Segregated Excitatory-Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex.
A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long-range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)-positive and somatostatin (SOM)-positive cells. PV cells have a fast-spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection-specific excitatory neurons within the neocortex.


The Association Between Adjuvant Pain Medication Use and Outcomes Following Pediatric Spinal Fusion.
A comparative effectiveness database study. The aim of this study was to describe variation in use of adjuvant therapies for managing postoperative pain in in patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and determine association between use of these therapies and patient outcomes. Variation in postoperative pain management for children undergoing PSF for AIS likely impacts outcomes. Minimal evidence exists to support strategies that most effectively minimize prolonged intravenous (IV) opioids and hospitalizations. We included patients aged 10 to 18 years discharged from one of 38 freestanding children's hospitals participating in a national database from December 1, 2012, to January 5, 2015, with ICD9 codes indicating scoliosis and PSF procedure. Use of ketorolac, gamma aminobutyric acid (GABA) analogues (GABAa), and benzodiazepines was compared across hospitals. Hierarchical logistic regression adjusting for confounders and accounting for clustering of patients within hospitals was used to estimate association between these therapies and odds of prolonged duration of IV opioids, prolonged length of stay (LOS), and early readmissions. Across hospitals, use of ketorolac and GABAa was highly variable and increased over time among 7349 subjects. Use of ketorolac was independently associated with significantly lower odds of prolonged LOS [odds ratio (OR) 0.75, 95% confidence interval (95% CI) 0.64-0.89] and prolonged duration of IV opioid (OR 0.84, 95% CI 0.73-0.98). GABAa use was significantly associated with decreased odds of prolonged IV opioid use (OR 0.63, 95% CI 0.53-0.75). Readmission rate at 30 days was 1.6% and most strongly associated with prolonged LOS. In this national cohort of children with AIS undergoing PSF, patients who received postoperative ketorolac or GABAa were less likely to have prolonged IV opioid exposure. Given the rapid increase in use of adjuvant therapies without strong evidence, resources should be devoted to multicenter trials in order to optimize effectiveness and outcomes. 3.


Expulsive choroidal hemorrhage.
An unusual case of expulsive choroidal hemorrhage is described. The hemorrhage developed sixteen days after an uneventful cataract extraction and after the removal of corneoscleral sutures. The different types of expulsive hemorrhage, their pathogenesis and management are discussed. Eye surgeons are urged to handle this condition with determination and optimism.


Chikungunya Fever: Obstetric Considerations on an Emerging Virus.
Chikungunya fever is an increasingly common viral infection transmitted to humans by species of the Aedes mosquitoes. Characterized by fevers, myalgias, arthralgias, headache, and rash, the infection is endemic to tropical areas. However, identification of disease vectors to Europe and the Americas has raised concern for possible spread of chikungunya to these areas. More recently, these concerns have become a reality; with more than 500,000 new cases in the Western hemisphere in the last 2 years, questions have arisen about the implications of infection during pregnancy and delivery. A literature review was performed using MEDLINE in order to gather information regarding the obstetric implications of this infection. It appears that although this virus can cross the placenta in the first and second trimester leading to fetal infection and miscarriage, this is a very rare occurrence. In contrast, active maternal infection within 4 days of delivery conveys a high risk of vertical transmission. Maternal infection during pregnancy does not appear to be more severe than infection on the nonpregnant female. Given the increasing incidence of chikungunya, obstetric providers should be aware of the disease and its implication for the gravid female.


Enteric-Coated Cysteamine Bitartrate in Cystinosis Patients.
Cystinosis is a severe inherited metabolic storage disease caused by the lysosomal accumulation of cystine. Lifelong therapy with the drug cysteamine bitartrate is necessary. Cysteamine cleaves intralysosomal cystine, and thereafter, it can exit from the organelle. The need for frequent dosing every 6 h and the high prevalence of gastrointestinal side effects lead to poor therapy adherence. The purpose of our study was to improve cysteamine treatment by comparing the efficacy of two cysteamine formulas. This is highly relevant for the long-term outcome of cystinosis patients. The cystine and cysteamine levels of 17 patients taking immediate-release cysteamine (IR-cysteamine/Cystagon®) and 6 patients taking encapsulated delayed-release cysteamine (EC-cysteamine) were analyzed. The EC-cysteamine levels showed a near-ideal pharmacokinetic profile indicative of delayed release (longer Tmax and Tmin), and the corresponding cystine levels showed few fluctuations. In addition, the Cmax of IR-cysteamine was greater, which was responsible for unbearable side effects (e.g., nausea, vomiting, halitosis, lethargy). Treatment with EC-cysteamine improves the quality of life of cystinosis patients because the frequency of intake can be reduced to 2-3 times daily and it has a more favorable pharmacokinetic profile than IR-cysteamine. In particular, cystinosis patients with no access to the only approved delayed-release cysteamine Procysbi® could benefit from a cost-effective alternative.


Muscarinic receptor binding and muscarinic receptor-mediated inhibition of adenylate cyclase in rat brain myelin.
High-affinity muscarinic cholinergic receptors were detected in myelin purified from rat brain stem with use of the radioligands 3H-N-methylscopolamine (3H-NMS), 3H-quinuclidinyl benzilate (3H-QNB), and 3H-pirenzepine. 3H-NMS binding was also present in myelin isolated from corpus callosum. In contrast, several other receptor types, including alpha 1- and alpha 2-adrenergic receptors, present in the starting brain stem, were not detected in myelin. Based on Bmax values from Scatchard analyses, 3H-pirenzepine, a putative M1 selective ligand, bound to about 25% of the sites in myelin labeled by 3H-NMS, a nonselective ligand that binds to both M1 and M2 receptor subtypes. Agonist affinity for 3H-NMS binding sites in myelin was markedly decreased by Gpp(NH)p, indicating that a major portion of these receptors may be linked to a second messenger system via a guanine-nucleotide regulatory protein. Purified myelin also contained adenylate cyclase activity; this activity was stimulated several fold by forskolin and to small but significant extents by prostaglandin E1 and the beta-adrenergic agonist isoproterenol. Myelin adenylate cyclase activity was inhibited by carbachol and other muscarinic agonists; this inhibition was blocked by the antagonist atropine. Levels in myelin of muscarinic receptors were 20-25% and those of forskolin-stimulated adenylate cyclase 10% of the values for total particulate fraction of whole brain stem. These levels in myelin are appreciably greater than would be predicted on the basis of contamination. Also, additional receptors and adenylate cyclase, added by mixing nonmyelin tissue with whole brain stem, were quantitatively removed during the purification procedure. In conclusion, both M1 and M2 muscarinic receptor subtypes and an adenylate cyclase system linked to at least some of these receptors are present as intrinsic components of myelin. The possibility that some of these muscarinic receptors may be involved in regulation of phosphinositide metabolism and the protein kinase activities of myelin is considered.


[Primary retroperitoneal approach for vessel-sparing D3-lymph node dissection in left colonic and rectal cancer resections - the first Russian experience].
To develop and describe a technique of primary retroperitoneal approach for vessel-sparing D3-lymph node dissection in the left colon and rectal cancer surgery; to evaluate the short-term results of the first series of patients treated with a new minimally invasive method. The first 10 patients with adenocarcinoma of the left colon and rectum, who underwent surgical treatment using the retroperitoneal approach with vessel-sparing D3 lymph node dissection, were included in the study. The primary retroperitoneal approach involved mobilization of the left side of the colon, D3 lymph node dissection with skeletonization of inferior mesenteric artery (IMA) and selective ligation of afferent vessels from retroperitoneal space using SILS access system at the first steps of surgery. Intersection of visceral and parietal peritoneum, as well as intersection of mesentery within the bowel resection borders was performed laparoscopically. Surgical specimen was removed through retroperitoneal access incision. Duration of retroperitoneal stage with lymph node dissection was 100 min (70.0-115.0). There were 28.5 (22-37) regional lymph nodes removed during vessel-sparing D3 lymph node dissection with IMA skeletalization, 3 (1-4) metastatic regional lymph nodes and 3.5 (2-5) apical nodes. In 4 out of 10 patients, we damaged visceral peritoneum during retroperitoneal dissection. Two patients developed Clavien-Dindo grade 1-2 complications. Mean postoperative hospital stay was 8 days (5-12). We developed retroperitoneal vessel-sparing D3 lymph node dissection for the treatment of left colon and rectal cancer. Initial results demonstrated safety and feasibility of this approach.


Chronic Pediatric Immune Thrombocytopenia Is Not Associated With Herpes Virus Infection Status.
Background: Immune thrombocytopenia (ITP) is characterized by non-chronic (transient, <12 months) and chronic (≥12 months) decline in the number of platelets. Herpes virus infections have been shown, in many studies, to be associated with the development of ITP. However, it remains unclear whether the herpes virus infection status is associated with the chronic ITP. Methods: We reviewed 480 primary pediatric patients with ITP in the period from January 2017 to December 2019. The prevalence of herpes virus antibodies including the Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Epstein Barr virus were recorded. The levels of serum complement C3 and C4, T (CD3+, CD4+, CD8+), B (CD19+) lymphocytes, and natural killer (CD16+ 56+) cells were also analyzed. Multivariate analysis was used to evaluate the associations between chronic ITP and herpes virus infection status. Results: Compared with non-chronic, patients with chronic ITP had older age (≥3 years), lower levels of hemoglobin and complement C3, and lower probability of CMV and HSV-2 infections (IgM positive; p < 0.05). Patients with herpes virus infection had lower serum platelet counts (p < 0.001), lower complement C3 levels and lower CD4+/CD8+ cells ratio (p < 0.05). Furthermore, platelet counts were positively correlated with CD4+/CD8+ cells ratios (r = 0.519; p = 0.0078), and negatively correlated with T cells (CD3+: r = -0.458, p = 0.0213; CD8+: r = -0.489, p = 0.0131). Multivariate analysis showed that age (OR, 1.644; 95%CI, 1.007-2.684; p = 0.047) was an adverse risk factor for chronic ITP and CMV IgM positive (OR, 0.241; 95%CI, 0.072-0.814; p = 0.022) had lower risk of chronic ITP development, while other herpes virus infection statuses and clinical features were not. Conclusion: Although herpes virus infections were associated with the onset of ITP, our findings indicated that herpes virus infection status might not be a risk factor for chronic ITP.


Transfusion-transmitted babesiosis leading to severe hemolysis in two patients with sickle cell anemia.
The intracellular parasites Babesia microti and Babesia duncani can be transmitted by blood transfusion and cause severe life-threatening hemolytic anemia in high-risk patients, including those with sickle cell disease. The rarity of the diagnosis, as well as its similar clinical presentation to delayed hemolytic transfusion reaction, may lead to a delay in diagnosis, as well as inappropriate treatment with steroids or other immunosuppressive agents. The morbidity caused by this disease in especially vulnerable populations justifies the need for a universal blood-screening program in endemic areas.


Developmental differences in depression: cognitive-perceptual distortion in adolescent versus adult female depressives.
This study was undertaken to determine differential cognitive-perceptual distortion in depression for adolescent versus adult females. Twenty-five female adolescent and twenty-five female adult psychiatric inpatients served as subjects. Each had received a primary diagnosis of neurotic or reactive depression and had completed the Beck Depression Inventory within five days of hospitalization. Results indicated significant similarities between the groups in anger at self and sense of failure. These may serve as unifying themes for adolescent and adult depressives. Results also indicated significant differences between the two groups. Adult female depressives demonstrated an internalized, ruminative focus to their depressive cognitions. Adolescent female depressives demonstrated an externalized focus to their depressive cognitions. Adults demonstrated a preoccupation with their own view of themselves and perceived themselves as a failure in their own eyes. Adolescents demonstrated a preoccupation with how others view them and perceived themselves as a failure in the eyes of others. These results are discussed in terms of developmental, theoretical, and treatment issues for adolescent versus adult depressives generally. Depression may exacerbate cognitive-perceptual distortions already existing within the adolescent population. In treatment, group psychotherapy may prove particularly efficacious for adolescent depressives.


Novel and detrimental effects of lipopolysaccharide on in vitro generation of immature dendritic cells: involvement of mitogen-activated protein kinase p38.
Dendritic cells (DCs) are recognized as major players in the regulation of immune responses to a variety of Ags, including bacterial agents. LPS, a Gram-negative bacterial cell wall component, has been shown to fully activate DCs both in vitro and in vivo. LPS-induced DC maturation involves activation of p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases, and NF-kappaB. Blocking p38 inhibits LPS-induced maturation of DCs. In this study we investigated the role of LPS in the in vitro generation of immature DCs. We report here that in contrast to the observed beneficial effects on DCs, the presence of LPS in monocyte culture retarded the generation of immature DCs. LPS not only impaired the morphology and reduced the yields of the cultured cells, but also inhibited the up-regulation of surface expression of CD1a, costimulatory and adhesion molecules. Furthermore, LPS up-regulated the secretion of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha; reduced Ag presentation capacity; and inhibited phosphorylation of ERK, but activated p38, leading to a reduced NF-kappaB activity in treated cells. Neutralizing Ab against IL-10, but not other cytokines, partially blocked the effects of LPS. Inhibiting p38 (by inhibitor SB203580) restored the morphology, phenotype, and Ag presentation capacity of LPS-treated cells. SB203580 also inhibited LPS-induced production of IL-1beta, IL-10, and TNF-alpha; enhanced IL-12 production; and recovered the activity of ERK and NF-kappaB. Thus, our study reveals that LPS has dual effects on DCs that are biologically important: activating existing DCs to initiate an immune response, and inhibiting the generation of new DCs to limit such a response.


Influence of some anesthetic agents on muscle responses to transcranial magnetic cortex stimulation: a pilot study in humans.
The effects of some commonly used intravenous and inhalational anesthetic agents on the motor evoked responses to transcranial magnetic cortex stimulation were assessed in 17 subjects. Compound motor action potentials (CMAPs) of the abductor digiti minimi muscle were recorded. Baseline values (12 stimulations/subject) were established before anesthesia was induced with a single agent administered in steps up to a maximal dose (MaxDose). Cortical stimulation was performed and depth of anesthesia was assessed according to Guedel after each dose. A common feature was the marked intra- and interindividual variability of baseline values of CMAPs in those patients not premedicated, those premedicated, and the anesthetized patients. The average amplitude of CMAPs was related to the depth of anesthesia in a given subject, whereas onset latencies of CMAPs did not systematically change. CMAPs were markedly reduced or abolished after administration of potent sedative drugs such as midazolam (MaxDose, 0.4 mg/kg body weight), pentothal (MaxDose, 8 mg/kg), propofol (MaxDose, 2 mg/kg), and isoflurane (MaxDose, 1.9 and 3.7 vol %), as soon as patients reached Stage II and Stage III anesthesia. When fentanyl (MaxDose, 8 micrograms/kg) or nitrous oxide (MaxDose, 79%) was used, the subjects reached Stages I and II, but not Stage III. With these drugs, reliable recording of CMAPs was possible even with the maximal administered dose.


Evaluation of the impact of live pig trade network, vaccination coverage and socio-economic factors in the classical swine fever eradication program in Peru.
Classical swine fever (CSF) is a viral infectious disease of swine with significant economic impact in the affected countries due to the limitation of trade, culling of infected animals and production losses. In Latin America, CSF is endemic in several countries including Ecuador, Bolivia, Brazil and Peru. Since 2010, the National Veterinary Services of Peru have been working to better control and eradicate the disease with an intensive vaccination program. The aim of this study was to evaluate the effectiveness of the vaccination program and determine which factors are still contributing to the persistence of the disease in certain regions of Peru. We integrated the data from the vaccination campaign, the live pig movement network and other socioeconomic indicators into a multilevel logistic regression model to evaluate their association with CSF occurrence at district level. The results revealed that high vaccination coverage significantly reduces the risk of CSF occurrence (OR = 0.07), supporting the effectiveness of the vaccination program. Districts belonging to large and medium pig trade network communities (as identified with walktrap algorithm) had higher probability to CSF occurrence (OR = 2.83 and OR = 5.83, respectively). The human development index (HDI) and the presence of a slaughterhouse in the district was also significantly associated with an increased likelihood of CSF occurrence (OR = 1.52 and OR = 3.25, respectively). Districts receiving a high proportion of the movements from districts that were infected in the previous year were also at higher risk of CSF occurrence (OR = 3.30). These results should be useful to guide the prioritization of vaccination strategies and may help to design other intervention strategies (e.g., target education, movement restrictions, etc.) in high-risk areas to more rapidly advance in the eradication of CSF in Peru.


Voltage-clamp studies of gap junctions between uterine muscle cells during term and preterm labor.
Gap junctions between myometrial cells increase dramatically during the final stages of pregnancy. To study the functional consequences, we have applied the double-whole-cell voltage-clamp technique to freshly isolated pairs of cells from rat circular and longitudinal myometrium. Junctional conductance was greater between circular muscle-cell pairs from rats delivering either at term (32 +/- 16 nS, mean +/- SD, n = 128) or preterm (26 +/- 17 nS, n = 33) compared with normal preterm (4.7 +/- 7.6 nS, n = 114) and postpartum (6.5 +/- 10 nS, n = 16); cell pairs from the longitudinal layer showed similar differences. The macroscopic gap junction currents decayed slowly from an instantaneous, constant-conductance level to a steady-state level described by quasisymmetrical Boltzmann functions of transjunctional voltage. In half of circular-layer cell pairs, the voltage dependence of myometrial gap junction conductance is more apparent at smaller transjunctional voltages (< 30 mV) than for other tissues expressing mainly connexin-43. This unusual degree of voltage dependence, although slow, operates over time intervals that are physiologically relevant for uterine muscle. Using weakly coupled pairs, we observed two unitary conductance states: 85 pS (85-90% of events) and 25 pS. These measurements of junctional conductance support the hypothesis that heightened electrical coupling between the smooth muscle cells of the uterine wall emerges late in pregnancy, in preparation for the massive, coordinate contractions of labor.


Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFβ, and Wnt/β-catenin signaling in adrenocortical carcinoma cells.
The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma.


[Empathy - a phenomenological approach].
The author presents some concepts of empathy according to some authors and the difficulties to perform these concepts. The empathy is suggested to study as a phenomenon by a phenomenologic method and through the envolvement between nurse and patient during the moment the patient passed away.


Catabolism of 3- and 4-hydroxyphenylacetate by the 3,4-dihydroxyphenylacetate pathway in Escherichia coli.
Various strains of Escherichia coli (but not strain K-12) were found to grow on 3-hydroxyphenylacetate and 4-hydroxyphenylacetate. Both compounds were catabolized by the same pathway, with 3,4-dihydroxyphenylacetate as a substrate for fission of the benzene nucleus, and with pyruvate and succinate as products. All the necessay enzymes were demonstrated in cell extracts prepared from induced cells but were essentially absent from uninduced cells. Mutants unable to grow on 3- and 4-hydroxyphenylactetate were defective in particular enzymes of the pathway. The characteristics of certain mutants indicated that either uptake or hydroxylation of 3- and 4-hydroxyphenylacetate may involve a common protein component. E. coli also grew on 3,4-hydroxyphenylacetate, with induction of the enzyme necessary for its degradation but not those for the uptake-hydroxylation of 3- and 4-hydroxyphenylacetate.


Endothelial microparticle formation in moderate concentrations of homocysteine and methionine in vitro.
Microparticles (MPs) are small membrane vesicles released by stimulated or apoptotic cells, including the endothelium. Hyperhomocysteinemia (HHcy) is a blood disorder characterized by an increase in the plasma concentrations of total homocysteine (Hcy). The plasma Hcy level is determined by environmental factors (dietary habits, i.e. the intake of folic acid, FA) and genetic factors (N (5),N (10)-methylenetetrahydro-folate reductase, MTHFR, polymorphism 677C>T). To evaluate whether moderate Hcy concentrations induce endothelial MP formation, the role of FA supplementation and the influence of MTHFR polymorphism were analysed. Human umbilical vein endothelial cells (HUVEC) were treated in vitro with 50 μM of Hcy and methionine (Met). The MP number and apoptotic phenotype were analyzed using flow cytometry. Increasing doses of FA (5, 15 and 50 μM) were used to reduce the HHcy effect. The MTHFR 677C>T polymorphism was determined. HUVEC stimulated by Hcy produced significantly more MPs than HUVEC under the control conditions: 3,551 ± 620 vs 2,270 ± 657 kMP (p = 0.02). Supplementation with FA at concentrations of 5, 15 and 50 μM reduced the MP count in the cell culture supernatant to 345 ± 332, 873 ± 329, and 688 ± 453 kMP, respectively (p = 0.03). MTHFR 677C>T heterozygosity was associated with a significant increase in MP formation after stimulation with Hcy compared to the control conditions: 3,617 ± 152 vs 1,518 ± 343 kMP (p = 0.02). Furthermore, the MTHFR genotype altered MP formation after Met loading. On average, 24% of the entire MP population was apoptotic (annexin V-positive). Endothelial function impairment due to HHcy is related to MP shedding, which may involve platelets and other blood and vascular cells. MP shedding is a physiological response to moderate HHcy.


A day in the life of a nebulizer: surveillance for bacterial growth in nebulizer equipment of children with cystic fibrosis in the hospital setting.
Cystic fibrosis (CF) is characterized by chronic lung infection. Minimizing exposure to pathogens is important. Treating a CF pulmonary exacerbation includes nebulizer therapies, but little is known about pathogen exposure from nebulizer equipment in CF. To assess microbial growth in nebulizer equipment used by hospitalized CF patients. The small-volume nebulizer would not support the growth of the important CF pathogens: Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia. During a 6-month period, we prospectively enrolled 30 patients who were admitted for pulmonary exacerbation of CF and were prescribed an aerosolized bronchodilator 4 times daily. Bronchodilator was administered via disposable small-volume nebulizer, prior to airway clearance. The nebulizer was not cleaned or disinfected between treatments, but instead was replaced after 24 hours. Sputum or throat cultures were obtained prior to admission or on the day of admission, and standard culture techniques were used for CF microbes. After the first bronchodilator treatment, a sample was taken from the residual fluid inside the nebulizer cup. The second, third, and fourth samples were taken from the nebulizer cup after it was filled with a unit dose of the bronchodilator but prior to administering the bronchodilator. At the 24th hour, the nebulizer was filled with 3 mL of sterile water, from which the fifth sample was obtained, then the nebulizer was disposed of. On respiratory culture, ten patients had Pseudomonas aeruginosa, 5 had both P. aeruginosa and S. aureus, 6 had only S. aureus, and 1 had both S. aureus and H. influenzae. Three had other organisms, 4 had normal flora, and 1 had no culture data. Of the 150 nebulizer sample cultures, only 3 showed bacterial growth. Bacillus species, Corynebacterium, coagulase-negative Staphylococcus, and Candida albicans were isolated at low colony counts. We suspect that the organisms identified were caused by skin contamination of the samples rather than contamination of the nebulizer cup. We conclude that there is a low risk of microbial contamination with CF pathogens from the interior of a disposable nebulizer over a 24 hour period.


Ectoprostheses in the treatment of facial defects: an analysis of a 7-year material.
The article presents the experiences based on facial ectoprostheses over a period of seven years. The material consists of 23 cases, 12 women and 11 men. In 19 cases the facial defects were caused by a malignant neoplasm, in 2 cases by a chronic infection and in 2 cases as a result of trauma. The age of the patients ranged from 23 to 83 years with a dominance in the sixth and seventh decade. The mean age was 62.9 years. The prosthetic problems and solutions are discussed in detail. The usefulness of the facial ectoprostheses is evaluated to be adequate, both in technologic and biologic respect.


Trajectory of prenatal anxiety and depression and its association with fetal growth development.
The stability of anxiety and depression during pregnancy and the impact on women and offspring has been recognized, yet the distinction of impact between them remains unclear. The aim of this study was to investigate the trajectory of prenatal anxiety and depression and their coexistence, as well as to examine the potential variations in pregnancy outcomes and fetal/neonatal growth development. At baseline (11-13+6 weeks), women were recruited and subsequently monitored in the second (16-20+6 weeks) and third (28-31+6 weeks) trimesters. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale. In the second (16-20+6 weeks), third (28-31+6 weeks), and prenatal period (37-40+6 weeks), fetal growth was assessed by ultrasound scans. The joint trajectory model was used to determine the trajectory groups of depressive/anxiety dominant or coexistence. Comparisons of fetal/neonatal growth between groups were conducted using analysis of covariance and a multilevel model. A total of 457 pregnant women were finally included. Four trajectory groups were identified: none-negative emotion (n = 190, 41.6 %), anxiety dominant (n = 195, 42.6 %), depression dominant (n = 33, 7.2 %), and anxiety and depression coexistence (n = 39, 8.6 %). There were significant differences in the antenatal abdominal circumference (335.44 vs 333.92 vs 330.82 vs 325.13 mm, p = 0.007) of fetuses and the birth length (50.14 vs 50.03 vs 49.91 vs 49.18, p = 0.008) of newborns among four groups, showing a clear decreasing trend. Anxiety and depression coexistence displayed a notable and statistically significant difference when compared to the other groups and had a lower increase of fetal abdominal circumference (β = -8.91, 95%CI: -16.15, -1.67, p = 0.016) after controlling for confounding factors. Anxiety and depression dominant groups found no difference in fetal/neonatal growth. The more severe the negative emotional state of mothers, the more restricted their offspring's development, especially in terms of fetal abdominal circumference and birth length. The impact of anxiety or depressive symptoms does not show a pronounced difference. However, what is noteworthy is the tendency and evident impact on offspring development when anxiety and depression coexistence work synergistically. As a result, healthcare professionals should place greater emphasis on addressing anxiety and depression in expectant mothers, particularly among those experiencing anxiety and depression coexisting symptoms.


Healthcare @ the speed of thought.
It is daunting to realize that we have just touched the surface of health-related Internet web sites. The use of the Internet as a vital patient care tool is a very real prospect on the near horizon. Yet most hospital systems and physicians groups today just use the Net to post "billboards.'' In the rest of America, the Internet has been much more than a billboard. It has changed the way business is conducted. There's e-mail. There's e-trading for those who invest. On mother's day moms receive e-cards, and there is e-commerce which includes buying and selling online, and also collecting and organizing data that will help a business serve customers better, building that relationship. The Internet is a transaction tool. The latest survey indicates that the volume of commerce on the Net has grown 300% this year over last. According to a survey sponsored by Cisco Systems. Net sales volume accounts for $200 billion and is doubling every 6 months. And, the search for health information is among the top three reasons people use the web. The surveys indicate that people would like better communication with their physicians and most would like to communicate by e-mail. Yet, very few physicians are interested. As part of the research for this article we reviewed dozens of web sites for hospitals and medical groups. While some of these sites are attractive, most simply don't do anything more than provide maps and telephone numbers. People might as well look in the Yellow Pages for the information they can find on th web. Meanwhile, a number of well-funded health sites have sprung up just in the past few months. We searched the web to find sites that would actually allow people to interact in ways that went beyond just finding information. Clearly there is movement toward the ability to conduct transactions over the Net, i.e, patient monitoring, checking on status of claims, ask-a-doc, etc. But, we are just at the front end of this movement and physicians and hospitals have an opportunity to play a leadership role. A number of the sites reviewed for this article, for example, offer the patient the ability to develop his or her own health record and maintain it on the web. It is not conceivable that a healthcare system, along with its affiliated physician, might develop a secure web site that included a combined inpatient and outpatient rcord, accessible electronically by patients and authorized providers from any telephone in the world. It is clear that armed with Internet data, consumers will play an increasingly important role in their own care. Employers are acquiescing to their demands for increasing choice. Copayments are also going up and employees are likely to vote with their feet in selecting providers. Companies like WebMd, Physicians Online, Planetrx.com, drugstore.com, Yahoo and the other mentioned above are filling a need. It should be a wakeup call for healthcare systems and physicians. According to the latest data from Medimetrix, (see medimetrix.com), the most frequently visited health sites on the web today are Intelihealth.com (Johns Hopkins), Mayohealth.org, and OnHealth.com. These sites provide a highly interactive experience for consumers and tons of news and information. They are compelling and traffic-building, have fresh news that is frequently updated and many are transaction. That's what people want. There are so many potential uses of the Internet for physicians and hospitals that it is difficult to properly cover them in this article. Why shouldn't a patient be able to check the status of their account? Has the insurance paid? Is there a patient balance? Consumers can check their bank balances on the Internet. Why not their hospital or medical office accounts? Why not let them pay their balances online? As noted above, some the the HMOs are providing account status information to patients already. Why not the hospitals and physicians? Web sites are multiplying like rabbits. It's going to take a lot of effort to


Celery Seed Extract Blocks Peroxide Injury in Macrophages via Notch1/NF-κB Pathway.
Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and injury is one of the major atherogenic factors. This study is aimed to investigate the protective effect of celery seed extract (CSE) on ox-LDL-induced injury of macrophages and the underlying signaling pathway. RAW264.7 macrophages were pre-incubated with CSE for 24 h, followed by stimulation with ox-LDL. Oil red O staining and enzymatic colorimetry indicated CSE significantly lessened lipid droplets and total cholesterol (TC) content in ox-LDL-injured macrophages. ELISA revealed that CSE decreased the secretion of inflammatory cytokine TNF-α and IL-6 by 12-27% and 5-15% respectively. MTT assay showed CSE promoted cell viability by 16-40%. Cell apoptosis was also analyzed by flow cytometry and laser scanning confocal microscope and the data indicated CSE inhibited ox-LDL-induced apoptosis of macrophages. Meanwhile, western blot analysis showed CSE suppressed NF-κBp65 and notch1 protein expressions stimulated by ox-LDL in macrophages. These results suggest that CSE inhibits ox-LDL-induced macrophages injury via notch1/NF-κB pathway.


Cockayne Syndrome group B protein stimulates NEIL2 DNA glycosylase activity.
Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2. Using both cell extracts and recombinant proteins, CSB and NEIL2 were found to physically interact independently of DNA. We further found that CSB is able to stimulate NEIL2 glycosylase activity on a 5-hydroxyl uracil lesion in a DNA bubble structure substrate in vitro. A novel 4,6-diamino-5-formamidopyrimidine (FapyA) specific incision activity of NEIL2 was also stimulated by CSB. To further elucidate the biological role of the interaction, immunofluorescence studies were performed, showing an increase in cytoplasmic CSB and NEIL2 co-localization after oxidative stress. Additionally, stalling of the progression of the transcription bubble with α-amanitin resulted in increased co-localization of CSB and NEIL2. Finally, CSB knockdown resulted in reduced incision of 8-hydroxyguanine in a DNA bubble structure using whole cell extracts. Taken together, our data supports a biological role for CSB and NEIL2 in transcription associated base excision repair.


Temperament and Social-Emotional Difficulties: The Dark Side of Learning Disabilities.
The authors compared the relations between general psychological difficulties and dimensions of temperament in children with and without learning disability (LD). The main aim was to analyze whether and to what extent children's temperament dimensions contribute to their general psychological difficulties when LD diagnosis, age, and gender are taken into account. Participants were 52 elementary school children 7-11 years old (M age = 8.61 years, SD = 1.21 years). Twenty-six of them had been diagnosed with LD. Six teachers rated their pupils with and without LD in relation to their general psychological difficulties (Strengths and Difficulties Questionnaire) and temperament dimensions (Italian Questionnaires of Temperament). In children with LD, the main dimensions of temperament with the power to predict general psychological difficulties (i.e., emotionality and social orientation) concern these students' relationships with others (teachers and peers). The findings of the current study draw educators' and practitioners' attention to the fact that children's temperamental characteristics may affect how they experience their LD, with significant implications for their later social adjustment.


Localized RanGTP accumulation promotes microtubule nucleation at kinetochores in somatic mammalian cells.
Centrosomes are the major sites for microtubule nucleation in mammalian cells, although both chromatin- and kinetochore-mediated microtubule nucleation have been observed during spindle assembly. As yet, it is still unclear whether these pathways are coregulated, and the molecular requirements for microtubule nucleation at kinetochore are not fully understood. This work demonstrates that kinetochores are initial sites for microtubule nucleation during spindle reassembly after nocodazole. This process requires local RanGTP accumulation concomitant with delocalization from kinetochores of the hydrolysis factor RanGAP1. Kinetochore-driven microtubule nucleation is also activated after cold-induced microtubule disassembly when centrosome nucleation is impaired, e.g., after Polo-like kinase 1 depletion, indicating that dominant centrosome activity normally masks the kinetochore-driven pathway. In cells with unperturbed centrosome nucleation, defective RanGAP1 recruitment at kinetochores after treatment with the Crm1 inhibitor leptomycin B activates kinetochore microtubule nucleation after cold. Finally, nascent microtubules associate with the RanGTP-regulated microtubule-stabilizing protein HURP in both cold- and nocodazole-treated cells. These data support a model for spindle assembly in which RanGTP-dependent abundance of nucleation/stabilization factors at centrosomes and kinetochores orchestrates the contribution of the two spindle assembly pathways in mammalian cells. The complex of RanGTP, the export receptor Crm1, and nuclear export signal-bearing proteins regulates microtubule nucleation at kinetochores.


Drying-induced hydrophobic polymer collapse.
We have used computer simulation to study the collapse of a hydrophobic chain in water. We find that the mechanism of collapse is much like that of a first-order phase transition. The evaporation of water in the vicinity of the polymer provides the driving force for collapse, and the rate limiting step is the nucleation of a sufficiently large vapor bubble. The study is made possible through the application of transition path sampling and a coarse-grained treatment of liquid water. Relevance of our findings to understanding the folding and assembly of proteins is discussed.


Clinical equivalence of salmeterol/fluticasone propionate in combination (50/100 microg twice daily) when administered via a chlorofluorocarbon-free metered dose inhaler or dry powder inhaler to patients with mild-to-moderate asthma.
This multi-centre, randomized, double-blind, double-dummy, parallel-group study was designed to investigate the hypothesis of equivalent efficacy and comparable safety of two inhaled presentations of salmeterol/fluticasone propionate combination product (SALM/FP) 50/100 microg administered twice daily to patients with mild-to-moderate asthma for 12 weeks. The delivery systems were a 25/50 microg strength hydrofluoroalkane (HFA) metered-dose inhaler (MDI) and a Diskus inhaler (50/100 microg strength). A third group received FP 100 microg twice daily via a chlorofluorocarbon MDI (50 microg strength). A total of 497 patients aged 11-79 years with reversible airways obstruction who were symptomatic on inhaled corticosteroid (ICS) therapy and had room for improvement in lung function were randomized to treatment in a double-blind, parallel-group design (SALM/FP MDI: n=165; SALM/FP Diskus: n=167; FP MDI: n=165) for 12 weeks. A total of 383 patients completed the study according to the protocol. According to the primary efficacy variable, increase in mean morning PEF over weeks 1-12, the two inhaled presentations of SALM/FP were clinically equivalent (adjusted mean increases 43 and 46 l min(-1); treatment difference 3 l min(-1); 95% confidence interval: -6 to 11 l min(-1)). Equivalence was also demonstrated by all secondary efficacy measures. The SALM/FP MDI was significantly superior to the FP MDI for increase in mean morning PEF (treatment difference 19 l min(-1); P<0.001) and for all secondary measures except FEV1 and symptom-free nights. There was no significant difference between the groups with respect to adverse events and serum cortisol levels. These results demonstrate that the SALM/FP 25/50 microg HFA MDI (two inhalations twice daily) is clinically equivalent to the SALM/FP 50/100 microg Diskus (one inhalation twice daily). Patients switching to SALM/FP from other MDI-based asthma treatments may now do so without a change of delivery device.


Mechanical distortion of single actin filaments induced by external force: detection by fluorescence imaging.
Actin is a major component of the cytoskeleton that transmits mechanical stress in both muscle and nonmuscle cells. As the first step toward developing a "bio-nano strain gauge" that would be able to report the mechanical stress imposed on an actin filament, we quantitatively examined the fluorescence intensity of dyes attached to single actin filaments under various tensile forces (5-20 pN). Tensile force was applied via two optically trapped plastic beads covalently coated with chemically modified heavy meromyosin molecules that were attached to both end regions of an actin filament. As a result, we found that the fluorescence intensity of an actin filament, where 20% of monomers were labeled with tetramethylrhodamine (TMR)-5-maleimide at Cys(374) and the filamentous structure was stabilized with nonfluorescent phalloidin, decreased by approximately 6% per 10 pN of the applied force, whereas the fluorescence intensity of an actin filament labeled with either BODIPY TMR cadaverin-iodoacetamide at Cys(374) or rhodamine-phalloidin showed only an approximately 2% decrease per 10 pN of the applied force. On the other hand, spectroscopic measurements of actin solutions showed that the fluorescence intensity of TMR-actin increased 1.65-fold upon polymerization (G-F transformation), whereas that of BODIPY-actin increased only 1.06-fold. These results indicate that the external force distorts the filament structure, such that the microenvironment around Cys(374) approaches that in G-actin. We thus conclude that the fluorescent dye incorporated into an appropriate site of actin can report the mechanical distortion of the binding site, which is a necessary condition for the bio-nano strain gauge.


Identification of an essential glutamic acid residue in beta-lactamase II from Bacillus cereus.
Beta-Lactamase II from Bacillus cereus was readily inactivated by incubation at pH 4.75 with a water-soluble carbodiimide plus a suitable nucleophile. In the early stages of the reaction, 1 equivalent of nucleophile was incorporated/equivalent of enzyme, whereas during the later stages a second equivalent of nucleophile was also incorporated. This latter process correlated with the blocking of the enzyme's single thiol group. Enzyme inactivated in the presence of the coloured nucleophile N-(2,4-dinitrophenyl)ethylenediamine was fragmented by pepsin digestion, and coloured peptides were isolated by gel filtration and h.p.l.c. Two major peptides, representing 52% of the incorporated label, were isolated and sequenced. Both peptides contained the incorporated label on glutamic acid-37, and it is concluded that this latter residue represents a catalytically essential carboxylic residue in beta-lactamase II.


Metal-on-metal total hip joint replacement: a minimum follow-up of five years.
The search for an ideal bearing surface for hip arthroplasty is ongoing. Over 1000 metal-on-metal total hip replacements have been performed at our institution since 1993. A review of 215 primary hip arthroplasties performed using Metasul (Sulzer, Winterthur, Switzerland) metal-on-metal articulation with a minimum follow-up of five years is presented. Six patients were lost to follow-up, leaving 209 hips for review. The average follow-up was 7.33 years (range 5-11.4 years). The mean preoperative Harris Hip Score (HHS) was 39.8 and mean postoperative hip scores rose to 89.5, 87.3, 88.4 and 85.8 at 1-year, 3-year, 5-year and final follow-up respectively. Two hips were revised for acetabular loosening and none due to loosening of the femoral stem. Implant survivorship was 95.5% at 12 years. No untoward systemic effects were noted in the cohort. Metasul metal-on-metal articulation has shown satisfactory results in the medium term with regard to osteolysis and aseptic loosening. IV (Case series).


The value of the facilities management function in the UK NHS community health-care sector.
This paper stresses the importance of the strategic integration of the organisational facilities management function as being an essential prerequisite towards facilities and organisational effectiveness. The impact of both the strategic and operational facilities management function on community health-care facility users is also documented. The value of the facilities management function in terms of other health-care related organisational core deliverables is also observed. Mechanisms for general organisational facilities management improvement are identified and a number of facilities management performance measuring tools outlined.


Enabling Early Health Care Intervention by Detecting Depression in Users of Web-Based Forums using Language Models: Longitudinal Analysis and Evaluation.
Major depressive disorder is a common mental disorder affecting 5% of adults worldwide. Early contact with health care services is critical for achieving accurate diagnosis and improving patient outcomes. Key symptoms of major depressive disorder (depression hereafter) such as cognitive distortions are observed in verbal communication, which can also manifest in the structure of written language. Thus, the automatic analysis of text outputs may provide opportunities for early intervention in settings where written communication is rich and regular, such as social media and web-based forums. The objective of this study was 2-fold. We sought to gauge the effectiveness of different machine learning approaches to identify users of the mass web-based forum Reddit, who eventually disclose a diagnosis of depression. We then aimed to determine whether the time between a forum post and a depression diagnosis date was a relevant factor in performing this detection. A total of 2 Reddit data sets containing posts belonging to users with and without a history of depression diagnosis were obtained. The intersection of these data sets provided users with an estimated date of depression diagnosis. This derived data set was used as an input for several machine learning classifiers, including transformer-based language models (LMs). Bidirectional Encoder Representations from Transformers (BERT) and MentalBERT transformer-based LMs proved the most effective in distinguishing forum users with a known depression diagnosis from those without. They each obtained a mean F1-score of 0.64 across the experimental setups used for binary classification. The results also suggested that the final 12 to 16 weeks (about 3-4 months) of posts before a depressed user's estimated diagnosis date are the most indicative of their illness, with data before that period not helping the models detect more accurately. Furthermore, in the 4- to 8-week period before the user's estimated diagnosis date, their posts exhibited more negative sentiment than any other 4-week period in their post history. Transformer-based LMs may be used on data from web-based social media forums to identify users at risk for psychiatric conditions such as depression. Language features picked up by these classifiers might predate depression onset by weeks to months, enabling proactive mental health care interventions to support those at risk for this condition.


A pilot feasibility study investigating the impact of increasing sucrose intakes on body composition and blood pressure.
Epidemiological and intervention studies have reported negative health effects of sucrose intake, but many of these studies were not representative of typical dietary habits. In this pilot study, we aimed to test the effect of increasing sucrose intakes for 1 week on body composition and blood pressure and explore the feasibility of consuming high intakes of sucrose in addition to a habitual diet. In a randomised crossover design study, twelve healthy participants (50 % female, age 28⋅4 ± 10 years, BMI 25 ± 3 kg/m2), consumed either 40, 80 or 120 g sucrose in 500 ml water in addition to their habitual diet every day for 1 week, with a 1-week washout between treatment periods. Body composition (assessed using bioelectrical impedance) and blood pressure measurements were taken before and after each intervention phase. All participants reported no issues with consuming the sucrose dose for the intervention period. There was a significant increase in systolic blood pressure following 120 g sucrose intake (P = 0⋅006), however there was no significant changes to blood pressure, body weight, BMI, percentage protein, fat or water (P > 0⋅05) when comparing change from baseline values. There was also no effect of sucrose intakes on energy or macronutrient intakes during the intervention (P > 0⋅05). We show here that varying doses of sucrose over a 1-week period have no effect on body composition or blood pressure. The amounts of sucrose used were an acceptable addition to the habitual diet and demonstrate the feasibility of larger-scale studies of chronic sucrose supplementation.


Fusiform gyrus face selectivity relates to individual differences in facial recognition ability.
Regions of the occipital and temporal lobes, including a region in the fusiform gyrus (FG), have been proposed to constitute a "core" visual representation system for faces, in part because they show face selectivity and face repetition suppression. But recent fMRI studies of developmental prosopagnosics (DPs) raise questions about whether these measures relate to face processing skills. Although DPs manifest deficient face processing, most studies to date have not shown unequivocal reductions of functional responses in the proposed core regions. We scanned 15 DPs and 15 non-DP control participants with fMRI while employing factor analysis to derive behavioral components related to face identification or other processes. Repetition suppression specific to facial identities in FG or to expression in FG and STS did not show compelling relationships with face identification ability. However, we identified robust relationships between face selectivity and face identification ability in FG across our sample for several convergent measures, including voxel-wise statistical parametric mapping, peak face selectivity in individually defined "fusiform face areas" (FFAs), and anatomical extents (cluster sizes) of those FFAs. None of these measures showed associations with behavioral expression or object recognition ability. As a group, DPs had reduced face-selective responses in bilateral FFA when compared with non-DPs. Individual DPs were also more likely than non-DPs to lack expected face-selective activity in core regions. These findings associate individual differences in face processing ability with selectivity in core face processing regions. This confirms that face selectivity can provide a valid marker for neural mechanisms that contribute to face identification ability.


[Reduced serotonin levels are predisposing to violence. A simple blood test predicts dangerous character].
Deficient serotonergic function in the brain is associated with a risk of impulsive violence. The level of serotonergic function can be assessed indirectly in several ways: 1. determination of CSF (cerebrospinal fluid) content of the serotonin metabolite 5-HIAA (5-hydroxyindoleacetic acid); 2. determination of the plasma level of the amino acid tryptophan, the serotonin precursor (passage of tryptophan into the brain is dependent on the ratio of tryptophan to other competing amino acids); 3. analysis of platelet monoamine oxidase content, a putative correlate of serotonergic capacity in the brain; 4. by determining response to an OGTT (oral glucose tolerance test), another putative correlate of serotonergic function.


Psychological and physiological predictors of response to carbon dioxide challenge in individuals with panic disorder.
Past studies in nonclinical samples have found that suffocation fear, but not a behavioral index of carbon dioxide (CO2) sensitivity (i.e., breath-holding duration), predicts anxious response to CO2 challenge. These associations were examined in individuals with panic disorder while adding more sensitive indices of CO2 sensitivity. Consistent with the earlier studies, the authors found that suffocation fear predicted anxious responding to CO2 challenge but breath-holding duration did not. However, highly precise measures of CO2 sensitivity, not included in earlier studies, did predict anxious challenge responding. These findings support the predictive value and possible etiological relevance of both specific psychological variables and physiological CO2 sensitivity in panic vulnerability. Further work is still needed to determine whether the findings are specific to panic disorder.


Chronic daily ethanol and withdrawal: 4. Long-term changes in plasma testosterone regulation, but no effect on GnRH gene expression or plasma LH concentrations.
Although ethanol has been repeatedly demonstrated to inhibit the hypothalamo-pituitary-testes axis by multiple mechanisms, plasma testosterone levels can be normal in alcoholics who do not exhibit severely compromised liver function and even increased in some abstinent alcoholics, suggesting that adaptive changes to chronic alcohol abuse may alter these regulatory mechanisms. To address this variability, we have investigated the effects of chronic ethanol and withdrawal on rat testosterone regulation using a well-characterized liquid diet model that we have previously demonstrated to (1) provide daily oral ethanol consumption that produces behaviorally relevant plasma ethanol levels during the active (awake) stage of the photoperiod; (2) establish physical dependence on ethanol; and (3) produce not only hypothalamo-pituitary-adrenal axis, but also behavioral (anxiety-like behavior, response to novelty, sucrose preference) changes consistent with those of actively drinking and subsequently abstinent alcoholics. The results demonstrate that chronic daily episodes of ethanol consumption and withdrawal by male Sprague-Dawley rats decreased (p < 0.01) plasma testosterone levels late in the afternoon (by 70% relative to ad libitum-fed controls and 63% relative to pair-fed controls), but not in the morning. During gradual cessation of daily ethanol consumption, morning plasma testosterone levels increased, and this 90-115% (p < 0.05) increase was maintained for 3 d after complete cessation of ethanol consumption. Three weeks after cessation of ethanol consumption, plasma testosterone levels were again increased by approx 100% (p < 0.01). Plasma luteinizing hormone (LH) concentrations and anterior hypothalamus/preoptic area gonadotropin-releasing hormone (GnRH) mRNA levels were not altered at any of these time points. Thus, chronic daily ethanol consumption and daily withdrawal induced changes in circulating testosterone regulation that (a) were time of day dependent and (b) included adaptive changes persisting long after consumption of ethanol ceased. Accordingly, resolution of changes in testosterone regulation and their potential roles in alcohol abuse and relapse will require evaluating changes throughout the circadian cycle during, shortly after, and long after active alcohol abuse.


Immature granulocyte detection by the SE-9000 haematology analyser during pregnancy.
The objective of this study was to determine the nature of the alarm for immature granulocytes appearing in haemograms from pregnant women, as detected by the immature cell information channel (IMI) of the SE-9000 automated haematology analyser. Of all tests run on pregnant women in a 4-month period (n = 698), the first 100 haemograms with immature granulocyte alarms (14.33%) were collected. Each of these samples was then stained with Wright-Giemsa stain. The following variables were also analysed: age of the mother, trimester and days of gestation, type of delivery, weight and sex of the baby, and Apgar score. Most pregnant women were in the third trimester of gestation (82%) when an alarm was noted on the IMI channel. Of the patients, 62% had normal deliveries. The most frequent complication was obstructed delivery (23%). Mean percentages by microscopic counts of band cells, metamyelocytes, and myelocytes were 2.99, 0.45, and 0.19%, respectively. There was a statistically significant correlation for all cell types between the SE-9000 and the manual count method. No association was observed between the presence of immature granulocytes and the clinical variables analysed. The SE-9000 analyser shows high sensitivity in the IMI channel for detection of immature forms.


Behavioural consequences of maternal exposure to natural cannabinoids in rats.
Cannabis sativa preparations (hashish, marijuana) are the most widely used illicit drugs during pregnancy in Western countries. The possible long-term consequences for the child of in utero exposure to cannabis derivatives are still poorly understood. Animal models of perinatal cannabinoid exposure provide a useful tool for examining the developmental effects of cannabinoids. Behavioral consequences of maternal exposure to either cannabis preparations or to its main psychoactive component, delta 9-tetrahydrocannabinol (THC) in rat models are reviewed in this paper. Maternal exposure to cannabinoids resulted in alteration in the pattern of ontogeny of spontaneous locomotor and exploratory behavior in the offspring. Adult animals exposed during gestational and lactational periods exhibited persistent alterations in the behavioral response to novelty, social interactions, sexual orientation and sexual behavior. They also showed a lack of habituation and reactivity to different illumination conditions. Adult offspring of both sexes also displayed a characteristic increase in spontaneous and water-induced grooming behavior. Some of the effects were dependent on the sex of the animals being studied, and the dose of cannabinoid administered to the mother during gestational and lactational periods. Maternal exposure to low doses of THC sensitized the adult offspring of both sexes to the reinforcing effects of morphine, as measured in a conditioned place preference paradigm. The existence of sexual dimorphisms on the developmental effects of cannabinoids, the role of sex steroids, glucocorticoids, and pituitary hormones, the possible participation of cortical projecting monoaminergic systems, and the mediation of the recently described cannabinoid receptors are also analyzed. The information obtained in animal studies is compared to the few data available on the long-term behavioral and cognitive effects on in utero exposure to cannabis in humans.


Time scales of auditory habituation in the amygdala and cerebral cortex.
Habituation is a fundamental form of learning manifested by a decrement of neuronal responses to repeated sensory stimulation. In addition, habituation is also known to occur on the behavioral level, manifested by reduced emotional reactions to repeatedly presented affective stimuli. It is, however, not clear which brain areas show a decline in activity during repeated sensory stimulation on the same time scale as reduced valence and arousal experience and whether these areas can be delineated from other brain areas with habituation effects on faster or slower time scales. These questions were addressed using functional magnetic resonance imaging acquired during repeated stimulation with piano melodies. The magnitude of functional responses in the laterobasal amygdala and in related cortical areas and that of valence and arousal ratings, given after each music presentation, declined in parallel over the experiment. In contrast to this long-term habituation (43 min), short-term decreases occurring within seconds were found in the primary auditory cortex. Sustained responses that remained throughout the whole investigated time period were detected in the ventrolateral prefrontal cortex extending to the dorsal part of the anterior insular cortex. These findings identify an amygdalocortical network that forms the potential basis of affective habituation in humans.


Subsystem Trace Distance in Quantum Field Theory.
We develop a systematic method to calculate the trace distance between two reduced density matrices in 1+1 dimensional quantum field theories. The approach exploits the path integral representation of the reduced density matrices and an ad hoc replica trick. We then extensively apply this method to the calculation of the distance between reduced density matrices of one interval of length ℓ in eigenstates of conformal field theories. When the interval is short, using the operator product expansion of twist operators, we obtain a universal form for the leading order in ℓ of the trace distance. We compute the trace distances among the reduced density matrices of several low lying states in two-dimensional free massless boson and fermion theories. We compare our analytic conformal results with numerical calculations in XX and Ising spin chains finding perfect agreement.


Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.
Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.


Absence of nonlinear responses in cells and tissues exposed to RF energy at mobile phone frequencies using a doubly resonant cavity.
A doubly resonant cavity was used to search for nonlinear radiofrequency (RF) energy conversion in a range of biological preparations, thereby testing the hypothesis that living tissue can demodulate RF carriers and generate baseband signals. The samples comprised high-density cell suspensions (human lymphocytes and mouse bone marrow cells); adherent cells (IMR-32 human neuroblastoma, G361 human melanoma, HF-19 human fibroblasts, N2a murine neuroblastoma (differentiated and non-differentiated) and Chinese hamster ovary (CHO) cells) and thin sections or slices of mouse tissues (brain, kidney, muscle, liver, spleen, testis, heart and diaphragm). Viable and non-viable (heat killed or metabolically impaired) samples were tested. Over 500 cell and tissue samples were placed within the cavity, exposed to continuous wave (CW) fields at the resonant frequency (f) of the loaded cavity (near 883 MHz) using input powers of 0.1 or 1 mW, and monitored for second harmonic generation by inspection of the output at 2f. Unwanted signals were minimised using low pass filters (≤ 1 GHz) at the input to, and high pass filters (≥ 1 GHz) at the output from, the cavity. A tuned low noise amplifier allowed detection of second harmonic signals above a noise floor as low as -169 dBm. No consistent second harmonic of the incident CW signals was detected. Therefore, these results do not support the hypothesis that living cells can demodulate RF energy, since second harmonic generation is the necessary and sufficient condition for demodulation.


Etoposide Combined with FLAG Salvage Therapy Is Effective in Multiple Relapsed/Refractory Acute Myeloid leukemia.
Managing acute myeloid leukemia (AML) is often hampered by repeated failure to achieve complete remission as well as recurrent relapse that causes an emergent need for alternative salvage therapies. The efficacy of most salvage therapies is based on anthracycline combinations. In highly pretreated patients who are not eligible for anthracycline-based protocols therapeutic alternatives are limited. For this particular group we evaluated the efficacy and safety of fludarabine, cytarabine, granulocyte colony-stimulating factor (FLAG) in combination with etoposide (FLAG-Eto) in 36 patients. The complete remission rate (CR) was 25.7% with a median overall survival of 6 months (95% CI 4.5-7.7). The median disease-free survival for CR/CRi/MLFS (CR/CR with incomplete he-matological recovery/morphologic leukemia-free state) patients was 8 months (95% CI 0.6-15.5). The mortality rate on day 30 was 8% and increased on day 60 to 17%. Our results show meaningful anti-leukemic activity of the FLAG-Eto regimen with a moderate toxicity profile in heavily pretreated relapsed/refractory AML patients enabling consolidating allogeneic stem cell transplantation.


A sequential Monte Carlo approach to gene expression deconvolution.
High-throughput gene expression data are often obtained from pure or complex (heterogeneous) biological samples. In the latter case, data obtained are a mixture of different cell types and the heterogeneity imposes some difficulties in the analysis of such data. In order to make conclusions on gene expresssion data obtained from heterogeneous samples, methods such as microdissection and flow cytometry have been employed to physically separate the constituting cell types. However, these manual approaches are time consuming when measuring the responses of multiple cell types simultaneously. In addition, exposed samples, on many occasions, end up being contaminated with external perturbations and this may result in an altered yield of molecular content. In this paper, we model the heterogeneous gene expression data using a Bayesian framework, treating the cell type proportions and the cell-type specific expressions as the parameters of the model. Specifically, we present a novel sequential Monte Carlo (SMC) sampler for estimating the model parameters by approximating their posterior distributions with a set of weighted samples. The SMC framework is a robust and efficient approach where we construct a sequence of artificial target (posterior) distributions on spaces of increasing dimensions which admit the distributions of interest as marginals. The proposed algorithm is evaluated on simulated datasets and publicly available real datasets, including Affymetrix oligonucleotide arrays and national center for biotechnology information (NCBI) gene expression omnibus (GEO), with varying number of cell types. The results obtained on all datasets show a superior performance with an improved accuracy in the estimation of cell type proportions and the cell-type specific expressions, and in addition, more accurate identification of differentially expressed genes when compared to other widely known methods for blind decomposition of heterogeneous gene expression data such as Dsection and the nonnegative matrix factorization (NMF) algorithms. MATLAB implementation of the proposed SMC algorithm is available to download at https://github.com/moyanre/smcgenedeconv.git.


Occurrence and distribution of lettuce mosaic disease in Tehran province from Iran.
Lettuce mosaic virus (LMV) Cucumber mosaic virus (CMV) and Tomato spotted wilt virus (TSWV) were identified in fields of Tehran province. In this study 452 leaf samples were collected from the fields throughout the Tehran province during 2002 and 2003. Distribution of Lettuce mosaic virus (LMV), Cucumber mosaic virus (CMV), Tomato spotted wilt virus (TSWV)and Arabis mosaic virus (ArMV) was determined with DAS-ELISA. Percentage of single Infection to LMV. CMV or TSWV was 20.58, 15.93 and 9.96% respectively. Also 15.28% of samples were co- infected with LMV+CMV, 8.19% with LMV+TSMV and 7.74% with CMV+TSWV. 4.65% of samples were Infected to all of these three viruses. LMV was found in 48.69%, CMV in 43.59% and TSWV in 30.54% of samples totally. Therefore LMV is major dominant agent of lettuce mosaic disease in Tehran province. This is the first report of occurrence of TSWV on lettuce in Iran and first report of CMV and LMV in Tehran province.


Perforin-expressing granulated metrial gland cells in murine deciduoma.
It has previously been shown that granulated metrial gland (GMG) cells of the pregnant uterus express abundant quantities of the lymphocyte pore-forming protein, perforin. No perforin was present before implantation of the embryo, but large numbers of perforin-producing GMG cells were observed after implantation, which coincides with decidualization of the uterus. The possible source of the activation factors responsible for perforin gene induction in GMG cells was studied here with the pseudopregnancy model, in which cervical stimulation of mice during estrus leads to a series of hormonal changes resembling those seen in pregnancy, but in the absence of an embryo. Subsequent stimulation of the uterus of pseudopregnant mice with oil causes the stimulated portion of the endometrium to differentiate into decidual tissue. Perforin-containing GMG cells were in fact present in the deciduomata, but not in adjacent nondecidualized tissues of the same mice. These results suggest that maternal factors associated with decidual tissue are responsible for the local expression of perforin in GMG cells.


Zonal changes in renal structure and phospholipid metabolism during reversal of potassium depletion nephropathy.
Structural changes and membrane metabolism were studied in the enlarged kidney of potassium-depleted rats during dietary repletion with potassium. Transmission and scanning electron microscopy of kidneys revealed two patterns of involutionary change in the collecting tubules following potassium repletion. Autophagocytosis was observed within 3 hours in the hyperplastic cells of the inner red medulla, and progressive condensation and reduction in the number and size of lysosomes which had formed during potassium depletion were observed in the renal papilla. After 3 days of potassium repletion, all types of cells had a normal ultrastructural appearance. Alterations in membrane metabolism during autophagocytosis and organelle regression were assessed by measuring the in vivo breakdown of [14C]phosphatidylcholine, phospholipase A activity, and the rate of [14C]choline incorporation into phospholipid in papilla, inner red medulla, and inner cortex. In each tissue the rate of [14C]phosphatidylcholine breakdown increased and the rate of [14C]choline incorporation into phospholipid decreased during potassium repletion. Phospholipase A activity, which was depressed in potassium-depleted animals, increased in each renal zone by 12 hours after potassium repletion. The results indicate that reversal of potassium depletion nephropathy is associated with increased membrane phospholipid catabolism, loss of renal mass, and specific morphologic changes in different renal zones: lysosome regression in the papilla and autophagocytosis in the hyperplastic cells of the inner red medulla.


Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy.
The use of levocarnitine for the treatment of valproic-acid-induced hyperammonemic encephalopathy (VHE) is reviewed. VHE is generally characterized by an acute onset of impaired consciousness, focal neurologic symptoms, and increased seizure frequency. The exact mechanism of VHE is unclear but relates to the accumulation of toxic valproic acid metabolites and elevated ammonia levels. Carnitine is an essential cofactor in the proper metabolism of valproic acid and ammonia elimination. A lack of carnitine is thought to contribute to hyperammonemia. Valproic acid is thought to increase renal metabolism of glutamate and may contribute to ammonia production. Levocarnitine, the active isomer of carnitine, has been used to treat VHE resulting from valproic acid overdose as well as usual dosages of valproic acid. A literature search of PubMed was conducted for all English-language articles published from 1948 to May 2011 regarding the use of levocarnitine for VHE. Search terms included levocarnitine, l-carnitine, valproic acid, and hyperammonemia encephalopathy. Although large, randomized controlled trials of levocarnitine treatment in VHE are lacking, levocarnitine has been shown to be generally safe and effective in retrospective trials and case reports. Overall, there is more literature supporting the use of levocarnitine in VHE associated with acute overdose than with short- or long-term treatment with usual dosages of valproic acid. No adverse events related to levocarnitine therapy were reported in any of the literature reviewed. Prospective trials are needed to further support the efficacy and safety of levocarnitine in the treatment of VHE. Levocarnitine may be effective and appears to be safe in the treatment of VHE.


Contribution of Time, Taxonomy, and Selective Antimicrobials to Antibiotic and Multidrug Resistance in Wastewater Bacteria.
The use of nontherapeutic broad-spectrum antimicrobial agents triclosan (TCS) and benzalkonium chloride (BC) can contribute to bacterial resistance to clinically relevant antibiotics. Antimicrobial-resistant bacteria within wastewater may reflect the resistance burden within the human microbiome, as antibiotics and pathogens in wastewater can track with clinically relevant parameters during perturbations to the community. In this study, we monitored culturable and resistant wastewater bacteria and cross-resistance to clinically relevant antibiotics to gauge the impact of each antimicrobial and identify factors influencing cross-resistance profiles. Bacteria resistant to TCS and BC were isolated from wastewater influent over 21 months, and cross-resistance, taxonomy, and monthly changes were characterized under both antimicrobial selection regimes. Cross-resistance profiles from each antimicrobial differed within and between taxa. BC-isolated bacteria had a significantly higher prevalence of resistance to "last-resort antibiotic" colistin, while isolates resistant to TCS exhibited higher rates of multidrug resistance. Prevalence of culturable TCS-resistant bacteria decreased over time following Food and Drug Administration (FDA) TCS bans. Cross-resistance patterns varied according to sampling date, including among the most clinically important antibiotics. Correlations between strain-specific resistance profiles were largely influenced by taxonomy, with some variations associated with sampling date. The results reveal that time, taxonomy, and selection by TCS and BC impact features of cross-resistance patterns among diverse wastewater microorganisms, which could reflect the variety of factors influencing resistance patterns relevant to a community microbiome.


Tobacco smoke sensitivity: a result of allergy?
In summary, we know that IgE antibodies against crude tobacco leaf are present in smokers, nonsmokers, and ex-smokers and that atopic individuals are far more likely to show such responses than nonatopic individuals. It has also been established that IgE antibodies can be detected against at least three specific tobacco leaf allergens, namely CIE antigens 19, 23, and 30, but these IgE antibodies do not correlate with any type of clinical smoke sensitivity. To date, there is no concrete evidence for the presence of IgE antibodies in man against smoke extract. Finally, there is at least preliminary evidence that smoke challenge under controlled conditions in an environmental chamber does not induce significant decreases in FEV1 or peak flow in smoke-sensitive subjects, even though they complain of symptoms. In essence, we know that tobacco leaf is immunogenic in rabbits, but it is not known if any tobacco incineration products per se are immunogenic in man. One can visualize many possible future extensions of this study. We should, for example, learn more about other immunoglobulin class-specific antibody responses in man to tobacco leaf antigens, and we should make an effort to identify those antigens that are collected in extract and condensate from unlit cigarettes. We should also undertake larger studies involving further inhalation challenge tests in patients, and employing more sensitive tests of airways obstruction. The problem of shared antigens between tobacco and many other members of the Solanaceae family and the possible clinical relevance of antibody responses to foods as they relate to inhalant allergens should also be studied. The increased interest in tobacco smoke and its relationship to putative immunologically mediated tobacco smoke hypersensitivity has necessitated further studies of clinical smoke sensitivity. To date, the role of hypersensitivity responses in tobacco smoke sensitivity is as yet undefined. In spite of the considerable number of previous studies and their supporting evidence of an allergic response to tobacco smoke, the obvious pitfalls of these studies (undefined study populations, inappropriate antigens, and inadequate documentation of smoke sensitivity) undermine any significant conclusions. In view of the lack of information relating to tobacco smoke hypersensitivity in man, it is difficult to recommend specific diagnostic or therapeutic strategies. Clearly, skin test and RAST studies have proved invaluable in studies of many IgE-mediated allergic disease syndromes related to certain environmental allergens.(ABSTRACT TRUNCATED AT 400 WORDS)


Work-related musculoskeletal disorders: a survey of physical therapists in Izmir-Turkey.
This study was planned to collect data about causes, prevalence and responses to work-related musculoskeletal disorders reported by physiotherapists employed in Izmir, Turkey. A two-page survey with closed ended questions was used as the data collected method. This survey was distributed to 205 physiotherapists working in Izmir, Turkey, and 120 physiotherapists answered. Questions included occupational history of physiotherapists and musculoskeletal symptoms, special areas, tasks, job-related risk factors, injury prevention strategies, and responses to injury. Eighty-five percent of the physiotherapists have had a musculoskeletal injury once or more in their lifetime. Injuries have been occurred mostly in low back (26 %), hand-wrist (18 %), shoulders (14 %) and neck (12 %). The highest risk factor in causing the injury was transferring the patient at 15%. Sixty-nine percent of physiotherapists visited a physician for their injury and sixty-seven percent of the respondents indicated that they had not limited their patient contact time as a result to their injury According to the results of this study, the rate of musculoskeletal disorders in physiotherapists in Izmir-Turkey has been found to be high due to their profession. Respondents felt that a change in work habits was required in order to decrease the risk of another injury.


Research Note on Whether Sexual Minority Individuals Are Over-Represented Among Suicide's Casualties.
Background: Past studies have repeatedly shown higher suicidal thoughts and attempts among sexual minority members, yet have remained opaque on whether these groups are more prone to taking their own lives. Aims: This short report focuses on suicide deaths among sexual minority members. Method: We utilized two large-scale surveys: one, among adults, the updated Cumulative General Social Surveys, and the other, among adolescents, The National Longitudinal Study of Adolescent Health (Add Health), where respondents' data were cross-linked to National Death Index death records. Results: Results confirmed pre-existent findings showing elevated suicide rates among sexual minority females but not among sexual minority males. Limitations: The shortfall of female adolescent suicides in the Add Health sample prevented us from examining the question of female sexual minority suicides within this population. Conclusion: Although ample evidence demonstrates higher suicidal thoughts and attempts among sexual minority males, three studies presently do not confirm their greater propensity to die by suicide, compared with heterosexual males; yet, for sexual minority females the evidence is steadily mounting showing their greater suicide risks.


Antiviral biflavonoids from Radix Wikstroemiae (Liaogewanggen).
Radix Wikstroemiae is a common Chinese herbal medicine. The ethyl acetate fraction of the ethanolic extract of W. indica possesses potent in vitro antiviral activity against respiratory syncytial virus (RSV). This study aims to identify the antiviral components of the active fraction. The active fraction of the Radix Wikstroemiae extract was isolated with chromatographic methods such as silica gel, Sephadex LH-20 and semi-preparative high performance liquid chromatography (HPLC) columns. The structures of the isolated compounds were determined based on spectroscopic analyses. The in vitro antiviral activity of the compounds against RSV was tested with the cytopathic effect (CPE) reduction assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Four biflavonoids, namely neochamaejasmin B, genkwanol B, genkwanol C and stelleranol, were isolated and characterized. Genkwanol B, genkwanol C and stelleranol, which are stereo isomers of spirobiflavonoids, showed potent anti-RSV activity whereas neochamaejasmin B did not. Neochamaejasmin B, genkwanol B, genkwanol C and stelleranol were isolated from Radix Wikstroemiae and the complete absolute configurations of five chiral carbons in stelleranol were substantiated for the first time. Furthermore, the anti-RSV activity of genkwanol B, genkwanol C and stelleranol was reported for the first time.


Workplace distress and ethical dilemmas in neuroscience nursing.
This study concerns Swedish nurses' experiences of workplace stress and the occurrence of ethical dilemmas in a neurological setting. Qualitative interviews were conducted with 21 nurses. The interview results were subjected to qualitative latent content analysis and sorted into 4 content areas: workplace distress, ethical dilemmas, managing distress and ethical dilemmas, and quality of nursing. Common workplace stressors were high workload and lack of influence. These were perceived to have negative consequences for the quality of nursing. Ethical dilemmas mainly concerned decision making on initiation or withdrawal of treatment, which was experienced as a troublesome situation where conflicts could arise. The nurses managed the distress and ethical dilemmas by accepting and adjusting to the situation and seeking support from colleagues. They also endeavored to gain new strength in their private lives.


Signaling cross-talk between IGF-binding protein-3 and transforming growth factor-(beta) in mesenchymal chondroprogenitor cell growth.
Cartilage formation is driven by mesenchymal chondroprogenitor cells (MCCs) that proliferate and differentiate into chondrocytes. The molecular mechanisms by which growth factors regulate MCC fate are not well defined. Insulin-like growth factor binding protein-3 (IGFBP-3) has intrinsic bioactivity that is independent of IGF binding. We previously reported that IGFBP-3 has IGF-independent antiproliferative and apoptotic effects in MCCs, and requires STAT-1 activation to mediate its apoptotic effect. Transforming growth factor-beta (TGF-beta) is a key chondroinductive growth factor. The objective of the study is to define the interactions between IGFBP-3 and TGF-beta in MCC growth and their intracellular signaling pathways. We used the RCJ3*1C5*18 mesenchymal chondrogenic cells that without biochemical or oncogenic transformation progress in culture from MCCs to differentiated chondrocytes. Cell proliferation was assessed in MCCs treated with IGFBP-3 or transfected with IGFBP-3, in the presence or absence of TGF-beta. To demonstrate that IGFBP-3 effects were IGF-independent an IGFBP-3 analog that lacks IGF binding was used (GGG-IGFBP-3). To determine the functional roles of the TGF-beta-mediated signaling and the STAT-1 pathway, cells were either stably transfected with a dominant negative TGF-beta type II receptor (MCC-DNTbetaRII) or treated with a STAT-1 morpholino antisense oligonucleotide. We found that in MCCs, TGF-beta antagonized the antiproliferative effect of IGFBP-3. IGFBP-3 increased the cyclin-dependent kinase inhibitor p21 expression and this effect was abolished by TGF-beta. Furthermore, TGF-beta inhibited STAT-1 phosphorylation induced by IGFBP-3. Similarly to TGF-beta, STAT-1 antisense oligonucleotide inhibited the IGFBP-3 antiproliferative action. Although TGF-beta in MCC-DNTbetaRII lacked Smad-mediated signaling, it persistently antagonized the IGFBP-3 antiproliferative action. However, TGF-beta even in MCC-DNTbetaRII cells induced ERK1/2 phosphorylation, and treatment with MEK inhibitor, UO126, inhibited the antagonistic effects of TGF-beta on IGFBP-3. Furthermore, UO126 blocked the TGF-beta inhibition of STAT-1 phosphorylation induced by IGFBP-3. Collectively, these results demonstrate cross-talk between the IGFBP-3-dependent STAT-1 signaling and the TGF-beta-dependent ERK pathway that regulates MCC proliferation.


Multiple Chemical Sensitivity: Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives.
Systematic bibliography analysis of about the last 17 years on multiple chemical sensitivity (MCS) was carried out in order to detect new diagnostic and epidemiological evidence. The MCS is a complex syndrome that manifests as a result of exposure to a low level of various common contaminants. The etiology, diagnosis, and treatment are still debated among researchers. Querying PubMed, Web of Science, Scopus, Cochrane library, both using some specific MESH terms combined with MESH subheadings and through free search, even by Google. The studies were analyzed by verifying 1) the typology of study design; 2) criteria for case definition; 3) presence of attendances in the emergency departments and hospital admissions, and 4) analysis of the risk factors. With this review, we give some general considerations and hypothesis for possible future research.


Facile synthesis of highly uniform selenium nanoparticles using glucose as the reductant and surface decorator to induce cancer cell apoptosis.
Selenium nanoparticles (SeNPs) have attracted increasing attention due to their potential application as an effective drug delivery system. However, the conventional synthetic methods are mostly confined to solution-based synthesis that are time consuming and with low efficiency. Herein, we demonstrate the facile synthesis of highly uniform SeNPs using glucose as the reductant and surface decorator (Glu-SeNPs) that could induce cancer cell apoptosis. Glucose was used as the reducing agent to reduce sodium selenite (Na2SeO3) at high temperature (115 °C), which also acted as the surface decorator of SeNPs to prevent aggregation in an aqueous solution, thus enhancing its stability under physiological conditions. The functionalized nanoparticles demonstrated high hemocompatibility and showed selective cytotoxicity towards various human cancer cells, but not normal cells, through induction of apoptosis by initiating both intrinsic and extrinsic pathways. Furthermore, studies on the action mechanisms revealed that internalized Glu-SeNPs significantly and rapidly triggered intracellular ROS overproduction and mitochondria dysfunction to regulate the cell fate. Taken together, this study provides a new and effective method for facile synthesis of SeNPs possessing potent anticancer efficacy.


Why, when, and how to prevent hepatitis B virus reactivation in cancer patients undergoing chemotherapy.
Hepatitis B virus (HBV) reactivation is a serious clinical problem in HBV carriers undergoing chemotherapy. The clinical course of HBV reactivation can be separated into 2 phases: 1) an increase in HBV replication and 2) hepatic injury. Patients with resolved HBV infections (negative for hepatitis B surface antigen [HBsAg], and positive for both hepatitis B core antibody [anti-HBc] and/or hepatitis B surface antibody) can experience HBV reactivation, and Western guidelines recommend that not only HBsAg but also anti-HBc be screened before initiation of chemotherapy or immunosuppressive therapy. Several meta-analyses have repeatedly confirmed the prophylactic role of lamivudine in preventing HBV reactivation. In conclusion, screening for HBV is required before chemotherapy, and prophylactic antiviral therapy can reduce not only the incidence of HBV reactivation but also HBV-related morbidity and mortality.


Ultrasonic energy. Effects on vascular function and integrity.
Ultrasonic energy transmitted via flexible wire probes provides a new means of ablating atherosclerotic plaque. We studied the effects of ultrasonic energy (20 kHz) delivered via a ball-tipped wire probe on arterial vasomotor behavior in rabbit thoracic aortas in a perfused whole-vessel model. After precontraction with phenylephrine (10(-5) M) or KCl (60 mM), the effects of ultrasonic energy (0.7-5.5 W x 60 seconds, 42-330 J) on arterial vasomotor behavior were measured using long-axis ultrasonic vessel imaging of the proximal (ultrasonic probe-treated) and distal (untreated) control segments. The efficacy of plaque ablation at these same probe-tip power outputs was evaluated in atherosclerotic, human cadaver iliofemoral arteries. Ultrasonic energy caused dose (energy)-dependent relaxation in rabbit aortas after precontraction with phenylephrine in arteries with endothelium (n = 8) and without endothelium (n = 8) (p less than 0.001 versus ultrasound treated at power outputs of 2.9 and 5.5 W). There was no difference in the relaxation dose responses between endothelialized and endothelially denuded segments (p = NS). Ultrasonic energy also caused significant relaxation (67 +/- 8%) after voltage-dependent precontraction with 60 mM KCl. Temperature measurements revealed less than 1 degrees C warming of the vessel wall during as long as 2 minutes of treatment at a power output of 5.5 W. Pathological examination showed no smooth muscle injury at (moderate) power outputs that caused arterial relaxation. At probe-tip power outputs of 2.9-5.5 W, ultrasonic energy recanalized two of two totally occluded cadaveric iliofemoral vessel segments. The ultrasonic ablation catheter was also demonstrated to cause arterial relaxation in a recanalized canine femoral artery in vivo. Ultrasonic energy delivered via a flexible-wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptor-mediated and voltage-dependent vasoconstriction in vitro. At moderate power outputs, this relaxation response does not appear to be due to thermal effects or irreversible smooth muscle cell injury. This vasorelaxant effect of ultrasonic energy is also apparent in vivo, at doses that effectively ablate atherosclerotic plaque, and may improve the safety of arterial recanalization using ultrasonic energy.


Selective mono-alkylation of N-methoxybenzamides.
We report our latest discovery of norbornene derivative modulated highly mono-selective ortho-C-H activation alkylation reactions on arenes bearing simple mono-dentate coordinating groups. The reaction features the use of readily available benzamides and alkyl halides. During the study, we prepared 30 mono-alkylated aryl amides in good yields with good mono-selectivity. We have also demonstrated that structurally rigid alkenes such as norbornene and its derivatives are a good class of ligand and could be used for future direct C-H functionalizations. The utilization of norbornene type ligands for assistance in C-H activation processes has opened a new window for future molecular design using direct C-H functionalization strategies.


Proguanil metabolism in relation to S-mephenytoin oxidation in a Turkish population.
The oxidation of proguanil was studied in 89 unrelated healthy Turkish volunteers after administration of proguanil (single dose, 200 mg, orally). Based on the distribution of the ratio of proguanil to cycloguanil excreted in urine, and using an antimode value of 15, the prevalence of poor metabolizers in a Turkish population was estimated to be 5.6% (95% confidence interval 2.0%-17.3%) which was similar to that in the other Caucasian populations. The relationship between the oxidative capacities of CYP2C19 for the two substrates, proguanil and mephenytoin, was studied in 39 subjects (two poor and 37 extensive metabolizers of proguanil). The two poor metabolizers of proguanil were also identified as poor metabolizers of S-mephenytoin and no misclassification by the two phenotyping methods was observed. The correlation between the metabolic ratio of proguanil to cycloguanil and the S/R-mephenytoin ratio as assessed by Spearman's rank test, was statistically significant (rs = 0.50, P < 0.001).