(+/-)Cyclazocine blocks the dopamine response to nicotine.
(+/-)Cyclazocine, synthesized by Archer in 1962, was originally tested as a treatment for heroin addiction. (+/-)Cyclazocine is a mu opioid antagonist and kappa opioid agonist, and because of these actions, would be expected to modulate dopamine release in the nucleus accumbens as well as the reinforcing effects of drugs of abuse. In a recent study (+/-)cyclazocine was reported to decrease cocaine self-administration in rats. The aim of the present study was to determine whether (+/-)cyclazocine would alter the dopaminergic effects of nicotine that are thought to mediate its rewarding effects. Using in vivo microdialysis in awake and freely moving rats, we investigated the effect of (+/-)cyclazocine (0.5 mg/kg, i.p.) on the acute dopamine response to nicotine (0.32 mg/kg, i.v. over a 5 min period, infused 30 min later) in the nucleus accumbens. (+/-)Cyclazocine significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusion and enhanced nicotine-induced increases in dopamine metabolites. (+/-)Cyclazocine alone did not significantly affect extracellular dopamine levels. However, both the (+) and (-) enantiomers of cyclazocine did alter basal dopamine levels and these effects made it difficult to assess their individual interactions with nicotine. The results suggest that the effects of both enantiomers contribute to the effects of the racemate; (+/-)cyclazocine may decrease the rewarding effect of nicotine and may be the prototype of a potentially novel treatment for smoking.


[Recognition and categorization of butterfly patterns].
Two experiments are reported which deal with the nature of categorization of visual patterns. Stimulus materials were schematic butterfly patterns. Systematic transformations of five physical features (fore wing, hind wing, size, body length and color) were applied to a prototype to generate a set of instances. In Experiment 1, subjects were asked to judge the visual similarity between each instance and the prototype. Similarity ratings were found to be related to an each instance's transformational distance from the prototype. In Experiment 2, subjects were exposed to a subset of instances of the pattern which varied in their transformational distance from the prototype, and then given a recognition test with confidence ratings. The recognition item consisted of the old and new instances including the prototype. Recognition ratings were found to be related to each instance's family resemblance score rather than its transformational distance and subjective similarity to the prototype. These results support Rosch and Mervis's family resemblance model of categorization.


Establishment of genetically diverse patient-derived xenografts of colorectal cancer.
Preclinical compounds tested in animal models often show limited efficacy when transitioned into human clinical trials. As a result, many patients are stratified into treatment regimens that have little impact on their disease. In order to create preclinical models that can more accurately predict tumor responses, we established patient-derived xenograft (PDX) models of colorectal cancer (CRC). Surgically resected tumor specimens from colorectal cancer patients were implanted subcutaneously into athymic nude mice. Following successful establishment, fourteen models underwent further evaluation to determine whether these models exhibit heterogeneity, both at the cellular and genetic level. Histological review revealed properties not found in CRC cell lines, most notably in overall architecture (predominantly columnar epithelium with evidence of gland formation) and the presence of mucin-producing cells. Custom CRC gene panels identified somatic driver mutations in each model, and therapeutic efficacy studies in tumor-bearing mice were designed to determine how models with known mutations respond to PI3K, mTOR, or MAPK inhibitors. Interestingly, MAPK pathway inhibition drove tumor responses across most models tested. Noteworthy, the MAPK inhibitor PD0325901 alone did not significantly mediate tumor response in the context of a KRAS(G12D) model, and improved tumor responses resulted when combined with mTOR inhibition. As a result, these genetically diverse models represent a valuable resource for preclinical efficacy and drug discovery studies.


Regulation of c-myc mRNA decay by translational pausing in a coding region instability determinant.
A 249-nucleotide coding region instability determinant (CRD) destabilizes c-myc mRNA. Previous experiments identified a CRD-binding protein (CRD-BP) that appears to protect the CRD from endonuclease cleavage. However, it was unclear why a CRD-BP is required to protect a well-translated mRNA whose coding region is covered with ribosomes. We hypothesized that translational pausing in the CRD generates a ribosome-deficient region downstream of the pause site, and this region is exposed to endonuclease attack unless it is shielded by the CRD-BP. Transfection and cell-free translation experiments reported here support this hypothesis. Ribosome pausing occurs within the c-myc CRD in tRNA-depleted reticulocyte translation reactions. The pause sites map to a rare arginine (CGA) codon and to an adjacent threonine (ACA) codon. Changing these codons to more common codons increases translational efficiency in vitro and increases mRNA abundance in transfected cells. These data suggest that c-myc mRNA is rapidly degraded unless it is (i) translated without pausing or (ii) protected by the CRD-BP when pausing occurs. Additional mapping experiments suggest that the CRD is bipartite, with several upstream translation pause sites and a downstream endonuclease cleavage site.


Lifestyle factors associated with geographic blood pressure variations among men and women in the UK.
The importance of various factors in explaining geographical BP variations in the UK has been examined among 2,596 men and women living in nine British towns. Associations between BP and potential explanatory variables have been examined first for individual subjects (within-population), and second for towns (between-populations). The factors showing associations with BP that were consistent within-population and between-towns were BMI, urine sodium/potassium ratio (Na/K), alcohol and anxiety at examination for men, and BMI, Na/K and anxiety at examination for women. After adjustment for these factors and age, the male BP differences between the nine towns were reduced from 10.1 mmHg systolic in men (P = 0.001) to 7.1 mmHg (P = 0.04), and from 5.9 mmHg diastolic (P = < 0.0001) to 5.5 mmHg (P < 0.0001). For women, adjustment only marginally reduced the between-town systolic differences from 5.6 mmHg (P = 0.05) to 5.5 mmHg (P = 0.3) and increased the diastolic differences from 3.7 mmHg diastolic (P = 0.03) to 5.0 mmHg (P < 0.0001). It is concluded that BMI, alcohol consumption and the Na/K ratio play an important part in the pattern of male SBP variations in the UK. The factors associated with female geographical differences in BP were less clear, but BMI and Na/K ratio appear to be important. This study has been unable to identify factors associated with geographical differences in DBP, with the possible exception of BMI in men. However, as systolic pressure is recognised to be more strongly associated with cardiovascular outcome than diastolic pressure, it can be recommended that primary prevention strategies aimed at reducing the population mean level of BP should involve efforts to reduce overweight, alcohol consumption and the Na/K ratio.


Indirect immunofluorescence and generation of cyclic-AMP investigation with Graves' patients' sera.
Generation of cAMP was measured on human thyroid slices and indirect immunofluorescence was carried out on frozen human thyroid sections. Sera from 16 previously not treated thyrotoxic patients and from 5 euthyroid patients were used. The majority of the thyrotoxic sera (13 out of 16) provoked enhanced generation of cAMP and the same cases showed positivity by indirect immunofluorescence. The possible connection between enhanced generation of cAMP and detectability of antibodies binding to different thyroid structures is discussed.


Population-based differences in Schistosoma mansoni- and hepatitis C-induced disease.
Two populations with differing histories of Schistosoma mansoni and hepatitis C infection were compared directly for severity of disease and extent of comorbidity. Demographic, parasitologic, and ultrasound surveys were conducted on 2038 Egyptians and on 2120 Kenyans. Hepatitis B and C serologies and transaminase levels were obtained from a subset at each site. Despite significantly lower prevalence and intensity of infection, Egyptians had a higher prevalence of severe schistosomal fibrosis than Kenyans (36.8% vs. 4.6%). Hepatitis C infection was 3 times more prevalent among Egyptians, and evidence of hepatocellular damage was significantly greater among Egyptians. There was no interaction between S. mansoni infection or disease and the prevalence or severity of hepatitis C. For both infections, the intensity or prevalence of infection was a poor predictor of morbidity. The prevalence of disease in the Egyptian population from different pathogens suggests a generalized susceptibility to inflammatory liver disease.


Anterior Cerebral Artery and Anterior Communicating Artery Variations: Assessment with Magnetic Resonance Angiography.
Although anterior cerebral artery (ACA) and anterior communicating artery (AcomA) variations have been frequently investigated by contrast-enhanced angiography, the number of studies performed with magnetic resonance angiography is quite low. Our aim in this study is to investigate ACA and AcomA variations with time of flight magnetic resonance angiography (TOF MRA). Source and maximum intensity projection images of 581 adult patients (273 males, 308 females) who were scanned for intracranial arteries with the TOF MRA method were retrospectively analyzed. We found the typical configuration rate of the ACA and AcomA complex to be 40.6%. The most common structural anatomic variations out of typical configuration were AcomA aplasia (18.9%) and AcomA hypoplasia (17.9%), respectively. The least frequent variation that we found was duplicated AcomA (0.9%). When we examined gender comparatively, unilateral A1 segment aplasia was found to be higher in males and azygos ACA was found to be higher in females (P = 0.001 and P = 0.029, respectively). In this study, in which we used the TOF MRA technique, we detected high rates of anatomic variations of ACA and AcomA. This method, which is noninvasive, does not require contrast material and does not contain ionizing radiation, can be preferred especially in the evaluation of patients with kidney disease and contrast allergy.


Effect of Calcium Hydroxide Based Intracanal Medicaments on the Apical Sealing Ability of Resin Based Sealer and Guttapercha Obturated Root Canals.
Calcium Hydroxide (CH) is one of the most commonly used intracanal medicaments which can be used with various vehicles. The aim of this in vitro study was to evaluate the effect of three CH based intracanal medicaments on the apical sealing ability of AH Plus - guttapercha obturation. Crowns of 100 extracted single rooted human teeth were sectioned at the Cemento-Enamel Junction (CEJ) to a standardized length. The root canals were instrumented upto ISO size 40 using step back technique and the specimens were randomly divided into two control and four experimental groups. The control groups were not medicated. Specimens in positive control group (Group I) were obturated with guttapercha without placing sealer and in negative control group (Group II) were obturated with guttapercha and AH Plus sealer. Among the experimental groups, specimens of Group III were not medicated while groups IV, V and VI were medicated with CH-saline, CH-2% Chlorhexidine (CHX) and Vitapex respectively for a period of 14 days. The medicaments were removed from the specimens and the teeth were obturated with AH Plus sealer and guttapercha using lateral compaction technique. The specimens were immersed in India ink dye, demineralized and diphanized. The extent of dye penetration was assessed using a 10X stereomicroscope. Data obtained was statistically analyzed by one-way ANOVA (p<0.05) followed by Post-hoc Tukey test. Amongst the three CH medicaments, CH-2% CHX when used as an intracanal medicament showed a significantly higher microleakage as compared to the other groups with p<0.001. The microleakage values between the remaining groups were not statistically significant. Under the conditions of this study it was concluded that all groups with or without intracanal medicament showed apical leakage. The vehicle used to carry CH may significantly influence the apical sealing ability of guttapercha - AH Plus obturated canals.


To Study the Prevalence of Various Enteric Parasitic Infections Among HIV Infected Individuals in the P.D.U. Medical College and Hospital, Rajkot, Gujarat, India.
Enteric parasites are a major cause of diarrhoea in HIV infected individuals. The present study was undertaken to detect the enteric parasites in HIV infected patients with diarrhoea, who were at different levels of immunity. This study was carried out in the P.D.U Medical College and Civil Hospital, Rajkot, India. during the period from June 2009 to June 2010. A total of 100 stool samples from HIV seropositive patients were examined for opportunistic, gastrointestinal parasitic infections. The samples were classified according to the age groups, sex, and occupation, a history of diarrhoea and different categories of the CD4 cell count. The stool samples were collected and examined for enteric parasites by microscopy and by special staining methods. The CD4 cell counts were estimated by using the FACS count system. The intestinal parasitic pathogens were detected in 28% patients. Among all, Isospora appeared to have the highest prevalence (18%), followed by Giardia lamblia (5%), Strongyloides stercoralies (3%) and Cryptosporidium parvum (2%). In the HIV infected patients with a CD4 count of < 200 cells/μl, Isospora was the most commonly observed (56%) pathogen. The proportion of the opportunistic pathogens in the patients with CD4 counts of <200 cells/μl was significantly higher as compared to those in the other two groups of patients with CD4 counts of >200 respectively. Parasitic infections were detected in 28% of the HIV infected patients and a low CD4 count was significantly associated with an opportunistic infection. The detection of the aetiologic pathogens might help the clinicians in deciding the appropriate management strategies.


[Meningoencephalitis caused by varicella zoster virus].
Varicella zoster virus (VZV) belongs to the group of herpes viruses. It can cause a number of nervous system infections. We present 2 of 4 patients seen recently suffering from acute meningoencephalitis, in which VZV proved to be the infectious agent. The first patient was a 57-year-old woman with headache, vomiting, and sudden aggressiveness. The second patient was a 60-year-old man with headache, nausea, and vomiting. Neither patient had skin eruptions usually associated with VZV reactivation, nor had either recently suffered from herpes zoster. Both patients had in their cerebrospinal fluid a lymphocytic pleocytosis, a decreased glucose concentration and and an elevated protein concentration. The patients recovered within a few days of starting intravenous treatment with aciclovir 10 mg/kg 3 times daily for one week. Recent literature shows that VZV is a common pathogen in meningoencephalitis and is probably underestimated as a putative cause of this condition. VZV meningoencephalitis usually has a mild course, but serious complications have been reported. Patients present with headache and usually fever. Nuchal rigidity and meningeal irritation are not always present. Since the advent of the PCR technique, VZV has been readily demonstrable. Anti-viral treatment is advised despite the lack of placebo-controlled studies, and may be combined with prednisone.


Diaphragmatic plication offers functional improvement in dyspnoea and better pulmonary function with low morbidity.
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was as follows: In adults with unilateral diaphragmatic paralysis, does diaphragmatic plication offer functional improvement in dyspnoea, better pulmonary function tests (PFTs) and return to activity? A total of 126 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The authors, date and country of publication, patient group studied, surgical approach, study type, relevant outcomes and results of these articles are tabulated. Those articles reporting improvement in PFTs following plication, documented this benefit in the following parameters: mean forced vital capacity (range 17-40%), forced expiratory volume at 1 sec (range 21-27%), functional residual capacity (range 20-21%) and total lung capacity (range 16-19%). The percentage of postoperative improvement in shortness of breath as measured by a dyspnoea score was reported to be between 90 and 96% in the thoracotomy group and 100% in the Video Assisted Thoracoscopic Surgery (VATS) group, the dyspnoea score that was used in all the studies was a visual analogue scale between 0 and 10 where 0 is no dyspnoea and 10 is the worst dyspnoea a patient can have. One of the studies reported postoperative normalization in ventilation perfusion scan (VQ) scan parameters when compared with the preoperative mismatch. Complication rate was similar between the two groups, while the mortality rate was 4% in the thoracotomy group and 0% in the VATS group. The total number of patients included in all the studies combined was 161. All reports included in this review are observational studies (one cohort study and the remainder being case series); therefore, the risk of selection, information and publication biases are high and conclusions should be implemented with caution. We conclude that diaphragmatic plication can improve the functional status, shortness of breath and PFTs of patients with unilateral diaphragm paralysis. Patients undergoing a VATS approach appear to have more advantages in objective and subjective measures (including PFTs, dyspnoea score, length of hospital stay and postoperative complications). Further research with high-quality study designs is advised, focussing mainly on the long-term benefits and assessment of health-related quality of life.


Childhood and early-onset anxiety: treatment and biomarker studies.
Increasing research attention is being applied to studies of early-onset anxiety, with a focus on its phenomenology, etiology, and strategies for treatment. The impetus for these studies includes well-confirmed findings from epidemiologic surveys clearly demonstrating that, as a group, the anxiety disorders represent the most highly prevalent form of psychopathology in children and adolescents. Overall rates of childhood anxiety disorders are estimated to be from 6% to 10%, depending upon categories included and strategies for ascertainment. New work is currently being conducted in the form of large-scale rigorous treatment studies, and new investigations explore etiopathophysiologic aspects of anxiety in children and adolescents. Significant progress is being made in this important clinical area that should translate to improved outcomes through refined diagnosis and empirically tested treatments.


Catestatin, vasostatin, cortisol, temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale and visual analog scale for stress and pain behavior in dogs before and after ovariohysterectomy.
The stress reaction induced by surgery and associated pain may be detrimental for patient recovery and should be minimized. The neuropeptide chromogranin A (CGA) has shown promise as a sensitive biomarker for stress in humans. Little is known about CGA and its derived peptides, catestatin (CST) and vasostatin (VS), in dogs undergoing surgery. The objectives of this study were to investigate and compare concentrations of CGA epitopes CST and VS, cortisol, body temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale (CMPS-SF) and visual analog scales (VAS) for stress and pain behavior in dogs before and after ovariohysterectomy. Thirty healthy privately owned female dogs admitted for elective ovariohysterectomy were included. Physical examination, CMPS-SF, pain behavior VAS, and stress behavior VAS were recorded and saliva and blood samples were collected before surgery, 3 h after extubation, and once at recall 7-15 days after surgery. Dogs were premedicated with morphine and received carprofen as analgesia for 7 days during the postoperative period. At 3 h after extubation, CMPS-SF and pain behavior VAS scores had increased (p < 0.0001) and stress behavior VAS scores, temperature, respiratory rate (p < 0.0001), plasma CST concentrations (p = 0.002) had decreased significantly compared to before surgery. No significant differences were observed in the subjective and physiological parameters between before surgery and at recall, but plasma CST (p = 0.04) and serum cortisol (p = 0.009) were significantly lower at recall. Plasma VS, saliva CST, and heart rate did not differ significantly at any observed time. Study parameters for evaluating surgery-induced stress and pain changed in dogs subjected to ovariohysterectomy. To further evaluate CST and VS usefulness as pain biomarkers, studies on dogs in acute painful situations are warranted.


Distracted Driving Among Patients with Trauma Attending Fracture Clinics in Canada: The Canadian Multicenter DRIVSAFE Study.
Globally, every 25 seconds, a person dies in a motor vehicle crash (MVC) and 58 people get injured. Adding to the rising distracted-driving rates is the rapid growth of the number of cars in circulation globally. This study examined the proportion of distracted drivers among patients attending orthopaedic fracture clinics, as well as associated factors. In this large, multicenter, cross-sectional study, we recruited 1,378 patients across 4 Canadian fracture clinics. Eligible patients completed an anonymous questionnaire about distracted driving. We calculated the percentages of specific distractions. Using questionnaire responses and published crash risk odds ratios (ORs), patients were grouped as distraction-prone and distraction-averse. Regression analyses to determine the association of demographic characteristics with distracting behaviors and the odds of being in a distraction-related crash were performed. In total, 1,358 patients (99.7%) self-reported distracted driving. Prevalent distractions included talking to passengers (98.7%), distractions outside the vehicle (95.5%), listening to the radio (97.6%), adjusting the radio (93.8%), and daydreaming (61.2%). Of the 1,354 patients who acknowledged mobile phone distractions, 889 (65.7%) accepted phone calls and continued driving, 675 (49.8%) read electronic messages, and 475 (35.1%) sent electronic messages. Younger age (OR, 0.94 [95% confidence interval (CI), 0.91 to 0.97]; p < 0.001) and household incomes of $80,000 to <$100,000 (OR, 1.92 [95% CI, 1.17 to 3.14]; p = 0.01) and ≥$100,000 (OR, 2.48 [95% CI, 1.57 to 3.91]; p < 0.001) were associated with being in the distraction-prone group. Distraction-prone patients were twice as likely to be in a distraction-related MVC (OR, 1.98 [95% CI, 1.43 to 2.74]; p < 0.001). Of 113 drivers who sustained injuries from MVCs, 20 (17.7%) acknowledged being distracted. Of 729 patients who reported being the driver in a previous MVC in their lifetime, 226 (31.0%) confirmed being distracted. This survey-based study showed that driving distractions were near universally acknowledged. The pervasiveness of distractions held true even when only the more dangerous distractions were considered. One in 6 patients in MVCs reported being distracted in their current crash, and 1 in 3 patients disclosed being distracted in an MVC during their lifetime.


Electric oral burns in Danish children with special reference to prevention.
68 children, most of them 1-3 years old, with electric burns of the mouth from slight cases to severe burns with extensive necroses were treated over a 30-year period. Principles of primary conservative treatment and secondary reconstructive surgery are mentioned. A Stein- Abbe flap procedure, single or double, has been the method-of-choice in severe defect of the lower lip. In the majority of the cases the accident was caused by a defective bakelite plug from the detachable cord of a popular electric vacuum cleaner of Danish origin. In 1968 a plea was made for a change of this kind of plug to a better type made of an unbreakable plastic material. As a prophylactic measure this intervention seems to have been very useful in so far as the number of these senseless accidents has decreased dramatically in Denmark during the last 15 years.


A prognostic scoring system for operated acute epidural hematoma based on gray-white matter ratio.
To determine the prognostic risk factors of patients with acute epidural hematoma (AEDH), a scoring system was established based on gray-white matter ratio (GWR) and internal verification was performed.All patients with AEDH who underwent surgical treatment in Qinghai Provincial People's Hospital from January 2013 to June 2019 were continuously collected. The clinical and imaging data of the patients were collected. According to Glasgow Outcome Scale at 3 months after operation, the patients were divided into poor and good prognosis groups, respectively. The GWR value of the nonhematoma side was measured at the inner capsule area. Univariate and multivariate analyses were used. Independent predictors significantly related to the prognosis of AEDH were screened out and a nomogram was established based on these factors.A total of 170 cases were included in this study, the Glasgow Coma Score (severe and moderate), cerebral hernia, midline shift, preoperative GWR, postoperative GWR, hematoma thickness/midline shift, time from coma to surgery, and decompression of bone flap were the independent risk factors for predicting the poor prognosis of AEDH. Moreover, the prediction ability of nomogram was higher than any other independent predictive factors.The nomogram model established represents the most effective factor to predict the prognosis of operated AEDH. The scoring system is characterized by high accuracy, simplicity and feasibility, with a wide range of clinical application prospects.


Alternative Anaphylactic Routes: The Potential Role of Macrophages.
Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators from effector cells. There are two potential pathways for anaphylaxis. The first one, IgE-dependent anaphylaxis, is induced by antigen (Ag) cross-linking of Ag-specific IgE bound to the high-affinity IgE receptor (FcεRI) on mast cells and basophils. The second one, IgG-dependent anaphylaxis is induced by Ag cross-linking of Ag-specific IgG bound to IgG receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA) on macrophages, neutrophils, and basophils. Macrophages exhibit a huge functional plasticity and are capable of exerting their scavenging, bactericidal, and regulatory functions under a wide variety of tissue conditions. Herein, we will review their potential role in the triggering and development of anaphylaxis. Thereby, macrophages, among other immune cells, play a role in both anaphylactic pathways (1) by responding to anaphylactic mediators secreted by mast cells after specific IgE cross-linking or (2) by acting as effector cells in the anaphylactic response mediated by IgG. In this review, we will go over the cellular and molecular mechanisms that take place in the above-mentioned anaphylactic pathways and will discuss the clinical implications in human allergic reactions.


Management and cleanup of legacy radium-contaminated sites in the United States.
The hazards associated with radium-containing materials were largely unknown when they were first introduced into household and other products over a century ago. Radium was also originally thought to have beneficial health properties, leading to confusion amongst the public about the safety of radium in household products and food items. When the adverse health effects associated with radium were discovered and became well known, radium products became unpopular and were prohibited in some countries. In the United States, after the hazards associated with radium became known, radium was first regulated by individual states in the late 1920s and early 1930s. Later, the US Nuclear Regulatory Commission (NRC) was given a role in the regulation of discrete sources of radium with the passage of the Energy Policy Act of 2005. After passage of the Act, the NRC began to systematically identify sites around the country where radium was used and reached out to site owners to determine whether existing radium contamination could pose a risk to public health and safety and the environment. The NRC devised a graded approach in response to its new regulatory responsibilities to address potential public health and safety issues at legacy radium sites. By September 2019, the NRC had dispositioned all the sites that were identified as having potential contamination from historical radium within its regulatory purview in non-Agreement States. The staff worked with site owners and federal, state and local officials, as needed, to properly disposition the sites to ensure that each site either meets the applicable criteria for unrestricted use or has controls in place to limit access during remediation so that no site poses an unacceptable risk to public health and safety and the environment.


Understanding the Reaction Mechanism of Ni-Catalyzed Regio- and Enantioselective Hydroalkylation of Enamines: Chemoselectivity of (Bi-oxazoline)NiH.
This density functional theory study explores the detailed mechanism of nickel-catalyzed hydroalkylation of the C═C bond of N-Cbz-protected enamines (Cbz = benzyloxycarbonyl) with alkyl iodides to give chiral α-alkyl amines. The active catalyst (biOx)NiH, a chiral bioxazoline (biOx)-chelated Ni(I) hydride, exhibits chemoselectivity that favors single electron transfer to the alkyl iodide over C═C hydrometalation with the enamine. This generates an alkyl radical and a Ni(II) intermediate, which takes up the enamine substrate CbzNHCH═CH2CH3 via a regio- and enantioselective C═C insertion into the NiII-H bond. The resulting Ni(II) alkyl complex combines with the alkyl radical, forming a Ni(III) intermediate, from which the alkyl-alkyl reductive elimination delivers the chiral amine product. The regioselectivity arises from a combination of orbital and noncovalent interactions, both of which are induced by the Cbz group. Thus, Cbz plays an additional role in controlling regioselectivity. The enantioselectivity stems from the differing distortion energies of CbzNHCH═CH2CH3. The reductive elimination is the rate-determining step (ΔG⧧ = 18.7 kcal/mol). In addition, the calculations show a noninnocent behavior of the biOx ligand induced by the insertion of CbzNHCH═CH2CH3 into the Ni-H bond of (biOx)NiH. These computationally gained insights can have implications for developing new Ni(I)-catalyzed reactions.


Evaluation of the use of portable ultrasonography to determine pregnancy status and fecundity in bonnethead shark Sphyrna tiburo.
This study examined the usefulness of portable ultrasonography in accurately predicting pregnancy and fecundity in the bonnethead shark Sphyrna tiburo by comparing ultrasound-obtained data with those obtained from animal dissection, the gold standard for elasmobranch reproduction studies. Mature female S. tiburo (n = 66) were collected throughout the period of reproduction and examined via portable ultrasonography using two different ultrasound transducers (8-5 MHz linear array transducer and a 5.0-2.5 MHz curvilinear array transducer) to determine pregnancy status and fecundity. Ultrasound-derived data were compared with validated assessments of pregnancy and litter size obtained using animal dissection to determine the level of agreement between the two approaches. Overall, there was strong agreement (90.9%) between pregnancy determinations obtained using ultrasonography and dissection. However, the effectiveness of portable ultrasonography in accurately determining specific stages of maturity and pregnancy differed slightly between transducer types (linear = 61.3%; curvilinear = 88.9%). Measurements of fecundity also agreed well between ultrasonography and dissection and there were no significant differences between mean fecundity estimates obtained using the two methods. In general, portable ultrasonography was found to be a good alternative to lethal sampling and animal dissection in obtaining reproductive data critical for the management and conservation of elasmobranchs. Special attention should be given to factors that can influence the reliability of ultrasound-derived data such as transducer type, embryo size and sound wave interference due to gut contents.


Effects of 960-nm diode laser irradiation on calcium solubility of dental enamel: an in vitro study.
The aim of this study was to investigate the effects of 960 nm diode laser and acidulated phosphate fluoride on calcium solubility of human dental enamel. Interest in diode lasers has grown steadily since its invention due to its inherent advantages and its range of applications. Several other laser types have shown good results in caries prevention; however, there are few studies on dental tissue interactions using diode lasers. Acid resistance was evaluated using 65 enamel specimens, divided into five groups: control (C), fluoride (F), laser (L), laser + fluoride (LF), and fluoride + laser (FL). The laser was operated using the parameters of 6.5-W peak power, 5-msec pulse duration, 10-Hz repetition rate, and 33-mJ pulse energy. These parameters were previously tested regarding pulpal temperature rise and enamel morphology, and were determined to be safe. The amount of calcium lost during demineralization was measured. The calcium solubility of the laser group was 12% higher than of the control group (p > 0.05). Group F showed a 33.6% increase of acid resistance (p < 0.05). When laser was associated with fluoride, the calcium solubility increased significantly (p < 0.05) compared to both the control group and the laser group. Groups treated with fluoride showed the same results (p > 0.05). The 960-nm diode laser promoted a slight increase in calcium solubility. A statistically significant reduction on calcium solubility was achieved with the three treatments that involve fluoride (F, FL, and LF). The additional application of laser irradiation did not cause any significant increase or decrease in calcium solubility.


Dendritic cell and effector cell infiltration in soft tissue sarcomas with reactive lymphoid hyperplasia.
The lymph node is the site of antigen presentation, and dendritic cells are sentinels for anti-tumor immunity. However, little is known about the histological features of lymph nodes and dendritic cells in soft tissue sarcomas. The reactive lymph node and infiltration of dendritic cells or effector cells were studied histologically in 10 soft tissue sarcomas with reactive lymphoid hyperplasia. The cases included four malignant fibrous histiocytomas, two malignant peripheral nerve sheath tumors, one synovial sarcoma, one epithelioid sarcoma, one malignant granular cell tumor, and one liposarcoma. The proportions of the T zone, lymphoid follicle, and lymphoid sinus (which was occupied by cells immunopositive for antibodies against CD3, CD20, or CD68) were 33.4% +/- 11.0%, 6.1% +/- 4.9%, and 13.5% +/- 6.5%, respectively. T zone hyperplasia was observed in all cases, and sinus histiocytosis was found in four. The proportion of the T zone in regional lymph nodes of soft tissue sarcoma patients was significantly higher than that in adult autopsy cases without a cancer history. CD8-, TIA-1-, or granzyme B-positive effector cells were found in each sarcoma tissue. Whereas CD1a-positive dendritic cells were not detected, S-100 protein-positive or CD83-positive dendritic cells were observed in five sarcoma tissues. The coefficient correlation between the numbers of effector cells and dendritic cells positive for CD83 or S-100 protein were demonstrated. Although this is a preliminary report, the present study demonstrated that some soft tissue sarcoma patients showed reactive lymphoid hyperplasia. Furthermore, the association between the infiltration of dendritic cells and that of effector cells was observed in patients with soft tissue sarcomas.


The Skin Microbiome in Atopic Dermatitis and Its Relationship to Emollients.
Human-associated bacterial communities on the skin, skin microbiome, likely play a central role in development of immunity and protection from pathogens. In atopic patients, the skin bacterial diversity is smaller than in healthy subjects. To review treatment strategies for atopic dermatitis in Canada, taking the skin microbiome concept into account. An expert panel of 8 Canadian dermatologists explored the role of skin microbiome in clinical dermatology, specifically looking at atopic dermatitis. The panel reached consensus on the following: (1) In atopic patients, the skin microbiome of lesional atopic skin is different from nonlesional skin in adjacent areas. (2) Worsening atopic dermatitis and smaller bacterial diversity are strongly associated. (3) Application of emollients containing antioxidant and antibacterial components may increase microbiome diversity in atopic skin. The skin microbiome may be the next frontier in preventive health and may impact the approach to atopic dermatitis treatment.


Gas Uptake of 3-D Printed Acrylonitrile Butadiene Styrene (ABS) Using a Vacuum Apparatus Designed for Absorption and Desorption Studies.
We describe a vacuum apparatus for determining the outgassing rate into vacuum, the diffusion coefficient, and the amount of gas absorbed for various materials. The diffusion coefficient is determined from a model applied to time-dependent desorption data taken using a throughput method. We used this method to determine the diffusion coefficient, D, for H2O in 3-D printed acrylonitrile butadiene styrene (ABS). We found DH2O = 8.3 × 10-8 cm2/s ± 1.3 × 10-8 cm2/s (k = 1; 67% confidence interval) at 23.2 °C. This result was compared to the diffusion coefficient determined another by a gravimetric method, in which the sample weight was monitored as it absorbed gas from the atmosphere. The two methods agreed to within 3%, which is well within the uncertainty of the measurement. We also found that at least 80% of the atmospheric gas (air) absorbed by the ABS is water. The total amount of all atmospheric gas absorbed by ABS was about 0.35% by weight when exposed to ambient air in the laboratory, which was at a pressure of 101 kPa with a relative humidity of 57% at 22.2 °C.


Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model.
Humans express a unique subset of high-density lipoproteins (HDLs) called trypanosome lytic factors (TLFs) that kill many Trypanosoma parasite species. The proteins apolipoprotein (apo) A-I, apoL-I, and haptoglobin-related protein, which are involved in TLF structure and function, were expressed through the introduction of transgenes in mice to explore their physiological roles in vivo. Transgenic expression of human apolipoprotein L-I alone conferred trypanolytic activity in vivo. Coexpression of human apolipoprotein A-I and haptoglobin-related protein (Hpr) had an effect on the integration of apolipoprotein L-I into HDL, and both proteins were required to increase the specific activity of TLF, which was measurable in vitro. Unexpectedly, truncated apolipoprotein L-I devoid of the serum resistance gene interacting domain, which was previously shown to kill human infective trypanosomes, was not trypanolytic in transgenic mice despite being coexpressed with human apolipoprotein A-I and Hpr and incorporated into HDLs. We conclude that all three human apolipoproteins act cooperatively to achieve maximal killing capacity and that truncated apolipoprotein L-I does not function in transgenic animals.


ABCA1, ABCG1, and ABCG4 are distributed to distinct membrane meso-domains and disturb detergent-resistant domains on the plasma membrane.
ATP-binding cassette A1 (ABCA1), ABCG1, and ABCG4 are lipid transporters that mediate the efflux of cholesterol from cells. To analyze the characteristics of these lipid transporters, we examined and compared their distributions and lipid efflux activity on the plasma membrane. The efflux of cholesterol mediated by ABCA1 and ABCG1, but not ABCG4, was affected by a reduction of cellular sphingomyelin levels. Detergent solubility and gradient density ultracentrifugation assays indicated that ABCA1, ABCG1, and ABCG4 were distributed to domains that were solubilized by Triton X-100 and Brij 96, resistant to Triton X-100 and Brij 96, and solubilized by Triton X-100 but resistant to Brij 96, respectively. Furthermore, ABCG1, but not ABCG4, was colocalized with flotillin-1 on the plasma membrane. The amounts of cholesterol extracted by methyl-β-cyclodextrin were increased by ABCA1, ABCG1, or ABCG4, suggesting that cholesterol in non-raft domains was increased. Furthermore, ABCG1 and ABCG4 disturbed the localization of caveolin-1 to the detergent-resistant domains and the binding of cholera toxin subunit B to the plasma membrane. These results suggest that ABCA1, ABCG1, and ABCG4 are localized to distinct membrane meso-domains and disturb the meso-domain structures by reorganizing lipids on the plasma membrane; collectively, these observations may explain the different substrate profiles and lipid efflux roles of these transporters.


Left ventricular strain and strain rate in a general population.
Strain and strain rate (SR) are measures of deformation that reflect left ventricular (LV) function. To our knowledge, no previous study described these indexes in a general population. We therefore described peak-systolic strain and SR of the LV in the general population and derived diagnostic thresholds for these measurements in a healthy subgroup. In 480 subjects enrolled in a family-based population study (50.5% women; mean age, 50.5 years; 37.2% hypertensive), we measured: (i) end-systolic longitudinal strain and peak-systolic SR from the basal portion of the LV inferior and inferolateral free walls; (ii) radial deformation of the LV inferolateral wall. Longitudinal (mean, 22.9%) and radial (59.2%) strain and longitudinal (1.31 s(-1)) and radial (3.40 s(-1)) SR decreased with age (P </= 0.007). Longitudinal and radial strain independently decreased (P </= 0.006) with relative wall thickness (RWT), longitudinal strain with the waist-to-hip ratio, and radial strain with body weight. In contrast, LV ejection fraction increased (P </= 0.0001) with age and RWT. Longitudinal and radial stain rate increased with heart rate (P </= 0.05). In healthy subgroup (n = 236), the fifth percentiles were 18.4 and 44.3%, and 0.99 and 2.43 s(-1), for longitudinal and radial strain and SR, respectively. We explored the early signs of LV systolic dysfunction in a general population, using tissue Doppler imaging technique. LV strain and SR decrease with age, body weight, central obesity, and RWT. Our current study resulted in the proposal for diagnostic thresholds for strain and SR, based on a healthy subgroup recruited via random sampling of the population.


[Variations in cell population size and reactive oxygen species level in the blood and the ascites liquid of tumor carrier].
Using Seidel ascites hepatoma as a model, we studied in detail changes in cell population size and in the level of reactive oxygen species in the tumor growth zone and in the blood plasma of tumor carrier. It was found that reduction-oxidation conditions in the blood plasma and in the tumor growth zone were different. Thus, because of hyperactivity and increase in the number of leukocytes, the blood plasma exhibited strong oxidative stress inducing damage to healthy cells, whereas the tumor growth zone showed the decrease in macrophage concentration, as well as in oxygen and ROS levels. These conditions favor intensive growth of tumor cells.


Paraganglioma of the Urinary Bladder: A Series of 22 Cases in a Single Center.
Paraganglioma of the urinary bladder (PUB) is rare in bladder cancer, and currently, a study examining large number of cases from a single center has not been reported. This study aimed to present the clinical features, treatments, pathological characteristics, and prognosis of PUB. From January 2006 to June 2016, 22 patients were pathologically diagnosed with PUB in our hospital. Their clinical records, operative notes, pathological reports, and follow-up records were retrospectively reviewed. The incidence of PUB in patients with bladder cancer was 0.92%. The mean age at diagnosis was 49.8 ± 14.6 years (range, 16-76 years) and the male to female ratio was 1:1. Fourteen cases (63.6%) were functional. The common indicative symptoms included hematuria (36.4%), hypertension (31.8%), micturition syncope (27.3%), headache (18.2%), and palpitation (13.6%). All neoplasms were completely resected via transurethral resection of bladder tumor (TURBT), en bloc transurethral resection with thulium-yag laser, or partial cystectomy. Most PUB samples were positive for immunohistochemical (IHC) staining markers such as chromogranin A (CgA), Synaptophysin (Syn), CD56, and S-100 protein, while negative for IHC markers such as cytokeratins (CKs) and Melan A. According to pathological reports, 72.7% of PUB cases were at stage T2, 18.2% at T3, and 9.1% at T4. Two cases (9.1%) with metastasis were malignant. Two patients (9.1%) were lost during follow-up, and the remaining 20 patients were followed up for a period of 67.8 ± 38.5 months (range, 6-130 months). Among them, 16 patients (80%) recovered after the surgery, 1 patient (5%) died of natural causes. PUB recurred in 3 patients (15%), and 1 patient among them died of PUB. Despite the rarity, PUB should be suspected in patients with unexplained symptoms such as micturition syncope, hematuria, hypertension, headache, or palpitation. Surgery and adjuvant therapies are effective treatments for PUB. Compared with open surgery, laparoscopic partial cystectomy and robot-assisted laparoscopic partial cystectomy are advantageous in the treatment of PUB. Long-term follow-up is recommended for patients with PUB.


Direct superresolution for realistic image reconstruction.
Traditional superresolution techniques employ optimizers, priors, and regularizers to deliver stable, appealing restorations even though deviating from the real, ground-truth scene. We have developed a non-regularized superresolution algorithm that directly solves a fully-characterized multi-shift imaging reconstruction problem to achieve realistic restorations without being penalized by improper assumptions made in the inverse problem. An adaptive frequency-based filtering scheme is introduced to upper bound the reconstruction errors while still producing more fine details as compared with previous methods when inaccurate shift estimation, noise, and blurring scenarios are considered.


Construction of a Band-Aid Like Cardiac Patch for Myocardial Infarction with Controllable H2 S Release.
Excessive or persistent inflammation incites cardiomyocytes necrosis by generating reactive oxygen species in myocardial infarction (MI). Hydrogen sulfide (H2 S), a gaseous signal molecule, can quickly permeate cells and tissues, growing concerned for its cardioprotective effects. However, short resident time and strong side effects greatly restrict its application. Herein, a complex scaffold (AAB) is first developed to slowly release H2 S for myocardial protection by integrating alginate modified with 2-aminopyridine-5-thiocarboxamide (H2 S donor) into albumin electrospun fibers. Next, a band-aid like patch is constructed based on AAB (center) and nanocomposite scaffold which comprises albumin scaffold and black phosphorus nanosheets (BPNSs). With near-infrared laser (808 nm), thermal energy generated by BPNSs can locally change the molecular structure of fibrous scaffold, thereby attaching patch to the myocardium. In this study, it is also demonstrated that AAB can enhance regenerative M2 macrophage and attenuate inflammatory polarization of macrophages via reduction in intracellular ROS. Eventually, this engineered cardiac patch can relieve inflammation and promote angiogenesis after MI, and thereby recover heart function, providing a promising therapeutic strategy for MI treatment.


Andropause: symptom management for prostate cancer patients treated with hormonal ablation.
Andropause, or the age-related decline in serum testosterone, has become a popular topic in the medical literature over the past several years. Andropause includes a constellation of symptoms related to lack of androgens, including diminished libido, decreased generalized feeling of well-being, osteoporosis, and a host of other symptoms. The andropause syndrome is very prominent in men undergoing hormonal ablation therapy for prostate cancer. Most significant in this population are the side effects of hot flashes, anemia, gynecomastia, depression, cognitive decline, sarcopenia, a decreased overall quality of life, sexual dysfunction, and osteoporosis with subsequent bone fractures. The concept of andropause in prostate cancer patients is poorly represented in the literature. In this article, we review the current literature on the symptoms, signs, and possible therapies available to men who cannot take replacement testosterone.


Acute, subchronic and chronic safety studies with genistein in rats.
Genistein is a phytoestrogen that occurs naturally in the diet, especially in soy based foods. There is wide spread interest in phytoestrogens as chemopreventive agents for a variety of diseases and cancers based on epidemiologic evidence. Although soy, and its constituents such as genistein, have been consumed at high levels in several Asian populations without apparent adverse effects, concern has been raised about potential adverse effects due to the estrogenic and other activities. Safety studies with genistein were conducted in the Wistar rat including two acute studies, two subchronic (4 weeks and 13 weeks) and a chronic 52-week dietary admix study. In the acute studies, genistein had a low order of toxicity. In the three repeated dose safety studies at doses up to 500 mg/kg/day, genistein was well tolerated. In all of the studies, decreased food consumption and body weight gain were observed at 500 mg/kg/day. The main hematological findings were decreased red blood cell parameters at 500 mg/kg/day with a compensatory increase in reticulocytes. For clinical chemistry, with the exception of a slight increase in gamma glutamyl transferase in male and female rats at the high dose, there were a number of other minor changes considered not toxicologically significant. At necropsy, there were relatively few macroscopic changes; in the 52-week study, dilation of the uterus with fluid at the high dose and cysts of the ovaries in treated animals were observed. Organ weight changes in male rats at the high dose of 500 mg/kg/day included increased kidney, spleen, adrenal and testes weights and for females included, increased liver, kidney, spleen, ovary and uterus weights. After 4 and 13 weeks of treatment with genistein, there were no treatment related histopathologic findings. After 26 and 52 weeks of treatment, histological changes were seen in the female reproductive organs (ovaries and uterus), and in males (epididymides and prostate), and bone, kidneys, heart, liver and spleen in both sexes. After 52 weeks of treatment of males, vacuolation of the epididymal epithelium at 500 mg/kg/day and inflammation of the prostate were recorded at a higher incidence at 50 and 500 mg/kg/day. In females, cytological changes in the uterus, squamous metaplasia at 50 and 500 mg/kg/day and hyperplasia at 500 mg/kg/day were observed. Furthermore, hydrometra of the uterus and findings in the vagina consisting of anestric or diestrus vaginal mucosa with vaginal mucification, hyperplastic epithelium and multifocal cystic degeneration were noted at 500 mg/kg/day. Atrophy of the ovaries increased in severity in animals at 50 and 500 mg/kg/day. Osteopetrosis (hyperostosis) was observed in male and female rats at 50 and 500 mg/kg/day along with a compensatory increase in extramedullary hemopoiesis in the spleen; females were more affected than males. Hepatocellular hypertrophy and minimal bile duct proliferation were recorded at a higher incidence in animals at 500 mg/kg/day. It is concluded that almost all of the treatment related findings in these studies are related to the estrogenic properties of genistein as a phytoestrogen and would be expected to occur with a compound with estrogenic activity. The hormonally related changes were considered to be functional in nature and thus not adverse effects. Most of the findings in these studies were limited to the high dose of 500 mg/kg/day and were reversible. The few findings observed at 50 mg/kg/day were relatively minor and in view of the functional (hormonally mediated) nature of the effects, were considered not adverse effects. The increased incidence of minimal bile duct proliferation and slightly increased gamma glutamyl transferase are indicative of a mild hepatic effect at the high dose of 500 mg/kg/day. The no observed adverse effect level (NOAEL) of genistein is considered to be 50 mg/kg/day based on the presence of mild hepatic effects at the high dose of 500 mg/kg/day. The no observed effect level (NOEL) is considered to be 5 mg/kg/day based on the hormonally induced functional changes at higher doses.


The advent of precision therapy in gastrointestinal malignancies: Targeting the human epidermal growth factor receptor family in colorectal and esophagogastric cancer.
Until recently, systemic therapy for gastrointestinal malignancies was restricted to relatively noncancer-specific cytotoxic chemotherapy. Over the last 15 years targeted therapies have become available, most notably bevacizumab in the case of advanced colorectal cancer. Unfortunately, there are no predictive biomarkers to guide the use of this agent. In this review article, we describe the advent of "Precision Medicine" (in part, the use of patient-specific molecular markers to inform treatment) in gastrointestinal cancers: The use of monoclonal antibodies targeting epidermal growth factor receptor in advanced colorectal cancer, and human epidermal growth factor receptor 2-neu in advanced esophagogastric cancer. In both instances, biomarkers help in selecting appropriate patients for such treatment.


Effects of an Integrated Neurofeedback System with Dry Electrodes: EEG Acquisition and Cognition Assessment.
Electroencephalogram (EEG) neurofeedback improves cognitive capacity and behaviors by regulating brain activity, which can lead to cognitive enhancement in healthy people and better rehabilitation in patients. The increased use of EEG neurofeedback highlights the urgent need to reduce the discomfort and preparation time and increase the stability and simplicity of the system's operation. Based on brain-computer interface technology and a multithreading design, we describe a neurofeedback system with an integrated design that incorporates wearable, multichannel, dry electrode EEG acquisition equipment and cognitive function assessment. Then, we evaluated the effectiveness of the system in a single-blind control experiment in healthy people, who increased the alpha frequency band power in a neurofeedback protocol. We found that upregulation of the alpha power density improved working memory following short-term training (only five training sessions in a week), while the attention network regulation may be related to other frequency band activities, such as theta and beta. Our integrated system will be an effective neurofeedback training and cognitive function assessment system for personal and clinical use.


Isolating, immunophenotyping and ex vivo stimulation of CD4+ and CD8+ gastric lymphocytes during murine Helicobacter pylori infection.
Helicobacter pylori infection is associated with severe chronic inflammation, yet the host immune response is rarely able to clear the bacterium. Thymus derived lymphocyte populations such as T helper 1, T helper 17, and T regulatory cells are known to play important roles in the chronicity of H. pylori infection as well as contributing to ongoing gastric pathology. It is yet to be established how these immune cell populations interact in the gastric environment during H. pylori infection. Mouse models of infection offer an opportunity to investigate these interactions in detail. Flow cytometric analysis provides excellent lymphocyte characterization due to its high specificity, sensitivity and potential to perform multiple simultaneous measurements. However, this requires a viable enriched single cell suspension after adequate tissue dissociation, which poses a challenge due to the heterogeneity of gastric tissue. We have evaluated several isolation techniques and have optimized a protocol to isolate and enrich lymphocytes from the H. pylori-infected murine stomach. EDTA/DTT followed by Collagenase IV digestion successfully dissociates an average of 1 × 10⁷ cells per mouse. Further enrichment using Lympholyte M gradient yields on average 4 × 106 CD45+ lymphocytes per stomach. Following isolation we compared lymphocyte stimulation by CD3/CD28, phorbol 12-myristate 13-acetate (PMA) and ionomycin or H. pylori lysate and determined that CD3/CD28 effectively induces stimulation of IFNγ and IL 17A, but impairs Foxp3 expression. Using an optimized protocol we observed a 2-fold increase of CD8+ IFNγ-expressing lymphocytes localized specifically to the gastric compartment during H. pylori infection. The mechanisms of H. pylori immunopathogenesis are still considered enigmatic, therefore this optimized protocol can help delineate further novel immune cell targets that mediate H. pylori-induced pathology and identify the correlates of immunity for vaccine development.


Pneumococcal nasopharyngeal carriage among children in Brazil prior to the introduction of the 10-valent conjugate vaccine: a culture- and PCR-based survey.
We performed two different approaches (broth enrichment step prior to culture (BEC) and PCR (BEPCR)) for detecting Streptococcus pneumoniae from nasopharyngeal specimens collected from 242 children aged <6 years attending one hospital (n = 140) and one childcare centre (n = 102) in a major urban area in Brazil. These specimens were collected immediately before the introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) and the 13-valent vaccine (PCV13) for routine use in Brazil. Results were compared with previous findings obtained with direct culture (DC) on a selective medium. Colonisation prevalence was 58·3% (n = 141), being higher among children attending the childcare centre (62·7% vs. 55%). The culture-based methods (DC and BEC) enabled the detection of S. pneumoniae in 119 (49·2%) and 115 (47·5%) children, respectively. The PCR-based method (BEPCR) was more sensitive and 137 (56·6%) carriers were identified. Twenty-six serogroups/serotypes were identified, predominantly 6B, 19F, 14, 6A, 15C and 23F. Multiple colonisation was observed in 13 (5·4%) children. The estimated serotypes coverage of available PCVs was 40·4% for the 10-valent (included in the Brazilian immunisation programme) and 55·8% for the 13-valent (only available in private clinics). The use of robust approaches to obtain a more realistic insight about the asymptomatic carrier status is of paramount importance to estimate and assess the impact of vaccine implementation. The combination between culture-based and molecular methods constitutes a suitable strategy.


Distinctive properties of biological neural networks and recent advances in bottom-up approaches toward a better biologically plausible neural network.
Although it may appear infeasible and impractical, building artificial intelligence (AI) using a bottom-up approach based on the understanding of neuroscience is straightforward. The lack of a generalized governing principle for biological neural networks (BNNs) forces us to address this problem by converting piecemeal information on the diverse features of neurons, synapses, and neural circuits into AI. In this review, we described recent attempts to build a biologically plausible neural network by following neuroscientifically similar strategies of neural network optimization or by implanting the outcome of the optimization, such as the properties of single computational units and the characteristics of the network architecture. In addition, we proposed a formalism of the relationship between the set of objectives that neural networks attempt to achieve, and neural network classes categorized by how closely their architectural features resemble those of BNN. This formalism is expected to define the potential roles of top-down and bottom-up approaches for building a biologically plausible neural network and offer a map helping the navigation of the gap between neuroscience and AI engineering.


Oscillating chemiluminescence systems: state of the art.
Oscillating chemiluminescence (CL) was reported for the first time about 30 years ago. Since then several systems based on addition of a chemiluminescent reagent to a known oscillator system or based on the light emitting features of one component of the oscillating system, have been described. This information, scattered in the scientific literature, is compiled in the present paper. Several oscillating CL systems, including those based on Belousov-Zhabotinskii and Orban oscillators, or horseradish peroxidase-catalyzed reactions, among others, are critically presented. The application of this type of oscillatory systems is also discussed, in analytical chemistry and for educational purposes.


Recyclable Polymer Supported DMAP Catalyzed Cascade Synthesis of α-Pyrones.
Polymer-supported catalysts have emerged as one of the sustainable and cost-effective alternatives in organic synthetic chemistry. We have developed the first polymer-supported DMAP catalyzed one-pot synthesis of diversely substituted α-pyrones. The cascade approach involves C5 conjugate addition of 5H-oxazol-4-ones to α,β-unsaturated-β-ketoesters followed by lactonization/elimination.


Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis.
The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and π-allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2 H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.


Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes.
Major changes in gene expression occur in the fetal brain to modulate the function of this organ postnatally. Thus, factors can alter the genomics of the fetal brain, predisposing to neurological disorders later in life. We hypothesized that the physiological dynamics of the immune system transcriptome of the fetal brain during the last stage of gestation will reveal patterns of immune function and development in the developing brain. In this study we applied weighted gene co-expression analysis of microarrays performed on ovine fetal brain samples, to model the changes in gene expression throughout the second half of gestation. Clusters of co-expressed genes that strongly increase in expression toward the first day of extra-uterine life are related to the hematopoietic lineage, while activation of immune pathways is induced after birth. Moreover, the pattern of gene expression suggests induction of tolerance mechanisms, probably necessary to protect highly produced proteins--such as myelin basic protein--from an autoimmune attack. This study provides insight into the dramatic changes in gene expression that take place in the brain during the fetal life, especially during the last stage of gestation, and suggests that the immune system may have an important role in maturation of the fetal brain, which if disrupted or altered, could have negative consequences in postnatal life.


Genetic polymorphisms: a cornerstone of translational biobehavioral research.
A new generation of interdisciplinary research seeks to use common functional genetic polymorphisms to model emergent variability in brain chemistry that regulates behaviorally relevant brain structure and function. This genetically mediated variability is then being mapped onto trajectories of risk for psychopathology, especially that precipitated by environmental adversity. This Perspective highlights a recent paper in Science that provides a powerful example of how a common functional genetic polymorphism can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways that mediate individual differences in behavior and in risk for psychopathology.


Lycopene Inhibits Metastasis of Human Liver Adenocarcinoma SK-Hep-1 Cells by Downregulation of NADPH Oxidase 4 Protein Expression.
NADPH oxidase 4 (NOX4), with the sole function to produce reactive oxygen species (ROS), can be a molecular target for disrupting cancer metastasis. Several studies have indicated that lycopene exhibited anti-metastatic actions in vitro and in vivo. However, the role of NOX4 in the anti-metastatic action of lycopene remains unknown. Herein, we first confirmed the anti-metastatic effect of lycopene (0.1-5 μM) on human liver adenocarcinoma SK-Hep-1 cells. We showed that lycopene significantly inhibited NOX4 protein expression, with the strongest inhibition of 64.3 ± 10.2% (P < 0.05) at 2.5 μM lycopene. Lycopene also significantly inhibited NOX4 mRNA expression, NOX activity, and intracellular ROS levels in SK-Hep-1 cells. We then determined the effects of lycopene on transforming growth factor β (TGF-β)-induced metastasis. We found that TGF-β (5 ng/mL) significantly increased migration, invasion, and adhesion activity, the intracellular ROS level, matrix metalloproteinase 9 (MMP-9) and MMP-2 activities, the level of NOX4 protein expression, and NOX activity. All these TGF-β-induced effects were antagonized by the incubation of SK-Hep-1 cells with lycopene (2.5 μM). Using transient transfection of siRNA against NOX4, we found that the downregulation of NOX4 could mimic lycopene by inhibiting cell migration and the activities of MMP-9 and MMP-2 during the incubation with or without TGF-β on SK-Hep-1 cells. The results demonstrate that the downregulation of NOX4 plays a crucial role in the anti-metastatic action of lycopene in SK-Hep-1 cells.


Registration of multi-modal images under a complex background combining multiscale features extraction and semantic segmentation.
Multi-modal imaging technology has a very broad application value in target recognition and other fields, and image registration is one of its key technologies. In this paper, a multi-modal image registration algorithm that combines multiscale features extraction and semantic segmentation is proposed to achieve accurate registration of polarized images and near-infrared images under complex backgrounds. A classical convolutional neural network ResNet is employed to capture the robust feature descriptors, and a convolutional neural network with an attention mechanism is trained to filter out the irrelevant feature points. Further, the two multi-modal images can be further registered. The experimental results show the feasibility and effectiveness of the proposed method.


Correction of Class III Malocclusion Treated with Carriere® Motion™.
Class III malocclusion needs complex orthodontic treatment. This case report describes a 16-year-old male patient with skeletal class III malocclusion with a negative overjet and overbite. Upper incisors were proclined with the accentuated curve of Wilson. Treatment has changed the functional curve of Wilson that has improved functional dynamic occlusion. The patient was treated using a Carriere® Motion™ Class III (CM3) and SLX 3D Brackets system. After a 25-month treatment, the patient reached class I molars and canines relationships on both sides with good facial aesthetics and good functional occlusion. The result was also satisfactory for the patient. A one-year follow-up confirmed that the outcome was stable.


Genomic and single-step evaluations of carcass traits of young bulls in dual-purpose cattle.
Genetic evaluations for carcass traits of young bulls in Normande and Montbeliarde breeds are currently being developed in France. In order to determine a suitable genomic evaluation for three carcass traits of young bulls, genomic breeding values were estimated for young candidates to selection using different approaches. Records of 111,789 Normande and 118,183 Montbeliarde were used. Average progeny pre-adjusted performances (DYD) were calculated for sires. Evaluation approaches were compared based on an assessment of their accuracy (correlation between DYD and estimated breeding values [EBVs]) and bias (regression coefficient of DYD on EBVs) on the 20% youngest AI sires. All genomic approaches were generally more accurate than BLUP (+.045 to +.116 correlation points), except for age at slaughter where single-step GBLUP (SSGBLUP) was the only genomic method leading to a greater accuracy (+.038 to +.126 points). The best setting of the SSGBLUP relationship matrix was characterized by a weight of 30% for pedigree information in the genomic relationship matrix. SSGBLUP was the most valuable evaluation approach for the evaluation of carcass traits of Normande and Montbeliarde young bulls.


Comment on "Effect of liquid temperature on sonoluminescence".
It has been suggested that bubble-wall velocities cannot exceed the sound speed in the liquid at the bubble wall [K. Yasui, Phys. Rev. E 64, 016310 (2001).10.1103/PhysRevE.64.016310]. Here we show that this upper bound was derived omitting the partial derivatives with respect to time, i.e., assuming that the flow was in the steady state. For collapsing bubbles, however, the steady-flow assumption requires justification, as the partial time derivatives appear to have the same orders of magnitude as the other terms in Euler's and the continuity equations. Furthermore, numerical solutions of the hydrodynamic equations with a hyades hydrocode yielded supersonic velocities in the liquid at and near the collapsing bubble. We also show the spatial distributions of pressure, density, sound speed, and mass flux density around the supersonically collapsing bubble.


Odour boosts visual object approach in flies.
Multisensory integration is synergistic-input from one sensory modality might modulate the behavioural response to another. Work in flies has shown that a small visual object presented in the periphery elicits innate aversive steering responses in flight, likely representing an approaching threat. Object aversion is switched to approach when paired with a plume of food odour. The 'open-loop' design of prior work facilitated the observation of changing valence. How does odour influence visual object responses when an animal has naturally active control over its visual experience? In this study, we use closed-loop feedback conditions, in which a fly's steering effort is coupled to the angular velocity of the visual stimulus, to confirm that flies steer toward or 'fixate' a long vertical stripe on the visual midline. They tend either to steer away from or 'antifixate' a small object or to disengage active visual control, which manifests as uncontrolled object 'spinning' within this experimental paradigm. Adding a plume of apple cider vinegar decreases the probability of both antifixation and spinning, while increasing the probability of frontal fixation for objects of any size, including a normally typically aversive small object.


Issues in implementing TANF in New York: the perspective of frontline workers.
The study discussed in this article examined the perspectives of front-line welfare workers on issues related to the implementation of TANF: domestic violence, work requirements, time limits for cash benefits, and functions of workers. Based on focus groups held in upstate New York, findings suggest a lack of criteria for the granting of exemptions from TANF requirements, worker resistance to serving those caught in the cycle of violence, and congruence between the legislation's "work first" strategy and worker preference. However, participants identified limitations to employment-focused welfare programs, including restrictions on education and job preparation. Further research is needed on the implementation of TANF, including use of the Family Violence Option, and on the use of administrative discretion by front-line workers.


A case-control study of early-stage radiological markers of endothelial dysfunction and cardiovascular findings in patients with osteogenesis imperfecta: genotype-phenotype correlations.
Osteogenesis imperfecta (OI) is a disease caused by defective collagen synthesis. Collagen type 1 is found in many structures in the cardiovascular system. Endothelial dysfunction, which develops prior to the emergence of structural and clinical signs of atherosclerosis, is believed to play a key role in atherogenesis. Endothelial dysfunction may be detected presymptomatically by non-invasive radiologic methods, such as flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT). These modalities may provide early indicators of endothelial dysfunction. This cross-sectional comparative study aimed to investigate early-stage radiological markers of endothelial dysfunction and cardiovascular diseases in OI patients and healthy controls and to investigate the correlation of findings with OI genotype. Thirty patients diagnosed with OI were paired with thirty healthy age- and gender-matched controls and echocardiogram findings were compared. None of the patients had known underlying cardiovascular disease. The mean age was 13.18 ± 2.91 years. According to Sillence classification, 15 patients had type 1 OI, 10 had type III, and 5 had type IV. Mean CIMT in the OI group was higher in the control group (OI group: 0.42 ± 0.06 vs. healthy controls: 0.34 ± 0.04 mm, p<0.01), and mean FMD percent was lower in the patient group (p<0.01). Left ventricular ejection fraction was 78.97 ± 10.32 vs. 77.56 ± 8.50 %, (OI group: 7.00 ± 3.06 vs. healthy controls: 12.14 ± 1.99, p=0.56), and fractional shortening was 42.68 ± 11.94 vs. 40.23 ± 7.99 %, (p=0.35), in OI patients and controls, respectively. Pediatric patients with OI without clinical signs of cardiovascular abnormality had significantly worse CIMT and FMD findings than healthy controls. However, no difference was determined when comparing left ventricular ejection fraction or fractional shortening. OI patients may need to be screened for cardiovascular system complications starting from an early age.


[Regulation of erythropoiesis in patients with suppressed hematopoiesis during mountain climatic treatment].
to estimate the regulation of erythropoiesis and the coagulation system in patients with suppressed hematopoiesis in a mountain hospital (3200 m above sea level). The investigation included 12 patients with aplastic anemia (AA) and 10 with idiopathic thrombocytopenic purpura (ITP). Blood was received at a Bishkek hospital, then on days 20 and 40 of stay in the mountains. The authors studied erythropoietin (EPO) by enzyme immunoassay (Protein Contour kit, Russia), serum ferritin (SF) by immunoradioassay (Immunotech kit, Czech Republic), hypoxia-inducible factor-1alpha (HIF-1alpha), homocysteine (HC), hepcidin, endothelin (ET), and thrombomodulin (TM) by sandwich enzyme immunoassay, by applying monospecific antisera and monoclonal antibodies against relevant antigens (IDG Int Inc, USA). On staying in the mountains, there was a gradual increase in the content of hemoglobin in patients with AA and ITP. On day 40, in keeping with higher hemoglobin (Hb) levels, both groups showed a decrease in HIF-1alpha concentrations to the normal values (from 8.2 to 4.5 pg/ml). Due to the anemic syndrome, baseline EPO was increased by 5-7 times in the patients from both groups. On days 20-40, the content of EPO showed a 1.3-2.5-fold increase. In AA, HC was almost 3 times greater than the normal values; in ITP, it was 1.5-fold increased. On day 20 and during the patients'stay in the mountains, the level of HC remained in the normal range in both groups. Hypoxic hypoxia positively affects a number of hematological parameters, by normalizing erythropoiesis (Hb, EPO, and HIF-1alpha), iron metabolism (SF), and the coagulation system (HC, ET, and TM).


Intrinsic and dynamical reaction pathways of an excited state proton transfer.
The detailed knowledge of excited state proton transfer mechanisms in complex environments is of paramount importance in chemistry. However, the definition of an effective reaction coordinate and the understanding of the driving force of the reaction can be difficult from both the experimental and the theoretical points of view. Here we analyzed by theoretical approaches the mechanism and the driving forces of the excited state proton transfer reaction occurring between the 7-hydroxy-4-(trifluoromethyl)coumarin photoacid and the 1-methylimidazole base molecules in toluene solution. In particular, we compared the intrinsic and the dynamical reaction pathways, obtained by integrating the reaction coordinate, and by performing ab initio simulations of molecular dynamics, respectively. Time-dependent density functional theory and polarizable solvation continuum models were adopted to define the excited state potential energy surface. Results were analyzed by means of the D(CT) electronic density based index. Our findings suggest that the reaction coordinate is mainly composed of several intra- and intermolecular modes of the reactants. An analysis of both the intrinsic coordinate and the dynamical results shows that the charge transfer induced by electronic excitation of the coumarin molecule is the main proton transfer driving force. With regards to the methodological validation, the combination of ab initio molecular dynamics with time-dependent density functional theory appears to be feasible and reliable to study excited state proton transfer reactions in the condensed phase.


Enhanced tumor development in mice lacking a functional type I interferon receptor.
The aim of this study was to investigate the contribution of endogenous - that is, without the addition of any interferon (IFN) inducer - type I IFN production in the defense against tumor development. To this purpose, the IFN-alpha receptor (IFNAR) knockout (KO)-induced mutation, resulting in the complete absence of IFN-alpha/beta activity, was introduced into a C3H genetic background by 10 backcross generations, followed by brother-sister matings for at least four generations. The resulting mice were inoculated either with syngeneic C3H melanoma K1735 cells, with allogeneic 3LL carcinoma cells, or with allogeneic B16F10 melanoma cells. With all three tumor cell lines, tumor development and ensuing mortality were enhanced in the IFNAR KO animals. This indicates that endogenous IFN-alpha/beta production is a mediator of natural immunity to tumor development.


TAT-SNAP-23 treatment inhibits the priming of neutrophil functions contributing to shock and/or sepsis-induced extra-pulmonary acute lung injury.
Respiratory burst function of neutrophils is thought to play a pivotal role in the development of pathologies such as indirect (extra-pulmonary) acute lung injury (iALI), as well as sepsis. The current study was conducted to determine the effect of an HIV transactivator of transcription (TAT)-fusion protein containing a soluble N-ethylmaleimide-sensitive factor attachment protein receptor domain from synaptosome-associated protein-23 (SNAP-23) on the shock/sepsis- and sepsis-enhanced neutrophil burst capacity using the clinical relevant two-hit iALI mouse model and the classical cecal ligation and puncture (CLP) septic model. TAT-SNAP-23 significantly decreased the blood neutrophil respiratory burst in vitro, and also in vivo in CLP and hemorrhaged mice. We found that the neutrophil influx to the lung tissue, as measured by myeloperoxidase levels and neutrophil-specific esterase(+) cells, was also decreased in the TAT-SNAP-23-treated group. Consistent with this, treatment of TAT-SNAP-23 significantly reduced the disruption of lung tissue architecture and protein concentration of bronchoalveolar lavage fluid in iALI mice compared with vehicle-treated iALI mice. In addition, although TAT-SNAP-23 did not alter the extent of local cytokine/chemokine expression, the in vitro migration capacity of neutrophils was blunted from septic and hemorrhagic mice. These data support our hypothesis that TAT-SNAP-23 reduces neutrophil dysfunction in iALI and sepsis by inhibiting neutrophil respiratory burst.


Diverse Distribution and Gene Expression on the 21-Gene Recurrence Assay in Breast Cancer Patients with Locoregional Recurrence Versus Distant Metastasis.
It remains uncertain whether the 21-gene recurrence score (RS) of a primary tumor has selective prognostic value for locoregional recurrence (LRR) or distant metastasis (DM). The current study aimed to compare the distribution and single-gene expression on the RS panel in breast cancer patients with LRR versus DM. Consecutive early breast cancer patients who had been operated on at the Comprehensive Breast Health Center, Ruijin Hospital from January 2009 to December 2016 were retrospectively reviewed. Patients were divided into LRR, DM, and no-recurrence groups according to the first reported recurrent event. Comparison and subgroup analysis of 21-gene RS, RS category, and single-gene expression on the RS panel were conducted among patients with different recurrence status. A total of 1,287 patients were included, with median follow-up of 61.5 months, and 27, 47, and 1,213 patients were classified as LRR, DM, and no recurrence groups, respectively. RS was significantly diversely distributed among the three groups (P<0.001). No-recurrence patients (median 22) presented much lower RS than LRR (median 39, P<0.001) and DM (median 30, P<0.001) patients. LRR patients had lower PR (P<0.001), BCL2 (P=0.010), and CEGP1 (P<0.001) expression, and DM patients had higher STMY3 (P=0.019) expression than no-recurrence patients. Moreover, CEGP1 expression was significantly lower in the LRR group than the DM one (P=0.028). RS was differently distributed between recurrent and nonrecurrent patients. PR, BCL2, CEGP1, and STMY3 expression was associated with LRR and DM, while CEGP1 was lower in the LRR group than DM patients, warranting further clinical evaluation.


[The peripheral vestibular disorders encountered in the routine out-patient practical work].
The objective of the present study was to elucidate the frequency of causes underlying the development of dizziness and vertigo in the patients seeking advice and care at an outpatient healthcare facility. A total of 590 patients with complaints of dizziness and vertigo were examined. It was found out that the peripheral disorders of the vestibular analyzer were the most frequent causes of dizziness and vertigo in the majority of the examined patients. These conditions were documented to occur in more than 65% of the patients. The most common forms of peripheral vestibular disorders were benign paroxysmal positional vertigo, Meniere's disease, and vestibular neuronitis. The central vestibular disorders occurred considerably less frequently than peripheral ones and were diagnosed only in 10.9% of the patients. The results of the study provided a basis for the development of the algorithm forthe bedside examination of the patients presenting with vertigo and dizziness associated with peripheral vestibular disorders. It is emphasized that such examination should include, besides the standard neurological studies, the neuro-otological tests making it possible to detect the most common forms of peripheral vestibular disorders.


Biology of PXR: role in drug-hormone interactions.
Hormonal homeostasis is essential for a variety of physiological and pathological processes. Elimination and detoxification of xenobiotics, such as drugs introduced into the human body, could disrupt the balance of hormones due to the induction of drug metabolizing enzymes (DMEs) and transporters. Pregnane X receptor (PXR, NR1I2) functions as a master xenobiotic receptor involved in drug metabolism and drug-drug interactions by its coordinated transcriptional regulation of phase I and phase II DMEs and transporters. Recently, increasing evidences indicate that PXR can also mediate the endocrine disruptor function and thus impact the integrity of the endocrine system. This review focuses primarily on the recent advances in our understanding of the function of PXR in glucocorticoid, mineralocorticoid, androgen and estrogen homeostasis. The elucidation of PXR-mediated drug-hormone interactions might have important therapeutic implications in dealing with hormone-dependent diseases and safety assessment of drugs.


Effect of hemodialysis session on the dynamics of carnitine ester profile changes in L-carnitine pretreated end-stage renal disease patients.
Carnitine deficiency is common in end-stage renal disease (ESRD) patients receiving hemodialysis (HD) treatment. We investigated the effects of L-carnitine supplementation on acyl carnitine (AC) profile and the changes of distinct ACs during a single HD session in long-term L-carnitine pretreated ESRD patients. Twenty non-diabetic adult patients and 37 healthy controls were studied. Blood samples were drawn before and after 12 weeks of carnitine supplementation, then hourly during an HD session, as well as 30 min after the end of the session. Free and individual AC plasma levels were determined by using ESI MS/MS technique. HD patients showed lower free- and total carnitine levels and elevated ACs and acyl/free carnitine ratio before carnitine supplementation. The L-carnitine supplementation resulted in dramatic elevation of all carnitine esters. The HD session induced a progressive decline in free, short-chain, and dicarboxylic ACs (~80 % of pre-HD amount was washed out); the decrease of medium-chain ACs proved to be more moderate (~60 % washed out), whereas the long-chain ACs remained unaffected. Already 30 min after HD, a substantial increase was seen in free carnitine concentration (reaching 26 % of predialysis level) and the ACs also started to replenish (to 21-52 % of predialysis levels), without further exogenous carnitine load. The washout induced by HD session results in variable depletion of short-, medium-, and long-chain carnitine esters in carnitine-pretreated patients; the recovery of the circulating carnitine esters from the body stores occurs within 30 min after the cessation of the HD procedure.


Facile and green assembly of nanocomposite membranes for fuel cells.
We report on a facile spray deposition method, which allows obtaining nanocomposite membranes for high-temperature polymer fuel cells characterized by high homogeneity and excellent proton conductivity. The proposed method is also green, as it requires much smaller amounts of solvents with respect to standard casting.


Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial).
Complications of catheter ablation for atrial fibrillation (AF) are frequently related to vascular access. We hypothesized that ultrasound-guided (USG) venipuncture may facilitate the procedure and reduce complication rates. We conducted a multicentre, randomized trial in patients undergoing catheter ablation for AF on uninterrupted anticoagulation therapy. The study enrolled consecutive 320 patients (age: 63 ± 8 years; male: 62%) and were randomized to USG or conventional venipuncture in 1:1 fashion. It was prematurely terminated due to substantially lower-than-expected complication rates, which doubled the population size needed to maintain statistical power. While the complication rates did not differ between two study arms (0.6% vs. 1.9%, P = 0.62), intra-procedural outcome measures were in favour of the USG approach (puncture time, 288 vs. 369 s, P < 0.001; first pass success, 74% vs. 20%, P < 0.001; extra puncture attempts 0.5 vs. 2.1, P < 0.001; inadvertent arterial puncture 0.07 vs. 0.25, P < 0.001; unsuccessful cannulation 0.6% vs. 14%, P < 0.001). Though these measures varied between trainees (49% of procedures) and expert operators, between-arm differences (except for unsuccessful cannulation) were comparably significant in favour of USG approach for both subgroups. Ultrasound-guided puncture of femoral veins was associated with preferable intra-procedural outcomes, though the major complication rates were not reduced. Both trainees and expert operators benefited from the USG strategy. (www.clinicaltrials.gov ID: NCT02834221).


Endocrine Aspects of Environmental "Obesogen" Pollutants.
Growing evidence suggests the causal link between the endocrine-disrupting chemicals (EDCs) and the global obesity epidemics, in the context in the so-called "obesogenic environment". Dietary intake of contaminated foods and water, especially in association with unhealthy eating pattern, and inhalation of airborne pollutants represent the major sources of human exposure to EDCs. This is of particular concern in view of the potential impact of obesity on chronic non-transmissible diseases, such as type 2 diabetes, cardiovascular disease, and hormone-sensitive cancers. The key concept is the identification of adipose tissue not only as a preferential site of storage of EDCs, but also as an endocrine organ and, as such, susceptible to endocrine disruption. The timing of exposure to EDCs is critical to the outcome of that exposure, with early lifetime exposures (e.g., fetal or early postnatal) particularly detrimental because of their permanent effects on obesity later in life. Despite that the mechanisms operating in EDCs effects might vary enormously, this minireview is aimed to provide a general overview on the possible association between the pandemics of obesity and EDCs, briefly describing the endocrine mechanisms linking EDCs exposure and latent onset of obesity.


The role of glycine and prolines in connective tissue fiber staining with hydrogen bonding dyes.
Extensive hydrogen bonding of dyes to connective tissue fibers is made possible by the high content of the amino acids proline and glycine in elastin and collagens. Proline confers an extended polypeptide structure and glycine is the only amino acid whose specific side group, -H, is so small that it forms no obstacle to hydrogen bonding between the peptide group and external molecules. Thus, a high proportion of the peptide groups in fibrous proteins are directly accessible to hydrogen bonding groups dye molecules.


Toposelective vapor deposition of hybrid and inorganic materials inside nanocavities by polymeric templating and vapor phase infiltration.
Selective deposition of hybrid and inorganic materials inside nanostructures could enable major nanotechnological advances. However, inserting ready-made composites inside nanocavities may be difficult, and therefore, stepwise approaches are needed. In this paper, a poly(ethyl acrylate) template is grown selectively inside cavities via condensation-controlled toposelective vapor deposition, and the polymer is then hybridized by alumina, titania, or zinc oxide. The hybridization is carried out by infiltrating the polymer with a vapor-phase metalorganic precursor and water vapor either via a short-pulse (atomic layer deposition, ALD) or a long-pulse (vapor phase infiltration, VPI) sequence. When the polymer-MO x hybrid material is calcined at 450 °C in air, an inorganic phase is left as the residue. Various suspected confinement effects are discussed. The infiltration of inorganic materials is reduced in deeper layers of the cavity-grown polymer and is dependent on the cavity geometry. The structure of the inorganic deposition after calcination varies from scattered particles and their aggregates to cavity-capping films or cavity-filling low-density porous deposition, and the inorganic deposition is often anisotropically cracked. A large part of the infiltration is achieved already during the short-pulse experiments with a commercial ALD reactor. Furthermore, the infiltrated polymer is more resistant to dissolution in acetone whereas the inorganic component can still be heavily affected by phosphoric acid.


Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study.
Among the most prominent features associated with antiphospholipid syndrome (APS) are cerebral ischaemic events (CVE). Pregnancy with APS increases the risk of thrombosis, including CVE. This study was undertaken to assess the risk of obstetric complications and recurrence of CVE during pregnancy in women with APS and previous CVE. We prospectively observed 23 pregnancies in 20 women (median age 31 years) with primary (n = 8) or secondary APS (n = 12). Eight patients had transient ischaemic attacks (TIA) and 12 had stroke before pregnancy. All patients received aspirin 100 mg daily in combination with low molecular weight heparin (LMWH) during their pregnancies. The live birth rate was 91.3% (n = 21). Obstetrical complications consisted mainly of preeclampsia (n = 8, 34.8%) and preterm delivery (n = 9, 42.9%). The risk for preeclampsia increased in patients who were positive for multiple antiphospholipid antibodies (aPL) (odds ratio (OR) 3.06 (95% confidence interval (CI) 1.01-9.32)) per positive aPL test (i.e anticardiolipin antibody, anti-ß2-glycoprotein I antibody, lupus anticoagulant) (p 0.049). Three patients experienced recurrent CVE in the context of pregnancy (one during pregnancy, two in the postpartum period). We found an increased, but not significant, risk of a new episode of cerebral ischaemia in patients with pregnancies complicated by preeclampsia (two out of the eight preeclampsia (p 0.15). Despite treatment, there is a significant risk for pregnancy complications in APS patients with previous CVE. Especially in the context of preeclampsia, anticoagulation should be given rigorously to prevent recurrence of CVE.


[Chinese expert surgical procedure consensus on open pericardial devascularization(2021)].
Although the treatment strategy of esophageal and gastric varices bleeding in portal hypertension has been diversified and multidisciplinary now,the surgical treatment represented by pericardial devascularization operation will still play an important and irreplaceable role in China. In order to standardize the surgical procedure,guide clinical practice and improve the level of surgical treatment of portal hypertension,Chinese Society of Spleen and Portal Hypertension Surgery,Chinese Surgical Society,Chinese Medical Association organized Chinese experts to formulate this consensus. The main contents include:the position of surgical treatment,surgical indications and contraindications,preoperative evaluation,key points and precautions of surgical procedure,perioperative treatment,prevention and treatment of postoperative complications. The consensus emphasizes the standardization of surgical treatment of portal hypertension,pay attention to the prevention and treatment of postoperative portal vein thrombosis,and expect to provide surgeons with clinical guidance.


Potentiation by guanine nucleosides of the growth-inhibitory effects of adenosine analogs on L1210 and sarcoma 180 cells in culture.
The growth-inhibitory effect of 6-methylmercaptopurine riboside (MMPR) against leukemia L1210 cells in culture was dramatically potentiated by the addition of guanine nucleosides to the medium. In the presence of either deoxyguanosine or guanosine, the concentration of MMPR that caused 50% inhibition of growth was 35 times lower than in the absence of these nucleosides. Similar potentiation was also observed against Sarcoma 180 cells in culture by guanosine. The metabolic basis of this synergism was approached in a study of the incorporation of [14C]glycine into 5'-phosphoribosyl-N-formylglycinamide in Sarcoma 180 cells. The results show that the site of inhibition resulting in synergism is an early step in purine biosynthesis, probably phosphoribosyl pyrophosphate amidotransferase (EC 188.8.131.52). In the L1210 cell system, the addition of hypoxanthine to the medium prevented the potentiation of MMPR by guanine nucleosides supporting the conclusion that the site of the synergistic interaction involves purine biosynthesis de novo. While hypoxanthine partially reversed the growth-inhibitory effects of MMPR, an even higher degree of protection was observed in the presence of both uridine and hypoxanthine, suggesting that MMPR may have additional sites of action concerned with pyrimidine metabolism.