography-tandem mass spectrometry. The structures of the conjugates suggested that the electrophilic reactive intermediate in each case was a quinone methide (quinomethane), 4-ethylidene-cyclohexa-2,5-dienone, generated from the 4-alkoxyphenyldiaziridines by removal of both of the diaziridine and the 4-alkyl groups. In conclusion, the determinant factor for the mechanism-based inactivator activity of the aryl diaziridines seems to be the formation of the reactive quinomethane intermediate, which is generated from the 4-alkoxyphenyl diaziridines by a cytochrome P450-catalyzed metabolic reaction.


A sigma54-dependent promoter in the regulatory region of the Escherichia coli rpoH gene.
The Escherichia coli rpoH gene is transcribed from four known and differently regulated promoters: P1, P3, P4 and P5. This study demonstrates that the conserved consensus sequence of the sigma54 promoter in the regulatory region of the rpoH gene, described previously, is a functional promoter, P6. The evidence for this conclusion is: (i) the specific binding of the sigma54-RNAP holoenzyme to P6, (ii) the location of the transcription start site at the predicted position (C, 30 nt upstream of ATG) and (iii) the dependence of transcription on sigma54 and on an ATP-dependent activator. Nitrogen starvation, heat shock, ethanol and CCCP treatment did not activate transcription from P6 under the conditions examined. Two activators of sigma54 promoters, PspF and NtrC, were tested but neither of them acted specifically. Therefore, PspFDeltaHTH, a derivative of PspF, devoid of DNA binding capability but retaining its ATPase activity, was used for transcription in vitro, taking advantage of the relaxed specificity of ATP-dependent activators acting in solution. In experiments in vivo overexpression of PspFDeltaHTH from a plasmid was employed. Thus, the sigma54-dependent transcription capability of the P6 promoter was demonstrated both in vivo and in vitro, although the specific conditions inducing initiation of the transcription remain to be elucidated. The results clearly indicate that the closed sigma54-RNAP-promoter initiation complex was formed in vitro and in vivo and needed only an ATP-dependent activator to start transcription.


5-HT6 receptor agonism facilitates emotional learning.
Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466-treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser(845)-GluA1 and phospho-Ser(217/221)-MEK in the caudate-putamen. Levels of phospho-Thr(202/204)-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via mechanisms that promote neuronal plasticity in caudate putamen, hippocampus, and PFC.


Drinking habit as a base for blood pressure elevation--difference in epidemiological significance by beverage type.
To investigate whether blood pressure differs by taking preferred alcoholic beverage among habitual drinkers, systolic and diastolic blood pressure (SBP, DBP) were compared among groups with different beverage types in 563 middle-aged Japanese males using data from a cross-sectional health survey conducted from February, 1989 through March, 1991 in five areas of Japan. Mean values of SBP and DBP, adjusted for residence, age and body mass index (BMI), were significantly greater in 'exclusively sake' drinkers (adjusted SBP: 127.2 mmHg, adjusted DBP: 83.0 mmHg) and in 'exclusively shochu' drinkers (adjusted SBP: 127.5 mmHg, adjusted DBP: 84.2 mmHg) than in non-drinkers (adjusted SBP: 120.9 mmHg, adjusted DBP: 77.3 mmHg). Adjusted SBP and DBP of 'exclusively beer' drinkers (adjusted SBP: 121.9 mmHg, adjusted DBP: 79.1 mmHg) were significantly (for SBP: p = 0.016, for DBP: p = 0.008) lower than those of 'exclusively sake' drinkers. Similar patterns of blood pressure differences between five beverage types of habitual drinkers were found especially in the group with less than 150 g of weekly ethyl-alcohol consumption. Even after adding ethyl-alcohol consumption as a covariate among 479 habitual drinkers, the significant differences in adjusted SBP and DBP between 'exclusively beer' drinkers and 'exclusively sake' drinkers (for SBP: p = 0.032, for DBP: p = 0.044) were noted. These results may suggest that the effects of drinking on blood pressure differ by beverage type in middle-aged Japanese males.


Update on radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: clinical aspects and survival effects.
To give an updated overview on clinical aspects and survival effects of lutetium-177-prostate-specific membrane antigen (PSMA) (177Lu-PSMA) radioligand therapy (RLT), a novel treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles. Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of 177Lu-PSMA RLT in mCRPC. However, current data rely predominantly on retrospective analyses, showing heterogeneity of patient population and treatment protocols. More recently, results from the first randomized phase II study (TheraP) demonstrated that 177Lu-PMSA therapy significantly improved prostate-specific antigen response rate (66% vs 37%) and had fewer grade 3/4 adverse events when compared to cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC. This review is intended to provide an updated overview of treatment protocols and responses, toxicity profile, and survival effects of 177Lu-PSMA RLT. 177Lu-PSMA RLT has emerged as a promising targeted treatment in mCRPC. It is currently applied in compassionate use programs and following exhaustion of approved therapies. Crucial for establishing this treatment in routine clinical management will be the results of the phase III VISION trial, which may confirm the encouraging patient outcomes reported to date.


[Circulating T cells in patients with breast or genital cancers in the pre-therapeutic phase].
There was the evaluation of circulating T-cells with the help of the E-rosette-assay in patients with breast cancer (n = 52), carcinoma of the cervix uteri (n = 29), carcinoma of the endometrium (n = 32) and carcinoma of the ovary (n = 7). Twenty seven healthy female blood donors were used as control group. There was no statistically significant difference between the total and active E-rosette values of the patients with tumours and the control group. Patients with breast cancer pT1N0 had significant lower total E-rosette values (Gpt/l) than patients with higher tumour stadium (p less than 0.05). The white blood cell count showed a statistically significant leucocytosis in cancer patient groups versus control persons (p less than 0.05).


Bioavailabilities of rectal and oral methadone in healthy subjects.
Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. Seven healthy subjects (six males, one female, aged 20-39 years) received 10 mg d(5)-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d(0)-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was performed at the same time as blood sampling. The mean absolute rectal bioavailability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care.


GMP manufacture of Shigella flexneri 2a Artificial Invaplex (InvaplexAR) and evaluation in a Phase 1 Open-label, dose escalating study administered intranasally to healthy, adult volunteers.
Shigella species cause severe disease among travelers to, and children living in, endemic countries. Although significant efforts have been made to improve sanitation, increased antibiotic resistance and other factors suggest an effective vaccine is a critical need. Artificial Invaplex (InvaplexAR) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens. In pre-clinical studies, the InvaplexAR vaccine demonstrated increased immunogenicity as compared to the first generation product and was subsequently manufactured under cGMP for clinical testing in a first-in-human Phase 1 study. The primary objective of this study was the safety of S. flexneri 2a InvaplexAR given by intranasal (IN) immunization (without adjuvant) in a single-center, open-label, dose-escalating Phase 1 trial and secondarily to assess immunogenicity to identify a dose of InvaplexAR for subsequent clinical evaluations. Subjects received three IN immunizations of InvaplexAR, two weeks apart, in increasing dose cohorts (10 µg, 50 µg, 250 µg, and 500 μg). Adverse events were monitored using symptom surveillance, memory aids, and targeted physical exams. Samples were collected throughout the study to investigate vaccine-induced systemic and mucosal immune responses. There were no adverse events that met vaccination-stopping criteria. The majority (96%) of vaccine-related adverse events were mild in severity (most commonly nasal congestion, rhinorrhea, and post-nasal drip). Vaccination with InvaplexAR induced anti-LPS serum IgG responses and anti-Invaplex IgA and IgG antibody secreting cell (ASC) responses at vaccine doses ≥250 µg. Additionally, mucosal immune responses and functional antibody responses were seen from the serum bactericidal assay measurements. Notably, the responder rates and the kinetics of ASCs and antibody lymphocyte secretion (ALS) were similar, suggesting that either assay may be employed to identify IgG and IgA secreting cells. Further studies with InvaplexAR will evaluate alternative immunization routes, vaccination schedules and formulations to further optimize immunogenicity. (Clinical Trial Registry Number NCT02445963).


Interleukin-23 mediates the pathogenesis of LPS/GalN-induced liver injury in mice.
Interleukin-23 (IL-23) is required for T helper 17 (Th17) cell responses and IL-17 production in hepatitis B virus infection. A previous study showed that the IL-23/IL-17 axis aggravates immune injury in patients with chronic hepatitis B virus infection. However, the role of IL-23 in acute liver injury remains unclear. The purpose of this study was to determine the role of the inflammatory cytokine IL-23 in lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury in mice. Serum IL-23 from patients with chronic hepatitis B virus (CHB), acute-on-chronic liver failure (ACLF) and healthy individuals who served as healthy controls (HCs) was measured by ELISA. An IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody was administered intravenously at the time of challenge with LPS (10μg/kg) and GalN (400mg/kg) in C57BL/6 mice. Hepatic pathology and the expression of Th17-related cytokines, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and the stabilization factor Csf3 were assessed in liver tissue. Serum IL-23 was significantly upregulated in ACLF patients compared with CHB patients and HCs (P<0.05 for both). Serum IL-23 was significantly upregulated in the non-survival group compared with the survival group of ACLF patients, which was consistent with LPS/GalN-induced acute hepatic injury in mice (P<0.05 for both). Moreover, after treatment, serum IL-23 was downregulated in the survival group of ACLF patients (P<0.001). Compared with LPS/GalN mice, mice treated with either an IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody showed less severe liver tissue histopathology and significant reductions in the expression of Th17-related inflammatory cytokine, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and stabilization factors Csf3 within the liver tissue compared with LPS/GalN mice (P<0.05 for all). High serum IL-23 was associated with mortality in ACLF patients and LPS/GalN-induced acute liver injury in mice. IL-23 neutralizing antibodies attenuated liver injury by reducing the expression of Th17-related inflammatory cytokines, neutrophil chemoattractants and stabilization factors within the liver tissue, which indicated that IL-23 likely functions upstream of Th17-related cytokine and chemokine expression to recruit inflammatory cells into the liver.


Supernumerary primary tooth with facial and palatal talon cusps: a case report.
Talon cusp is a tooth anomaly originating from the tooth's lingual surface in most cases. To date, very rare cases have been reported documenting talon cusps both on the facial and palatal surface of an affected tooth in the dental literature. The purpose of this case report was to describe the facial and palatal talon cusps on an ectopic supernumerary primary maxillary tooth. A micro-CT investigation indicated no pulpal extensions within facial and palatal talon cusps.


Observation of chemical reactions at the solid-water interface by quick XAFS combined with a column reactor.
A simple method for the observation of the kinetics of the reactions at the solid-water interface was developed using quick X-ray absorption fine structure combined with a column reactor. We applied the method to the oxidation reaction of As(III) by manganese oxide, a strong oxidizer in natural systems. A reliable reaction rate constant k', 3.9 x 10(-4) %(-1) min(-1) at pH 7.1, was obtained, where the effect of photooxidation under X-ray beam can be eliminated. Considering the average Mn/As molar ratio in the system, the value is reasonable compared with other reported values. Since this method is very simple, we can apply it to various elements and reaction systems at the solid-water interface as a tool to understand the kinetics of various reactions in detail.


Game Theory Paradigm: A New Tool for Investigating Social Dysfunction in Major Depressive Disorders.
Social dysfunction is a prominent source of distress and disability in patients with major depressive disorder (MDD) but is commonly omitted from current clinical studies, although some researchers propose an evolutionary strategy to understand these negative outcomes. Limited knowledge about the neural basis of social dysfunction in MDD results from traditional paradigms, which lack insights into social interactions. Game theoretical modeling offers a new tool for investigating social-interaction impairments in neuropsychiatric disorders. This review first introduces three widely used games from game theory and the major behavioral and neuroimaging findings obtained using these games in healthy populations. We also address the factors that modulate behaviors in games and their neural bases. We then summarize the current findings obtained by using these games in depressed patients and discuss the clinical implications of these abnormal game behaviors. Finally, we briefly discuss future prospects that may further elucidate the clinical use of a game theory paradigm in MDD.


Pride in all Who Served: Development, Feasibility, and Initial Efficacy of a Health Education Group For LGBT Veterans.
Many of the more than 1 million military veterans who identify as lesbian, gay, bisexual, and/or transgender (LGBT) have encountered "rejecting experiences in the military" and stigma from prior "Don't Ask Don't Tell" policies. Associated minority stress and social isolation have been linked to a disproportionate risk for depression and suicide, as well as a reluctance to seek medical care at Veterans Health Administration (VHA) facilities. This paper describes feasibility and preliminary outcomes of the newly developed, Pride in All Who Served Health Education Group created to meet the unique needs of sexual and gender minority veterans. The 10-week, closed, health education group (e.g., continuums of identity, military culture) enables open dialogue, fosters social connectedness, and empowers veterans to be more effective self-advocates within the healthcare system. Feedback from formative evaluations (n = 29 LGBT veterans and n = 25 VHA stakeholders) was incorporated before conducting a small scale, non-randomized pilot. Preliminary pre-post surveys (n = 18) show promise (i.e., Cohen's d range ± 0.40 to 1.59) on mental health symptoms (depression/anxiety, suicidal ideation), resilience indicators (identity affirmation, community involvement, problem-focused coping), and willingness to access care within the VA system (satisfaction with VA services, perception of staff competence). Results suggest that the 10-week Pride Group may be an effective tool for addressing minority-related stress in LGBT veterans. A full-scale, randomized clinical trial of this intervention is needed to determine short and long-term impacts on clinical and healthcare access-related outcomes.


Expression of platelet-derived growth factor-A (PDGF-A), PDGF-B, and PDGF receptor-alpha and -beta during human testicular development and disease.
Platelet-derived growth factor (PDGF) plays a critical role in regulating the development and functional control of various tissues and has been implicated in the pathogenesis of serious diseases, including cancer and atherosclerosis. Given the emerging role of PDGF in the development and function of male gonads, we compared the expression profiles of the mRNAs of the PDGF A- and B-chains and of the PDGF receptor (PDGFR) alpha- and beta-subunits in fetal and adult human testis. The immunohistochemical localization of the corresponding proteins in fetal, adult, and diseased human testicular tissues was also analyzed. PDGFs and PDGFRs mRNAs were readily detected by both Northern analysis and RT-PCR. The transcript levels were higher during 16-20 wk gestation, significantly lower at 24-28 wk, and increased in the adult. An identical pattern of protein expression was confirmed by immunohistochemistry, although the cellular localization of the PDGF system changes during postnatal development, concomitantly with the progression of spermatogenesis. In the testicular samples from patients affected by either complete aplasia of germ cells or various grades of spermatogenic arrest, the immunohistochemical localization of PDGFs and PDGFRs was different from normal, confirming a close connection between germ cells and PDGF system distribution. These results indicate that PDGF, through complex interactions, could play a leading role in ontogenesis and testicular pathophysiology in humans. Finally, the expression of PDGF ligands and receptor proteins in Leydig cell tumors suggests a relationship of the PDGF system to tumorigenesis or tumor progression in this testicular neoplasm.


Virulence of Egyptian Blumeria graminis f. sp. tritici Population and Response of Egyptian Wheat Cultivars.
Powdery mildew, caused by Blumeria graminis (DC.) Speer f. sp. tritici (Em. Marchal), is a serious disease of wheat that can cause a large reduction in yield. In Egypt, high powdery mildew severity has been observed in the past few years on many commercial cultivars of both bread and durum wheat. Little information is available about virulence characteristics of the Egyptian B. graminis f. sp. tritici population in Egypt or the resistance of Egyptian wheat cultivars to powdery mildew. Virulence frequencies of a representative sample of the Egyptian B. graminis f. sp. tritici population were studied. Seven provinces were chosen to represent the country: two in Upper Egypt (Qena and Sohag), one in Middle Egypt (El Minia), and four in the north (Alexandria, Kafr Elsheikh, Dakahlia, and Sharqia). Ten isolates from each province (70 isolates total) were derived from single ascospores and used for this study. They were inoculated individually on 21 powdery mildew differential lines, each bearing a single resistance (Pm) gene. Also, the responses of 14 Egyptian bread wheat cultivars and 6 durum cultivars to each of the 70 isolates were evaluated individually. Among all tested Pm genes, only seven (Pm1b, Pm2, Pm21, Pm34, Pm36, Pm37, and Pm53) were effective against B. graminis f. sp. tritici isolates from all provinces. Several other genes were effective against most or all isolates from a majority of provinces. All tested bread wheat cultivars showed full susceptibility to all isolates, whereas two durum wheat cultivars, Beni-Suef-5 and Beni-Suef-6, had intermediate responses to a large percentage of the isolates, likely indicating partial resistance. To enhance mildew resistance in Egyptian wheat cultivars, it is recommended to use combinations of genes that are nationally effective or effective against multiple provincial B. graminis f. sp. tritici populations.


Early recognition and treatment of post-traumatic pulmonary microembolism.
There is a special form of pulmonary dysfunction which most often occurs following massive tissue damage, such as major fractures accompanied by hypovolemia. This syndrome may be appropriately called post-traumatic pulmonary microembolism to distinguish it from other causes of respiratory failure. We believe that pathophysiology is initiated at the time of trauma and consists of platelet aggregation and fibrin deposition in the pulmonary microcirculation caused by release of tissue-thromboplastin products. Whether this acute traumatic pulmonary microembolism will progress to a fully developed post-traumatic pulmonary microembolism with respiratory symptoms depends upon the magnitude and duration of tissue-thromboplastin release and the efficiency of the fibrinolytic system to clear the lungs. The early microembolic effects on the lungs consist mainly of ventilatory derangements with a low ventilation/perfusion ratio; not until a later stage does true shunting of mixed venous blood across fluid-filled alveoli and small airways occur. Frequently determinations of Pao2 and AaDO2 during air breathing ("air-test") to reveal a low ventilation/perfusion ratio is, therefore, preferable to true shunt determinations in patients who may develop this syndrome; caution must be exercised in giving room air to critically ill patients. These ventilatory variables, combined with frequent platelet counts, allow early recognition of post-traumatic pulmonary microembolism.


Water striders (Heteroptera: Gerromorpha: Gerridae) of Romania with an update on the distribution of Gerris gibbifer and G. maculatus in southeastern Europe.
The Romanian fauna comprises two species of Aquarius Schellenberg, 1800, eight species of Gerris Fabricius, 1794 and one species of Limnoporus Stål, 1868, and we hereby update the distribution and provide insights on the phenology and ecology of all eleven species in this country. We furthermore update the distribution of the two closely related species Gerris gibbifer Schummel, 1832 and G. maculatus Tamanini, 1946 in southeastern Europe. Gerris maculatus is recorded for the first time from Hungary, Montenegro and Slovenia, and the first detailed localities from Romania and Serbia are given. All bibliographic records of G. gibbifer from Romania, Macedonia and Serbia are based on misidentification and this species is thus excluded from the faunal lists of these countries. Both G. gibbifer and G. maculatus occur in Croatia, Hungary, Ukraine, and probably Slovenia.


American trypanosomiasis and associated risk factors in owned dogs from the major city of Yucatan, Mexico.
The American trypanosomiasis is a zoonosis caused by the protozoa Trypanosoma cruzi (T. cruzi). The disease is widely distributed throughout the American continent, affecting a wide range of hosts, including dogs. It is present in the canine population in the State of Yucatan, Mexico. However, no significant studies in owned dogs have been performed in the metropolitan area of Merida. A transversal study was conducted in 370 owned dogs from Merida, Yucatan, Mexico. A cross-sectional study including 370 dogs was performed in a major city of Yucatan, Mexico, to detect IgG antibodies against T. cruzi. A commercial ELISA test kit was used and a chi-square test used to evaluate associated risk factors; odds ratio (OR) and 95 % confidence interval (CI) were also estimated. The indirect ELISA and western blot (WB) tests were used to detect specific immunoglobulin G antibodies against T. cruzi in serum samples. A prevalence of 12.2 % was found; age and area of residence were statistically associated with seropositivity in dogs (p <0.05). Results from the present study suggests the presence and abundance of the vector in urban conditions where a high number of seropositive cases of T. cruzi cases were found.


Opening the black box: Soil microcosm experiments reveal soot black carbon short-term oxidation and influence on soil organic carbon mineralisation.
Soils hold three quarters of the total organic carbon (OC) stock in terrestrial ecosystems and yet we fundamentally lack detailed mechanistic understanding of the turnover of major soil OC pools. Black carbon (BC), the product of the incomplete combustion of fossil fuels and biomass, is ubiquitous in soils globally. Although BC is a major soil carbon pool, its effects on the global carbon cycle have not yet been resolved. Soil BC represents a large stable carbon pool turning over on geological timescales, but research suggests it can alter soil biogeochemical cycling including that of soil OC. Here, we established two soil microcosm experiments: experiment one added 13C OC to soil with and without added BC (soot or biochar) to investigate whether it suppresses OC mineralisation; experiment two added 13C BC (soot) to soil to establish whether it is mineralised in soil over a short timescale. Gases were sampled over six-months and analysed using isotope ratio mass spectrometry. In experiment one we found that the efflux of 13C OC from soil decreased over time, but the addition of soot to soil significantly reduced the mineralisation of OC from 32% of the total supplied without soot to 14% of the total supplied with soot. In contrast, there was not a significant difference after the addition of biochar in the flux of 13C from the OC added to the soil. In experiment two, we found that the efflux 13C from soil with added 13C soot significantly differed from the control, but this efflux declined over time. There was a cumulative loss of 0.17% 13C from soot over the experiment. These experimental results represent a step-change in understanding the influence of BC continuum on carbon dynamics, which has major consequences for the way we monitor and manage soils for carbon sequestration in future.


Use of shape-from-shading to characterize mucosal topography in celiac disease videocapsule images.
To use a computerized shape-from-shading technique to characterize the topography of the small intestinal mucosa. Videoclips comprised of 100-200 images each were obtained from the distal duodenum in 8 celiac and 8 control patients. Images with high texture were selected from each videoclip and projected from two to three dimensions by using grayscale pixel brightness as the Z-axis spatial variable. The resulting images for celiac patients were then ordered using the Marsh score to estimate the degree of villous atrophy, and compared with control data. Topographic changes in celiac patient three-dimensional constructs were often more variable as compared to controls. The mean absolute derivative in elevation was 2.34 ± 0.35 brightness units for celiacs vs 1.95 ± 0.28 for controls (P = 0.014). The standard deviation of the derivative in elevation was 4.87 ± 0.35 brightness units for celiacs vs 4.47 ± 0.36 for controls (P = 0.023). Celiac patients with Marsh IIIC villous atrophy tended to have the largest topographic changes. Plotted in two dimensions, celiac data could be separated from controls with 80% sensitivity and specificity. Use of shape-from-shading to construct three-dimensional projections approximating the actual spatial geometry of the small intestinal substrate is useful to observe features not readily apparent in two-dimensional videocapsule images. This method represents a potentially helpful adjunct to detect areas of pathology during videocapsule analysis.


Self-assembly of basement membrane collagen.
The in vitro self-assembly of murine type IV collagen was examined by using biochemical and morphological techniques. Dimeric collagen undergoes a rapid and reversible thermal gelation at neutral pH without an appreciable lag period. The process is seen to be concentration dependent and inhibited by 2 M urea. The formed complex can be visualized by electron microscopy rotary shadowing as an irregular polygonal lattice network with extensive side by side associations within the collagenous triple-helical part of the molecules, two and three strands thick. Measurements on the matrix suggest a median stagger dimension of 170 nm, one-fifth the length of a dimer. The conversion of pepsin-generated monomers into N-terminally bound tetramers can also be demonstrated in vitro. This process is also concentration dependent and inhibited and reversed by 2 M urea but is thermally irreversible and occurs at a slow rate relative to the lateral associations. These tetramers can be seen by rotary shadowing as four-armed "spider" structures. It is proposed that lateral associations, by virtue of their faster rate of formation, precede 7S bond formation, and several models for the assembly of basement membrane collagen are discussed.


Selective preparation of pyridines, pyridones, and iminopyridines from two different alkynes via azazirconacycles.
Selective preparation of pyridine derivatives from two different alkynes and a nitrile was achieved by a novel procedure in which an alkyne and a nitrile couple first to give an azazirconacyclopentadiene followed by reaction with the second alkyne in the presence of 1 equiv of NiCl(2)(PPh(3))(2). This procedure gives only single products of pyridine derivatives from two different symmetrical alkynes and a nitrile. Our novel procedure can be used even with two similar alkyl-substituted alkynes such as 3-hexyne and 4-octyne. Two possible pyridine isomers from 3-hexyne, 4-octyne, and acetonitrile could be completely and independently prepared as single products by this method. The origin of the selectivity comes from the addition order of two different alkynes. This method was applied for the formation of pyridones and iminopyridines using isocyanate and carbodiimide derivatives instead of nitriles, respectively. Reaction of an alkyne with Cp(2)ZrEt(2) and an isocyanate or a carbodiimide gives an azazirconacycle. Treatment of the azazirconacycle with the second alkyne in the presence of 1 equiv of NiCl(2)(PPh(3))(2) gave a pyridone or an iminopyridine derivative. The use of two different unsymmetrical alkynes afforded the pyridine with five different substituents when the first alkyne has a trialkylsilyl group and the second alkyne has a phenyl group as functional groups. On the other hand, azazirconacyclopentadienes reacted with propargyl bromide in the presence of CuCl with excellent regioselectivity to give tetrasubstituted pyridine derivatives as single products. With the assistance of the trialkylsilyl groups, pyridines with all different substituents including H were also prepared.


Performance Evaluation of Serum Free Light Chain Analysis: Nephelometry vs Turbidimetry, Monoclonal vs Polyclonal Reagents.
Free light chain (FLC) measurement gained a lot of interest for diagnostic workup of monoclonal gammopathy. We evaluated the performance of turbidimetric polyclonal Freelite (The Binding Site, Birmingham, UK) assays on Cobas 6000 (Roche Diagnostics, Rotkreuz, Switzerland) and nephelometric monoclonal N Latex (Siemens Healthcare Diagnostics, Marburg, Germany) assays on BN ProSpec (Dade Behring, Deerfield, IL) vs established nephelometric Freelite assays on BN ProSpec. Analytical performance was acceptable. Method comparison (n = 118) showed significant proportional FLC differences for N Latex assays. However, good correlation and clinical concordance were shown. Recovery study in the low concentration range demonstrated consistent over- and underrecovery for Freelite reagents, hampering future research on prognostic value of suppressed noninvolved FLC. Antigen excess detection was successful for κ FLC in three-fourths of cases with Freelite reagents and in all cases with N Latex reagents. However, the latter resulted in underestimated κ FLC concentrations. FLC analysis requires continuous awareness of analytical limitations. Monitoring of disease response requires FLC analysis on the same platform using the same reagents.


Metachronous Germ Cell Tumors of the Mediastinum.
We report a rare case of mediastinal nonseminomatous germ cell tumor arising after 2 complete resections of mediastinal mature teratomas 18 and 10 years prior. After three cycles of chemotherapy for the mediastinal nonseminomatous germ cell tumor, the serum α-fetoprotein and β-human chorionic gonadotropin levels were normalized. However, chest radiography revealed that the mediastinal tumor had remarkably increased in size, and thus growing teratoma syndrome was diagnosed. The patient underwent urgent resection of the tumor, and a pathologic examination showed an encapsulated mature teratoma without any malignant viable cells. The patient was well without disease 54 months after the third operation.


Changes of the intestinal endocrine cells in the C57BL/6 mouse after implantation of murine lung carcinoma (3LL): an immunohistochemical quantitative study.
To study the distributions and frequencies of intestinal endocrine cells in the C57BL/6 mouse with immunohistochemical method using seven types of specific antisera against chromogranin A (CGA), serotonin, somatostatin, glucagons, gastrin, cholecystokinin (CCK)-8 and human pancreatic polypeptide (hPP) after abdominal subcutaneous implantation of murine lung carcinoma (3LL). The experimental animals were divided into two groups, one is non-implanted Sham and the other is 3LL-implanted group. Samples were collected from six regions of intestinal tract at 28(th) d after implantation of 3LL cells (1X10(5) cell/mouse). In this study, five types of immunoreactive (IR) cells were identified except for gastrin and hPP. The regional distributions of the intestinal endocrine cells in the 3LL-implanted group were similar to those of the non-implanted Sham. However, significant decreases of IR cells were detected in 3LL-implanted group compared to those of non-implanted Sham. CGA- and serotonin-IR cells significantly decreased in 3LL-implanted groups compared to that of non-implanted Sham. Somatostatin-IR cells in the jejunum and ileum and CCK-8-IR cells in the jejunum of 3LL-implanted groups significantly decreased compared to that of non-implanted Sham. In addition, glucagon-IR cells were restricted to the ileum and colon of non-implanted Sham. Implantation of tumor cell mass (3LL) induced severe quantifiable changes of intestinal endocrine cell density and the abnormality in density of intestinal endocrine cells may contribute to the development of gastrointestinal symptoms such as anorexia and indigestion, frequently encountered in patients with cancer.


Fat Mass and Obesity-Associated (FTO) Gene Polymorphisms Are Associated with Risk of Intervertebral Disc Degeneration in Chinese Han Population: A Case Control Study.
BACKGROUND The present study aimed to evaluate whether the fat mass and obesity-associated (FTO) gene polymorphisms are associated with risk of intervertebral disc degeneration (IDD) in a largest Chinese Han population. MATERIAL AND METHODS There were 502 IDD patients and 497 healthy controls enrolled in this study. Nineteen single nucleotide polymorphisms (SNPs) in the FTO gene were tested using the Sequenom MassARRAY platform. The Hardy-Weinberg equilibrium test, followed by allelic, genotypic, haplotypic association, and SNP interaction analyses were used for SNP evaluation. The Genotype-Tissue Expression (GTEx) database was used to evaluate expression quantitative trait loci (eQTL) value of polymorphism. Spearman rank correlation and logistic regression analyses were used for assessing the internal relation between genotypic changes and the risk of IDD. RESULTS Seventeen SNPs survived the Hardy-Weinberg equilibrium test. Allelic analysis showed that allele T of SNP rs1121980 was a risk allele. Haplotypic and SNP interaction analyses suggested that 2 haplotypes and 5 SNP combinations were associated with the predisposition of IDD respectively. GTEx database revealed that the SNP rs1121980 might interfere with the expression of the FTO gene in the muscle-skeletal system. Through clinical statistics analysis, the different genotypes of rs1121980 can present different disease severity of IDD. CONCLUSIONS Our study suggests that rs1121980 can become a biomarker for the screening and prognosis of IDD. The 2 haplotype blocks and 5 SNP-SNP combinations that we discovered might be indicative of the onset of IDD. Therefore, our study might serve as evidence for future IDD molecular diagnosis.


Noise-assisted instantaneous coherence analysis of brain connectivity.
Characterizing brain connectivity between neural signals is key to understanding brain function. Current measures such as coherence heavily rely on Fourier or wavelet transform, which inevitably assume the signal stationarity and place severe limits on its time-frequency resolution. Here we addressed these issues by introducing a noise-assisted instantaneous coherence (NAIC) measure based on multivariate mode empirical decomposition (MEMD) coupled with Hilbert transform to achieve high-resolution time frequency representation of neural coherence. In our method, fully data-driven MEMD, together with Hilbert transform, is first employed to provide time-frequency power spectra for neural data. Such power spectra are typically sparse and of high resolution, that is, there usually exist many zero values, which result in numerical problems for directly computing coherence. Hence, we propose to add random noise onto the spectra, making coherence calculation feasible. Furthermore, a statistical randomization procedure is designed to cancel out the effect of the added noise. Computer simulations are first performed to verify the effectiveness of NAIC. Local field potentials collected from visual cortex of macaque monkey while performing a generalized flash suppression task are then used to demonstrate the usefulness of our NAIC method to provide highresolution time-frequency coherence measure for connectivity analysis of neural data.


Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial.
We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB), and evaluated the acceptance of the video. Randomized controlled trial. We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania). They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100) or standard of care (control group, n = 100). Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups. Median age was 39.1 years (interquartile range 37.0-50.0); 94 (47%) were females, 106 (53%) were males, and 49 (24.5%) were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7-65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p <0.0001), an increase in volume of specimen defined as a volume ≥3ml (78%, 95% CI 68.6-85.7%, versus 45%, 95% CI 35.0-55.3%, p <0.0001), and specimens less likely to be salivary (14%, 95% CI 7.9-22.4%, versus 39%, 95% CI 29.4-49.3%, p = 0.0001). Older age, but not the HIV status or sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%). Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%). Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum samples. If confirmed in larger studies, instructional videos may have a substantial effect on the case yield using sputum microscopy and also molecular tests. This low-cost strategy should be considered as part of the efforts to control TB in resource-limited settings. Pan African Clinical Trials Registry PACTR201504001098231.


Orexin, Stress and Central Cardiovascular Control. A Link with Hypertension?
Orexin, the arousal peptide, originates from neurons located in an area of the dorsal hypothalamus well known for integrating defense responses and their cardiovascular component. Orexin neurons, which are driven in large part by the limbic forebrain, send projections to many regions in the brain, including regions involved in cardiovascular control, as far down as sympathetic preganglionic neurons in the spinal cord. Central injections of orexin evoke sympathetically mediated cardiovascular responses. Conversely, blockade of orexin receptors reduce the cardiovascular responses to acute stressors, preferentially of a psychological nature. More importantly, lasting upregulation of orexin signaling can lead to a hypertensive state. This can be observed in rats exposed to chronic stress as well as in strains known to display spontaneous hypertension such as the spontaneously hypertensive rat (SHR) or the hypertensive BPH/2J Schlager mouse. Thus, there is a link between orexin, stress and hypertension, and orexin upregulation could be a factor in the development of essential hypertension. Orexin receptor antagonists have anti-hypertensive effects that could be of clinical use.


[Area differentials of sex imbalance in births].
Along with a rapid decline in fertility to below replacement levels in South Korea, a new demographic phenomenon has emerged: a distorted sex ratio at birth. In 1993, the sex ratio was 115.6, with significant differences in this ratio by region. "An analysis of national survey data showed that in the areas with the most distorted imbalance, people not only have a stronger preference for sons and more favoring attitude toward sex-selective induced abortion, but also actually have more sex-selective induced abortions after checking the sex of the fetus. This analysis proved that the sex imbalance is being caused by means of sex-selective induced abortions after checking the sex of the fetus." (SUMMARY IN ENG)


Enhanced toxicity for mice of combinations of bacterial lipopolysaccharide and vincristine.
Sublethal doses of vincristine (VNC) and bacterial lipopolysaccharide (LPS) administered simultaneously to adult male mice resulted in markedly enhanced mortality. All of 10 strains of Pseudomonas aeruginosa tested, 4 of 7 strains of Bacteroides, and 6 of 10 strains of Listeria monocytogenes were able to substitute for purified LPS in enhancing mortality in VNC-treated mice. Inoculation of mice with each of 10 strains of Pseudomonas, each of 7 strains of Bacteroides, and about half of the 10 strains of Listeria tested elicited increased resistance to the lethal action of purified LPS. The patterns of responses of mice receiving a lethal combination of 2 mg of LPS/kg and 1 mg of VNC/kg resembled those of mice receiving a lethal dose of 10 mg of VNC/kg alone or 15 mg of LPS/kg alone with respect to (i) serum glutamic pyruvate transaminase activity, (ii) hematocrit values, and (iii) thrombocytopenia. The patterns of responses of mice receiving a lethal combination of LPS and VNC resembled those of mice receiving a lethal dose of LPS alone with respect to (i) hypothermia, (ii) retention of sulfobromophthalein, (iii) fibrinogen level, (iv) prothrombin activity, (v) blood urea nitrogen levels, and (vi) time of death. These data are consistent with the proposition that the combination of VNC and LPS produces a fatal renal failure. Histological studies confirmed that there was extensive renal damage in mice treated with lethal doses of LPS alone or a lethal combination of LPS and VNC.


Schedules for hepatitis B vaccination of risk groups: balancing immunogenicity and compliance.
Vaccination is an important tool in hepatitis B prevention. However, several vaccine doses are required to induce long-term protection. Several at-risk groups have difficulties in adhering to the standard vaccination schedule. This paper aims to review the use of accelerated hepatitis B vaccination schedules, in terms of immunogenicity and compliance. Accelerated schedules (0.1.2.12 months) or super-accelerated schedules (0.7.21.360 days) have been shown to result in higher proportions of healthy vaccinees reaching anti-HBs antibody levels >or=10 IU/l more rapidly. A fourth completing dose is required to lift antibody levels to an equal height, as does a standard (0.1.6 months) schedule. Accelerated schedules do also increase the uptake of hepatitis B vaccine, that is the proportion of vaccinees who receive three doses. However, completing the schedule with a fourth dose is usually more difficult than completing a standard 0.1.6-month schedule. Several additional tools can help to increase the compliance (eg, reminder systems, outreach services and incentive schemes). For rapid seroconversion and almost immediate protection in the short term, a (super)accelerated schedule could be used in at-risk groups. As long-term protection data with these (super) accelerated schedules have not been documented yet, a fourth dose at month 12 is still required. A shortened schedule (0.1.4 months) might be an alternative worth considering compared with the standard 0.1.6, as it convenes to internationally accepted minimum dose intervals and offers earlier protection. There is a clear need to study the long-term protection and effectiveness of the primary part of (super)accelerated schedules.


Three Perspectives on Mental Health Told through StoryCorps' "Liza Long and 'Michael'".
By examining mental illness through the lens of intimate firsthand accounts of caregivers and patients, including caregiver blogposts and a conversation between Liza Long and her son as recorded by StoryCorps, we demonstrate how new media can be leveraged to shift societal perceptions of those with mental illness from blameworthy potential perpetrators of terror to vulnerable persons in need of compassion and support. Exploring patient, caregiver, and societal roles through a close reading of new media firsthand accounts, we argue for shared responsibility in caring for those with mental illness and, in particular, for physicians to leverage their unique knowledge of the patient experience by promoting media coverage of stories of mental illness recovery.


Drug interactions involving cimetidine--mechanisms, documentation, implications.
In summary, cimetidine is a potent inhibitor of liver microsomal activity, which may also decrease hepatic blood flow. Other effects of the drug include inhibition of gastric secretion and intrinsic toxic properties. These effects, combined with the common use of cimetidine in clinical practice, make the risk of adverse drug interactions a relatively frequent risk in the clinical setting. Although a multitude of interactions with cimetidine has been evaluated, many of these are incompletely described or understood. At the present time, a potentially significant alteration of absorption appears to exist with only ketoconazole, elemental iron, vitamin B12 (long-term therapy), and pancreatic enzyme supplements (increased activity). Significant metabolic inhibition or decreased excretion appears to exist with warfarin, propranolol, theophylline, phenytoin, quinidine, possibly lidocaine and procainamide, and certain benzodiazepines. Other potential, but less well ascertained interactions may involve the narcotic analgesics, caffeine, ethanol, pentobarbital, imipramine, chlormethiazole, and metronidazole. In these settings, the clinician must be aware of interaction potential, and astutely monitor the patient during combination therapy. Other data indicate that concomitant administration of antacids may reduce the absorption of cimetidine, that the drug may protect against the toxic effects of acetaminophen overdose, and that combination with certain other myelosuppressants may carry a significant risk. Thus, in regard to these reports, cimetidine is a drug with complex effects on the absorption, elimination, and toxicity of other drugs. When used in the setting of multiple drug therapy, the clinician must be alert to potentially increased or decreased effects of the drugs mentioned in this review. In addition, one must be aware that other hepatically metabolised agents not mentioned here may be affected by the addition of cimetidine therapy. Because of the therapeutic successes demonstrated in the treatment of various disorders with cimetidine, one cannot disregard this agent. Thus, the responsibility for understanding and monitoring for the complex effects of this drug falls with the practicing physician.


[Cyotchemical indices of the protein-synthesizing apparatus of hyperchromic nerve cells].
Cytophotometric, interferometric and autoradiographic methods were applied to evaluate hyperchromic motoneurons (HM) from spinal cord of mice which were allowed to swim for 4 hours. The HM in comparison with the normochromic motor nerve cells are characterized by a higher RNA content and a lower dry weight of perikaria. The autoradiographic data with H3-uridane make it possible to suggest that RNA exchange between the nucleus and cytoplasm of HM is accelerated. The mode of distribution of labelled proteins along the sciatic nerve 6 days after the local injection of H3-leucine in the ventral horn of L3--L4 spinal cord segments allows to conclude that the amount of protein transported with the slow component of axonal flow in the cases connected with the increase of the number of HM in corresponding nuclei is changed.


On measures of dissimilarity between point patterns: classification based on prototypes and multidimensional scaling.
This paper presents a collection of dissimilarity measures to describe and then classify spatial point patterns when multiple replicates of different types are available for analysis. In particular, we consider a range of distances including the spike-time distance and its variants, as well as cluster-based distances and dissimilarity measures based on classical statistical summaries of point patterns. We review and explore, in the form of a tutorial, their uses, and their pros and cons. These distances are then used to summarize and describe collections of repeated realizations of point patterns via prototypes and multidimensional scaling. We also show a simulation study to evaluate the performance of multidimensional scaling with two types of selected distances. Finally, a multivariate spatial point pattern of a natural plant community is analyzed through various of these measures of dissimilarity.


Effects and Mechanism of Tanshinone II A in Proliferation, Apoptosis, and Migration of Human Colon Cancer Cells.
BACKGROUND The aim of this study was to explore the effect and mechanism of tanshinone II A on proliferation, apoptosis, and migration of human colon cancer cells. MATERIAL AND METHODS CCK-8 approach was carried out to evaluate proliferation after applying various levels of tanshinone II A to SW620 colon carcinoma cells. Flow cytometry (FC) was used to assess apoptosis. Transwell assay was performed to assess invasion in vitro, and the wound-healing assay was applied to assess migration. Western blot analysis was performed to evaluate translation of mTOR, while RT-PCR was carried out to assess transcription of VEGF. RESULTS CCK-8 assay showed that tanshinone II A inhibited SW620 proliferation in comparison to the control group subsequent to 24 h, 48 h, and 72 h (P<0.001). FC revealed that tanshinone II A promoted SW620 apoptosis (P<0.001). The cell migration test revealed that the migration index of cells receiving tanshinone II A decreased. mTOR translation as well as VEGE transcription in cells receiving tanshinone II A was noticeably prohibited compared to control group (P<0.001). CONCLUSIONS Tanshinone II A is able to inhibit proliferation and migration of human colon cancer SW620 cells and promoted cell death. Its mechanism may be by downregulation of mTOR protein and VEGF mRNA.


Adenoid cystic carcinoma of the breast. Data from the Connecticut Tumor Registry and a review of the literature.
The case records of the Connecticut Tumor Registry were reviewed from 1952-1982. There were 37 cases of adenoid cystic carcinoma of the breast (ACC) from a total of 40,350 invasive breast tumors. Patient survival, complications, and pathologic sections were reviewed. Only 14 of 27 surgical pathology slides available for review could be confirmed histologically as ACC. All patients were white females with a mean age of 64 years. The tumor remained localized to the breast in all cases. Nine patients had either radical or modified radical mastectomy, four patients had either simple mastectomy or lumpectomy, and one patient refused treatment. There was no evidence of axillary node involvement, metastases, or local recurrence after excision. At the time of follow-up, nine patients were alive and disease free and four died of disease unrelated to their breast cancer. The one patient who died of breast cancer had a radical mastectomy and survived 11.7 years after diagnosis. It is concluded that ACC has a favorable biologic behavior characterized by a prolonged clinical course and good prognosis. Simple mastectomy is all that is required as initial treatment, and a chest x-ray and thorough physical examination looking for local recurrence is all that is needed for follow-up.


Psychosocial outcomes at 18 months after good neurological recovery from aneurysmal subarachnoid haemorrhage.
To evaluate functioning, 18 months after surgery, of 49 patients with good neurological recovery following aneurysmal subarachnoid haemorrhage (SAH), and to determine the extent of any improvements in disturbances of mood, cognitive functioning, and levels of activity and participation previously observed at 9 month follow up. SAH patients, matched for age, gender, and occupation with healthy control participants, completely quantitative measures of mood (HADS, FIES, BDI) and activity/participation (BICRO-39 scales), and a brief cognitive assessment battery (verbal fluency, digit span, prose recall). Controls completed the HADS and the BICRO-39. Patients showed some recovery of cognitive functioning, though impairments of prose recall persisted. Anxiety and depression symptoms were higher in patients than in controls, but fewer than 20% scored in the clinical range on any questionnaires except for RIES-Intrusive thoughts (22%); only three showed signs of full blown post-traumatic stress disorder. Almost half showed elevated dependence on others for domestic activities and organisation and abnormally low levels of employment. Very little variance in outcome was predicted by demographic variables, neurological or cognitive impairment, prior life stress, or mood. However, levels of social activity and self-organisation were related to persisting fatigue. The observed decline in intrusive thoughts and avoidance over time is consistent with that seen after life threatening illness or trauma. The persistent reductions in independence and levels of employment may in some cases reflect considered lifestyle adjustments rather than adverse and unwanted changes but in others indicate a need for focused rehabilitation.


Mingmu Xiaoyao granules regulate the PI3K/Akt/mTOR signaling pathway to reduce anxiety and depression and reverse retinal abnormalities in rats.
Objective: To investigate the effects of Mingmu Xiaoyao granules (MMXY) on the morphology and function of the retina and the mechanism of PI3K/Akt/mTOR pathway-related proteins in rats with anxiety and depression induced by chronic unpredictable mild stress (CUMS). Methods: Fifty-two male Sprague Dawley rats were randomly allocated to either a control (n = 14) or a simulated CUMS group (n = 38). The CUMS model was established successfully at 4 weeks. Six rats in each group were randomly selected to be sacrificed and their retinas isolated for histological examination. At 5 weeks, rats in the CUMS group were randomly allocated to the following groups: Model (CUMS + pure water), MMXY-H (CUMS + MMXY 7.2 g/kg/d), MMXY-L (CUMS + MMXY 3.6 g/kg/d), and CBZ (CUMS + Carbamazepine 20 mg/kg/d), with eight rats in each group. All rats were given the relevant intervention once a day. At 12 weeks, sucrose preference and open field tests were performed to evaluate the anxiety and depression status of rats. In live rats, optical coherence tomography angiography was used to measure retinal thickness and blood flow, while electroretinograms (ERGs) and visual evoked potentials (VEPs) were used to evaluate retinal function. The next day, the specimens were sacrificed for serological, histological, immunofluorescence, Western blot and transmission electron microscopy examinations to explore the mechanism of MMXY in CUMS rats. Results: MMXY improved the anxiety and depression-like behavior of rats. Results of optical coherence tomography angiography showed that MMXY improved retinal inner thickness and blood flow in CUMS rats. MMXY improved the amplitude of a- and b-waves in the scotopic and photopic ERG, as well as N2 and P2 peak time and amplitude in the flash-VEP in CUMS rats. Retinal histological staining and transmission electron microscopy showed that MMXY reversed retinal morphology and ultrastructure in CUMS rats. MMXY reduced the expression of Beclin1 and LC3I/II proteins, regulated the PI3K/Akt/mTOR pathway, inhibited autophagy, and had a protective effect on the retina in CUMS rats. Conclusion: MMXY may effectively improve retinal morphology and function as well as anxiety and depression-like behaviors in CUMS rats by regulating the PI3K/Akt/mTOR signaling pathway.


[Inflammatory cloacogenic polyp].
Cloacogenic Polyps are characterized by the presence of inflammatory lesions in the lower rectum, and the anal transition zone. The polyps can prolaps; this is due to the malfunction of the internal anal sphincter; and the smooth muscle that covers the rectum. This is the result of the chronic inflammatory process. The lesions are more common in women during the third and fourth decade of life, however lesion have been described in 10 and 83 year olds. 85% lesions are located above the anal border and predominantly in the anterior lateral wall. The polyps vary in size from 3-4 cm in diameter, and have a sessile appearance. 10-year-old female presents with a 3-month history of irregular abdominal pain, with occasional vomiting, constipation, and occasional diarrhea. This entity of colon polyps is somewhat rare, and is seen in young adults; however its presence in infancy requires that we think of this entity when we formulate our differential diagnosis. Due to the character of the lesions, this entity could be confused with colorectal malignant tumors. All children and infants with a rectal mass, and blood in their stools should get a biopsy sent for histopathology. This technique can aid in analyzing the origin of the lesion.


RN as gatekeeper: Student understanding of the RN buddy role in clinical practice experience.
Students may be informally buddied with registered nurses (RNs), during their clinical experience. This paper describes one component of a larger phenomenographic study that explored the qualitatively different ways students understand the RN buddy role during clinical experience and the implications of this understanding for student learning. The perception of the RN as gatekeeper was an unexpected finding and is the focus of this report. Phenomenography is a field of descriptive research concerned with the variation in ways people experience and understand similar phenomena. This approach was used to identify the variation in experience and understanding of students with buddy RNs. Individual semi-structured interviews were conducted with a purposive sample of 24 students from one university in Queensland, Australia. The two variations in understanding of the role discussed in this paper are: understanding as an expectation, and RN as gatekeeper: gatekeeping as access. The research highlights that the various ways RNs promote or block access for students influence the quality of the learning experience. Formal recognition of the complexity of the RN role is essential to ensure RNs have adequate preparation for their role with students.


Second bioluminescence-activating component in the luminous fungus Mycena chlorophos.
Mycena chlorophos is an oxygen-dependent bioluminescent fungus. The mechanisms underlying its light emission are unknown. A component that increased the bioluminescence intensity of the immature living gills of M. chlorophos was isolated from mature M. chlorophos gills and chemically characterized. The bioluminescence-activating component was found to be trans-3,4-dihydroxycinnamic acid and its bioluminescence activation was highly structure-specific. 13 C- and 18 O-labelling studies using the immature living gills showed that trans-3,4-dihydroxycinnamic acid was synthesized from trans-4-hydroxycinnamic acid in the gills by hydroxylation with molecular oxygen as well as by the general metabolism, and trans-3,4-dihydroxycinnamic acid did not produce hispidin (detection-limit concentration: 10 pmol/1 g wet gill). Addition of 0.01 mM hispidin to the immature living gills generated no bioluminescence activation. These results suggested that the prompt bioluminescence activation resulting from addition of trans-3,4-dihydroxycinnamic acid could not be attributed to the generation of hispidin. Copyright © 2016 John Wiley & Sons, Ltd.


Dose-dependent immune response to Mycobacterium bovis BCG vaccination in neonates.
In 10-week-old infants vaccinated at birth with Japanese Mycobacterium bovis BCG, the number of dermal needle penetrations correlated positively with frequency of proliferating CD4(+) T cells in whole blood following BCG stimulation for 6 days but did not correlate with secreted cytokine levels after 7 h or interferon CD4(+) T-cell frequency after 12 h of BCG stimulation.


[Quenching of ethidium-DNA fluorescence by novel acridines with antitumor activities. II. The structure-activity relationship in acridines with fluorescence quenching of ethidium-DNA].
In order to elucidate the structure-activity relationship between the antitumor activity and the molecular structure of novel DNA-intercalator acridine derivatives (1a-g and 2a-i in Chart 1), DNA-binding properties (intercalation) of these acridines were examined by quenching in the fluorescence of the ethidium-DNA complex. The mechanism of quenching is caused by the displacement of DNA-bound ethidium by a second DNA binding ligand, acridines. The concentration (C50 value) of acridine necessary to reduce the initial fluorescence of DNA-bound ethidium by 50% showed a good correlation with their antitumor activities. The quenching of fluorescence for acridines was examined using amsacrine (AMSA) as a typical standard of the second DNA-bound ligand, and calf thymus DNA with an apparent site size of two base pair. Some of the acridine derivatives showed more potent quenching of fluorescence than amsacrine (AMSA).


Potential Biomarkers in Lewis Negative Patients With Pancreatic Cancer.
To examine potential biomarkers in Lewis negative patients with pancreatic cancer. Carbohydrate antigen 19-9 (CA19-9) is currently the most important and widely used biomarker in pancreatic cancer. However, approximately 5 to 10% of the population are Lewis negative individuals, and they are documented to have scarce or no CA19-9 secretion. Therefore, it is necessary to explore potential biomarkers to compensate for this drawback. Lewis genotypes were determined in a large cohort of patients with pancreatic cancer (682 cases) and controls (525 cases) by sequencing the Fucosyltransferase 3 (FUT3) gene from genomic DNA. Potential biomarkers were examined in patients with Lewis negative genotypes and normal subjects. The impact of potential biomarkers on tumor burden and survival was analyzed. Forty-seven (6.9%) patients with pancreatic cancer had Lewis negative genotypes. Carcinoembryonic antigen (CEA) and CA125 had greater sensitivity than other biomarkers in Lewis negative patients with pancreatic cancer [CEA, 63.8%; CA125, 51.1%; CA72-4, 25.5%; CA15-3, 21.3%; CA19-9, 19.1%; CA50, 12.8%; CA242, 10.6%; and alpha-fetoprotein (AFP), 0.0%]. In addition, both CEA (98.0%) and CA125 (93.8%) showed a high specificity. Compared with other biomarkers, CEA (60.9%) was sensitive for stage I, II diseases and CA125 (75.0%) was sensitive for stage III, IV diseases. CEA and CA125 were associated with tumor metastasis and therapeutic response. CEA and CA125 have the potential to be applied as biomarkers in Lewis negative patients with pancreatic cancer. CEA and CA125 should be routinely measured for all patients with pancreatic cancer.


Petroleum industry effluents and other oxygen-demanding wastes in Niger Delta, Nigeria.
In this article, we review the fundamental phenomenon of oxygenation within the overriding context of petroleum-industry effluents and the other oxygen demanding wastes in Niger Delta, Nigeria. Drill cuttings, drilling mud (fluids used to stimulate the production processes), and accidental discharges of crude petroleum constitute serious land and water pollution in the oil-bearing province. Effluents from other industrial establishments such as distilleries, pulp and paper mills, fertilizer plants, and breweries, as well as thermal effluents, plant nutrients (such as nitrates and phosphates), and eroded sediments have also contributed to the pollution of their surrounding environment. Since these wastes are oxygen-demanding in nature, their impact on the recipient environment can be reversed by the direct application of simple chemistry. The wastes can be reduced, particularly in natural bodies of water, by direct oxidation-reduction processes or simple chemical combinations, acid-base reactions, and solubility equilibria; these are pH- and temperature-dependent. A shift in pH and alkalinity affects the solubility equilibria of Na+, Cl-, SO(2-), NO3(-), HCO3(-), and PO4(3-), and other ions and compounds.


Using case vignettes to measure HIV-related stigma among health professionals in China.
We examined Chinese health professionals' attitudes towards patients with AIDS vs patients with hepatitis B. A representative sample of 1101 Chinese health professionals was used. Prejudicial attitudes and willingness to interact were measured based on two case vignettes. Statistical analyses revealed that health professionals had negative biases against acquired immunodeficiency syndrome (AIDS) patients and reported much less willingness to interact with AIDS patients than hepatitis B patients. Perceived risk of infection at work was also negatively associated with willingness to interact with patients with human immunodeficiency virus (HIV)/AIDS, but relationships varied by profession. This study underscores the importance of developing and implementing stigma reduction interventions in health care settings to address attitudinal biases and discrimination in clinical practice.


Metal complexes of mitomycins.
The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these complexes had antitumor activity in mice. However, they were less active than mitomycin C. Weak associations between mitomycin C and metal ions were demonstrated by 13C and 15N NMR spectrometry.


[Effects of acute ozone exposure on genotoxicity of lung cells in rats].
To clarify the genotoxicity induced by acute exposure of ozone with different concentrations on pulmonary cells in rats. Thirty-six Wistar rats were randomly divided into control group (filtered air exposure) and ozone exposure group (0.12 ppm, 0.5 ppm, 1.0 ppm, 2.0 ppm, 4.0 ppm) with 6 in each group. After rats were exposed to different concentrations of ozone for 4 h, lung tissues were taken and single cells were isolated. Then, 8-hydroxydeoxyguanosine (8-OHdG) was quantitatively detected by enzyme-linked immunosorbent assay. Comet assay, micronucleus test and DNA- protein cross-linking assay were used to analyze DNA and chromosome damages. Compared with the control group, the content of 8-OHdG in lung tissue was increased significantly from the ozone exposure concentration of 0.12 ppm, reaching the highest value at 0.5 ppm. With the increase of ozone exposure concentration, the tail rate of comets was increased gradually, and there was a significant dose-effect relationship. The cross-linking rate of DNA- protein was increased first and then was decreased with a maximum value at 2.0 ppm group. Although the micronucleus rate of lung cells showed an upward trend, there was no significant difference compared with the control group. Acute exposure of ozone at low concentrations (0.12 ppm) could lead to DNA damage in the pulmonary cells of rats, while no significant chromosome damage was found even in the group with ozone concentration reached to 4 ppm.


The glycoprotein Ten-m3 mediates topography and patterning of thalamostriatal projections from the parafascicular nucleus in mice.
The striatum is the key input nucleus of the basal ganglia, and is implicated in motor control and learning. Despite the importance of striatal circuits, the mechanisms associated with their development are not well established. Previously, Ten-m3, a member of the Ten-m/teneurin/odz family of transmembrane glycoproteins, was found to be important in the mapping of binocular visual pathways. Here, we investigated a potential role for Ten-m3 in striatal circuit formation. In situ hybridisation revealed a patchy distribution of Ten-m3 mRNA expression superimposed on a high-dorsal to low-ventral gradient in a subregion of the striatal matrix. A survey of afferent/efferent structures associated with the matrix identified the parafascicular thalamic nucleus (PF) as a potential locus of action. Ten-m3 was also found to be expressed in a high-dorsal to low-ventral gradient in the PF, corresponding topographically to its expression in the striatum. Further, a subset of thalamic terminal clusters overlapped with Ten-m3-positive domains within the striatal matrix. Studies in wild-type (WT) and Ten-m3 knockout (KO) mice revealed no differences in overall striatal or PF structure. Thalamostriatal terminals in KOs, however, while still confined to the matrix subregion, lost their clustered appearance. Topography was also altered, with terminals from the lateral PF projecting ectopically to ventral and medial striatum, rather than remaining confined dorsolaterally as in WTs. Behaviorally, Ten-m3 KOs displayed delayed motor skill acquisition. This study demonstrates that Ten-m3 plays a key role in directing the formation of thalamostriatal circuitry, the first molecular candidate reported to regulate connectivity within this pathway.


Manipulation of Carotenoid Content in Plants to Improve Human Health.
Carotenoids are essential components for human nutrition and health, mainly due to their antioxidant and pro-vitamin A activity. Foods with enhanced carotenoid content and composition are essential to ensure carotenoid feasibility in malnourished population of many countries around the world, which is critical to alleviate vitamin A deficiency and other health-related disorders. The pathway of carotenoid biosynthesis is currently well understood, key steps of the pathways in different plant species have been characterized and the corresponding genes identified, as well as other regulatory elements. This enables the manipulation and improvement of carotenoid content and composition in order to control the nutritional value of a number of agronomical important staple crops. Biotechnological and genetic engineering-based strategies to manipulate carotenoid metabolism have been successfully implemented in many crops, with Golden rice as the most relevant example of β-carotene improvement in one of the more widely consumed foods. Conventional breeding strategies have been also adopted in the bio-fortification of carotenoid in staple foods that are highly consumed in developing countries, including maize, cassava and sweet potatoes, to alleviate nutrition-related problems. The objective of the chapter is to summarize major breakthroughs and advances in the enhancement of carotenoid content and composition in agronomical and nutritional important crops, with special emphasis to their potential impact and benefits in human nutrition and health.


Classification of proximal humeral fractures based on a pathomorphologic analysis.
The purpose of this study was to analyze the pathomorphology of proximal humeral fractures to determine relevant and reliable parameters for fracture classification. A total of 100 consecutive acute proximal humeral fractures in adult patients were analyzed by 2 non-independent observers from a single shoulder department using a standardized protocol based on biplane radiographs and 3-dimensional computed tomography scans. A fracture classification system based on the most reliable key features of the pathomorphologic analysis was created, and its reliability was tested by 6 independent shoulder experts analyzing another 100 consecutive proximal humeral fractures. The head position in relation to the shaft (varus, valgus, sagittal deformity) and the presence of tuberosity fractures showed a higher interobserver reliability (κ > 0.8) than measurements for medial hinge, shaft, and tuberosity displacement, metaphyseal extension, fracture impaction, as well as head-split component identification (κ < 0.7). These findings were used to classify nondisplaced proximal humeral fractures as type 1, fractures with normal coronal head position but sagittal deformity as type 2, valgus fractures as type 3, varus fractures as type 4, and fracture dislocations as type 5. The fracture type was further combined with the fractured main fragments (G for greater tuberosity, L for lesser). Interobserver and intraobserver reliability analysis for the fracture classification revealed a κ value (95% confidence interval) of 0.700 (0.631-0.767) and 0.917 (0.879-0.943), respectively. The new classification system with emphasis on the qualitative aspects of proximal humeral fractures showed high reliability when based on a standardized imaging protocol including computed tomography scans.


Infections caused by non-tuberculous mycobacteria in recipients of hematopoietic stem cell transplantation.
Non-tuberculous mycobacteria (NTM) are acid-fast bacteria that are ubiquitous in the environment and can colonize soil, dust particles, water sources, and food supplies. They are divided into rapidly growing mycobacteria such as Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus as well as slowly growing species such as Mycobacterium avium, Mycobacterium kansasii, and Mycobacterium marinum. About 160 different species, which can cause community acquired and health care-associated infections, have been identified. NTM are becoming increasingly recognized in recipients of hematopoietic stem cell transplantation (HSCT) with incidence rates ranging between 0.4 and 10%. These infections are 50-600 times commoner in transplant recipients than in the general population and the time of onset ranges from day 31 to day 1055 post-transplant. They have been reported following various forms of HSCT. Several risk factors predispose to NTM infections in recipients of stem cell transplantation and these are related to the underlying medical condition and its treatment, the pre-transplant conditioning therapies as well as the transplant procedure and its complications. Clinically, NTM may present with: unexplained fever, lymphadenopathy, osteomyelitis, soft tissue and skin infections, central venous catheter infections, bacteremia, lung, and gastrointestinal tract involvement. However, disseminated infections are commonly encountered in severely immunocompromised individuals and bloodstream infections are almost always associated with catheter-related infections. It is usually difficult to differentiate colonization from true infection, thus, the threshold for starting therapy remains undetermined. Respiratory specimens such as sputum, pleural fluid, and bronchoalveolar lavage in addition to cultures of blood, bone, skin, and soft tissues are essential diagnostically. Susceptibility testing of mycobacterial isolates is a basic component of optimal care. Currently, there are no guidelines for the treatment of NTM infections in recipients of stem cell transplantation, but such infections have been successfully treated with surgical debridement, removal of infected or colonized indwelling intravascular devices, and administration of various combinations of antimicrobials. Monotherapy can be associated with development of drug resistance due to new genetic mutation. The accepted duration of treatment is 9 months in allogeneic stem cell transplantation and 6 months in autologous setting. Unfortunately, eradication of NTM infections may be impossible and their treatment is often complicated by adverse effects and interactions with other transplant-related medication.


Real-time image fusion involving diagnostic ultrasound.
The aim of our article is to give an overview of the current and future possibilities of real-time image fusion involving ultrasound. We present a review of the existing English-language peer-reviewed literature assessing this technique, which covers technical solutions (for ultrasound and endoscopic ultrasound), image fusion in several anatomic regions, and electromagnetic needle tracking. The recent progress of real-time ultrasound in image fusion may provide several new possibilities, including diagnosis, treatment, and follow-up of oncologic patients.


[Tongue cancer: an ongoing problem which needs new therapeutic approaches].
Oral cancer together with oropharyngeal cancer constitutes the tenth most common malignancy in men worldwide. In spite of a general trend of mild decreases in the frequency of oral and pharyngeal cancers, there appears to be an increasing trend in the occurrence of oral tongue cancer (Localized in the anterior two-thirds of the tongue). Furthermore, in recent years, tongue cancer is on the rise in young patients (fifth decade and less). Tongue cancer is the most frequent type of malignancy in the oral cavity and is characterized by remarkable aggressive biological behavior. The 5-year survival rate in patients with tongue cancer has steadily remained lower than 50% during the last 40 years. This is in contrast to the considerable improvement in the survival rates that have been achieved in patients with solid tumors in other parts of the body, due to the introduction of advanced diagnostic means and new treatment modalities. Our recent studies have shown an important role that components of the tumor microenvironment (TME) play in the proliferation, invasion and local and distant spread of tongue cancer, which is not less than that of the cancer cells. The results of these studies suggest the development of new therapeutic modalities in tongue cancer, which should combine anti-cancer and anti-TME agents.