Redox-dependent control of FOXO/DAF-16 by transportin-1.
Forkhead box O (FOXO; DAF-16 in worms) transcription factors, which are of vital importance in cell-cycle control, stress resistance, tumor suppression, and organismal lifespan, are largely regulated through nucleo-cytoplasmic shuttling. Insulin signaling keeps FOXO/DAF-16 cytoplasmic, and hence transcriptionally inactive. Conversely, as in loss of insulin signaling, reactive oxygen species (ROS) can activate FOXO/DAF-16 through nuclear accumulation. How ROS regulate the nuclear translocation of FOXO/DAF-16 is largely unknown. Cysteine oxidation can stabilize protein-protein interactions through the formation of disulfide-bridges when cells encounter ROS. Using a proteome-wide screen that identifies ROS-induced mixed disulfide-dependent complexes, we discovered several interaction partners of FOXO4, one of which is the nuclear import receptor transportin-1. We show that disulfide formation with transportin-1 is required for nuclear localization and the activation of FOXO4/DAF-16 induced by ROS, but not by the loss of insulin signaling. This molecular mechanism for nuclear shuttling is conserved in C. elegans and directly connects redox signaling to the longevity protein FOXO/DAF-16.


Understanding Factors Contributing to Inappropriate Critical Care: A Mixed-Methods Analysis of Medical Record Documentation.
Factors leading to inappropriate critical care, that is treatment that should not be provided because it does not offer the patient meaningful benefit, have not been rigorously characterized. We explored medical record documentation about patients who received inappropriate critical care and those who received appropriate critical care to examine factors associated with the provision of inappropriate treatment. Medical records were abstracted from 123 patients who were assessed as receiving inappropriate treatment and 66 patients who were assessed as receiving appropriate treatment but died within six months of intensive care unit (ICU) admission. We used mixed methods combining qualitative analysis of medical record documentation with multivariable analysis to examine the relationship between patient and communication factors and the receipt of inappropriate treatment, and present these within a conceptual model. One academic health system. Medical records revealed 21 themes pertaining to prognosis and factors influencing treatment aggressiveness. Four themes were independently associated with patients receiving inappropriate treatment according to physicians. When decision making was not guided by physicians (odds ratio [OR] 3.76, confidence interval [95% CI] 1.21-11.70) or was delayed by patient/family (OR 4.52, 95% CI 1.69-12.04), patients were more likely to receive inappropriate treatment. Documented communication about goals of care (OR 0.29, 95% CI 0.10-0.84) and patient's preferences driving decision making (OR 0.02, 95% CI 0.00-0.27) were associated with lower odds of receiving inappropriate treatment. Medical record documentation suggests that inappropriate treatment occurs in the setting of communication and decision-making patterns that may be amenable to intervention.


Treatment of a cluster headache patient in a hyperbaric chamber.
A patient with severe cluster headaches was treated in a hyperbaric chamber on two occasions. Her symptoms had been refractory to other treatment modalities including conventional oxygen therapy. On both occasions her pain was promptly relieved while breathing 100% oxygen at two atmospheres of pressure. This is the first known reported case of a cluster headache treated with hyperbaric oxygen. A prospective study is needed to substantiate the efficacy of this treatment modality for cluster headaches.


Quality of dying in head and neck cancer patients: a retrospective analysis of potential indicators of care.
The objective of this study was to evaluate the quality of the dying experience in a cohort of head and neck cancer patients by a retrospective analysis of potential indicators of care. The study design included retrospective case note analysis of previously evaluated factors considered important in the care of terminally ill patients and validated indicators of care obtainable from administrative data. The documented factors were analyzed to indicate specific elements of the quality of death and dying experience. Pain was a common symptom (84%) and was managed successfully in all patients, with 93% receiving opioids. Management of other symptoms, except neuropsychological problems, were satisfactory. Sixty-three percent of patients died in hospital and only 22% had a relative present at the time of death. Resuscitation status was documented in only 65% of the notes, though none were admitted to the intensive care unit or underwent resuscitation. Fifty-three percent of patients were admitted as an emergency in the last month of life and bleeding was the most common cause of admission. Valuable information can be obtained from a focused retrospective analysis. The indicators evaluated suggest that biomedical aspects of care are being recognized and addressed, although there is room for improvement. Psychosocial and spiritual aspects of care were not documented and must be taken into account to assess the "complete quality of dying" experience.


CPR or DNR? End-of-life decision in Korean cancer patients: a single center's experience.
Whether or not physicians should conduct cardiopulmonary resuscitation (CPR) in terminal cancer patients has long been debated. We conducted this prospective observational study to characterize current CPR and do-not-resuscitate (DNR) practice among terminal cancer patients in South Korea. The study involved patients with terminal cancer who were admitted at the Seoul National University Boramae Hospital for supportive care only, and who died between January 1, 2003 and April 30, 2004. We investigated the practices relating to the DNR directive, i.e., how many days before death was the directive effective, and from whom was it obtained. Of the enrolled 165 patients, 97 were male with a mean age of 65. Median duration of admission to death was 24 days (range 7-207, mean 31.7). The DNR directive was implemented in 143 patients (86.7%). All discussions about DNR took place between physician and family members, except in only one case. DNR directives were enacted at a median of 8.0 days (range 0-79, mean 12.15) before death. For 18 patients, the DNR directive was formally taken on the day of admission. In contrast, 14 cases (9.8%) were agreed on the day of death, 18.8% within 48 h of death, and 46.8% (67 of 143) within 1 week before death, 62% before 10 days, and 71.3% within 2 weeks. The worse the performance status of the patient, the earlier the DNR discussion was issued. Also, the lower the economic and educational status of the family member, the earlier the DNR directive was attained. Of the 165 patients with terminal cancer, CPR was performed in 13 cases (7.9%): in seven cases (4.2%) CPR was requested by a family member, and in six cases arrest occurred before DNR discussion was issued. None of the resuscitated patients survived. In relation to DNR decisions in South Korean cancer patients, proxy decision-making is overwhelming and issuance of DNR discussion is raised at a late stage.


Expression of the gene coding for the major outer capsid protein of SA-11 rotavirus in a baculovirus system.
The gene coding for the major outer capsid protein (VP7) of simian rotavirus SA-11 has been expressed in a baculovirus-insect cell system. The resulting protein is 35 kDa and is primarily associated with the endoplasmic reticulum. Neutralizing SA-11 polyclonal antiserum and VP7 monospecific antiserum reacted specifically with the expressed gene product. Antiserum derived against the recombinant VP7 protein neutralized SA-11 rotavirus infectivity in a fluorescent focus assay.


Right heart in septic shock: prospective observational study.
The right heart often receives less attention during echocardiography. The situation is no different in septic shock. We prospectively investigated the echocardiographic indices of the right heart in septic shock adult patients. Septic shock ICU patients within 24 h of admission were subjected to transthoracic echocardiography (TTE) as per the 2005 guidelines from the American Society of Echocardiography. Eighty-eight septic shock patients (M:F = 52:36) underwent TTE. Thirty-six patients survived. Significant differences in demographic and biochemical (laboratory and metabolic) parameters, severity scores, life-support therapies (vasopressors, ventilation), and length of ICU stay were observed between survivors and non-survivors. Right heart abnormalities of chamber dimension and systolic and diastolic function existed in 79, 25, and 86 % of patients, respectively. Right ventricle subcostal wall thickness (91 %), pulse Doppler myocardial performance index (73 %), and E/E' (63 %) were the predominant abnormalities in chamber dimension, systolic function, and diastolic function of the right heart, respectively. However, the presence of these abnormalities did not signify poor survival in our study. Right heart dimensional and functional abnormalities exist in high proportions in septic shock. However, their predictability of poor outcomes remains questionable.


Isolation of a CENTRORADIALIS/TERMINAL FLOWER1 homolog in saffron (Crocus sativus L.): characterization and expression analysis.
Genes in the phosphatidyl-ethanolamine-binding protein (PEBP) family are instrumental in regulating the fate of meristems and flowering time. To investigate the role of these genes in the monocotyledonous plant Crocus (Crocus sativus L), an industrially important crop cultivated for its nutritional and medicinal properties, we have cloned and characterized a CENTRORADIALIS/TERMINAL FLOWER1 (CEN/TFL1) like gene, named CsatCEN/TFL1-like, the first reported CEN/TFL1 gene characterized from such a perennial geophyte. Sequence analysis revealed that CsatCEN/TFL1 shows high similarity to its homologous PEBP family genes CEN/TFL1, FT and MFT from a variety of plant species and maintains the same exon/intron organization. Phylogenetic analysis of the CsatCEN/TFL1 amino acid sequence confirmed that the isolated sequences belong to the CEN/TFL1 clade of the PEBP family. CsatCEN/TFL1 transcripts could be detected in corms, flower and flower organs but not in leaves. An alternative spliced transcript was also detected in the flower. Comparison of expression levels of CsatCEN/TFL1 and its alternative spliced transcript in wild type flower and a double flower mutant showed no significant differences. Overexpression of CsatCEN/TFL1 transcript in Arabidopsis tfl1 plants reversed the phenotype of early flowering and terminal flowering of the tfl1 plants to a normal one. Computational analysis of the obtained promoter sequences revealed, next to common binding motifs in CEN/TFL1-like genes as well as other flowering gene promoters, the presence of two CArG binding sites indicative of control of CEN/TFL1 by MADS-box transcription factors involved in crocus flowering and flower organ formation.


The effect of large milk meals on digestive physiology and behaviour in dairy calves.
It is commonly believed that young calves should not be fed more than about 2l of milk per meal. If calves are fed beyond this volume, it is said that the capacity of the abomasum may be exceeded and that milk could enter the rumen. This can disturb the microbial flora/fauna of the rumen and increase the risk of indigestion, diarrhoea and reduced growth. The aim of this study was to examine the effect of large milk meals on digestive physiology and behaviour in dairy calves. Six calves (19-23days of age at the beginning of the experiment) were fed 2l of warm whole milk by teat bottle three times per day, which was the recommended Norwegian feeding regime at the time. The calves were given free access to hay, concentrates and water. During three morning feeding sessions, each separated by 48h, all calves were offered larger meals. The offered amounts were calculated according to the within patient 3-level Response Surface Pathway (RSP) design. The milk given on the three test days contained a contrast medium (barium sulphate), and the animals were radiographed before, during and immediately after intake to reveal whether milk entered the rumen. Four out of the six calves drank more than 5l in one meal and the highest voluntary intake was 6.8l in one meal (13.2% of BW). Abdominal radiographs showed that the abomasum has a large ability for distension. Milk in the rumen was not observed in any of the calves, regardless of intake. The behaviour of the calves was observed for 2h after each test session. No behaviour indicating abdominal pain or discomfort was observed regardless of intake. The results indicate that when warm whole milk is administered from a teat bottle, farmers can increase the amount of milk they offer their calves beyond the traditionally recommended portion size without risk of milk entering the rumen. Hence, farmers who want to feed their calves more milk can do so by increasing meal sizes, and not necessarily by introducing an additional meal.


Near-ultraviolet light-induced strand breaks in DNA pretreated with the carcinogen, N-acetoxy-2-acetylaminofluorene.
Neutral sucrose gradients of supercoiled DNA (phiX-174 RF I) were used to measure the in vitro production of strand breaks by the carcinogen, N-acetoxy-2-acetylaminofluorene (AcO-AAF). Treatment with AcO-AAF in 10% dimethyl sulfoxide did not directly yield strand breaks. Breaks in relatively low yield appeared after alkali treatment (pH 13, 60 min) of the RF I previously reacted with AcO-AAF. The DNA treated with AcO-AAF was sensitive to single-strand breakage by 303 nm near-ultraviolet light under neutral conditions. The greater the prior AcO-AAF treatment, the greater the sensitivity to 303 nm light. Post-irradiation alkali treatment greatly enhanced the light-induced strand breakage.


[Application of ultrahigh-field MRI in neuro-oncology].
The introduction of high-field magnetic resonance imaging (MRI) into neuro-oncological imaging allows improved visualization of tumor structures even in the field of T1 and T2-weighted imaging. Susceptibility-weighted imaging (SWI) and time of flight (TOF) angiography in particular greatly benefit from the high field strength. The visualization of tumor vasculature in MRI, which was made possible by high-field technology can potentially be applied to monitoring antiangiogenic therapy. Cerebral metastases can potentially be discovered earlier using high-field technology. Furthermore, high-field technology permits the use of new technologies, such as sodium imaging, which is expected to provide new information in the field of tumor pathophysiology.


A single exon codes for the enzyme domain of a protozoan cysteine protease.
Theileria parva is an intracellular protozoan parasite of cattle. We have determined the nucleotide sequence of a gene and cDNA coding for a cysteine protease of T. parva. The gene is divided into two exons. The first exon codes for a signal sequence and for part of the "pro" region of the zymogen. The second exon codes for the remainder of the pro region, including residues thought to be involved in zymogen processing, and for the entire enzyme domain. Part of this exon cross-hybridizes, at high stringency, with DNA isolated from Plasmodium falciparum. It is likely that the T. parva gene is functionally active. Parasite extracts contain hydrolytic activity against benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin. This activity is optimal at pH 6.0 and is inhibited by the cysteine protease inhibitor L-trans-epoxysuccinyl-leucylamido(4-guanidino)butane (E-64). This is, to our knowledge, the first description of a gene coding for a eukaryotic cysteine protease which lacks an intron in DNA coding for the enzyme domain.


[Study of the chemical and immunogenic properties of the capsular Staphylococcus aureus antigen. 2. Evaluation of the immunogenic properties of the capsular antigen in experiments in vitro].
Albino mice were immunized with a purified capsular antigen isolated from the S. aureus strain 1193/74. The presence of specific anticapsular antibodies in the sera of animals were determined by two methods: 1) by conversion of diffuse growth of a homologous strain into compact one, and 2) by determination of opsonic index in phagocytosis of homologous staphylococci by human neutrophils. It was revealed that antibodies converting the microbical growth were absent in the sera of normal mice and reached the highest level after the second antigen injection; opsonins were present in the sera of normal mice in widely varying quantities; their maximal level was noted after the 3rd immunization.


Novel delivery of pancreatic islet cells to treat insulin-dependent diabetes mellitus.
Immune protective devices containing pancreatic islets are designed to treat insulin-dependent diabetes mellitus by providing glycaemic control without immunosuppression. The immune protection is achieved by separating allogeneic or xenogeneic islets from the host by semipermeable membranes that allow only small molecules such as glucose, insulin and nutrients to pass through. Lymphocytes and immunoglobulins are excluded by the membrane and unable to cause rejection of the islets. Three types of immune protective devices, i.e. microcapsules, diffusion chambers and perfusion devices (vascularised artificial pancreas), have been studied. Microcapsules injected into the abdominal cavity in a large quantity achieved glycaemic control, but required a small amount of immunosuppression to prevent fibrosis around the the capsules. A clinical attempt to use microcapsulated human islets in a diabetic patient who has maintained functional kidney allografts has been reported. Intra-abdominal placement of diffusion chambers containing allogeneic islets achieved excellent glycaemic control without immunosuppression in diabetic dogs. However, their use was limited by the eventual breakage of tubular chambers. We have extensively used the vascularized artificial pancreas for treatment of experimental diabetes mellitus. Excellent biocompatibility of the device was evidenced by the extraordinary longevity of the patency of the device in healthy dogs. Long term control of severe diabetes mellitus was achieved in totally pancreatectomised dogs without immunosuppression by devices seeded with allogeneic (canine) and xenogeneic (porcine) islets. The vascularised artificial pancreas could be an excellent alternative to Diabetes Control and Complication Trial (DCCT)-type intensive insulin therapy or pancreatic transplantation by providing tight glycaemic control with minimal exogenous insulin therapy without immunosuppression.


[Construction and characterization of a mutant strain of Listeria monocytogenes with a deletion of actA and plcB].
The virulence of Listeria monocytogenes is directly related to its ability to spread from cell to cell without leaving the intracellular milieu. Among the bacterial factors involved in cell-to-cell spread, actin-polymerizing protein ActA is required for bacterial spread to adjacent cells, while the broad-range phospholipase C (PC-PLC) contributes to bacterial escape from secondary vacuoles. Based on homologous recombination technology, we constructed a double gene-mutant strain by deleting two virulence factors, ActA and PC-PLC. Its toxicity and immunopotency was evaluated in murine model. And then, the mutant strain was further verified the absence of ActA and PC-PLC using Western blot analysis and phospholipase activity assay. It showed highly attenuated and its 50% lethal dose in BLAB/c mice was increased at least 10(3)-fold compared to the parent strain. Nevertheless, mice preimmunized with the mutant strain elicited strong T-cell responses and fully protected against a lethal challenge with the virulent strain. These results not only verified that ActA and PC-PLC were essential virulence factors for L. monocytogenes, but also demonstrated that the mutant strain possessed good immunogenicity with higher safety. The mutant strain could be further studied as a vaccine candidate to prevent listeriosis and used as a vector to deliver heterologous antigens. Furthermore, it provided the possibilities to elucidate the molecular mechanisms of pathogenesis and immune response triggered by L. monocytogenes.


Differential effects of morphine and D-amphetamine on self-stimulation from closely adjacent regions in rat midbrain.
The effects of morphine were investigated on self-stimulation from numerous electrode placements in the area of the substantia nigra or in the ventral half of mesencephalic central gray matter. Before pharmacological testing, current intensity was reduced to yield stable, submaximal rates of self-stimulation. Rats were then injected daily with morphine for 10 days, and were tested three hours after injection. Between days 5 and 10 of treatment, many rats self-stimulated at more than 150% of baseline, but some others reduced self-stimulation to as little as 3% of baseline. Histological evaluation revealed that morphine facilitated self-stimulation when the electrode tip was located more than 0.3 mm from substantia nigra or more than 0.2 mm from the midline of central gray. In rats with electrode tips closer to substantia nigra or to the midline of central gray, morphine often reduced or failed to alter self-stimulation rates. The effects of a low dose of D-amphetamine (0.1 mg/kg) were investigated on electrode placements in the substantia nigra area. Placements close to the dorsal border of substantia nigra yielded less facilitation of self-stimulation by D-amphetamine than did placements located more dorsally or medially. Possible catecholaminergic substrates of these differential effects are discussed.


Rates of iron(III) reduction coupled to elemental sulfur or tetrathionate oxidation by acidophilic microorganisms and detection of sulfur intermediates.
Bioleaching processes and acid mine drainage (AMD) generation are mainly driven by aerobic microbial iron(II) and inorganic sulfur/compound oxidation. Dissimilatory iron(III) reduction coupled to sulfur/compound oxidation (DIRSO) by acidophilic microorganisms has been described for anaerobic cultures, but iron reduction was observed under aerobic conditions as well. Aim of this study was to explore reaction rates and mechanisms of this process. Cell-specific iron(III) reduction rates for different Acidithiobacillus (At.) strains during batch culture growth or stationary phase with iron(III) (∼40 mM) as electron acceptor and elemental sulfur or tetrathionate as electron donor (1% or 5 mM, respectively) were determined. The rates were highest under anaerobic conditions for the At. ferrooxidans type strain with 6.8 × 106 and 1.1 × 107 reduced iron(III) ions per second per cell for growth on elemental sulfur and tetrathionate, respectively. The iron(III) reduction rates were somehow lower for the anaerobically sulfur grown archaeon Ferroplasma acidiphilum, and lowest for the sulfur grown At. caldus type strain under aerobic conditions (1.7 × 106 and 7.3 × 104 reduced iron(III) ions per second per cell, respectively). The rates for five strains of At. thiooxidans (aerobe) were in between those for At. ferrooxidans (anaerobe) and At. caldus (aerobe). There was no pronounced pH dependence of iron(III) reduction rates in the range of pH 1.0-1.9 for the type strains of all species but rates increased with increasing pH for four other At. thiooxidans strains. Thiosulfate as sulfur intermediate was found for At. ferrooxidans during anaerobic growths on tetrathionate and iron(III) but not during anaerobic growths on elemental sulfur and iron(III), and a small concentration was measured during aerobic growths on tetrathionate without iron(III). For the At. thiooxidans type strain thiosulfate was found with tetrathionate grown cells under aerobic conditions in presence and absence of iron(III), but not with sulfur grown cells. Evidence for hydrogen sulfide production at low pH was found for the At. ferrooxidans as well as the At. thiooxidans type strains during microaerophilic growth on elemental sulfur and for At. ferrooxidans during anaerobic growths on tetrathionate and iron(III). The occurrence of sulfur compound intermediates supports the hypothesis that chemical reduction of iron(III) ions takes place by sulfur compounds released by the microbial cells.


Axoplasmic transport of transfer RNA in the chick optic system.
It has previously been shown that 4S RNA is transported in the optic nerve of the chick, but that no movement of rRNA can be detected. The 4S component behaved as though it were composed mainly of transfer RNA (tRNA), but the possibility remained that it could contain significant amounts of material resulting from RNA degradation. The transport of this 4S component has been examined in more detail to determine its nature. In addition, the transported material was examined to establish whether the transport of tRNA is a general phenomenon or that there are only a limited number of species involved. This was done using the same principles applied in the previous study; i.e., the specific activities of separated 4S RNA species appearing in the optic tectum 4 days after intraocular injection of [3H]uridine were compared with that of 5S RNA, a nontransported species. The separation was accomplished using 2.8-5-10-17% slab polyacrylamide gels, and 18 separate regions of 4S species could be identified. The results show that at least most, if not all 4S RNA species are transported. In a separate series of experiments the 4S RNA was aminoacylated and again separated on slab gels. In this instance, the RNA was labelled with [3H]uridine and the aminoacyl component with [14C]amino acids. Gel profiles of these dual-labelled components showed excellent correspondence between the two labels, demonstrating that 4S RNA species could be aminoacylated and were therefore tRNA species.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence of binge-eating and bulimia among adolescent women in Japan.
This study examined by questionnaire the prevalence of binge-eating and bulimia among 220 women at a school of nursing and 236 women at a junior college, all from 18 to 21 years old, in two different areas of Japan. Binge-eating more than once a week was found in 14 (6.5%) of the nursing school students and 21 (9.1%) of the college women. Self-induced vomiting and use of purgatives were found in 19 (8.7%) and 12 (5.5%) of the nursing school students, and 19 (8.1%) and 9 (3.8%) of the college women, respectively. The difference between these two groups was not significant. The prevalence of binge-eating more than once a week, together with self-induced vomiting or purgative use, was 3.6% in the nursing school students, 2.1% in the college women, and 2.9% in the total sample. These women appeared to meet both DSM-III criteria for bulimia and Russell's criteria for bulimia nervosa.


The profiles of chiral pesticides in peri-urban areas near Yangtze River: Enantioselective distribution characteristics and correlations with surface sediments.
Chiral pesticides account for 30% of pesticides. Pesticides are inevitably leached into the groundwater by runoff. At the watershed level, the distribution characteristics of enantiomers in sediments collected from the river network of an agricultural area near the middle and lower reaches of the Yangtze River were tested, and their potential correlations with the physicochemical properties and microbial communities of the sediments were analyzed. The sediment pollution was serious at sites 8 and 9, with their pollution source possibly being agricultural or industrial sewage. Moreover, there were higher cumulative contents of pesticide residues at sites 4, 8, and 9. Specifically, Cycloxaprid was the most detected chiral pesticide in the study area, followed by Dinotefuran and Diclofop-methyl. Additionally, Ethiprole and Difenoconazole had strong enantioselectivity in the study area. Interestingly, the enantiomers of some chiral pesticides, such as Tebuconazole, had completely different distributions at different sites. Pearson correlation analysis showed that sediment catalase and microbial biomass carbon were important factors for enantioselectivity of chiral pesticides. The effect of sediment physicochemical properties on enantioselective distribution was achieved by influencing the microorganisms in the sediment. Furthermore, the enantioselective distribution of Tebuconazole was closely related to the genus Arenimonas. Overall, the enantioselective distribution of most of the chiral pesticides was positively correlated with the prokaryotic microbial community. This study provides empirical support for agricultural non-point source pollution caused by chiral pesticides, and also lays a research foundation for exploring the factors that affect the fate of chiral pesticides in the environment.


Contemporary Strategies and Outcomes of Dedicated Chronic Total Occlusion Percutaneous Coronary Intervention Programs: A Prospective Multicentre Registry.
The field of CTO PCI is expanding, but successful and safe percutaneous coronary intervention (PCI) of coronary chronic total occlusions (CTO) requires a substantial resource and experience investment. We aimed to assess temporal trends in strategies and outcomes of 2 dedicated programs for CTO PCI. Between 2011 and 2020, 920 CTO PCI procedures were prospectively included at 2 referral centres in Belgium. Temporal trends were assessed, and logistic regression models were built to identify predictors of outcome. Despite an increase in lesion complexity (the J-CTO score increased from 1.3 in year 1 to 1.7-2.0 in years 8-9, p < 0.001), technical success improved from 70.0% to 85.6% in year 9 (p value for trend <0.001). We observed the most significant improvement starting at years 3-4 (OR 2.3 in year 4 versus year 1, p=0.018). Together with an increase in success rates and lesions complexity, there was an increase in the use of dual injections, retrograde approaches, the number of balloons and stents, and the use of microcatheters. Conversely, there was a decrease in large bore access, an increase in radial approach, and a shift towards contemporary dissection/reentry techniques. This strategy resulted in a stable major complication rate of 4.7% (p value for trend 0.33). The rate of coronary procedure-related myocardial injury was high (71.0%) and was associated with the use of more intracoronary devices. Three to four years after initiation of a dedicated CTO PCI program with 50 CTO PCIs per year, consistent high technical success and low complication rates are achieved using contemporary strategies.


Treatment of Middle Cerebral Artery Aneurysms with Flow-Diverter Stents: A Systematic Review and Meta-Analysis.
The safety and efficacy of flow-diversion treatment of MCA aneurysms have not been well-established. Our aim was to evaluate angiographic and clinical outcomes after flow diversions for MCA aneurysms. A systematic search of PubMed, MEDLINE, and Embase was performed for studies published from 2008 to May 2017. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we selected studies with >5 patients describing angiographic and clinical outcomes after flow-diversion treatment of MCA aneurysms. Random-effects meta-analysis was used to pool the following outcomes: aneurysm occlusion rate, procedure-related complications, rupture rate of treated aneurysms, and occlusion of the jailed branches. Twelve studies evaluating 244 MCA aneurysms were included in this meta-analysis. Complete/near-complete occlusion was obtained in 78.7% (95% CI, 67.8%-89.7%) of aneurysms. The rupture rate of treated aneurysms during follow-up was 0.4% per aneurysm-year. The rate of treatment-related complications was 20.7% (95% CI, 14%-27.5%), and approximately 10% of complications were permanent. The mortality rate was close to 2%. Nearly 10% (95% CI, 4.7%-15.5%) of jailed arteries were occluded during follow-up, whereas 26% (95% CI, 14.4%-37.6%) had slow flow. Rates of symptoms related to occlusion and slow flow were close to 5%. Small and retrospective series could affect the strength of the reported results. Given the not negligible rate of treatment-related complications, flow diversion for MCA aneurysms should be considered an alternative treatment when traditional treatment methods are not feasible. However, when performed in this select treatment group, high rates of aneurysm occlusion and protection against re-rupture can be achieved.


Is there a secular trend in age of menopause?
A review of the difficulties encountered in analyzing a secular trend in age of menopause is given with emphasis on the advantages and disadvantages of the recollective and "status quo" methods. It is suggested that no methodology except that which is prospective will give accurate ages of menopause. Accepting this given, a review of the literature from 1864 to 1964 is undertaken, that suggests there may be a secular trend in Denmark, England, France, Germany, Russia and the USA. This must, however, be corroborated by longitudinal, cross cultural, generational research of mothers' and daughters' ages at menopause, or at least, cohort analysis of specific populations.


Heterogeneity of human natural killer recognition demonstrated by cloned effector cells and differential blocking of cytotoxicity with monoclonal antibodies.
Monoclonal antibodies (MoAb) against cell surface determinants were employed to investigate the specificity of natural killer (NK)-like lysis by cloned human effector cells recognizing only K562, only HSB2, or both K562 and HSB2 target cells. MoAb W6/32.HL, TU39, YD1/48.HLK, and anti-Tac failed to inhibit lysis despite the expression of antigens bound by these MoAb on the effector cell surface. MoAb OKT3 moderately (less than or equal to 50%) blocked lysis of K562 and HSB2 targets, whereas MoAb 13.1, which binds T200 molecules, strongly (up to 95%) blocked lysis of K562, but not HSB2, targets. MoAb 13.1 inhibited lysis by clones which killed only K562, as well as lysis by those which killed both HSB2 and K562. In the latter case, however, only lysis of K562 was inhibited. Taken together, these results may suggest the existence of multiple receptor specificities on a single NK-active clone.


Helicobacter pylori-pulsed dendritic cells induce H. pylori-specific immunity in mice.
The growing concern over the emergence of antibiotic-resistant Helicobacter pylori infection is propelling the development of an efficacious vaccine to control this highly adaptive organism. We studied the use of a dendritic cell (DC)-based vaccine against H. pylori infection in mice. The cellular immune responses to murine bone marrow-derived DCs pulsed with phosphate-buffered saline (PBS-DC) or live H. pylori SS1 (HP-DC) were assessed in vitro and in vivo. The protective immunity against H. pylori SS1 oral challenge was compared between HP-DC or PBS-DC immunized mice. The effect of regulatory T-cell (Treg) depletion by anti-CD25 antibody on HP-DC vaccine efficacy was also evaluated. HP-DC induced a Th1-dominant response in vitro. In vivo, HP-DC immunized mice were characterized by a mixed Th1/Th2 peripheral immune response. However, in the stomach, HP-DC immunized mice expressed a higher level of IFN-gamma compared to PBS-DC immunized mice; no difference was found for interleukin-5 expressions in the stomach. A lower bacterial colonization post-H. pylori challenge was observed in HP-DC immunized mice compared to PBS-DC immunized mice with no significant difference in gastritis severity. H. pylori-specific Th1 response and protective immunity were further enhanced in vivo by depletion of Treg with anti-CD25 antibody. DC-based anti-H. pylori vaccine induced H. pylori-specific helper T-cell responses capable of limiting bacterial colonization. Our data support the critical role of effector cellular immune response in the development of H. pylori vaccine.


The use of analgesic drugs in postoperative patients: the neglected problem of pain control in intensive care units. An observational, prospective, multicenter study in 128 Italian intensive care units.
The use of analgesic drugs in patients admitted to Italian intensive care units (ICUs) was assessed. An observational, prospective, cohort study was conducted, involving all adult patients admitted during a 1-month period in 128 Italian general ICUs. The use of analgesic drugs was evaluated for the first 2 postoperative days in surgical patients who stayed in ICU for at least 2 days. We observed 661 postoperative patients who underwent elective (72%) or emergency surgery. Of the patients with an ICU stay of at least 2 days, 49% did not receive any opioids in the first 48 postoperative hours, and more than 35% did not receive any analgesic at all. The most used opioid was fentanyl, followed by morphine and buprenorphine. Among the 336 patients who received at least one opioid, as many as 42% had only a single bolus per day. Pain control was reported as the reason for drug use in 54.5% of opioid administrations, while control of anxiety covered 10.3% of them. The probability of receiving an opioid was lower for patients in coma. Management of postoperative pain in Italian ICUs was insufficient, particularly in neurosurgical and comatose patients. A general lack of knowledge about pain and misconceptions about pain drugs may be at the basis of these results.


Levels of miR-31 and its target genes in dermal mesenchymal cells of patients with psoriasis.
Psoriasis is characterized by chronic inflammatory dermatosis, and the pathogenesis of psoriasis is associated with mesenchymal stem cells (MSCs) and deregulation of the expression of miR-31. This study aimed to clarify the function of miR-31 in dermal MSCs (DMSCs) in the pathogenesis of psoriasis. The expression of miR-31 was assayed by a microarray and that of target genes of miR-31 was tested by quantitative PCR. The expression of miR-31 in the psoriasis group was 0.2677 folds that of the control group. The expression of EMP1 and EIG121L genes, whose products are located on the cell membrane, in the psoriasis group was 4.095579 and 5.367017 folds that in the control group, respectively. The expression of GRB10, PTPN14, QKI, RNF144B, and TACC2 genes, whose products are located in the cytoplasm, in the psoriasis group was 1.440428, 1.198335, 1.737285, 7.379546, and 1.531947 folds that of the control. The expression of PRELP, whose products are secreted in the extracellular space, in the psoriasis group was 1.351684 folds that of the control. The expression of RBMS1, KHDRBS3, and SATB2, whose products play a role in the nucleus, in the psoriasis group was 2.237199, 1.277159, and 1.005742 folds that of the control, respectively. Our results suggest that the low expression of miR-31 in DMSCs in patients with psoriasis causes an increase in the expression of some of its target genes, which in turn facilitates T lymphocyte activation by inhibiting the proliferation of DMSCs and therefore participates in the pathogenesis of psoriasis.


Septic bursitis in immunocompromised patients.
A retrospective analysis of 29 patients with septic bursitis was undertaken to ascertain if immunocompromised patients differed in their clinical presentations, type of organisms cultured, and outcome when compared with their non-immunocompromised cohorts. Thirty episodes of septic bursitis occurred in 29 patients, 43 percent of which occurred in immunocompromised patients. Despite similar clinical presentations, the bursae of immunocompromised patients took three times longer to sterilize and had a much higher bursal white blood cell count when compared with the bursae of non-immunocompromised patients. The bacteriologic spectrum was essentially identical in both groups; there were no cases in which gram-negative organisms were recovered from infected bursae. No cases of septic bursitis were seen in neutropenic patients. The most common factors contributing to an immunocompromised state were alcoholism or steroid therapy. A successful resolution of septic bursitis was seen in all the patients in the immunocompromised groups.


Botanical origin discrimination of Greek honeys: physicochemical parameters versus Raman spectroscopy.
The authenticity of honey is of high importance since it affects its commercial value. The discrimination of the origin of honey is of prime importance to reinforce consumer trust. In this study, four chemometric models were developed based on the physicochemical parameters according to European and Greek legislation and one using Raman spectroscopy to discriminate Greek honey samples from three commercial monofloral botanical sources. The results of physicochemical (glucose, fructose, electrical activity) parameters chemometric models showed that the percentage of correct recognition fluctuated from 92.2% to 93.8% with cross-validation 90.6-92.2%, and the placement of test set was 79.0-84.3% successful. The addition of maltose content in the previous discrimination models did not significantly improve the discrimination. The corresponding percentages of the Raman chemometric model were 95.3%, 90.6%, and 84.3%. The five chemometric models developed presented similar and very satisfactory results. Given that the recording of Raman spectra is simple, fast, a minimal amount of sample is needed for the analysis, no solvent (environmentally friendly) is used, and no specialized personnel are required, we conclude that the chemometric model based on Raman spectroscopy is an efficient tool to discriminate the botanical origin of fir, pine, and thyme honey varieties. © 2020 Society of Chemical Industry.


Changes in Surface Charge Density of Blood Cells in Fatal Accidental Hypothermia.
The objective of this research was to evaluate postmortem changes concerning electric charge of human erythrocytes and thrombocytes in fatal accidental hypothermia. The surface charge density values were determined on the basis of the electrophoretic mobility measurements of the cells conducted at various pH values of electrolyte solution. The surface charge of erythrocyte membranes after fatal accidental hypothermia increased compared to the control group within whole range of experimental pH values. Moreover, a slight shift of the isoelectric point of erythrocyte membranes towards high pH values was observed. The surface charge of thrombocyte membranes in fatal accidental hypothermia decreased at low pH compared to the control group. However, at pH range 4-9, the values increased compared to the control group. The isoelectric point of thrombocyte membranes after fatal accidental hypothermia was slightly shifted towards low pH values compared to the control group. The observed changes are probably connected with the partial destruction and functional changes of the blood cell structure.


Particular pollutants, human health risk and ecological risk of oil-based drilling fluid: a case study of Fuling shale gas field.
Samples of new oil-based drilling fluid (NOBDF) and circulating oil-based drilling fluid (COBDF) in Chongqing were tested and analyzed to evaluate the possible impact of oil-based drilling fluid (OBDF) on human health and ecological environment. Organic matter, metals, and naturally occurring radionuclide materials (NORMs) in OBDF samples were analyzed and determined by gas chromatography-mass spectrometry, high-performance liquid chromatography, PANalytical Axios Fast XRF spectrometer, and gamma ray spectrometer. The results revealed that the contents of trace metals and NORMs in OBDF were less, which would not cause local ecological risk or health risk to the drilling crew. However, the concentrations of various aromatics analyzed in OBDF were very high, which was easy to pose serious environmental and health hazards. There were 8 aromatic hydrocarbons (AHs) in NOBDF and 15 AHs in COBDF. And the total carcinogenic risk value of each aromatic hydrocarbon was far greater than 10-4, which belonged to an unacceptable level. In addition, the inhalation pathway seemed to be the most significant source of carcinogenic risk, accounting for 99% of the total carcinogenic risk. Meanwhile, it is recommended to equip drilling workers with gas masks and develop all-oil biodiesel drilling fluid.


Myofibroblasts in subepicardium after local cold injury.
Rat hearts were exposed and injured locally by direct cryoapplication. The hearts were examined 2, 4, 20 and 48 hours, 7 and 12 days later. In the first 48 hours mast cell and polymorphonuclear (mainly eosinophilic) granulocyte infiltration was followed by proliferation of mononuclear phagocytic and fibroblastic cells and new capillaries. The underlying muscle showed freeze-thaw-rigor damage, segmental intramyofiber necrosis, phagocytosis and focal regeneration. After 7 days numerous myofibroblasts appeared and they were intimately related to myofibers undergoing degeneration and repair. After 12 days there was increased fibrosis while mesothelial covering cells of the epicardium and myofibers returned to normal. It is suggested that amines released from mast cells are involved in the formation of myofibroblasts.


Investigation of diffusion length distribution on polycrystalline silicon wafers via photoluminescence methods.
Characterization of the diffusion length of solar cells in space has been widely studied using various methods, but few studies have focused on a fast, simple way to obtain the quantified diffusion length distribution on a silicon wafer. In this work, we present two different facile methods of doing this by fitting photoluminescence images taken in two different wavelength ranges or from different sides. These methods, which are based on measuring the ratio of two photoluminescence images, yield absolute values of the diffusion length and are less sensitive to the inhomogeneity of the incident laser beam. A theoretical simulation and experimental demonstration of this method are presented. The diffusion length distributions on a polycrystalline silicon wafer obtained by the two methods show good agreement.


Monte Carlo modelling of live-timed anticoincidence (LTAC) counting for Cu-64.
The radionuclide copper-64 is a promising candidate for nuclear medicine, but its complex decay creates challenges in the primary standardization of its activity. Monte Carlo simulations of live-timed anticoincidence (LTAC) counting of 64Cu were used to calculate corrections to extrapolation intercepts, resulting in improved activity determinations. A small correction (-0.33%) to the linear extrapolation of LTAC data acquired with a γ-gate over the 1346keV gamma peak was determined. We discuss the physical origin of the correction. We also use experimental data to demonstrate a Monte Carlo scaling that allows for inclusion of data acquired with a γ-gate set over the annihilation photon peak(s).


P3a from white noise.
P3a and P3b event-related brain potentials (ERPs) were elicited with an auditory three-stimulus (target, distracter, and standard) discrimination task in which subjects responded only to the target. Distracter stimuli consisted of white noise or novel sounds with stimulus characteristics perceptually matched. Target/standard discrimination difficulty was manipulated by varying target/standard pitch differences to produce relatively easy, medium, and hard tasks. Error rate and response time increased with increases in task difficulty. P3a was larger for the white noise compared to novel sounds, maximum over the central/parietal recording sites, and did not differ in size across difficulty levels. P3b was unaffected by distracter type, decreased as task difficulty increased, and maximum over the parietal recording sites. The findings indicate that P3a from white noise is robust and should be useful for applied studies as it removes stimulus novelty variability. Theoretical perspectives are discussed.


[Surgical treatment of proximal humeral fractures anatomical plate versus palm tree pinning (26 cases)].
The aim of this study is to compare functional and radiological results of two surgical techniques in treatment of proximal humeral fractures. A prospective study was performed, which included 12 patients operated for a proximal humeral fracture by open reduction and internal fixation using an anatomical humeral plate, and another group of patient (14 patients) treated for the same lesion using a palm tree pinning technique of Kapandji. The comparison of results of the two techniques was based on three parameters: the time of healing, quality of reduction, and the functional result. The global mean age was 48.6 (±13,7), and the sex ratio (M/W) was 1. Statistical analysis of functional and radiological results showed no superiority of one technique over another; so the mean time of healing was 6.1 (± 0.7) weeks in the group treated by plate, and 6 (± 0.7) weeks in the group treated by pinning (P=0.5), the mean absolute Constant score was respectively 86 (±10.4) and 90.92 (±2.5) (P=0.09), and the mean measuring of cephalic angle was respectively 46.91 (±17.68) and 55.71 (±19.48) (P=0.24). Univariate analysis showed no statistically significant association between endpoints and the two surgical techniques studied. Therefore the study showed no statistical superiority of one surgical technique over another.


Experimental investigation of biostimulatory effects after polydioxanone thread insertion in a pig model.
Polydioxanone (PDO) threads have been widely used to tighten and lift the facial soft tissue. This research aims to determine the collagenation and inflammation changes that occur in the adipose tissue over time when different types of threads are implanted. Three threads types, PDO, poly glycolic-co-lactic acid (PGLA), and nylon, were inserted in the subcutaneous fat of 12-month-old Bama miniature pigs. Collagen production and inflammatory response were evaluated by hematoxylin and eosin and Masson trichrome staining at 1, 4, 12, 24, and 48 weeks. The integrity of the PDO thread lasted up to 24 weeks with mild inflammation and collagen production. The PGLA thread integrity lasted until 12 weeks and had a strong inflammatory response. The nylon thread's integrity was maintained for 48 weeks and showed minor inflammation and collagen production. Our data suggest that PDO thread is the best choice for clinicians, as it has a mild action process with minimal irritation, moderate collagen production, a reasonable explanation time, with obvious bridging fibrous tissue, and thickening action for the superficial fascia.


Stimulus-secretion coupling and insulin secretion in aging: evaluation of glucose oxidation and ATP-sensitive potassium channel responsiveness.
The purpose of this study was to evaluate possible age-related alterations in the glucose-stimulus/insulin-secretion coupling mechanism of islets of Langerhans. To this end, the interaction among insulin secretion, glucose oxidation, and ATP-sensitive potassium (K ATP) channel responsiveness was determined in islets of Langerhans isolated from 6-, 12-, and 26-month-old male Fischer 344 (F344) rats. Groups of 20 islets were incubated for 40 min at 37 degrees C in a buffer containing: (1) either 1.7 or 11.1 mM glucose; (2) 1.2 microM glyburide and either 1.7 or 11.1 mM glucose; (3) 5 microM epinephrine and 11.1 mM glucose; or (4) 1.2 microM glyburide, 5 microM epinephrine, and either 1.7 or 11.1 mM glucose. Insulin release of islets incubated in the presence of glyburide and 1.7 or 11.1 mM glucose was greater than that of islets incubated in glucose alone, while glucose oxidation did not increase. Epinephrine inhibited insulin release and glucose oxidation at 11.1 mM glucose and abolished glyburide-enhanced insulin release at 11.1 mM glucose. No effect of age was observed in any of the treatment categories. These results indicate that if age-related alterations are occurring in glucose-stimulus/insulin-secretion coupling, then such alterations are not associated with changes in K ATP channel-mediated responsiveness.


The use of slow heating and slow cooling regimens to strengthen porcelain fused to zirconia.
Porcelain fused to zirconia prostheses are widely used. However, porcelain chipping, spalling, fracture, and delamination are common clinical problems. Residual stresses of thermal origin have received attention, but clear data and firing guidelines remain absent. The purpose of this study was to measure the influence of heating and cooling protocols on the strength of porcelain fused to zirconia. A modified 4-point flexural testing technique was used to measure strength, and porcelain buttons were bonded to the beam between the 2 central loading points. Beams (n=54) were made of a tetragonal polycrystalline zirconium dioxide that was partially stabilized with an yttria core and a feldspathic dental porcelain. Three different heating rates and 3 different cooling regimens were used during firing. Two-way analysis of variance (ANOVA) was used to evaluate the 2 main effects of the heating and cooling regimens and their interaction with the delamination force (α=.05). The Tukey multiple comparisons test was used to identify differences among heating or cooling regimens. During loading, the porcelain buttons separated from the zirconia beams because of delamination within the porcelain, which was close to the porcelain to zirconia interface. ANOVA revealed that the effects of the cooling regimen and heating rate had statistically significant effects on failure load (P<.05). The effect of the cooling regimen was greater than that of the heating regimen. Slow cooling and slow heating regimens should be used when firing porcelain to zirconia. Cooling regimens were found to be more influential than heating rates. Failure was localized to the porcelain adjacent to the porcelain-zirconia interface, not to the interface itself, indicating that the residual stresses of thermal origin within the porcelain dominated. The preparation of zirconia with 50 μm aluminum oxide at a pressure of 0.34 MPa was sufficient to prevent interfacial failure.


Correction to: Goats in the city: prevalence of Giardia duodenalis and Cryptosporidium spp. in extensively reared goats in northern India.
In the original publication of this article [1] the supplementary file was missing two primers for the PCR reaction and the PCR conditions of Giardia and Cryptosporidium. In this correction article the updated additional file (Additional file 1) is available, in which the two primers are included.


The phenomenon of strain degeneration in biotechnologically relevant fungi.
Fungi are widely exploited for large-scale production in the biotechnological industry to produce a diverse range of substances due to their versatility and relative ease of growing on various substrates. The occurrence of a phenomenon-the so-called fungal strain degeneration-leads to the spontaneous loss or decline of production capacity and results in an economic loss on a tremendous scale. Some of the most commonly applied genera of fungi in the biotechnical industry, such as Aspergillus, Trichoderma, and Penicillium, are threatened by this phenomenon. Although fungal degeneration has been known for almost a century, the phenomenon and its underlying mechanisms still need to be understood. The proposed mechanisms causing fungi to degenerate can be of genetic or epigenetic origin. Other factors, such as culture conditions, stress, or aging, were also reported to have an influence. This mini-review addresses the topic of fungal degeneration by describing examples of productivity losses in biotechnical processes using Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, and Penicillium chrysogenum. Further, potential reasons, circumvention, and prevention methods are discussed. This is the first mini-review which provides a comprehensive overview on this phenomenon in biotechnologically used fungi, and it also includes a collection of strategies that can be useful to minimize economic losses which can arise from strain degeneration. KEY POINTS: • Spontaneous loss of productivity is evident in many fungi used in biotechnology. • The properties and mechanisms underlying this phenomenon are very versatile. • Only studying these underlying mechanisms enables the design of a tailored solution.


Cryovolcanism on the Earth: Origin of a Spectacular Crater in the Yamal Peninsula (Russia).
Geological activity on icy planets and planetoids includes cryovolcanism. Until recently, most research on terrestrial permafrost has been engineering-oriented, and many related phenomena have received too little attention. Although fast processes in the Earth's cryosphere were known before, they have never been attributed to cryovolcanism. The discovery of a couple of tens of meters wide crater in the Yamal Peninsula aroused numerous hypotheses of its origin, including a meteorite impact or migration of deep gas as a result of global warming. However, the origin of the Yamal crater can be explained in terms of cryospheric processes. Thus, the Yamal crater appears to result from collapse of a large pingo, which formed within a thaw lake when it shoaled and dried out allowing a large talik (that is layer or body of unfrozen ground in a permafrost area) below it to freeze back. The pingo collapsed under cryogenic hydrostatic pressure built up in the closed system of the freezing talik. This happened before the freezing completed, when a core of wet ground remained unfrozen and stored a huge amount of carbon dioxide dissolved in pore water. This eventually reached gas-phase saturation, and the resulting overpressure came to exceed the lithospheric confining stress and the strength of the overlying ice. As the pingo exploded, the demarcation of the crater followed the cylindrical shape of the remnant talik core.


The effectiveness and cost of passive warming in adult ambulatory surgery patients.
Hypothermia is a common problem for surgical patients and can result in many complications. Because few studies compare methods of passive warming, we used an unblinded, prospective, experimental, randomized design to compare the effectiveness of two passive methods of normothermia management in the postanesthesia care unit (PACU). We assigned a total of 578 adult ambulatory surgery patients to either a control group that was given two folded, warmed cotton blankets or a treatment group that was given a warmed, unfolded cotton sheet and cotton blanket. We recorded patients' temperatures on their arrival in the PACU and at 30 minutes after arrival. The treatment group had temperatures that were significantly higher than those of the control group 30 minutes after arrival in the PACU, and the treatment group experienced a greater change in temperature from baseline measurements to those taken at 30 minutes. The treatment group also used fewer warmed blankets, resulting in cost savings for the PACU.


Neural discharge in the superior colliculus during target search paradigms.
Neural studies of oculomotor function in the past have been conducted with the use of very simple visual stimuli. More recently there has been a new emphasis on using more natural stimuli to extend our knowledge of oculomotor organization. Visual search paradigms are an example of the use of these more natural visual surrounds. In search a subject must locate and saccade to a target that appears simultaneously with an array of distractors. When monkeys are used in this paradigm, it is possible to record from neurons located in various central structures in the brain while the initial visual response, subsequent discrimination processes and final saccadic movement unfold. In the present study we used an array of four visual stimuli, and the target was distinguished by its odd color from three distractors of uniform color. Location of the target within the array and its color were randomly selected on each trial. Neurons located in the deeper layers of the superior colliculus (SC) were recorded by standard methods in blocks of search trials. We found several new features in the discharge of SC neurons using this search paradigm that have not previously been reported in studies using single-target visual displays. (1) In contrast to the "winner take all" behavior previously reported for the SC, we found evidence of concurrent processing of alternative movement vectors. When incorrect movements were made to distractor locations, this concurrent activity was associated with significantly shorter intersaccadic intervals. (2) The discharge profile of the visual response in many units was modified by the appearance of a second prominent peak which followed the initial phasic visual response, but which was clearly differentiated from a third burst in activity associated with a saccade into the cell's response field. In some neurons, the activity in this second peak was discriminatory for the impending saccade vector. That is, it was larger when the target appeared in the response field of the cell than when it contained a distractor. This target selection signal was thus distinct from the burst normally associated with saccades into the movement fields of SC neurons. (3) Some saccades in search had a curved trajectory bowing toward the location of a distractor. These saccades were accompanied by an elevated discharge of neurons coding that distractor.


Contribution of the transmembrane domain 6 of melanocortin-4 receptor to peptide [Pro5, DNal (2')8]-gamma-MSH selectivity.
The melanocortin receptor (MCR) subtype family is a member of the GPCR superfamily and each of them has a different pharmacological profile regarding the relative potency of the endogenous and synthetic melanocortin peptides. Substitution of Trp with DNal (2') in gamma-MSH resulted in the loss of binding affinity and potency at hMC4R. However, the molecular mechanism of this ligand selectivity is unclear. In this study, we utilized chimeric receptors and site-directed mutagenesis approaches to investigate the molecular basis of MC4R responsible for peptide [Pro5, DNal (2')8]-gamma-MSH selectivity. Cassette substitutions of the second, third, fourth, fifth, and sixth TM of the human MC4R (hMC4R) with the homologous regions of hMC1R were constructed and the binding affinity of peptide [Pro5, DNal (2')8]-gamma-MSH at these chimeric receptors was evaluated. Our results indicate that the cassette substitutions of TM2, TM3, TM4 and TM5 of hMC4R with homologous regions of the hMC1R did not significantly increase peptide [Pro5, DNal (2')8]-gamma-MSH binding affinity and potency but substitution of the TM6 of the hMC4R with the same region of the hMC1R significantly enhances [Pro5, DNal (2')8]-gamma-MSH binding affinity and potency. Further site-directed mutagenesis study indicates that four amino acid residues, Phe267, Tyr268, Ile269 and Ser270, in TM6 of the hMC4R may play an important role in [Pro5, DNal (2')-gamma-MSH selective activity at MC4R.


Publishing in Journals Outside the Box: Attaining Mainstream Prominence Requires Demonstrations of Mainstream Relevance.
Primary pediatric medical care is as mainstream as any major cultural practice in the USA. Thus, publishing behavior analytic papers that pertain to problems that present in pediatric settings in pediatric medical journals is one route to mainstream relevance. With sufficient numbers of such papers, it could even lead to prominence. This article describes examples of publishing in pediatric journals and some lessons I learned from the experience. For example, (1) all child behavior problems that present in pediatric settings are of social importance but most are high-frequency, low-intensity problems that are not necessarily exotic or representative of serious pathology, and they usually respond to straightforward behavioral applications; (2) it is usually best to use a "colloquialized version of learning theory" when writing for and speaking to pediatric providers (and the families for whom they provide care); (3) pediatricians often have limited knowledge about behavior analytic research designs; and (4) when submissions are rejected by pediatric journals, the rejection can be exploited as an opportunity to educate pediatric editors and reviewers.


A people-centered approach to primary health care implementation in Mvumi, Tanzania.
The Mvumi community-based health care programme in Dodoma Region has been attempting to involve communities in promoting their health. It established a dialogue using communication and adult training skills and assisted communities only in those activities which they themselves planned and which they were ready to finance. Such activities included training of community resource persons such as traditional midwives and village health promoters/workers. Within only 4 years substantial output and outcome results could be demonstrated. Many village communities, for example, have assumed responsibility for the village-based nutrition rehabilitation of their severely malnourished children.


Brain protection by transamniotic stem cell therapy (TRASCET) in a model of intrauterine growth restriction (IUGR).
Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) has been shown experimentally to reverse some of the effects of intrauterine growth restriction (IUGR), apparently by attenuating placental inflammation. Neurodevelopmental deficits driven by neuroinflammation are major complications of IUGR. We sought to determine whether MSC-based TRASCET also mitigates inflammation in the fetal brain. Pregnant Sprague-Dawley dams (n = 8) were exposed to alternating 12-hour hypoxia (10.5% O2) cycles from gestational day 15 (E15) until term (E21). One group remained untreated (n = 28 fetuses). Three groups received volume-matched intra-amniotic injections into all fetuses (n = 72) of either saline (sham; n = 19), or a suspension of amniotic fluid-derived MSCs, either in native state (TRASCET; n = 20), or primed by exposure to interferon-gamma (IFN-γ) and interleukin-1beta (IL-1β) for 24 h prior to administration in vivo (TRASCET-Primed; n = 29). Donor MSCs were syngeneic Lewis rat cells phenotyped by flow cytometry. Normal fetuses served as controls (n = 20). Multiple analyses were performed at term, including ELISA in fetal brains for the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and IL-1β. Statistical comparisons were by Wilcox-rank sum test, including Bonferroni-adjusted significance. Overall survival was 75% (88/116). Gross brain weights were significantly decreased from normal in both the untreated and sham groups (both p<0.001) and significantly increased in both TRASCET groups when compared to untreated and sham (p = 0.003 to <0.001). TRASCET-Primed led to significantly lower levels of TNF-α and IL-1β compared to untreated (both p<0.001) and sham (p = 0.017 and p = 0.011, respectively). Non-primed TRASCET led to significantly lower levels of TNF-α and IL-1β compared to untreated (p = 0.009 to <0.001), but not sham (p = 0.133 and p = 0.973, respectively). Transamniotic stem cell therapy with primed mesenchymal stem cells reverses some of the central nervous system effects of intrauterine growth restriction in a rat model, possibly by modulating neuroinflammation. Animal and laboratory study. N/A (animal and laboratory study).


The source of urinary epidermal growth factor in humans.
To clarify the source of human urine EGF, we studied EGF renal clearance in 20 healthy, young adult subjects. Immunoreactive EGF was measured hourly in EDTA plasma, heparin plasma, serum and urine of 12 males and 8 females during a 3 h study period. Plasma and urine creatinine and creatinine clearance were measured and calculated hourly. Mean (and SEM) creatinine clearance was similar in males and females (118 +/- 12 vs 105 +/- 6 ml/min). EGF was not detectable in plasma, whereas relatively high levels were measured in serum (2.5 +/- 0.25 vs 1.5 +/- 0.18 ng/ml in males and females respectively p less than 0.05). Urine EGF excretion averaged 1641 +/- 233 ng/h in males and 1507 +/- 191 ng/h in females (p greater than 0.05). A significant correlation was observed between urine creatinine and urine EGF concentrations in both male (r = 0.98, p less than 0.01) and female (r = 0.94, p less than 0.01) subjects. EGF immunoreactivity in urine and serum eluted from G-75 sephadex columns similarly to recombinant 6000 Mr hEGF. Urine excretion of EGF approximated 1.5 micrograms/h or 25 ng/mg creatine. The high concentrations of EGF found in urine in the face of non-detectable levels of EGF in plasma favor the hypothesis that EGF in urine is derived from kidney synthesis and secretion. The significant positive correlation between urine creatinine and urine EGF suggests a functional correlation between glomerular filtration and the process of tubular EGF excretion.


Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial.
Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. A three year double-blind, randomized controlled trial of oral 100mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged ≥70years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL.


A biopsy tool with integrated piezoceramic elements for needle tract cauterization and cauterization monitoring.
This paper reports the feasibility of biopsy needle tract cauterization and cauterization monitoring using an embedded array of piezoceramic microheaters. Circular heaters of lead zirconate titanate (PZT-5A), with 200 μm diameter and 70-80 μm thickness, are fabricated using a batch mode micro ultrasonic machining process. These are then assembled into cavities in the walls of 20-gauge stainless steel needles and sealed with epoxy. Experiments are performed by inserting the proposed biopsy needle into porcine tissue samples. The needle surface exceeds the minimum target temperature rise of 33°C for either radial or thickness mode vibrations. The corresponding input power levels are 236 mW and 325 mW, respectively. The tissue cauterization extends 1-1.25 mm beyond the perimeter of the needle and is uniform in all directions. After cauterization, the fundamental anti-resonance frequency and the corresponding impedance magnitude of the PZT heater decrease by 4.1% and 42.6%, respectively, thereby providing a method to monitor the extent of tissue cauterization. A sensing interface circuit capable of measuring the resonance frequency shift of the PZT elements is built and tested using discrete integrated circuit components. The circuit detects the resonance frequency shift from 8.22 MHz to 7.96 MHz of the PZT elements when the biopsy needle is inserted into wax medium. An interface circuit for actuation of the PZT elements for tissue cauterization is also described.


Influence of Parental Fatty Acid Desaturase 2 (fads2) Expression and Diet on Gilthead Seabream (Sparus aurata) Offspring fads2 Expression during Ontogenesis.
Previous studies have shown that it is possible to increase the ability of marine fish to produce long-chain polyunsaturated fatty acid from their 18C precursors by nutritional programming or using broodstock with a higher fatty acyl desaturase 2 (fads2) expression. However, those studies failed to show the effect of these interventions on the expression of the fads2 gene in the developing egg. Moreover, there were no studies on the temporal expression of the fads2 during ontogeny in the gilthead sea bream (Sparus aurata). In order to determine the changes in expression of fads2 during ontogeny, gilthead sea bream broodstock with a high (HRO) or low (LRO) fads2 expression fed a diet previously used for nutritional programming, or a fish oil-based diet (LFO) were allowed to spawn. The samples were taken at the stages of spawning, morula, high blastula, gastrula, neurula, heart beating, hatch and 3 day-old first exogenous feeding larvae to determine fads2 expression throughout embryonic development. The results showed the presence of fads2 mRNA in the just spawned egg, denoting the maternal mRNA transfer to the developing oocyte. Later, fads2 expression increased after the neurula, from heart beating until 3-day-old larvae, denoting the transition from maternal to embryonic gene expression. In addition, the eggs obtained from broodstock with high fads2 expression showed a high docosahexaenoic acid content, which correlated with the downregulation of the fads2 expression found in the developing embryo and larvae. Finally, feeding with the nutritional programming diet with the partial replacement of fish oil by rapeseed oil did not affect the long chain polyunsaturated fatty acid (LC-PUFA) contents nor fads2 expression in the gilthead sea bream developing eggs.


Gradient elution in micellar liquid chromatography. II. Organic modifier gradients.
The application of organic modifier gradients in micellar liquid chromatography (MLC) is discussed. The equation derived by Snyder and co-workers describing gradient elution in hydro-organic reversed-phase LC was verified for organic solvent gradients in the presence of micelles. It is also demonstrated that the use of these gradients require little re-equilibration time due to the limited range of organic modifier concentration used in the gradient. This would result in shorter analysis time. Lastly, a practical application of the use of propanol and acetonitrile gradients in MLC is described.


Correction: Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer.
[This corrects the article DOI: 10.18632/oncotarget.22760.].


Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system.
Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.


Calcium and cAMP mediated stimulation of Fos in cultured hypothalamic tyrosine hydroxylase-immunoreactive neurons.
Immediate-early genes, such as c-fos, couple extracellular signals to genetic changes in the cell. We have previously demonstrated that depolarization with 50 mM KCl increases Fos immunoreactivity in hypothalamic tyrosine hydroxylase (TH) and oxytocin immunoreactive (-ir) neurons in primary culture. This Fos activation occurs within 1.5-2 h in TH-ir cells. In the present study, we examined the effects of depolarization, glutamate receptor activation and adenylyl cyclase stimulation on Fos-ir to determine the possible mechanism(s) of Fos activation in TH-ir neurons. Hypothalamic cultures were treated with KCl, glutamate or forskolin, and Fos and TH were visualized immunocytochemically. Forskolin increased the percentage of Fos/TH-ir neurons in a dose-dependent manner, with a maximal stimulation of 53.4 +/- 4.5% Fos/TH-ir neurons at 30 microM forskolin. The dose-response curve for glutamate was steep, with a maximal stimulation of 24.8 +/- 2.1% Fos-ir neurons at 100 microM. 50 mM KCl resulted in 50.0 +/- 0.8% Fos/TH-ir neurons. Pretreatment with verapamil decreased KCl induced Fos-ir by 57%, glutamate by 65% and forskolin by 39%. Combined drug administration demonstrated significant additivity between forskolin and glutamate, and forskolin and KCl, however, no significant additivity was found with KCl and glutamate. The results are discussed in terms of cAMP and calcium mediation of the Fos response to these stimuli.


Decisions regarding resident advancement and dismissal.
An orthopaedic resident had been counseled repeatedly regarding his unprofessional behavior. He had indicated, on multiple occasions, that patient-care tasks had been completed when, in fact, they had not. He had shifted his responsibilities to other residents both with and without their knowledge. Despite acceptable technical skills, he had often been poorly prepared for surgical cases. After repeated guidance sessions, warnings, and admonishments, he was dismissed from his training program.


Immunophenotypic parameters and RBC alloimmunization in children with sickle cell disease on chronic transfusion.
Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non-responders), a cross-sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC alloimmunization was present in 26/90 (29%) patients, with anti-E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non-alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non-alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non-alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent alloimmunization.


Exploring spatial characteristics of city-level CO2 emissions in China and their influencing factors from global and local perspectives.
In China, cities are the basic units for implementing CO2 abatement policies. However, few studies have comprehensively explored the spatial characteristics of CO2 emissions (CEs) and their influencing factors at the city level from different perspectives. After collecting spatial data from 280 Chinese prefecture-level cities for 2005, 2012, and 2015, this work firstly uncovered the overall and local spatial characteristics of CEs by adopting spatial autocorrelation analysis. Then, five influencing factors, including the total resident population (POP), per capita GDP (PCGDP), energy intensity (EI), the proportion of secondary industry (SI), and climate factor-heating degree days (HDD), were examined using global and local regression models. The analyses revealed that (1) CEs presented spatial agglomeration features from global and local perspectives, indicating spatial association between neighboring cities; and (2) POP, PCGDP, EI, and HDD had statistically significant spatial correlations with CEs, and their effect sizes were as follows: PCGDP > POP > EI > HDD. More importantly, the impacts of these influencing factors on CEs varied across cities, exhibiting obvious spatial heterogeneity. According to these findings, local governments should strengthen coordination and cooperation with their surrounding cities to promote regional synergistic action on emission reduction. In addition, policymakers should also design differentiated abatement policies based on regional characteristics and differences instead of applying similar policies to all cities.


Unwavering excellence: How to be a competent cardiovascular doctor in "panvascular medicine +".
It is essential to create a sustainable and all-encompassing panvascular ecosystem that integrates medical care, industry-academia research, prevention, and management, necessitating the in-depth participation of every cardiovascular doctor on their journey of unwavering excellence. "From doctors, by researchers/engineers, for patients" is the foundation of sustainable development in the "panvascular medicine +" ecosystem. Medical education can make knowledge tangible and serve as a conduit for inheritance and innovation. Prevention covers intelligent decision-making, primary prevention, and the popularization of knowledge. Furthermore, management is a potent tool for promoting development through overall coordination with social governance. Thus, in the "panvascular medicine +" ecosystem, cardiovascular doctors need to prioritize the doctor-patient collaboration, serving patients while possessing capabilities in scientific research, engineering applications, education, prevention, and management. This enables them to promote comprehensive and lifelong health management for patients.


Fiber probe for nonlinear imaging applications.
Over the past years it had been demonstrated that multimodal imaging combining the nonlinear modalities coherent anti-Stokes Raman scattering (CARS), two-photon excited auto-fluorescence (TPEF) and second harmonic generation (SHG) show a great potential for tissue diagnosis and tumor identification. To extend the applicability of this multimodal imaging approach for in-vivo tissue screening of difficult to access body regions the development of suitable fiber optic probes is required. Here we report about a novel CARS imaging fiber probe consisting of 10,000 coherent light guiding elements preserving the spatial relationship between the entrance and the output of the fiber. Therefore the scanning procedure can be shifted from the distal to the proximal end of the fiber probe and no moving parts or driving current are required to realize in-vivo CARS endoscopy.


Lenticulostriate arterial distribution pathology may underlie pediatric anoxic brain injury in drowning.
Drowning is a leading cause of neurological morbidity and mortality in young children. Anoxic brain injury (ABI) can result from nonfatal drowning and typically entails substantial neurological impairment. The neuropathology of drowning-induced pediatric ABI is not well established. Specifically, quantitative characterization of the spatial extent and tissue distribution of anoxic damage in pediatric nonfatal drowning has not previously been reported but could clarify the underlying pathophysiological processes and inform clinical management. To this end, we used voxel-based morphometric (VBM) analyses to quantify the extent and spatial distribution of consistent, between-subject alterations in gray and white matter volume. Whole-brain, high-resolution T1-weighted MRI datasets were acquired in 11 children with chronic ABI and 11 age- and gender-matched neurotypical controls (4-12 years). Group-wise VBM analyses demonstrated predominantly central subcortical pathology in the ABI group in both gray matter (bilateral basal ganglia nuclei) and white matter (bilateral external and posterior internal capsules) (P < 0.001); minimal damage was found outside of these deep subcortical regions. These highly spatially convergent gray and white matter findings reflect the vascular distribution of perforating lenticulostriate arteries, an end-arterial watershed zone, and suggest that vascular distribution may be a more important determinant of tissue loss than oxygen metabolic rate in pediatric ABI. Further, these results inform future directions for diagnostic and therapeutic modalities.


Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization.
Nicotinic receptors are implicated in memory, learning, locomotor activity, and addiction. Identification of the specific receptor subtypes that mediate these behaviors is essential for understanding their role in central nervous system (CNS) function. Although expression of nicotinic receptor transcript has been studied in rodent brain, their localization in the monkey CNS, which may be a better model for the human brain, is not yet known. We therefore investigated the distribution of alpha4, alpha6, alpha7, beta2, beta3, and beta4 receptors subunit mRNAs in the monkey brain by using in situ hybridization. alpha4 and alpha7 mRNAs were very widely expressed, with a substantial degree of overlap in their distribution, except for the reticular nucleus of the thalamus in which alpha7 mRNA was much more prominently expressed. beta2 and beta4 mRNA were also widely distributed, although beta4 was more prominently localized in thalamic nuclei than beta2. The distribution of alpha6 and beta3 mRNA was very distinct from that of the other transcripts, being restricted to catecholaminergic nuclei, the cerebellum, and a few other areas. Although there were similarities in distribution of the nicotinic receptor subunit mRNAs in monkey and rodent brain, there were prominent differences in areas such as the caudate, putamen, locus coeruleus, medial habenula, and cerebellum. In fact, the distribution of alpha4 and alpha7 mRNAs in the monkey caudate and putamen was more similar to that reported in the human than rodent brain. These findings have implications for the development of drug therapies for neurological disorders, such as Alzheimer's and Parkinson's disease, in which nicotinic receptors are decreased.


Pediatric hand dressing: technical report.
A compressive or conforming dressing is an important aspect of hand surgery, particularly the role of uniform pressure to the entire hand. Pediatric hand patients require special considerations with respect to appropriate postoperative dressing to maintain equal limb compression and to maintain the dressing during the postoperative period. This article describes a specific upper-limb hand dressing that can be used in the infant and young child.


Influence of fasting on circulating levels of alpha-tocopherol and beta-carotene. Effect of short-term supplementation.
We investigated the influence of fasting on the levels of alpha-tocopherol in plasma, erythrocytes and platelets, and on plasma beta-carotene. Six apparently healthy adults were subjected to 17-h feed-fasting experiments at various days before, during and after supplementation with alpha-tocopherol (455 mg/day, 41 days) and beta-carotene (25 mg/day, 24 days). Adipose tissue alpha-tocopherol and beta-carotene were measured at regular intervals. Supplementation increased alpha-tocopherol and beta-carotene in all compartments, except for beta-carotene in adipose tissue. Discontinuation caused a rapid return to baseline, except for adipose tissue alpha-tocopherol and plasma beta-carotene. Fasting caused linear increases of free fatty acids, consistent (but small) increases of plasma alpha-tocopherol and inconsistent increases of plasma beta-carotene. There were no fasting-related changes in other compartments. We conclude that fasting is unable to increase alpha-tocopherol and beta-carotene in circulating lipoproteins and cells to a considerable extent, both at baseline levels and after short-term supplementation. Maintenance of high levels may necessitate regular high oral intakes.


The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist.
The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).


Juvenile fibromatosis resembling aponeurotic fibroma and congenital multiple fibromatosis. One case with pleuropulmonary involvement.
This article deals with a young school boy born in 1971 with a tumor in the palm of his right hand. We have considered this a juvenile aponeurotic fibroma. This tumor has recurred several times, leading to unavoidable amputation of the right wrist and hand. Seven years after the initial diagnosis, the axillary area became involved, then the pleura and lung. Such an unusual process leads to reconsidering the diagnosis and to regard this case as an intermediate form between Keasbey's juvenile aponeurotic fibroma and generalized fibromatosis.


In vitro pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a nicotinic acetylcholine receptor ligand.
SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which displaced the binding of [3H]nicotine (NIC) to the rat brain nAChRs with an IC(50) value of 110 nM with no appreciable affinity to the alpha7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H3) and serotonergic (5-HT1 and 5-HT2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1-5 microM), in contrast to nicotine, showed a greater selectivity for beta4-subunit containing recombinant hnAChRs (alpha2beta4, alpha3beta4 and alpha4beta4) vs. beta2-subunit containing nAChRs (alpha4beta2 and alpha3beta2) both in terms of efficacy and potency. While NIC (10-30 microM) and epibatidine (0.01-0.1 microM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 microM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (< or =30 microM) evoked [3H]DA release from striatum, olfactory tubercles and prefrontal cortex (PFC), and [3H]NE release from hippocampus and PFC, and this evoked release was sensitive to mecamylamine (MEC). SIB-1553A-evoked neurotransmitter release exhibited region- and transmitter-specific antagonism by dehydro-beta-erythroidine (DHbetaE). SIB-1553A was less efficacious than NIC at evoking [3H]NE from the rat hippocampus and antagonized NIC response upon co-application implying partial agonist properties. SIB-1553A did not evoke basal [3H]ACh release from the rat striatum or hippocampus, but attenuated NMDA-evoked [3H]ACh release from the rat striatum. SIB-1553A did not inhibit rat brain cholinesterase for up to 1 mM. Multiple receptor affinities and release of several neurotransmitters may underlie the cognitive-enhancing effects of SIB-1553A documented in rodent and primate models.


Time-Controlled Adaptive Ventilation Does Not Induce Hemodynamic Impairment in a Swine ARDS Model.
The current standard of care during severe acute respiratory distress syndrome (ARDS) is based on low tidal volume (VT) ventilation, at 6 mL/kg of predicted body weight. The time-controlled adaptive ventilation (TCAV) is an alternative strategy, based on specific settings of the airway pressure release ventilation (APRV) mode. Briefly, TCAV reduces lung injury, including: (1) an improvement in alveolar recruitment and homogeneity; (2) reduction in alveolar and alveolar duct micro-strain and stress-risers. TCAV can result in higher intra-thoracic pressures and thus impair hemodynamics resulting from heart-lung interactions. The objective of our study was to compare hemodynamics between TCAV and conventional protective ventilation in a porcine ARDS model. In 10 pigs (63-73 kg), lung injury was induced by repeated bronchial saline lavages followed by 2 h of injurious ventilation. The animals were then randomized into two groups: (1) Conventional protective ventilation with a VT of 6 mL/kg and PEEP adjusted to a plateau pressure set between 28 and 30 cmH2O; (2) TCAV group with P-high set between 27 and 29 cmH2O, P-low at 0 cmH2O, T-low adjusted to terminate at 75% of the expiratory flow peak, and T-high at 3-4 s, with I:E > 6:1. Both lung elastance and PaO2:FiO2 were consistent with severe ARDS after 2 h of injurious mechanical ventilation. There was no significant difference in systemic arterial blood pressure, pulmonary blood pressure or cardiac output between Conventional protective ventilation and TCAV. Levels of total PEEP were significantly higher in the TCAV group (p < 0.05). Driving pressure and lung elastance were significantly lower in the TCAV group (p < 0.05). No hemodynamic adverse events were observed in the TCAV group compared as to the standard protective ventilation group in this swine ARDS model, and TCAV appeared to be beneficial to the respiratory system.


High-resolution melting analysis for molecular detection of multidrug resistance tuberculosis in Peruvian isolates.
The emergence of multidrug-resistant strains is a major health problem especially for countries with high TB incidence such as Peru. In this study, we evaluated High Resolution Melting (HRM) assay in Peruvian isolates for the detection of mutations within rpoB, katG genes and promoter region inhA to determine isoniazid and rifampicin resistance in Mycobacterium tuberculosis (Mtb). DNA samples extracted from a total of 167 clinical isolates of Mtb, 89 drug-sensitive and 78 multidrug-resistant, were blindly analyzed by HRM analysis and verified by DNA sequencing. The HRM analysis generated patterns that were specific to distinguish between sensitive and resistance isolates. The sensitivity and specificity of the HRM assays in comparison with drug susceptibility testing (DST) for detection of rifampicin resistance were 98.7 % and 97.5 %, and for isoniazid resistance were 98.7 % and 100 %. This study suggests that HRM Analysis could help with rapid diagnosis of MDR-TB cases in Peru.


The accuracy of radionuclide ventriculography in the analysis of left ventricular ejection fraction.
To assess the reliability of using ejection fraction values derived from gated blood pools scans as a way to classify patients, we reviewed 76 radionuclide studies. Each study was processed in 10 different ways (varying or fixed left ventricular region of interest in association with 5 different backgrounds), and compared with contrast ventriculograms performed within one week of the radionuclide study. Correlation values with contrast results varied from 0.76 to 0.94 (mean 0.84 +/- 0.06, +/- 1 SD), and linear fit slopes varied from 0.39 to 0.90 (mean 0.75 +/- 0.15). Based on contrast results, patients were divided first into four groups (severely reduced, reduced, normal, and high ejection fractions). Predictive accuracy of the radionuclide estimates for these four groups was poor, ranging from 0.39 +/- 0.08 to 0.82 +/- 0.06%. Sensitivity was somewhat better (range 0.53 +/- 0.11 to 0.78 +/- 0.08%), and specificity better yet (0.78 +/- 0.08 to 0.95 +/- 0.02%). The results were better with techniques resulting in higher correlation values, and further improved when patients were regrouped into two populations (normal or reduced), though 90% of subjects were correctly identified only when correlation values exceeded 0.90. We conclude that care must be taken in the identification of patients using radionuclide angiography who have normal and abnormal left ventricular function; it can be done with confidence only when linear fits with contrast ventriculographic results have high correlation coefficients. Stratification attempts should be reduced to a minimum, as multiple population subgroups result in substantial patient mislabeling.


High-resolution chiral separation using microfluidics-based membrane chromatography.
A plastic microfluidic system, containing porous poly(vinylidene fluoride) (PVDF) membranes adsorbed with bovine serum albumin (BSA), is demonstrated for high resolution chiral separation of racemic tryptophan and thiopental mixtures. Microfluidic networks on poly(dimethylsiloxane) (PDMS) substrates are fabricated by capillary molding technique. This miniaturized chiral separation system consists of two layers of PVDF membranes which are sandwiched between two PDMS slabs containing microchannels facing the membranes. On-line adsorption of BSA onto the membranes is employed for the preparation of chiral stationary phase and the evaluation of solution conditions in an effort to achieve maximum protein adsorption. Variations in the mobile phase conditions, including solution pH and ammonium sulfate concentration, are studied for their effects on chiral separation. Based on the large surface area to volume ratio of porous membrane media, adsorbed BSA onto the PVDF membranes enables high resolution separation of racemic mixtures with sample consumption of sub-nanogram or less in the integrated microfluidic networks. In addition, the membrane pore diameter in the submicron range eliminates the constraints of diffusional mass-transfer resistance during protein adsorption and chiral chromatographic processes.