Validation of the Godin-Shephard questionnaire in prepubertal girls.
This study was designed to provide validation of the Godin-Shephard questionnaire for the assessment of habitual activity in prepubertal children. Twenty-nine female competitive gymnasts and 32 recreational and nongymnasts, aged 7-11 yr, underwent multiple measures of physical activity over a 15 month period. The Godin-Shephard questionnaire (G-S) was completed once, in the middle of the study period. The Physical Activity Checklist Inventory (PACI) was completed 6 times, at intervals throughout the study, for 2 weekend days and 4 weekdays. Caltrac activity monitors (Hemokinetics, Madison, WI) were worn by each subject in two waves consisting of 2 weekdays and 1 weekend day each. Self-reported activity (h/wk) was recorded by the gymnasts in daily logs and for the nongymnasts through quarterly queries regarding participation in organized activities. A rank order was assigned to each subject for each tool. Spearman rank order correlations assessed the relationship between the G-S versus each measure and combination of measures. Subjects were also divided into gymnast and recreational/nongymnast groups, and alternately into 7-9 yr old and >or= 10 yr old groups, re-ranked and re-analyzed. The average rank of combined PACI, Caltrac and h/wk scores showed only moderate correlation with ranked G-S scores for the overall group and for the 7-9 yr old subset, rho = 0.380 (P = 0.003) and rho = 0.422 (P = 0.043), respectively. The average rank of combined PACI and Caltrac scores also showed only moderate correlation with the ranked G-S scores for the gymnast subset, rho = 0.423 (P = 0.025). No measure or combination of measures correlated significantly with the ranked G-S scores for the >or= 10 yr old subset or the nongymnast subset. Based upon comparison with multiple single day measures of activity, the G-S did not provide a good estimate of habitual activity in preadolescent females.


K+ transport in isolated rat liver cells stimulated by glucagon and insulin in vitro.
Unidirectional K+ fluxes were measured in suspensions of isolated rat liver parenchymal cells incubated with 42K+ in vitro. By tracer exchange analysis fluxes in both directions were estimated to 8-9 10(-12) mol/cm2. Glucagon in concentrations above 2 x 10(-8) M increased both influx and efflux to 160% of control values. Insulin increased influx by 12-14%, whereas efflux was apparently unaffected. Using an extracellular marker 51Cr EDTA, intracellular level of some ions was estimated in isolated liver cells: K+ = 172 mmol/kg water, Na+ = 25 mmol/kg water, Cl = 53 mmol/kg water. Cellular water content: 60%. Incubation with insulin for 1 h increased the intracellular concentration of K+ 1.7 mmol/kg water. The results indicate that glucoagon increased primarily the K+-permeability of the cell membrane, while insulin stimulates active K+ transport into the cell.


Poor Outcome in Postpartum Breast Cancer Patients Is Associated with Distinct Molecular and Immunologic Features.
Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data. We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC. We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups. These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer.


Limonoids from the Seeds of Swietenia macrophylla and Their Anti-Inflammatory Activities.
A new limonoid, swietemacrophin (1), was isolated from the seeds of Swietenia macrophylla, together with five known compounds 2-6. The structure of 1 was determined through extensive 1D/2D-NMR and mass-spectrometric analyses. Swietemacrophin (1), humilinolide F (2), 3,6-O,O-diacetylswietenolide (3), 3-O-tigloylswietenolide (4), and swietemahonin E (5) exhibited inhibition (IC50 values≤45.44 μM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). Compounds 1, 4, 5, and swietenine (6) showed potent inhibition with IC50 values≤36.32 μM, against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation.


Risk factors for voluntary interruption of pregnancy and possible preventive public health actions.
Voluntary interruption of pregnancy (VIP) is one of the most frequent healthcare procedures in the world and a Public Health concern in many countries, especially after liberalization of the abortion laws. The study has been carried out to identify the factors that still influence a fraction of female population towards abortion in the absence of fetal malformations. We conducted a cross-sectional study in the period 2012-2016. The survey was carried out on all VIPs performed at the Gynecology and Obstetrics Unit of the University Hospital "G. Martino" in Messina, Italy. The analyzed sample consisted of 1131 women, aged between 16 and 50 years. Only 4% of VIPs was due to a diagnosis of fetal malformation. In relation to the presence or absence of fetal malformations as the possible reason for VIP, the sample was split up into two groups and the socio-demographic characteristics were considered. VIPs in the absence of malformations were significantly more frequent in younger women with a lower educational level, in unmarried and unemployed women and in women who already had children. These results were confirmed to Pearson test that indicated that all these variables were related to VIP in the absence of malformations. Based on our results, it is crucial to further prevent requests for VIPs through information and sex education programs for adolescents in schools and consultants, and responsible procreation promotion programs.


Is polypropylene mesh safe and effective for repairing infected incisional hernia in renal transplant recipients?
Infected incisional hernias are common in kidney transplant patients. Treating them in immunosuppressed patients can take months, increasing costs and implying loss of working productivity. Abdominal wall prostheses have not been used in infected immunosuppressed patients because of poor infection control. We evaluated the outcome of the surgical treatment of these patients with polypropylene mesh to shorten the hospitalization time and patient recovery. The records of 462 consecutive kidney transplant patients (March 2000 to February 2004) were reviewed. Of these 462 patients, 13 (2.8%) had infected or contaminated herniations at the transplant incision. They developed between 2 and 60 days (mean 14) after transplantation. The racial distribution was not significant, but herniations were more common in patients from cadaveric donors (4.5% versus 0%, P = 0.005). Predisposing factors were found in 6 patients (46.2%) and included complications from transplant surgery in 2, obesity in 1, leukopenia in 3, sepsis in 1, diabetes mellitus in 1, and wall weakness in 1 patient (3 had more than one risk factor). A prospective protocol of surgical correction with polypropylene mesh was established. After wound cleansing with normal saline, repair was done by primary fascial approximation and polypropylene mesh reinforcement. Broad-spectrum antibiotics and large-bore drains were used. Follow-up ranged from 1 to 40 months (mean 14.5). All patients did well except for one recurrence, 14 months after correction. Surgical repair with polypropylene mesh is safe and effective in treating infected or contaminated herniations in kidney transplant patients, with an acceptable (9.1%) incidence of recurrence.


Vanilloid (capsaicin) receptor in the rat: positive cooperativity of resiniferatoxin binding and its modulation by reduction and oxidation.
Specific [3H]resiniferatoxin (RTX) binding is thought to represent the postulated vanilloid (capsaicin) receptor. In the present report, this binding has been reevaluated using a modified [3H] RTX binding assay in which the high nonspecific binding, which limited the previous characterization, was reduced by adding alpha 1-acid glycoprotein, a plasma protein that binds RTX, to the usual binding assay after RTX binding by the vanilloid receptor had been terminated. Specific [3H]RTX binding by both dorsal root ganglion (DRG) and spinal cord membranes of the rat followed sigmoidal saturation kinetics indicating apparent positive cooperativity. The cooperativity index determined by fitting the data to the Hill equation was 1.7 in DRG and 1.9 in spinal cord. Apparent dissociation constants were estimated as 24 pM for DRG and 11 pM for spinal cord preparations. As predicted by the modified Hill equation, at low receptor occupancy nonradioactive agonists (RTX, tinyatoxin, capsaicin) produced biphasic competition curves. The initial (enhancement) phase of these curves correlated with the biological potency of the agonist. Dithiothreitol reduced both positive cooperativity and apparent binding affinity; the oxidizing agent 5,5'-dithiobis-(2-nitrobenzoic acid) reduced the cooperativity index without a major effect on binding affinity. These findings suggest that the vanilloid receptor is a receptor cluster in which the subunits cooperate; cooperation is, at least in part, subject to redox modulation.


The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway.
In recent years, nanomaterials have been increasingly developed and applied in the field of bone tissue engineering. However, there are few studies on the induction of bone regeneration by tantalum nanoparticles (Ta NPs) and no reports on the effects of Ta NPs on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms. The main purpose of this study was to investigate the effects of Ta NPs on bone regeneration and BMSC osteogenic differentiation and the underlying mechanisms. The effects of Ta NPs on bone regeneration were evaluated in an animal experiment, and the effects of Ta NPs on osteogenic differentiation of BMSCs and the underlying mechanisms were evaluated in cell experiments. In the animal experiment, hematoxylin-eosin (HE) staining and hard-tissue section analysis showed that Ta NPs promoted bone regeneration, and immunohistochemistry revealed elevated expression of BMP2 and Smad4 in cells cultured with Ta NPs. The results of the cell experiments showed that Ta NPs promoted BMSC proliferation, alkaline phosphatase (ALP) activity, BMP2 secretion and extracellular matrix (ECM) mineralization, and the expression of related osteogenic genes and proteins (especially BMP2, Smad4 and Runx2) was upregulated under culture with Ta NPs. Smad4 expression, ALP activity, ECM mineralization, and osteogenesis-related gene and protein expression decreased after inhibiting Smad4. These data suggest that Ta NPs have an osteogenic effect and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway, which in turn causes BMSCs to undergo osteogenic differentiation. This study provides insight into the molecular mechanisms underlying the effects of Ta NPs in bone regeneration.


Roux-en-Y gastric bypass reverses the effects of diet-induced obesity to inhibit the responsiveness of central vagal motoneurones.
Diet-induced obesity (DIO) has been shown to alter the biophysical properties and pharmacological responsiveness of vagal afferent neurones and fibres, although the effects of DIO on central vagal neurones or vagal efferent functions have never been investigated. The aims of this study were to investigate whether high-fat diet-induced DIO also affects the properties of vagal efferent motoneurones, and to investigate whether these effects were reversed following weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Whole-cell patch-clamp recordings were made from rat dorsal motor nucleus of the vagus (DMV) neurones in thin brainstem slices. The DMV neurones from rats exposed to high-fat diet for 12-14 weeks were less excitable, with a decreased membrane input resistance and decreased ability to fire action potentials in response to direct current pulse injection. The DMV neurones were also less responsive to superfusion with the satiety neuropeptides cholecystokinin and glucagon-like peptide 1. Roux-en-Y gastric bypass reversed all of these DIO-induced effects. Diet-induced obesity also affected the morphological properties of DMV neurones, increasing their size and dendritic arborization; RYGB did not reverse these morphological alterations. Remarkably, independent of diet, RYGB also reversed age-related changes of membrane properties and occurrence of charybdotoxin-sensitive (BK) calcium-dependent potassium current. These results demonstrate that DIO also affects the properties of central autonomic neurones by decreasing the membrane excitability and pharmacological responsiveness of central vagal motoneurones and that these changes were reversed following RYGB. In contrast, DIO-induced changes in morphological properties of DMV neurones were not reversed following gastric bypass surgery, suggesting that they may be due to diet, rather than obesity. These findings represent the first direct evidence for the plausible effect of RYGB to improve vagal neuronal health in the brain by reversing some effects of chronic high-fat diet as well as ageing. Vagovagal neurocircuits appear to remain open to modulation and adaptation throughout life, and understanding of these mechanisms may help in development of novel interventions to alleviate environmental (e.g. dietary) ailments and also alter neuronal ageing.


Precocious puberty in a girl with an hCG-secreting suprasellar immature teratoma. Case report.
Although precocious puberty is common in boys with human chorionic gonadotropin (hCG)-secreting brain tumors, it is extremely rare in girls. The authors describe a 6-year-old girl with an hCG-secreting suprasellar immature teratoma who presented with diabetes insipidus, increased intracranial pressure, and precocious puberty. On admission, breast budding was observed. The serum hCG level was 1230 mIU/ml. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) remained below detectable levels, even after gonadotropin-releasing hormone stimulation. Serum estrogen and androgen were moderately elevated. After chemotherapy, breast budding disappeared with normalization of serum hCG. It has been believed that hCG does not produce precocious puberty in girls in the absence of FSH, and this has been used as an explanation for the rarity of precocious puberty in girls with hCG-secreting brain tumors. However, it has also been reported that hCG has not only LH activity but also intrinsic, although weak, FSH-like activity. In the present case, this FSH-like activity was considered to have played a role in the development of precocious puberty. It is speculated that a very high level of serum hCG can produce precocious puberty in girls. The rarity of intracranial germ-cell tumors with a high potential of hCG secretion may be one of the reasons why hCG-induced precocious puberty is uncommon in girls.


Comparison of the endotoxin-binding capacity of human transferrin and a human applicable immunoglobulin preparation.
Data obtained by in vitro experiments concerning the binding kinetics of the transferrin-endotoxin interactions are provided. The separation of protein-bound and free tritiated endotoxin of E. coli O 111:B4 is achieved by a simple precipitation method using ethanol. The main features of this reaction are the velocity of the saturation--saturation is reached after 2-3 min--and the requirement of divalent cations. EDTA (ethylenediaminetetraacetic acid) strongly inhibits the binding reaction of endotoxin to transferrin. The specificity of this interaction as well as the physiological importance can be demonstrated by the replacement of the radioactively labelled lipopolysaccharide preparation of E. coli 0 111:B4, by non-radioactive preparations of Salmonella minnesota, Serratia marcescens, E. coli 0 55:B5 and E. coli 0 111:B4. The described ethanol precipitation procedure for separating protein-bound and free endotoxin was applied to a commercially available immunoglobulin preparation. Although this preparation is known to exhibit high antibody titers against the lipid A moiety of lipopolysaccharides, no specific binding with the intact lipopolysaccharide can be found.


Coherent scattering of a multiphoton quantum superposition by a mirror BEC.
We present the proposition of an experiment in which the multiphoton quantum superposition consisting of N approximately 10{5} particles generated by a quantum-injected optical parametric amplifier, seeded by a single-photon belonging to an Einstein-Podolsky-Rosen entangled pair, is made to interact with a mirror-Bose-Einstein condensate (BEC) shaped as a Bragg interference structure. The overall process will realize a macroscopic quantum superposition involving a microscopic single-photon state of polarization entangled with the coherent macroscopic transfer of momentum to the BEC structure, acting in spacelike separated distant places.


Marked and rapid change of bone shape in acutely ACL injured knees - an exploratory analysis of the Kanon trial.
To investigate changes in knee 3D bone shape over the first 5 years after acute anterior cruciate ligament (ACL) injury in participants of the randomized controlled KANON-trial. Serial MR images over 5 years from 121 young (32 women, mean age 26.1 years) adults with an acute ACL tear in a previously un-injured knee were analyzed using statistical shape models for bone. A matched reference cohort of 176 individuals was selected from the Osteoarthritis Initiative (OAI). Primary endpoint was change in bone area of the medial femoral condyle; exploratory analyses compared results by treatment and examined other knee regions. Comparisons were made using repeated measures mixed model ANOVA with adjustment for age, sex and body mass index (BMI). Mean medial femur bone area increased 3.2% (78.0 [95% CI 70.2 to 86.4] mm2) over 5 years after ACL injury and most prominently in knees treated with ACL reconstruction (ACLR). A higher rate of increase occurred over the first 2 years compared to the latter 3-years (66.2 [59.3 to 73.2] vs 17.6 [12.2 to 23.0] mm2) and was 6.7 times faster than in the reference cohort. The pattern and location of shape change in the extrapolated KANON data was very similar to that observed in another knee-osteoarthritis cohort. 3D shape modelling after acute ACL injury revealed rapid bone shape changes, already evident at 3 months. The bone-change pattern after ACL injury demonstrated flattening and bone growth on the outer margins of the condyles similar to that reported in established knee osteoarthritis.


Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
In Caenorhabditis elegans, ROS generated in response to intestinal infection induces SKN-1, a protective transcription factor homologous to nuclear factor erythroid 2-related factor 1 or 2 (NRF1/2) in mammals. Many factors regulate SKN-1, including the p38 mitogen-activated protein kinase (MAPK) cascade that activates SKN-1 by phosphorylation. In this work, another positive regulator of SKN-1 is identified: NIPI-3, a Tribbles pseudokinase. NIPI-3 has been reported to protect against intestinal infection by negatively regulating the CCAT enhancer binding protein (C/EBP) bZIP transcription factor CEBP-1. Here we demonstrate that CEBP-1 positively regulates the vhp-1 transcript, which encodes a phosphatase that dephosphorylates the p38 MAPK called PMK-1. The increased levels of VHP-1 caused by CEBP-1 transcriptional enhancement result in less PMK-1 phosphorylation, affecting SKN-1 activity and intestinal resistance to the pathogen. The data support a model in which NIPI-3's negative regulation of CEBP-1 decreases VHP-1 phosphatase activity, allowing increased stimulation of SKN-1 activity by the p38 MAPK phosphorylation cascade in the intestine.


Standardization of teleradiology using Dicom e-mail: recommendations of the German Radiology Society.
Until recently there has been no standard for an interoperable and manufacturer-independent protocol for secure teleradiology connections. This was one of the main reasons for the limited use of teleradiology in Germany. Various teleradiology solutions have been developed in the past, but the vast majority have not been interoperable. Therefore an ad hoc teleradiology connection was impossible even between partners who were already equipped with teleradiology workstations. Based on the evaluation of vendor-independent protocols in recent years the IT Working Group (AGIT) of the German Radiology Society set up an initiative to standardize basic teleradiology. An e-mail based solution using the Dicom standard for e-mail attachments with additional encryption according to the OpenPGP standard was found to be the common denominator. This protocol is easy to implement and safe for personalized patient data and fulfills the legal requirements for teleradiology in Germany and other countries. The first version of the recommendation was presented at the 85th German Radiology Convention in 2004. Eight commercial and three open-source implementations of the protocol are currently available; the protocol is in daily use in over 50 hospitals and institutions.


The regulation of arginine biosynthesis in Saccharomyces cerevisiae. The specificity of argR- mutations and the general control of amino-acid biosynthesis.
The regulation of arginine biosynthetic enzymes in yeast is subjected to a double control. One level of arginine enzyme synthesis is under the control of an apo-repressor, called ARGR. ARGR molecules control specifically the arginine pathway. A second level of control of arginine biosynthesis has been disclosed. It also controls tryptophan, histidine, lysine, isoleucine-valine and probably many more biosyntheses. The general mechanism is turned on in leaky mutants in any of the amino acid pathways mentioned above.


The excitatory action of acetylcholine on intradental sensory units.
In order to test the hypothesisthat ACh mediates the transmission of pain stimuli from dentin to sensory intradental nerve endings the following experiments were performed. Intradental nerve impulses were recorded by means of low impedance electrodes inserted in dentinal cavities in the tooth of the cat. An air blast proved to be an efficient physical stimulus to excite the intradental nerves. Local application of acetylcholine caused a similar response. This respinse to acetylcholine was followed by a transient blockage to repeated application. The response to acetylcholine could be blocked by d-tubocurarine, atropine, succinylcholine and hexamethonium administered locally. In contrast, the response to physical stimuli (air blasts) could not be blocked by these drugs. Moreover, during the period of depression following acetylcholine the preparation responded to physical stimuli. These findings suggest that acetllcholine is not a mediator in the intradental pain transmission provoked by physical stimuli.


Myricitrin regulates proliferation, apoptosis and inflammation of chondrocytes treated with IL-1β.
Osteoarthritis (OA) is a clinical disease which seriously affects the quality of life of sufferers. Although the pathogenesis of OA has not been fully unraveled, it is may be due to increased levels of pro-inflammatory cytokines, activation of inflammation-related signaling pathways, and degradation of extracellular matrix. Osteoarthritis is characterized by chronic joint pain, swelling, stiffness, limited movement or joint deformity, all of which seriously affect the quality of life and health of the affected individuals. Myroside (Myr) is a polyphenolic hydroxyflavone glycoside extracted from the fruits, bark and leaves of myroside and other natural plants. It has many pharmacological properties, especially anti-inflammatory effects. In the present study, primary chondrocytes of IL-1β rats were used to simulate pathological environment of chondrocytes in OA, and to explore the effect of Myr on chondrocytes. It was found that Myr improved the viability and proliferation of chondrocytes, and also inhibited apoptosis in these cells. Moreover, Myr reduced the expressions of inflammatory factors, and inhibited inflammatory reactions in chondrocytes. These findings provide good experimental basis for the clinical application of Myr in the prevention and treatment of progressive degeneration of cartilage in OA.


Early cellular responses in the peritoneal cavity of mice to antitumor immunomodulators.
The early cellular responses to antitumor immunomodulators and conventional inducers, especially the polymorphonuclear leukocyte (PMN) responses, were examined in the peritoneal cavity of mice to investigate their effect on primary defense mechanisms. Immunomodulators were classified into 5 groups in terms of PMN response on the basis of its duration (declining or persistent) and extent (high or low induction): 1) TAK (beta-1,3-glucan)-type (high, persistent), 2) lentinan-type (high, declining), 3) yeast mannan-type (low, declining), 4) LPS (lipopolysaccharide)-type (low, persistent), 5) others (no effect). Since the general PMN response is of the declining type, the persistence of PMN with TAK- and LPS-type immunomodulators is a characteristic of the PMN-inducing activity. With respect to the extent, TAK- and lentinan-type immunomodulators induced larger numbers of PMN and macrophages than conventional inducers. These results suggest that some types of immunomodulators have effects on the early host-defense mechanism. From the viewpoint of the general self-defense mechanism we also compared these PMN responses with those to bacteria and to tumor inoculation, and the properties of substances inducing high PMN response, i.e., those with the quality of "foreignness," are discussed.


Pharmacokinetic study on saturated hepato-biliary transport of acetyl procainamide ethobromide.
Pharmacokinetic analysis of plasma concentration of acetyl procainamide ethobromide (APAEB) after single injection of 1.5, 8.8 and 20 mumol/300 g rat of APAEB showed that its elimination from plasma followed saturation kinetics. The existence of saturable step in transport of APAEB from blood to bile was also evident from the data of the biliary excretion at three dose levels. The data of the biliary excretion were well fitted to two compartment model with two saturable processes at the hepatic uptake and the biliary excretion. The Michaelis-Menten parameters were calculated according to that model. The model was also applicable to the data of biliary excretion obtained by constant infusion of APAEB Simulation of liver and plasma content gave a good agreement to the experimental data. All these results indicate that the pharmacokinetics of APAEB is satisfactorily represented by the proposed model.


Trainees' knowledge, attitudes, and practices towards caring for the substance-exposed mother-infant dyad.
As rates of substance use disorder during pregnancy rise, pediatric trainees are increasingly caring for infants with neonatal abstinence syndrome (NAS). This study evaluated the knowledge, attitudes, and practices of trainees caring for substance-exposed newborns and their families, comparing differences by level and type of training, and personal experience with addiction or trauma. A cross-sectional survey of medical students and pediatric, medicine/pediatric, and family medicine residents in 2015-2106. Measures included knowledge about NAS, attitudes towards mothers who use drugs, and practices around discussing addiction and trauma with families. Descriptive and bivariate analyses were conducted. The overall response rate was 70%, with 229 trainees included in the final sample (99 students, 130 residents). Fifty percent of trainees endorsed personal experience with addiction, 50% with trauma, and 35% with both addiction and trauma. Increasing years of pediatric training was associated with greater comfort in managing symptoms of NAS but decreased comfort discussing addiction and trauma. Family medicine and medicine/pediatric residents were more comfortable discussing addiction and trauma than categorical pediatric residents (P < .01). Twenty-two percent of trainees felt confident that mothers would disclose illicit drug use, 39% felt that they would actively care for their infants with NAS, and 43% felt that mothers would not make unreasonable demands. Personal experience with addiction or trauma did not significantly impact trainees' attitudes towards women with substance use disorder. Trainees may benefit from educational interventions focused on developing a 2-generational model of trauma-informed care to improve attitudes and ultimately the care of substance-exposed infants and their families.


Ectopic testes in the Norway rat.
Animals with ectopic testes, some unilateral (on either the right or left side) and some bilateral, have appeared in a colony of King-Holtzman rats. This heritable defect has been given the genetic symbol "ect." Females carrying the gene are unaffected by it. When such females are bred to apparently normal males, they produce no ect offspring. Since 25% of their F2 generation carry the gene, it is assumed it is autosomal recessive. Studies involving selective breeding for males with ectopic testes indicate that some males have genomes resistant to the expression of the ect gene and that the apparent thresholds essential to left side, right side, and bilateral expression appear to be a secondary control of the multifactorial type.


Effectiveness of amodiaquine, sulfadoxine-pyrimethamine, and combinations of these drugs for treating chloroquine-resistant falciparum malaria in Hainan Island, China.
The study was carried out in 1985-86 in Hainan Island where Plasmodium falciparum is resistant to chloroquine. Fifty cases of falciparum malaria were treated with 1800 mg amodiaquine for 3 days: the cure rate was 65.3%, and the mean time to clear fever and asexual parasitaemia was 30.7 and 60.3 hours, respectively; 34.7% of cases showed RI or RII recrudescence, and one patient's temperature did not come down to normal within 7 days.Twenty-one cases were treated with sulfadoxine-pyrimethamine (1500 mg and 75 mg, respectively): 19 were cured, I showed RI and another had an S or RI response; the mean time for fever control was 56.1 hours.Fifty cases were treated with amodiaquine plus sulfadoxine and 49 received amodiaquine plus sulfadoxine-pyrimethamine: the cure rate was 97.9% and 100%, respectively; the mean time for fever clearance was 25.0 and 25.7 hours and for parasite clearance 57.1 and 52.8 hours, respectively. These drug combinations gave much better results for cure and for symptom control than amodiaquine or sulfadoxine-pyrimethamine alone, and may be considered for treatment of chloroquine-resistant falciparum malaria.


Molecular dynamics in rod-like liquid crystals probed by muon spin resonance spectroscopy.
Muoniated spin probes were produced by the addition of muonium (Mu) to two rod-like liquid crystals: N-(4-methoxybenzylidene)-4'-n-butylaniline (MBBA) and cholesteryl nonanoate (CN). Avoided level crossing muon spin resonance spectroscopy was used to characterize the muoniated spin probes and to probe dynamics at the molecular level. In MBBA Mu adds predominantly to the carbon of the bridging imine group and the muon and methylene proton hyperfine coupling constants (hfccs) of the resulting radical shift in the nematic phase due to the dipolar hyperfine coupling, the ordering of the molecules along the applied magnetic field and fluctuations about the local director. The amplitude of these fluctuations in in the nematic phase of MBBA is determined from the temperature dependence of the methylene proton hfcc. Mu adds to the double bond of the steroidal ring system of CN and the temperature dependence of the Δ(1) line width provides information about the amplitude of the fluctuations about the local director in the chiral nematic phase and the slow isotropic reorientation in the isotropic phase.


NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor.
Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-MSH analogues, c[NH-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH₂ (CycN-K6) and c[NH-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH₂ (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by ¹H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH₂ (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 ± 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 ± 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 ± 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction.


The efficacy of brimonidine in preventing intraocular pressure elevation in the provocative test for primary angle-closure glaucoma.
The purpose of this study was to evaluate the efficacy of 0.2% brimonidine tartrate in preventing intraocular pressure (IOP) elevation in the dark-prone provocative test for primary angle-closure glaucoma (PACG). Twenty-two eyes from 22 patients with angle-closure glaucoma were enrolled in this study. Each of the selected eyes had previously tested positive in a recent dark-prone test. One drop of 0.2% brimonidine tartrate was then instilled in each eye 2 hours prior to a second dark-prone test. An IOP elevation of greater than 8 mmHg was regarded as a positive result. The IOP elevation in the first dark-prone test was 11.91 +/- 5.17 (range: 5.7 - 27.3) mmHg, while the IOP only increased 5.70 - 2.96 (range: 2.9 - 12.2) mmHg in the second dark-prone test that was pre-treated with 0.2% brimonidine tartrate (p < 0.001). A significant difference was also noted in the pre-test IOP (15.59 +/- 3.86 mmHg vs. 13.33 +/- 3.65 mmHg, p = 0.008) as well as in the post-test IOP (27.62 +/- 7.27 mmHg vs. 19.03 +/- 3.50 mmHg, p < 0.001) in the two sequential dark-prone tests. All but three of the initially positive dark-prone tests (86.46%) converted to negative tests after pre-treatment with brimonidine. There was a significant effect of 0.2% brimonidine tartrate in the prevention of IOP elevation in PACG patients previously found to test positive in the dark-prone provocative test.


Mutational cascade of SARS-CoV-2 leading to evolution and emergence of omicron variant.
Emergence of new variant of SARS-CoV-2, namely omicron, has posed a global concern because of its high rate of transmissibility and mutations in its genome. Researchers worldwide are trying to understand the evolution and emergence of such variants to understand the mutational cascade events. We have considered all omicron genomes (n = 302 genomes) available till 2nd December 2021 in the public repository of GISAID along with representatives of variants of concern (VOC), i.e., alpha, beta, gamma, delta, and omicron; variant of interest (VOI) mu and lambda; and variant under monitoring (VUM). Whole genome-based phylogeny and mutational analysis were performed to understand the evolution of SARS CoV-2 leading to emergence of omicron variant. Whole genome-based phylogeny depicted two phylogroups (PG-I and PG-II) forming variant specific clades except for gamma and VUM GH. Mutational analysis detected 18,261 mutations in the omicron variant, majority of which were non-synonymous mutations in spike (A67, T547K, D614G, H655Y, N679K, P681H, D796Y, N856K, Q954H), followed by RNA dependent RNA polymerase (rdrp) (A1892T, I189V, P314L, K38R, T492I, V57V), ORF6 (M19M) and nucleocapsid protein (RG203KR). Delta and omicron have evolutionary diverged into distinct phylogroups and do not share a common ancestry. While, omicron shares common ancestry with VOI lambda and its evolution is mainly derived by the non-synonymous mutations.


The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly.
Small leucine-rich proteoglycans (SLRPs) are involved in a variety of biological and pathological processes. This review focuses on their regulatory roles in matrix assembly. SLRPs have protein cores and hypervariable glycosylation with multivalent binding abilities. During development, differential interactions of SLRPs with other molecules result in tissue-specific spatial and temporal distributions. The changing expression patterns play a critical role in the regulation of tissue-specific matrix assembly and therefore tissue function. SLRPs play significant structural roles within extracellular matrices. In addition, they play regulatory roles in collagen fibril growth, fibril organization and extracellular matrix assembly. Moreover, they are involved in mediating cell-matrix interactions. Abnormal SLRP expression and/or structures result in dysfunctional extracellular matrices and pathophysiology. Altered expression of SLRPs has been found in many disease models, and structural deficiency also causes altered matrix assembly. SLRPs regulate assembly of the extracellular matrix, which defines the microenvironment, modulating both the extracellular matrix and cellular functions, with an impact on tissue function.


Accurate diagnosis of bronchopulmonary Talaromyces marneffei infection in an anti-IFN-γ autoantibodies positive patient assisted by endobronchial ultrasound-guided TBNA and mNGS: a case report.
T. marneffei is opportunistic and dimorphic fungus, which can cause systemic mycosis in human beings. It's being difficult to obtain histopathological or microbiological evidence in T. marneffei infection. We reported a rare non-HIV case of T. marneffei infection of bronchopulmonary and mediastinal lymph nodes which was diagnosed by EBUS-TBNA combined with mNGS. The high titer of anti-IFN-γ autoantibodies in serum was probably the cause of T. marneffei infection,which has yet to be fully known. A 56-year-old Chinese man presented with a 5-month history of intermittent low or high fever and dry cough, followed by fatigue, night sweating, and chest pain when coughing. A large hilar lesion in the left lung and multiple mediastinal lymph node enlargements were found on his chest CT scan. The patient received EBUS-TBNA of hilar tissue and lymph node biopsy for mNGS at the second Ultrasonic bronchoscopy. No fungal hyphae or spores were found in the histopathology. There were high sequencing reads of T. marneffei in samples of lymph node fluid and bronchogenesis tissue detected by mNGS. His plasma anti-IFN-γ autoantibodies level was positive with a high titer at 1:2500↑. The patient went through atrial fibrillation at the first dose of amphotericin B liposomes and treated with voriconazole later. His fever, cough and dyspnea quickly disappeared since the fourth day of treatment. After six months, there was not any focus in his chest CT scans. But his plasma anti-IFN-γ autoantibodies remained unchanged. Complementing the traditional laboratory and bronchoscopy, mNGS combined with EBUS-TBNA facilitate rapid and precise diagnosis of bronchopulmonary mediastinal lymph nodes T. marneffei infection. Clinicians should be aware of anti-INF-γ autoantibodies in opportunistic infections of non-HIV patients.


Progressive sutural cataract associated with a BFSP2 mutation in a Chinese family.
To identify the mutation underlying the segregation of progressive sutural congenital cataracts in a four-generation Chinese pedigree. Genomic DNA was extracted from the peripheral blood samples of members of the pedigree. A genome-wide scan was performed using microsatellite markers spaced at about 10 cM intervals. Linkage analysis was carried out using a Linkage software package. Ten additional microsatellite markers for the positive region were selected for precise targeting, and haplotype data were processed using Cyrillic software to define the region of the disease gene. Mutation detection was carried out by sequencing candidate genes. Significant evidence of linkage was obtained at marker D3S1279 (LOD score [Z] =2.32, recombination fraction [theta]=0.0). Precise targeting and haplotype analysis traced the disease gene to a 38.6 cM region bounded by D3S1267 and D3S1614 at 3q21.1- q26.2 near BFSP2, which encodes a lens-specific beaded filament protein. Sequencing results revealed a 3-bp deletion of nucleotides 696-698 (GAA) in exon 3 of BFSP2, which is predicted to cause an in-frame deletion of glutamic acid residue 233 from the polypeptide encoded by the mutant gene. This deletion was seen neither in any unaffected member of the family nor in 50 unrelated control individuals. We observed progressive isolated sutural cataract associated with a deletion mutation of the BFSP2 gene in a Chinese pedigree. It highlights the physiological importance of the beaded filament protein and supports the role of BFSP2 in human cataract formation.


Challenges of audit of care on clinical quality indicators for hypertension and type 2 diabetes across four European countries.
The purpose of the study was to measure clinical quality by doing an audit of clinical records and to compare the performance based on clinical quality indicators (CQI) for hypertension and type 2 diabetes across seven European countries: Estonia, Finland, Germany, Hungary, Italy, Lithuania and Spain. Two common chronic conditions in primary care (PC), hypertension and type 2 diabetes, were selected for audit. The assessment of CQI started with a literature review of different databases: Organization for Economic Co-operation and Development, World Health Organization, European Commission European Community Health Indicators, US National Library of Medicine. Data were collected from clinical records. Although it was agreed to obtain the clinical indicators in a similar way from each country, the specific data collection process in every country varied greatly, due to different traditions in collecting and keeping the patients' data, as well as differences in regulation regarding access to clinical information. Also, there was a huge variability across countries in the level of compliance with the indicators. Measurement of clinical performance in PC by audit is methodologically challenging: different databases provide different information, indicators of quality of care have insufficient scientific proof and there are country-specific regulations. There are large differences not only in quality of health care across Europe but also in how it is measured.


Placental growth disorders and perinatal adverse outcomes in Brazilian HIV-infected pregnant women.
Fetal and placental growth disorders are common in maternal human immunodeficiency virus (HIV) infection and can be attributed to both the infection and comorbidities not associated with HIV. We describe placental growth disorders and adverse reproductive outcomes in HIV-infected pregnant women whose delivery occurred between 2001-2014 in Vitoria, Brazil. Cases with gestational age (GA) ≥ than 22 weeks validated by ultrasonography, with placental and fetal weight dimensions at birth, were studied. Outcomes were summarized as proportions of small (SGA), appropriate (AGA), and large (LGA) for GA when the z-score values were below -1.28, between -1.28 and +1.28, or above +1.28, respectively. Of 187 fetal attachment requisitions, 122(65.2%) women and their newborns participated in the study. The median maternal age was 28 years and 81(66.4%) underwent ≥ 6 prenatal visits. A total of 81(66.4%) were diagnosed before current pregnancy; 68(55.7%) exhibited criteria for acquired immunodeficiency syndrome (AIDS); 64(52.4%) had detectable viral load; 25(20.5%) cases presented SGA placental weight and 6(4.9%) SGA placental thickness. SGA placental area was observed in 41(33.6%) cases, and among the SGA placental weight cases 12(48%) were also SGA fetal weight. Preterm birth (PTB) occurred in 15.6%(19/122) of cases; perinatal death in 4.1%(5/122) and HIV vertical transmission in 6 of 122 (4.9%). Women, ≥36 years old, were 5.7 times more likely to have PTB than those under 36. Also, patients with AIDS-defining criteria were 3.7 times more likely to have PTB. Prenatal care was inversely associated with PTB. Statistically significant associations were observed between AGA placental area and Protease Inhibitor usage and between SGA placental weight and SGA area. We found a prevalence of placental growth disorders in HIV-infected pregnant women and values higher than international reference values. The restriction of placental growth was a common disorder, possibly attributed to virus effects or a combination of antiretroviral regimens.


The value of systemic inflammatory markers in identifying malignancy in mucinous pancreatic cystic neoplasms.
The treatment decision-making of mucinous pancreatic cystic neoplasm (PCN) has become a common clinical problem since the diagnostic accuracy of current tests in identifying malignancies in pancreatic cysts is limited. In this study, we aimed to validate the predictive value of systemic inflammatory factors in detecting malignant PCNs. Two hundred and forty-five patients with pathologically confirmed mucinous PCNs in a single Chinese institution were retrospectively analyzed. Receiver operating characteristic (ROC) curves were calculated to determine the optimal cut-off values and measure the diagnostic value. The results showed that neutrophil count (P = 0.009), lymphocyte count (P = 0.002), neutrophil-to-lymphocyte ratio (NLR, P < 0.001), platelet-to-lymphocyte ratio (PLR, P < 0.001) and lymphocyte-to-monocyte ratio (LMR, P < 0.001) were distributed differently among the various differentiation groups of PCN. The univariate analyses indicated that a neutrophil count ≥ 2.8 × 109/L (P = 0.024), lymphocyte count ≤ 1.9 × 109/L (P < 0.001), PLR ≥ 125 (P < 0.001), NLR ≥ 1.96 (P < 0.001), and LMR ≤ 4.29 (P < 0.001) were significantly associated with invasive carcinomas in PCN patients. In addition, the multivariate analyses demonstrated that PLR ≥ 125 and LMR ≤ 4.29 were independent predictors of invasive malignancies. The ROC curves exhibited the malignant detection utility of the independent factor-based predictive model with an area under the curve (AUC) of 0.858 (P < 0.001). In conclusion, systemic inflammatory markers provide a supportive and easily accessible tool for the preoperative diagnoses of malignant PCNs.


Morphological studies of the neuromuscular mechanism shifting from sucking to biting of mice.
In order to give a neuroanatomical evidence to the mechanism of shifting from sucking to biting, we investigated in prenatal, newborn and postnatal mice whether there is a time difference in the neurogenesis of the neurons relative to sucking and biting or in the histogenesis of their peripheral effector organs by the HRP labeling technique and electron microscopy. The results obtained are as follows. (1) At birth the facial motoneurons exceed the trigeminal motoneurons in cell area and development. (2) After birth, the trigeminal motoneurons grow rapidly and outstrip the growth of the facial motoneurons at the age of 6 days. (3) Thereafter, the cell area of both neuron types continues to increase gradually. (4) The initial sign of the alpha motor end plates is found in the orbicularis oris muscle innervated by the facial nerve in 17-day-old fetuses, while that of the trigeminal nerve is delayed in the masseter muscle of 18-day-old fetuses. (5) The initial sign of the muscle spindle appears with the sensory terminals in the masseter muscle of 17-day-old fetuses and the fundamental structure of the muscle spindle is formed in 4-day-old youngs. (6) Myelination of the facial nerve begins in 3-day-old youngs, while that of the trigeminal nerve becomes apparent in 4- or 5-day-old youngs. From these bases, it is obvious that the facial nerve elements related to sucking are firstly developed at birth and that the differentiation of the trigeminal nerve elements related to biting is rapidly accelerated after birth.


Antibody and cellular immunotherapies for acute lymphoblastic leukemia in adults.
Despite improvements in the outcomes of patients with acute lymphoblastic leukemia (ALL), traditional therapies (including hematopoietic stem cell transplant) often still fail. Antigen-specific immunotherapies for the treatment of ALL such as monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cells have demonstrated remarkable clinical efficacy and are rapidly evolving. With indisputable activity in patients with relapsed or refractory ALL, efforts now hope to integrate these agents into earlier phases of treatment. In this review, we will discuss the available antibody and cellular-based immunotherapies for the treatment of patients with ALL and provide a clinical and biologic framework with which to inform treatment approaches.


Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in mice.
The efficacy of drug delivery systems can be significantly enhanced by making them target-specific via the attachment of various ligands to their surface. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded long-circulating liposomes (Doxil, ALZA Corp.) by coupling to their surface the anticancer monoclonal antibody 2C5 (mAb 2C5) with nuclesome (NS)-restricted activity, that can recognize the surface of various tumor but not normal cells via the surface-bound nucleosomes released from the apoptotically dying neighboring tumor cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Antibody coupling to PEGylated doxorubicin-liposomes was performed by the "post-insertion" technique. The pharmacokinetics of plain and immuno-targeted Doxil-mimicking liposomes, as well as their accumulation in primary Lewis lung carcinoma (LLC) tumors in mice was followed by real-time gamma-scintigraphy upon liposomal membrane labeling with (111)In. Therapeutic action of various liposomal formulations was followed by registering primary tumor growth, determining tumor weigh upon mice sacrifice, and by counting the number of metastases in the liver and lungs. 2C5 antibody-targeted liposomes demonstrate significantly enhanced accumulation in LLC tumors. Targeted doxorubicin-loaded PEG-liposomes were significantly more effective in inhibiting tumor growth and metastatic process in the LLC tumor models in mice. Our results clearly show the remarkable capability of 2C5-targeted Doxil to specifically deliver its cargo into various tumor manifestations (solid and metastatic) significantly increasing the efficacy of therapy.


A preparation for the study of secretory function of the human bronchus in vitro.
Bronchi, not involved in tumor, were removed from resected human lungs. They were mounted in Ussing chambers containing Krebs-Henseleit solution with radiolabelled precursors of mucus. Airway was examined by both light and electron microscopy. Tissues recently removed from resected lungs exhibited both intra- and extra-cellular oedema and hypoxic changes in mitochondria, but tight junctions between epithelial cells appeared intact, indicating an effective epithelial barrier. Tissues removed from Ussing chambers after up to 6 h showed little oedema and their mitochondria were normal. Their appearance had returned to that of specimens taken that biopsy and fixed immediately. Autoradiographs of specimens from Ussing chambers showed that the mucus-producing cells had concentrated the radiolabels . Mucus in gland ducts was also radiolabelled. Damaged areas of mucous membrane were rare and probably pre-operative. We conclude that resected bronchi, suspended in Ussing chambers, have a structure and secretory activity suitable for investigations of the control of secretion.


Effects of psychotherapy in schizophrenia: II. Comparative outcome of two forms of treatment.
This study compares the effects of exploratory, insight-oriented (EIO) and reality-adaptive, supportive (RAS) forms of psychotherapy on a sample of 95 schizophrenic patients. Analyses of 2-year outcomes revealed a complex interaction between the type of psychotherapy provided and the domain of psychopathology affected. RAS psychotherapy exerted clear preferential effects in the areas of recidivism and role performance. The EIO psychotherapy exerted preferential, albeit more modest, action in the areas of ego functioning and cognition. Overall, however, the magnitude of the differences was low. The results highlighted the need for more focused studies of subgroups, and of process and contextual influences on outcome.


SEXUAL SELECTION AGAINST HYBRIDS BETWEEN SYMPATRIC STICKLEBACK SPECIES: EVIDENCE FROM A FIELD EXPERIMENT.
Sexual selection against viable, fertile hybrids may contribute to reproductive isolation between recently diverged species. If so, then sexual selection may be implicated in the speciation process. Laboratory measures of the mating success of hybrids may underestimate the amount of sexual selection against them if selection pressures are habitat specific. Male F1 hybrids between sympatric benthic and limnetic sticklebacks (Gasterosteus aculeatus complex) do not suffer a mating disadvantage when tested in the laboratory. However, in the wild males choose different microhabitats and parental females tend to be found in the same habitats as conspecific males. This sets up the opportunity for sexual selection against male hybrids because they must compete with parental males for access to parental females. To test for sexual selection against adult F1 hybrid males, we examined their mating success in enclosures in their preferred habitat (open, unvegetated substrate) where limnetic males and females also predominate. We found significantly reduced mating success in F1 hybrid males compared with limnetic males. Thus, sexual selection, like other mechanisms of postzygotic isolation between young sister species, may be stronger in a wild setting than in the laboratory because of habitat-specific selection pressures. Our results are consistent with, but do not confirm, a role for sexual selection in stickleback speciation.


Organometallic iron complexes as potential cancer therapeutics.
Metal-containing drugs have long been used for medicinal purposes in more or less empirical way. The potential of these anticancer agents has only been fully realised and explored since the discovery of the biological activity of cisplatin. Cisplatin and carboplatin have been two of the most successful anti-cancer agents ever developed, and are currently used to treat ovarian, lung and testicular cancers. They share certain side effects, so their clinical use is severely limited by dose-limiting toxicity. Inherent or acquired resistance is a second problem often associated with platinum-based drugs, with further limits of their clinical use. These problems have prompted chemists to employ different strategies in development of the new metal-based anticancer agents with different mechanisms of action. There are various metal complexes still under development and investigation for the future cancer treatment use. In the search for novel bio-organometallic molecules, iron containing anti-tumoral agents are enjoying an increasing interest and appear very promising as the potential drug candidates. Iron, as an essential cofactor in a number of enzymes and physiological processes, may be less toxic than non essential metals, such as platinum. Up to now, some of iron complexes have been tested as cytotoxic agents and found to be endowed with an antitumor activity in several in vitro tests (on cultured cancer cell lines) and few in vivo experiments (e. g. on Ehrlich's ascites carcinoma). Although the precise molecular mechanism is yet to be defined, a number of observations suggest that the reactive oxygen species can play important role in iron-induced cytotoxicty. This review covers some relevant examples of research on the novel iron complexes.


Parental losses.
In a review article parental losses (PL) of children in different age and sex groups are psycho-analytically examined from the view point of the triangular family relationship, cognitive development of the children and their ability to mourn, delinquency, schizophrenia and affective illnesses, and lastly the controversies about and objections to bereavement study findings. It is concluded that many methodological problems make it difficult to compare study findings. Some unchallengeable laws have been found, but any single explanation of their aetiological meaning could not be shown. It is obvious that many psycho-social variables are involved in the interpretation of PL.


Perceived Social Support and Heart Rate Variability: An Integrative Review.
The purpose of this integrative review is to explore and synthesize literature about the relationship between perceived social support and cardiac vagal modulation, measured by heart rate variability (HRV), during phases of an acute stress response to assess this potential relationship underlying the stress-buffering effects of perceived social support. A systematic search of seven databases was conducted, including MEDLINE, CINAHL, PsychINFO, Embase, ProQuest, medRxiv, and clinicaltrials.gov. Eight studies met the inclusion criteria and were systematically synthesized. A quality appraisal was completed for each included study. Majority of studies focused on time and frequency domain measures of HRV thought to reflect parasympathetic modulation of heart rate and identified them as positively associated with perceived social support during rest, stress induction, and recovery from an acute stressor. Results highlight the importance for nurses and other health care professionals to assess patients' perceived social support, as increased perceived social support may contribute to an adaptive stress response.


Lung Ultrasound for the Emergency Diagnosis of Pneumonia, Acute Heart Failure, and Exacerbations of Chronic Obstructive Pulmonary Disease/Asthma in Adults: A Systematic Review and Meta-analysis.
Lung ultrasound can accelerate the diagnosis of life-threatening diseases in adults with respiratory symptoms. Systematically review the accuracy of lung ultrasonography (LUS) for emergency diagnosis of pneumonia, acute heart failure, and exacerbation of chronic obstructive pulmonary disease (COPD)/asthma in adults. PubMed, Embase, Scopus, Web of Science, and LILACS (Literatura Latino Americana e do Caribe em Ciências da Saúde; until 2016) were searched for prospective diagnostic accuracy studies. Rutter-Gatsonis hierarchical summary receiver operating characteristic method was used to measure the overall accuracy of LUS and Reitsma bivariate model to measure the accuracy of the different sonographic signs. This review was previously registered in PROSPERO (Centre for Reviews and Dissemination, University of York, York, UK; CRD42016048085). Twenty-five studies were included: 14 assessing pneumonia, 14 assessing acute heart failure, and four assessing exacerbations of COPD/asthma. The area under the summary receiver operating characteristic curve of LUS was 0.948 for pneumonia, 0.914 for acute heart failure, and 0.906 for exacerbations of COPD/asthma. In patients suspected to have pneumonia, consolidation had sensitivity of 0.82 (95% confidence interval [CI] 0.74-0.88) and specificity of 0.94 (95% CI 0.85-0.98) for this disease. In acutely dyspneic patients, modified diffuse interstitial syndrome had sensitivity of 0.90 (95% CI 0.87-0.93) and specificity of 0.93 (95% CI 0.91-0.95) for acute heart failure, whereas B-profile had sensitivity of 0.93 (95% CI 0.72-0.98) and specificity of 0.92 (95% CI 0.79-0.97) for this disease in patients with respiratory failure. In patients with acute dyspnea or respiratory failure, the A-profile without PLAPS (posterior-lateral alveolar pleural syndrome) had sensitivity of 0.78 (95% CI 0.67-0.86) and specificity of 0.94 (95% CI 0.89-0.97) for exacerbations of COPD/asthma. Lung ultrasound is an accurate tool for the emergency diagnosis of pneumonia, acute heart failure, and exacerbations of COPD/asthma.


Nanomechanical Infrared Spectroscopy with Vibrating Filters for Pharmaceutical Analysis.
Standard infrared spectroscopy techniques are well-developed and widely used. However, they typically require milligrams of sample and can involve time-consuming sample preparation. A promising alternative is represented by nanomechanical infrared spectroscopy (NAM-IR) based on the photothermal response of a nanomechanical resonator, which enables the chemical analysis of picograms of analyte directly from a liquid solution in only a few minutes. Herein, we present NAM-IR using perforated membranes (filters). The method was tested with the pharmaceutical compound indomethacin to successfully perform a chemical and morphological analysis on roughly 100 pg of sample. With an absolute estimated sensitivity of 109±15 fg, the presented method is suitable for ultrasensitive vibrational spectroscopy.


Dynamically Monitoring the Photodeposition of Single Cocatalyst Nanoparticles on Semiconductors via Fluorescence Imaging.
Loading of cocatalysts through photodeposition has been considered as one of the most promising methods to improve the photocatalytic activities of semiconductors, because of the advantages of intimate contact, easy preparation, and site-directed loading. While extensive efforts have been made to characterize the cocatalysts after synthesis, the growth kinetics of cocatalysts during photodeposition is largely a black box, thus leading to relatively empirical optimizations on the loading strategies of cocatalysts to date. Herein, we dynamically imaged the photodeposition of single cocatalysts on semiconductors via a wide-field fluorescence (FL) microscope, utilizing g-C3N4 sheets and CdS nanowires as models. This capability was based on the quenching effect of cocatalysts on the intrinsic FL emission of semiconductors. Single cocatalyst study revealed that FL emission of photocatalysts decayed monoexponentially during photodeposition, and cocatalysts possessed a self-limited growth. The significant heterogeneities (differences) of cocatalysts during photodeposition were also uncovered, regarding the apparent induction time, deposition rate and FL quenching amplitude. These informations were difficult to be accessed using the ex situ characterization. Programmable photodeposition and dissolution of CoxP were also realized, utilizing a focused laser beam with a spot size of <1 μm. This work explored the hidden details of the growth of cocatalysts during photodeposition, opening up a new avenue to optimize photodeposition for rationally designing more efficient photocatalysts.


A simple electrochemical strategy for the detection of the cancer marker CA19-9 by signal amplification using copper organic framework nanocomposite.
In this work, label-free electrochemical immunosensing of the cancer biomarker carbohydrate antigen 19-9 (CA19-9) is reported using [Fe(CN)6]3-/4- as a signal probe and a copper organic framework (Cu-BTC) nanocomposite for the amplification of the signal. The immunosensor was fabricated by the following process. First, the Cu-BTC nanomaterial with a larger surface area and good biocompatibility was synthesized to improve the dispersion of gold nanoparticles (Au NPs). Then, nitrogen-doped graphene (N-GR) was combined with Cu-BTC to form the nanocomposite. The synthesized Cu-BTC@N-GR@AuNPs@CS nanocomposite was employed to modify the surface of the immunosensor to accelerate the electron transfer rate and improve the immobilization amount of CA19-9 antibodies (Ab). Various techniques, including TEM, SEM and XPS were used to characterize Cu-BTC and nanocomposites. Differential pulse voltammetry (DPV) was used to measure the electrochemical response of the immunosensor in [Fe(CN)6]3-/4-. The signal intensity of the immunosensor was linearly changed upon increasing the concentration of CA19-9 antigen from 10 μU mL-1 to 100 U mL-1, and a detection limit of 4.2 μU mL-1 was achieved. Furthermore, the immunosensor showed good stability, reproducibility and specificity, indicating its potential application in clinical analysis.


Current treatment of optic nerve gliomas.
Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm, optic tracts and radiations and can either be sporadic or associated with neurofibromatosis type one. Gliomas isolated to the optic nerve (ONG) represent a subgroup of optic pathway gliomas, and their treatment remains controversial. New developments in ONG treatment have emerged in recent years, and it is necessary for clinicians to have a current understanding of available therapies. The current review of the literature covers the background of and recent developments in ONG treatment, with a focus on standard chemotherapy, new molecularly targeted therapies, radiation therapy and surgical resection and debulking. Although standard chemotherapy remains the mainstay of ONG treatment, newer molecularly targeted therapies such as mitogen-activated protein kinase kinase inhibitors and bevacizumab represent a promising new treatment modality, and clinical studies are ongoing.


Double Photoionization of Nitrosyl Chloride by Synchrotron Radiation in the 24-70 eV Photon Energy Range.
The behavior of nitrosyl chloride (ClNO) exposed to ionizing radiation was studied by direct probing valence-shell electrons in temporal coincidence with ions originating from the fragmentation process of the transient ClNO2+. Such a molecular dication was produced by double photoionization with synchrotron radiation in the 24-70 eV photon energy range. The experiment has been conducted at the Elettra Synchrotron Facility of Basovizza (Trieste, Italy) using a light beam linearly polarized with the direction of the polarization vector parallel to the ClNO molecular beam axis. ClNO molecules crossing the photon beam at right angles in the scattering region are generated by effusive expansion and randomly oriented. The threshold energy for the double ionization of ClNO (30.1 ± 0.1 eV) and six dissociation channels producing NO+/Cl+, N+/Cl+, N+/O+, O+/Cl+, ClN+/O+, NO+/Cl2+ ion pairs, with their relative abundance and threshold energies, have been measured.


Specificity of oxytocin and vasopressin immunofluorescence.
A total inhibition of immunofluorescence could not be obtained using the technique of preincubating either anti-vasopressin or anti-oxytocin plasmas with their homologous antigens. An alternative test of specificity was therefore developed. Lysine-vasopressin (LVP), arginine-vasopressin (AVP) or oxytocin were covalently bound to CNB-activated agarose beads. These hormone-coupled beads were then either placed immediately on glass slides and treated in the same way as tissue sections for immunofluorescence, or pre-incubated in test-tubes with the antibodies and then prepared for immunofluorescence. Fluorescence was measured quantitatively using a Leitz orthoplan microscope with epi-illumination and a photometer attachment. Without pre-incubation the anti-oxytocin plasmas produced intensive fluorescence on those beads containing their homologous antigen (oxytocin) but only slight fluorescence with the heterologous antigens (AVP or LVP). Anti-vasopressin plasmas produced intensive fluorescence of AVP-, LVP- and oxytocin-containing beads. Because the neurohypophysial hormones were bound to agarose beads, antibodies binding to these hormones could be removed by simple centrifugation. Anti-oxytocin and anti-vasopressin lost their fluorescence capacity after pre-incubation with oxytocin- or vasopressin-containing beads respectively, showing that all the antibodies important for fluorescence were bound to homologous antigens. Pre-incubation of anti-oxytocin or anti-vasopressin with beads coupled to their heterologous hormones completely removed the components binding to the heterologous hormone, leaving antibodies that showed fluorescence only with oxytocin or vasopressin respectively. This purification showed that in contrast to the findings with homologous antigens, not all of the antibody population bound to its heterologous antigen. Using non-purified anti-vasopressin, immunofluorescence was observed in neurohypophyses of homozygous Brattleboro rats. This was evidently due to those antibodies which bind to oxytocin, since the fluorescence was abolished after pre-incubating the antibody-containing plasmas with oxytocin-coupled beads. Immunofluorescence was still observed, however, in the suprachiasmatic nucleus of both Wistar and heterozygous Brattleboro rats, if purified anti-vasopressin was used. This was probably due to either vasopressin storage or production in these hypothalamic cells.


A simplified method for mitochondrial DNA extraction from head hair shafts.
DNA isolation from hair shafts can involve a number of steps, each of which adds time to the procedure and increases the risk of contamination. A simple alkaline digestion procedure that directly dissolves hairs was developed and compared with a widely used glass grinding/organic extraction method, using samples collected from 30 volunteers with varying population ancestries, hair colors, and hair treatments. A 203 bp mtDNA product could be amplified from 90% of samples extracted by alkaline digestion and 73% of hairs extracted by glass grinding. DNA obtained from alkaline digested hair generated equal or greater amplification success for virtually all criteria examined, and mtDNA sequences matched buccal control sequences in all cases. The two methods were similar in DNA yield (amplification success at template dilution) and quality of DNA obtained (amplicon length). Alkaline digestion of hair shafts required 6-7 h to complete, compared to 22-24 h for glass grinding, and proved a less laborious yet equally robust method for mtDNA extraction.


Predicting outcomes and drug resistance with standardised treatment of active tuberculosis.
New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment. A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance. Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48-86 fewer persons will require retreatment, and 3-12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50-94% of failures and 3-56% of relapses will have multidrug-resistant TB. We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.


Effect of vanadium on insulin sensitivity in patients with impaired glucose tolerance.
Impaired glucose tolerance (IGT) is considered a risk factor for developing type 2 diabetes mellitus (T2DM) and is associated with insulin resistance. Vanadium seems to block protein tyrosine phosphatase with the consequent increment in insulin sensitivity (INS) in T2DM patients, but this effect has not been studied in IGT patients. The aim of this study was to evaluate the effect of vanadium on INS in IGT patients. A randomized, double-blind, placebo-controlled clinical trial was carried out in 14 overweight/obese patients with IGT. Intervention consisted of vanadyl sulfate (VS, 50 mg p.o. twice daily) or placebo for 4 weeks. Before and after the intervention, a metabolic profile was performed and INS was assessed using the euglycemic-hyperinsulinemic clamp technique. Mann-Whitney U and Wilcoxon rank tests were used for statistical analyses. There were no significant differences in basal characteristics between groups. VS did not affect INS [2.7+/-0.8 vs. 2.9+/-0.9 mg/(kg/min), p=0.735] but increased triglyceride levels (1.35+/-0.61 vs. 1.70+/-0.46 mmol/l, p=0.018). VS administration in IGT patients increased triglyceride concentrations without changes in INS.


Brain-derived neurotrophic factor-dependent unmasking of "silent" synapses in the developing mouse barrel cortex.
Brain-derived neurotrophic factor (BDNF) is a critical modulator of central synaptic functions such as long-term potentiation in the hippocampal and visual cortex. Little is known, however, about its role in the development of excitatory glutamatergic synapses in vivo. We investigated the development of N-methyl-D-aspartate (NMDA) receptor (NMDAR)-only synapses (silent synapses) and found that silent synapses were prominent in acute thalamocortical brain slices from BDNF knockout mice even after the critical period. These synapses could be partially converted to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-containing ones by adding back BDNF alone to the slice or fully converted to together with electric stimulation without affecting NMDAR transmission. Electric stimulation alone was ineffective under the BDNF knockout background. Postsynaptically applied TrkB kinase inhibitor or calcium-chelating reagent blocked this conversion. Furthermore, the AMPAR C-terminal peptides essential for interaction with PDZ proteins postsynaptically prevented the unmasking of silent synapses. These results suggest that endogenous BDNF and neuronal activity synergistically activate AMPAR trafficking into synaptic sites.


Pharmacokinetics of cefquinome in healthy and Pasteurella multocida-infected rabbits.
The pharmacokinetics of cefquinome were studied in healthy and Pasteurella multocida-infected rabbits after a single intramuscular (IM) injection at 2 mg/kg of its sulfate salt. Twelve female New Zealand white rabbits (2.0-2.5 kg) were used; six of them served as controls, and the other six had been infected with P. multocida; the experiments were conducted 1-2 days after nasal inoculation of P. multocida when rabbits showed the signs of respiratory infection. Plasma concentrations of cefquinome were determined using high-performance liquid chromatography. The values of elimination half-life, area under the curve, area under the first moment curve, and mean residence time were significantly lower in infected rabbits (0.48 hr, 4.54 hr*μg/ml, 3.63 hr* hr*μg/ml and 0.8 hr, respectively) than healthy rabbits (0.72 hr, 9.11 hr*μg/ml, 9.85 hr* hr*μg/ml and 1.1 hr, respectively), whereas total body clearance was significantly higher in infected than healthy rabbits. Therefore, P. multocida infection caused significant changes in some of the pharmacokinetic parameters of cefquinome in rabbits. These pharmacokinetic changes may affect dose regimen when used in P. multocida-infected rabbits.


A Multicenter Study on the Clinical Characteristics and Outcomes Among Children With Moderate to Severe Abusive Head Trauma.
We aimed to identify clinical characteristics, risk factors for diagnosis, and describe outcomes among children with AHT. We performed an observational cohort study in tertiary care hospitals from 14 countries across Asia and Ibero-America. We included patients <5 years old who were admitted to participating pediatric intensive care units (PICUs) with moderate to severe traumatic brain injury (TBI). We performed descriptive analysis and multivariable logistic regression for risk factors of AHT. 47 (12%) out of 392 patients were diagnosed with AHT. Compared to those with accidental injuries, children with AHT were more frequently < 2 years old (42, 89.4% vs 133, 38.6%, p < 0.001), more likely to arrive by private transportation (25, 53.2%, vs 88, 25.7%, p < 0.001), but less likely to have multiple injuries (14, 29.8% vs 158, 45.8%, p = 0.038). The AHT group was more likely to suffer subdural hemorrhage (SDH) (39, 83.0% vs 89, 25.8%, p < 0.001), require antiepileptic medications (41, 87.2% vs 209, 60.6%, p < 0.001), and neurosurgical interventions (27, 57.40% vs 143, 41.40%, p = 0.038). Mortality, PICU length of stay, and functional outcomes at 3 months were similar in both groups. In the multivariable logistic regression, age <2 years old (aOR 8.44, 95%CI 3.07-23.2), presence of seizures (aOR 3.43, 95%CI 1.60-7.36), and presence of SDH (aOR 9.58, 95%CI 4.10-22.39) were independently associated with AHT. AHT diagnosis represented 12% of our TBI cohort. Overall, children with AHT required more neurosurgical interventions and the use of anti-epileptic medications. Children younger than 2 years and with SDH were independently associated with a diagnosis of AHT. Observational cohort study. III.


Cobalt bis(dicarbollide) is a DNA-neutral pharmacophore.
Cobalt bis(dicarbollide) (COSAN) is a metallacarborane used as a versatile pharmacophore to prepare biologically active hybrid organic-inorganic compounds or to improve the pharmacological properties of nucleosides, antisense oligonucleotides, and DNA intercalators. Despite these applications, COSAN interactions with nucleic acids remain unclear, limiting further advances in metallacarborane-based drug development. Although some studies showed that COSAN intercalates into DNA, COSAN-containing intercalators do not, and while COSAN shows low cytotoxicity, intercalators are often highly toxic. The present study aimed at comprehensively characterizing interactions between COSAN and DNA using a wide range of techniques, including UV-Vis absorption, circular (CD) and linear (LD) dichroism, nuclear magnetic resonance (NMR) spectroscopy, thermal denaturation, viscosity, differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), and equilibrium dialysis measurements. Our results showed that COSAN has no effect on DNA structure, length, stability, or hybridization, with no or only faint signs of COSAN binding to DNA. Moreover, DNA is not necessary for COSAN to induce cytotoxicity at high concentrations, as shown by in vitro experiments. These findings demonstrate that COSAN is a DNA-neutral pharmacophore, thus confirming the general safety and biocompatibility of metallacarboranes and opening up new opportunities for further developing metallacarborane-based drugs.


Ex vivo allotransplantation engineering: Delivery of mesenchymal stem cells prolongs rejection-free allograft survival.
Current pharmacologic regimens in transplantation prevent allograft rejection through systemic recipient immunosuppression but are associated with severe morbidity and mortality. The ultimate goal of transplantation is the prevention of allograft rejection while maintaining recipient immunocompetence. We hypothesized that allografts could be engineered ex vivo (after allotransplant procurement but before transplantation) by using mesenchymal stem cell-based therapy to generate localized immunomodulation without affecting systemic recipient immunocompetence. To this end, we evaluated the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in vitro and activated them toward an immunomodulatory fate by priming in inflammatory or hypoxic microenvironments. Using an established rat hindlimb model for allotransplantation, we were able to significantly prolong rejection-free allograft survival with a single perioperative ex vivo infusion of bone marrow-derived mesenchymal stem cells through the allograft vasculature, in the absence of long-term pharmacologic immunosuppression. Critically, transplanted rats rejected a second, nonengineered skin graft from the same donor species to the contralateral limb at a later date, demonstrating that recipient systemic immunocompetence remained intact. This study represents a novel approach in transplant immunology and highlights the significant therapeutic opportunity of the ex vivo period in transplant engineering.


Continental igneous rock composition: A major control of past global chemical weathering.
The composition of igneous rocks in the continental crust has changed throughout Earth's history. However, the impact of these compositional variations on chemical weathering, and by extension on seawater and atmosphere evolution, is largely unknown. We use the strontium isotope ratio in seawater [(87Sr/86Sr)seawater] as a proxy for chemical weathering, and we test the sensitivity of (87Sr/86Sr)seawater variations to the strontium isotopic composition (87Sr/86Sr) in igneous rocks generated through time. We demonstrate that the 87Sr/86Sr ratio in igneous rocks is correlated to the epsilon hafnium (εHf) of their hosted zircon grains, and we use the detrital zircon record to reconstruct the evolution of the 87Sr/86Sr ratio in zircon-bearing igneous rocks. The reconstructed 87Sr/86Sr variations in igneous rocks are strongly correlated with the (87Sr/86Sr)seawater variations over the last 1000 million years, suggesting a direct control of the isotopic composition of silicic magmatism on (87Sr/86Sr)seawater variations. The correlation decreases during several time periods, likely reflecting changes in the chemical weathering rate associated with paleogeographic, climatic, or tectonic events. We argue that for most of the last 1000 million years, the (87Sr/86Sr)seawater variations are responding to changes in the isotopic composition of silicic magmatism rather than to changes in the global chemical weathering rate. We conclude that the (87Sr/86Sr)seawater variations are of limited utility to reconstruct changes in the global chemical weathering rate in deep times.


Synergistic inhibition of leukemia WEHI-3 cell growth by arsenic trioxide and Hedyotis diffusa Willd extract in vitro and in vivo.
Arsenic trioxide (ATO) is clinically used to treat acute promyelocytic leukemia (APL); however, the therapeutic dose of ATO may prompt critical cardiac side effects. Combination therapy may be used to improve the therapeutic efficiency. To evaluate this possibility, the present study determined the combined effects of Hedyotis diffusa Willd (HDW) extract and ATO in leukemic WEHI-3 cells. The results demonstrated that co-treatment of HDW with ATO resulted in a synergistic augmentation of cytotoxicity in cells at the concentration tested. In order to investigate the potential therapeutic application for leukemia, the combined effects of HDW and ATO were analyzed on the WEHI-3 cell-induced orthotopic leukemia animal model in vivo. The WEHI-3 cells in mice with leukemia were established by injecting murine WEHI-3 cells into BALB/c mice, and treating them with HDW and/or combined with ATO. The results indicated that HDW alone or HDW combined with ATO promoted the total survival rate of mice with leukemia, and these effects are dose-dependent. HDW alone or HDW combined with ATO did not affect the body weight, decreased the spleen weight and did not affect the liver weight. Furthermore, the results demonstrated that HDW alone or HDW combined with ATO resulted in a synergistic augmentation of apoptosis in WEHI-3 cells at the concentration tested. In order to further reveal the detailed mechanism of this synergistic effect on apoptosis, apoptosis-related proteins were also evaluated. The data revealed that HDW alone or HDW combined with ATO induced the expression of death receptor 4 (DR4) and DR5 and the activation of poly adenosine diphosphate ribose polymerase, caspase-3, -8 and -9. Furthermore, HDW alone or HDW combined with ATO decreased the expression levels of B-cell lymphoma 2, B-cell lymphoma-extra large and survivin, and increased the expression levels of Bak and t-Bid. Altogether, the results indicate that the combination of HDW with ATO may be a promising strategy used to increase the clinical efficacy of ATO in the treatment of APL.


Global and phylogenetic distribution of quorum sensing signals, acyl homoserine lactones, in the family of Vibrionaceae.
Bacterial quorum sensing (QS) and the corresponding signals, acyl homoserine lactones (AHLs), were first described for a luminescent Vibrio species. Since then, detailed knowledge has been gained on the functional level of QS; however, the abundance of AHLs in the family of Vibrionaceae in the environment has remained unclear. Three hundred and one Vibrionaceae strains were collected on a global research cruise and the prevalence and profile of AHL signals in this global collection were determined. AHLs were detected in 32 of the 301 strains using Agrobacterium tumefaciens and Chromobacterium violaceum reporter strains. Ethyl acetate extracts of the cultures were analysed by ultra-high performance liquid chromatography-high resolution mass spectrometry (MS) with automated tandem MS confirmation for AHLs. N-(3-hydroxy-hexanoyl) (OH-C6) and N-(3-hydroxy-decanoyl) (OH-C10) homoserine lactones were the most common AHLs found in 17 and 12 strains, respectively. Several strains produced a diversity of different AHLs, including N-heptanoyl (C7) HL. AHL-producing Vibrionaceae were found in polar, temperate and tropical waters. The AHL profiles correlated with strain phylogeny based on gene sequence homology, however not with geographical location. In conclusion, a wide range of AHL signals are produced by a number of clades in the Vibrionaceae family and these results will allow future investigations of inter- and intra-species interactions within this cosmopolitan family of marine bacteria.


Effect of bombesin on plasma cholecystokinin in normal persons and gastrectomized patients measured by sequence-specific radioimmunoassays.
Since bombesin is known to stimulate pancreatic enzyme secretion and gallbladder contraction, we have measured plasma cholecystokinin (CCK) concentrations during bombesin infusion using sequence-specific radioimmunoassays. Antibody 1703 binds to COOH terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulfated tyrosine region of CCK. In nine normal persons infusion of increasing doses of bombesin (2.4, 6, 18, and 60 pmol/kg X 20 min) induced dose-related integrated plasma CCK responses (58.5 +/- 9.7, 70.5 +/- 12.2, 79.5 +/- 11.1, and 101.4 +/- 15.4 pmol/L X 20 min [antibody 1703] and 50.4 +/- 11.9, 62.0 +/- 13.4, 74.7 +/- 9.2, and 116.1 +/- 11.3 pmol/L X 20 min [antibody T204]). Infusion of 60 pmol bombesin/kg X 20 min in eight patients with partial gastrectomy resulted in similar increases in plasma CCK (8.1 +/- 1.8 pmol/L, antibody 1703; 9.5 +/- 2.0 pmol/L, antibody T204) as in eight normal control subjects (6.5 +/- 0.9 pmol/L, antibody 1703; 8.8 +/- 1.0 pmol/L, antibody T204). During infusion of bombesin, plasma gastrin levels increased from 16.7 +/- 1.4 to 49.6 +/- 8.1 pmol/L (P less than 0.005) in the normal persons, while there was no significant change in plasma gastrin levels in gastrectomized patients. Bombesin did not significantly influence gastric acid secretion in three patients with partial gastrectomy studied. It is concluded that infusion of bombesin releases CCK in humans by a gastrin-independent mechanism.


[Diagnosis of epilepsy].
0.5-1% of the population suffers from epilepsy, while another 5% undergoes diagnostic evaluations due to the possibility of epilepsy. In the case of suspected epileptic seizures we face the following questions: Is it an epileptic seizure? The main and most frequent differential-diagnostic problems are the psychogenic non-epileptic seizures ("pseudo-seizures") and the convulsive syncope, which is often caused by heart disorders. Is it epilepsy? After an unprovoked seizure, the information on recurrence risk is an important question. The reoccurrence is more possible if a known etiological factor is present or the EEG shows epileptiform discharges. After an isolated epileptic seizure, the EEG is specific to epilepsy in 30-50% of cases. The EEG should take place within 24 hours postictally. If the EEG shows no epileptiform potentials, a sleep-EEG is required. What is the cause of seizures? Hippocampal sclerosis, benign tumors, and malformations of the cortical development are the most frequent causes of the focal epilepsy. Three potentially life-threatening conditions may cause chronic epilepsy: vascular malformations, tumors, and neuroinfections. The diagnosis in theses cases can usually be achieved by MRI, therefore, MRI is obligatory in all epilepsies starting in adulthood. The presence of epileptogenic lesion has a prognostic significance in treatment. If the MRI shows a circumscribed lesion then the pharmacological treatment will likely to be unsuccessful, while surgery may result in seizure freedom. The new and quantitative MRI techniques, such as volumetry, T2-relaxometry, MR-spectroscopy, and functional MRI play a growing role in the epilepsy diagnosis.


Nasal cytotoxic and carcinogenic activities of systemically distributed organic chemicals.
Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.


Thoracic Meningioma In Combination With Severe Lumbar Spinal Stenosis Presenting With Atypical Neurological Deficit.
We report on a case of a 47-year-old female patient with a long history of low back pain irradiating bilaterally to the legs. Twenty days before admission to our clinic, she had developed progressive weakness in the legs, more pronounced on the left side. The initial neurological examination revealed signs of damage to both the cauda equina and the spinal cord. The neuroimaging studies (computed tomography, myelography and magnetic-resonance tomography) found spinal stenosis most severe at L4-L5 level, and right lateral thoracic intradural-extramedullary tumor at T9-T10 level. The patient underwent two neurosurgical procedures. The first stage included microsurgical resection of the thoracic lesion and the second stage aimed at decompressing the lumbar spinal stenosis. To avoid missing a diagnosis of thoracic lesions, it is necessary to perform a thorough neurological examination of the spinal cord motor and sensory functions. In addition, further MRI examination of upper spinal segment is needed if the neuroimaging studies of the lumbar spine fail to provide reasonable explanation for the existing neurological symptoms.


Simultaneous ambient pressure x-ray photoelectron spectroscopy and grazing incidence x-ray scattering in gas environments.
We have developed an experimental system to simultaneously measure surface structure, morphology, composition, chemical state, and chemical activity for samples in gas phase environments. This is accomplished by simultaneously measuring x-ray photoelectron spectroscopy (XPS) and grazing incidence x-ray scattering in gas pressures as high as the multi-Torr regime while also recording mass spectrometry. Scattering patterns reflect near-surface sample structures from the nano-scale to the meso-scale, and the grazing incidence geometry provides tunable depth sensitivity of structural measurements. Scattered x rays are detected across a broad range of angles using a newly designed pivoting-UHV-manipulator for detector positioning. At the same time, XPS and mass spectrometry can be measured, all from the same sample spot and under ambient conditions. To demonstrate the capabilities of this system, we measured the chemical state, composition, and structure of Ag-behenate on a Si(001) wafer in vacuum and in O2 atmosphere at various temperatures. These simultaneous structural, chemical, and gas phase product probes enable detailed insights into the interplay between the structure and chemical state for samples in gas phase environments. The compact size of our pivoting-UHV-manipulator makes it possible to retrofit this technique into existing spectroscopic instruments installed at synchrotron beamlines. Because many synchrotron facilities are planning or undergoing upgrades to diffraction limited storage rings with transversely coherent beams, a newly emerging set of coherent x-ray scattering experiments can greatly benefit from the concepts we present here.


Functional results after treatment of retinoblastoma.
Because of the long-term complications associated with external beam radiation in retinoblastoma, alternative treatment methods have been investigated. We conducted a retrospective study to evaluate the functional results of new treatment modalities. Thirty-seven eyes were treated without external beam irradiation in 31 patients. The median diameter of the largest tumor in each eye was 6 mm. Primary chemotherapy was used in 25 cases, chemothermotherapy was used in 32 cases, cryotherapy was used in 28 cases, iodine 125 Plaques were used in 15 cases, diode laser thermotherapy was used alone in 11 cases, and photocoagulation was performed in 5 cases. The median follow-up after diagnosis of retinoblastoma was 41 months. The visual results were evaluated at a median age of 54 months. The median visual acuity of the treated eyes was 20/33. Twenty-four eyes presented a visual acuity better than 20/40, 4 eyes had a visual acuity between 20/200 and 20/40, and 9 eyes had a visual acuity less than 20/200. Maculopathy was observed in 16 cases, associated with papillopathy in 1 case. A cataract was observed in 1 case and a vitreous hemorrhage was observed in another case. Twenty-one eyes did not develop any complications. No corneal dryness and very few lens changes were observed. The functional results after local treatments for retinoblastoma are very good. The most frequent complication is maculopathy, particularly when the tumor involves or is situated close to the macula.


Migration of Cymetra after vocal fold injection for laryngeal paralysis.
Injection laryngoplasty is a common operative technique used in the management of unilateral vocal fold paralysis. Cymetra is a micronized particulate injectable form of acellular human dermis that is commonly used for vocal cord medialization procedures. We report migration of an intracordal bolus of Cymetra into the medial wall of the pyriform sinus. Histopathology from endoscopic resection of the migrated Cymetra demonstrated a localized foreign body reaction with characteristic giant cells. Specific anatomic considerations through cadaveric laryngeal dissection are presented to demonstrate the likely pathway of intralaryngeal bolus migration.