The influence of the profile of brain retractors on regional cerebral blood flow in the rat.
Self-retaining brain retractors with different profiles have been constructed in order to decrease the risk of cerebral ischaemia during intracranial operations. Flat retractors are more easy to handle than curved, because the flat retractors can be bent into the desirable shape. To estimate the regional cerebral blood flow (rCBF) using retractors with three different profiles (flat, flat with rounded edges and curved) autoradiography with carbon-14 (14C) iodoantipyrine was performed in rats. After craniotomy over the parietal cortex lead weights with the three different profiles corresponding to 20 mm Hg of brain retractor pressure (BRP) were placed on the cortex for 15 minutes. rCBF (average values) in cortex beneath the flat retractors was 80 ml/100 gm/min (n = 10), for flat ones with rounded edges 90 ml/100 gm/min (n = 5) and for the curved retractors 75 ml/100 gm/min (n = 5). The differences were not significant. Even with a BRP of 30 mm Hg no differences were observed between flat (n = 3) and curved (n = 3) weights. In control animals craniotomy showed no influence on the rCBF (n = 3). No further risk for ischaemic nerve cell damage could be demonstrated by using the most easily-handled retractors, the flat ones, instead of those more or less curved.


Proton pump inhibitor prescribing patterns in the UK: a primary care database study.
To determine the prevalence and pattern of proton pump inhibitor (PPI) prescription and the practices employed to reduce PPI use in the UK general population. The UK's Clinical Practice Research Database was used to identify individuals who were issued with ≥1 PPI prescription during the period 1990-2014. Point and period prevalence of PPI use were estimated annually. Additionally, new users of PPI therapy who had 5 years of follow-up data were included in a cohort analysis to describe patterns of cessation and duration of PPI use. Both the period and point prevalence of PPI use increased between 1990 and 2014 (period prevalence increased from 0.2 to 15.0% and point from 0.03 to 7.7%). A total of 596 334 new users of PPI therapy in the cohort study received 8 784 272 prescriptions. Of these, 26.7% used PPI therapy long term (≥1 year continuously), while 3.9% remained on PPI therapy for 5 years. Clear attempts to step down dose were identified in 39.9% of long-term users, while this was 47% in patients whose initial indication did not mandate long-term use. A considerable increase in PPI use was observed in UK general practice. Of long-term PPI users, 60% did not have an attempt to discontinue or step down. Considerable opportunities may therefore exist to reduce the cost and side effects of PPI use through improving adherence to recommended withdrawal strategies. Copyright © 2016 John Wiley & Sons, Ltd.


Incorporating Polarizability of Backbone Hydrogen Bonds Improved Folding of Short α-Helical Peptides.
Reliability of force fields is an essential aspect of protein-folding simulation. In this work, we introduced a newly developed on-the-fly charge-updating scheme called the polarized structure-specific backbone charge (PSBC) model. The PSBC model was designed with the purpose of building the polarizability of backbone hydrogen bonds into the force field by updating the partial charges of backbone hydrogen-bond donor and acceptor atoms during folding simulation. This implementation was intended to mimic the heterogeneity of the protein surrounding during folding. Multiple single-trajectory molecular dynamics simulations were performed to fold a polyalanine peptide, namely ER (Ac-A(EAAAR)3A-NH2), using both polarizable (PSBC) and nonpolarizable (Amber03) force fields. Through the PSBC model, ER was folded into a helical peptide with helix content that agrees well with experiments. Comparison between simulations performed using the aforementioned force fields demonstrably showed the importance of electrostatic polarization effect in the folding of the short α-helical peptide. The PSBC model was further validated by folding two other short peptides with different helicities.


Accumulation and loss of cholesterol esters in monkey arterial smooth muscle cells exposed to normal and hyperlipemic serum lipoproteins.
The effects of high low and very low density lipoprotein fractions from normal or hyperlipemic rhesus monkey serum on the accumulation or removal of cholesterol esters from rhesus monkey smooth muscle cells in tissue culture were determined. Serum or serum lipoproteins were labeled with [14C] free cholesterol and adjusted to the same free cholesterol level in the incubation medium. Of the two normal lipoproteins examined, the LDL fraction caused more esterification than the HDL. Cells incubated in hyperlipemic serum showed a 2-fold stimulation in esterification as compared to cells in normal serum. This was contributed by hyperlipemic VLDL and LDL and led to a concomitant increase in cellular cholesterol ester content. Both hyperlipemic LDL and HDL stimulated esterification when compared to their normal counterparts. Cholesterol ester removal was examined by incubating the serum or lipoprotein fractions with cells enriched in cholesterol ester through a prior exposure to hyperlipemic serum. The cells incubated in normal or hyperlipemic HDL or lipoprotein-deficient serum had the lowest cholesterol ester content. Thus, the lipoprotein fractions which caused the lowest levels of cholesterol esterification were also the most efficient in the removal of cellular cholesterol esters.


Lack of gonadotropic response to pulsatile gonadotropin-releasing hormone in isolated hypogonadotropic hypogonadism associated to congenital adrenal hypoplasia.
Congenital adrenal hypoplasia (AH) is a rare condition, known to be associated with isolated hypogonadotropic hypogonadism (IHH). Three studies have reported attempts to stimulate gonadotropin secretion with pulsatile gonadotropin-releasing hormone (GnRH) in a total of 4 patients presenting such a syndrome, with conflicting results. In the present study, one patient with idiopathic IHH and AH was treated with pulsatile sc GnRH--doses ranging from 2.5 to 10.0 micrograms/pulse, every 90 min--during 8 weeks in an attempt to induce puberty. The prepubertal basal plasma levels of LH, FSH and testosterone, and saliva testosterone levels remained unaltered throughout treatment, at all doses of GnRH tested. The gonadotropin response to an acute iv GnRH administration (0.1 mg) also remained at the prepubertal level after pulsatile GnRH treatment. No circulating anti-GnRH antibodies were detected. The absence of gonadotropic response to exogenous pulsatile GnRH suggests that the IHH of patients with AH is due to an abnormal pituitary function rather than to a lack of endogenous GnRH.


Arterioureteral Fistula in the Setting of Radical Cystoprostatectomy and Ileal Conduit Creation.
Arterioureteral fistulas (AUF) following ileal conduit reconstruction are rare and not well-studied. We present a life-threatening bleed from an AUF due to an ileal conduit urinary diversion. In addition, we identify the challenges in the diagnostic process as well as management strategies. We present a 63-year-old male with ileal conduit reconstruction for bladder cancer with an AUF developing years after the reconstruction, which was ultimately managed with angioplasty.


Late small bowel toxicity after adjuvant treatment for rectal cancer.
For locally advanced rectal cancer surgery as sole treatment results in poor local control and survival. After adjuvant radiotherapy for locally advanced rectal cancer, small bowel toxicity has been the most frequent and serious side effect. The gain in survival and local control was accompanied by severe late chronic toxicity reducing the benefit of adjuvant treatment. Clinical factors, pathology and treatment of late small bowel toxicity after adjuvant radiotherapy for locally advanced rectal cancer will be discussed. This review will focus on different surgical and radiotherapeutic means reducing the risk of late small bowel damage.


The Binding Interactions between Cyclohexanocucurbit[6]uril and Alkyl Viologens Give Rise to a Range of Diverse Structures in the Solid and the Solution Phases.
The binding interactions between the cyclohexanocucurbit[6]uril (Cy6CB6) host and a series of dialkyl-4,4'-bipyridinium (viologen) dicationic guests were investigated in the solution phase, using (1)H NMR spectroscopy, and in the solid phase, using X-ray diffraction methods. In D2O solution, methyl viologen (MV(2+)) and ethyl viologen (EV(2+)) form 1:1 complexes in which the bipyridinium aromatic nucleus is partially included inside the Cy6CB6 cavity. Propyl viologen (PV(2+)), butyl viologen (BV(2+)), pentyl viologen (FV(2+)), and heptyl viologen (HV(2+)) form 2:1 complexes with Cy6CB6, in which each of the viologen aliphatic chains is included by a host molecule. In the solid state, EV(2+) forms a polypseudorotaxane via pseudorotaxane interdigitation of Cy6CB6 hosts. The PV(2+) guest forms a dumbbell-shaped structure with a Cy6CB6 host residing over each of the terminal propyl groups of the guest. In contrast to this, the BV(2+) guest and Cy6CB6 form a different polypseudorotaxane structure in which dumbbell-shaped structures, formed by two host molecules interacting with a single guest, are interconnected through metal-host coordination.


Development of the dopamine-immunoreactive system in the central nervous system of the sea lamprey.
The development of dopamine-immunoreactive (DAir) populations in the central nervous system of the sea lamprey, a modern representative of the earliest vertebrates, was studied to achieve further understanding of dopaminergic systems in vertebrates. The first DAir cell groups appeared in the spinal cord, the posterior tubercle nucleus and the dorsal hypothalamic nucleus of prolarval stages. In larvae, new DAir cell groups were observed in the caudal preoptic nucleus, the postoptic commissure nucleus, the postinfundibular commissure nucleus and the caudal rhombencephalon. All these DAir cell groups observed in larvae were also DA-positive in adults, which showed only one new DAir cell group found in the ventral hypothalamic nucleus. Occasional DAir cells were observed in the telencephalon, the ventral thalamus and/or the isthmus of large larvae and adults. From medium-sized larvae to adults, the regions most richly innervated by DAir fibers were the neurohypophysis, the striatum, the pretectum and the midbrain tegmentum. Striking differences are observed between lampreys and other vertebrates in regard to the relative time of appearance of DAir cells, which is probably related with the complex life cycle of the sea lamprey.


PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.
The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3-10. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors11. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.


Development of an ultrasound-assisted extraction method for biomonitoring of vanadium and nickel in the coastal environment under the influence of the Prestige fuel spill (North east Atlantic Ocean).
As a consequence of the Prestige shipwreck occurred in the Northeast Atlantic Ocean in November 2002, the need for establishing the environmental impact caused by metals has been of primary concern. Among the different metals contained in the fuel spill, V and Ni are particularly of interest since they appear at relatively high concentration in the original fuel. Biomonitoring of V and Ni using wild mussels (Mytilus edulis) collected along the Galician Coast (NW Iberian Peninsula) has been performed. Ultrasound-assisted extraction of V and Ni from dried mussel tissues using probe sonication allowed a fast solid-liquid extraction thus facilitating sample preparation from large sample batches used for biomonitoring. V and Ni were determined in shellfish caught in the Galician littoral and tar balls from the Prestige spill by electrothermal-atomic absorption spectrometry and inductively coupled plasma-optical emission spectrometry, respectively. A Plackett-Burman saturated design was applied for screening optimization of variables influencing the ultrasound-assisted extraction of V and Ni from shellfish. Efficient extraction of both metals was obtained from slurries prepared in 2 mL capacity sample vials (10 mg sample with a particle size less than 100 microm) using a 3% (v/v) HNO3 diluent and subjected to probe sonication (3 min; 30% vibrational amplitude of the probe). The method was successfully validated by means of three certified reference materials: NRCC-TORT-2 Lobster hepatopancreas, NIST-SRM 1566b Oyster tissue and NIST-SRM 2977 Mussel tissue. The detection limit (LOD) of V and Ni in the marine biological tissues, calculated according to the 3sigma criterion, were 0.24 microg g(-1) and 0.15 microg g(-1) for V and Ni, respectively. V and Ni concentrations in M. edulis were in the range 1.7-4.8 and 0.8-2.8 microg g(-1), respectively. Whilst no significant variations in Ni contents were observed in regard to reference values, an important increase in V concentration is observed at some sampling points, thereby indicating bioaccumulation.


Atypical nucleosome spacing of rat neuronal identifier elements in non-neuronal chromatin.
Rat neuronal identifier (ID) elements are located in chromatin regions that are organized in nucleosomal structures in both neuronal and non-neuronal cells. A subpopulation of ID sequences in chromatin of liver and kidney cells are relatively resistant to micrococcal nuclease digestion and are organized in nucleosomes exhibiting an atypically short repeat length. Other repetitive elements do not show this organization.


Gene expression and distribution of antibacterial L-amino acid oxidase in the rockfish Sebastes schlegeli.
Antibacterial factors in the epidermal mucus of fish have a potential importance in the first line of the host defense response to bacterial pathogens. We previously isolated a novel antibacterial protein termed SSAP (Sebastes schlegeli antibacterial protein) from the skin mucus of the rockfish S. schlegeli and identified it as a new member of the L-amino acid oxidase (LAO) family. In the present study, the localization of SSAP in S. schlegeli was investigated by reverse transcription (RT)-PCR, quantitative real time RT-PCR, Western blotting and measurements of LAO and antibacterial activities. SSAP mRNA was expressed dominantly in skin and gill and weakly in ovary or kidney as shown by RT-PCR and real time RT-PCR. The quantity of SSAP mRNA in skin varied among the individuals, ranging from 1.1 to 13.9 ng microg(-1) total RNA, although no relationship was found between the size of fish and gene expression. SSAP was exclusively detected in skin and gill by Western blotting using a specific anti-SSAP antiserum. In addition, the extracts of both tissues apparently showed LAO activity and antibacterial activity against Photobacterium damselae subsp. piscicida. This study demonstrates that SSAP is predominantly synthesized in skin and gill and probably functions as an antibacterial LAO in both tissues.


Laccase production from sucrose by recombinant Yarrowia lipolytica and its application to decolorization of environmental pollutant dyes.
Laccases are used in decolorization and biodegradation of synthetic dyes, bioremediation of industrial wastewaters and delignification of lignocellulosic compounds. The aims of the present study were the optimization of a recombinant laccase production in Yarrowia lipolytica yeast using sucrose as a main carbon source, and the application of the resulting enzyme to decolorization of synthetic dyes, which are problematic environmental pollutants. Taguchi's experimental design method was employed to optimize medium compounds. Recombinant laccase production by Y. lipolytica YL4 strain increased to 900 U L-1 after optimization of sucrose, ammonium chloride, yeast extract and thiamine levels in the modified PPB medium. Furthermore, the production rate reached 6760 U L-1 in a 5 L bioreactor which represents 4.5- and 33.5-fold increases compared to cultures that were in shake-flask with optimized and primary media, respectively. The supernatant containing secreted recombinant laccase was applied for decolorization of seven dyes. The effects of pH, the amount of enzyme and incubation period were verified. The effect of incubation time on dye decolorization by recombinant laccase was important, which has an influence of greater extent than 90% after 48 h for all dyes. The Trametes versicolor laccase can be efficiently produced in Y. lipolytica and the recombinant enzyme has a considerable potential in the decolorization of pollutant synthetic dyes.


Association between phase angle and coronary artery calcium score in patients on peritoneal dialysis.
The phase angle (PhA) has been used as a nutritional marker and predictor of mortality in patients on peritoneal dialysis (PD). The coronary artery calcium (CAC) score has shown to predict the incidence of acute myocardial infarction and death from cardiovascular disease in these patients. However, the association between PhA and CAC score in patients with PD is not well-established, which is the objective of this study. Cross-sectional study with patients on PD, followed up at a University Hospital, between March 2018 and August 2019. PhA was evaluated by unifrequency bioimpedance (BIA). The CAC score was calculated based on cardiovascular computed tomography, considering positive when greater than or equal to 100 Agatston and negative when less than 100 Agatston. We evaluated 44 patients on dialysis, with a mean age of 56 years and median time on dialysis therapy was 11.7 months. In the statistical analysis, a significant association was only observed between the CAC score and the PhA. The PhA is associated with a positive CAC score in patients with PD, and despite other factors, may be useful as a risk marker for coronary artery disease in this population.


In vitro study of role of trace amount of Cu release from Cu-bearing stainless steel targeting for reduction of in-stent restenosis.
A novel 316L type Cu-bearing stainless steel was developed in present work, aiming at reducing the occurrence of the in-stent restenosis after implantations of coronary stents, through trace amount of Cu release from surface of the steel in body fluid. It was found that there was a trace amount of Cu released from the Cu-bearing steel in a simulated body fluid, with no cytotoxicity. All the in vitro experimental results proved that this Cu-bearing steel could not only inhibit the proliferation of vascular smooth muscle cells, reducing the formation of thrombosis, which are the main reasons for happening of the in-stent restenosis, but also promote the proliferation of vascular endothelial cells needed for the revascularization, showing that this novel steel is prospective to be a new material for manufacturing coronary stents with function of reducing the in-stent restenosis.


Age-related alterations of default mode network in autobiographical memory: Recent versus remote events.
Previous studies have shown that the vividness of autobiographical memory decreases over time, and older adults often retrieve fewer details than young adults. However, the age-by-temporal distance (i.e., recent versus remote events) effect on autobiographical memory and underlying neural mechanisms are less understood. We recruited 25 young adults and 27 older adults to perform an fMRI-adapted autobiographical memory task with different temporal distances. The results showed that older adults' vividness ratings were generally higher than that of young adults, but were less sensitive to temporal distances. For neural imaging, an age-by-temporal distance effect was found in the left precuneus, manifested as young adults had more activation for recent events than for remote events, whereas no temporal distance effect was found in older adults. Interestingly, for older adults, the temporal distance effect was reflected by functional connectivity within the default mode network (DMN), with a stronger anterior DMN-posterior DMN coupling for remote events than for recent events, whereas no temporal distance difference on functional connectivity was found in young adults. The results suggest that older adults exhibit age-related neural differences in both activation and functional connectivity during the processing of autobiographical memory with different temporal distances, shedding new light for the understanding of the relationship between the DMN, autobiographical memory, and aging.


Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours.
The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA. RT-PCR, denaturing gradient gel electrophoresis and S1 nuclease protection experiments were used to analyse V3 mRNA structure in ACTH-secreting tumours. We also developed a competitive RT-PCR system to compare the levels of expression of POMC, V3 and CRH-R genes. This system used as competitor a single mutant template (termed multi-mutant) containing primers for the three genes flanking an unrelated core sequence allowing multiple quantifications from the same cDNA preparations. We analysed 12 normal pituitaries, 15 corticotroph pituitary adenomas and 6 ACTH-secreting bronchial carcinoids. The V3 mRNA structure and sequence were found to be identical in normal and tumoural pituitary indicating that the tumoural Vs mRNA codes for a normal receptor. POMC RT-PCR signals in the pituitary tumour group were approximately 7-fold higher than in the normal pituitary group. Similarly, V3 and CRH-R signal were increased in pituitary tumors (mean +/- SEM: 5.87 x 10(-6) +/- 1.73 x 10(-6), and 2.33 x 10(-4) +/- 1.4 x 10(-4), respectively), when compared to normal pituitaries (1.19 x 10(-7) +/- 2.39 x 10(-8), and 1.7 x 10(-6) +/- 4.65 x 10(-7), respectively) suggesting that these two genes are expressed at very high levels in corticotroph tumours. When expressed relative to the corresponding POMC signals, increases in V3 and CRH-R signals reached 49-fold and 137-fold, respectively, in pituitary tumours. In ACTH-secreting bronchial carcinoids V3 gene expression level was also higher than in normal pituitary, whereas CRH-R signals were detected in only 4 of the 6 tumours with wide variations. Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.


Mothers' sources of information about feeding their children ages 2 months to 54 months.
The purpose of this study was to determine sources and types of information about child feeding practices that were received by 62 mothers with children aged 2 to 54 months. Each mother participated in 10 or 11 in-home interviews. Data analyses included chi-square testing for differences in information sources over time and content analyses to develop information themes. As sources, citations for professionals and magazines decreased, with no significant changes for relatives over time. After 24 months, newspapers, television, and friends were reported more frequently than earlier. Mothers reported multiple and concurrent information sources over time. Thus, nutrition educators have concurrent and multiple opportunities to disseminate nutrition information.


Cochlear prostheses in use: recent speech comprehension results.
Speech-comprehension tests were performed with several deaf volunteers who were equipped with different cochlear prostheses. These prostheses work with inductive transcutaneous signal transmission and contain a multi-channel scala tympani electrode or, in two cases, a disc electrode situated external to the cochlea in the round window niche. The external portable single-channel speech-processor/transmitter used is the same in all cases. The comprehension (stimulation only, no lip reading) of numbers between 1 and 99 on first contact with the stimulator and therefore without any training was around 38% showing that through well designed single-channel stimulation of the auditory nerve it is possible to generate hearing sensations sounding very much like nature hearing impressions. Some open speech comprehension was reached: Through the help of the stimulator, without lip reading, between 60 and 100% of sentences unknown to the completely deaf volunteer, spoken only a little more slowly than normal, are correctly understood. The percentage for isolated unknown words is 60%. Also an important improvement of word comprehension can be achieved through additional stimulation as compared to unaided lip reading. It appears that the most recent design of our cochlear prosthesis can already be regarded as a useful aid for the deaf.


Dynamic SARS-CoV-2-specific B-cell and T-cell responses following immunization with an inactivated COVID-19 vaccine.
The dynamic adaptive immune responses elicited by the inactivated virus vaccine CoronaVac remain elusive. In a prospective cohort of 100 healthcare professionals naïve for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received two doses of CoronaVac, we analysed SARS-CoV-2-specific humoral and cellular responses at four different timepoints, including before vaccination (T1), 2 weeks after the first dose (T2), 2 weeks after the booster dose (T3), and 8-10 weeks after the booster dose (T4). SARS-CoV-2-specific antibodies, serum neutralizing activities, peripheral B cells, CD4+ and CD8+ T cells and their memory subsets were simultaneously measured in this cohort. SARS-CoV-2 spike-specific IgG responses reached a peak (geometric mean titre (GMT) 54827, 30969-97065) after two doses and rapidly declined (GMT 502, 212-1190) at T4, whereas suboptimal IgA responses were detected (GMT 5, 2-9). Spike-specific circulating B cells (0.60%, 0.46-0.73% of total B cells) and memory B cells (1.18%, 0.92-1.44% of total memory B cells) were effectively induced at T3 and sustained over time (0.33%, 0.23-0.43%; 0.87%, 0.05-1.67%, respectively). SARS-CoV-2-specific circulating CD4+ T cells (0.57%, 0.47-0.66%) and CD8+ T cells (1.29%, 1.04-1.54%) were detected at T3. At T4, 0.78% (0.43-1.20%) of memory CD4+ T cells and 0.68% (0.29-1.30%) of memory CD8+ T cells were identified as SARS-CoV-2-specific, while 0.62% (0.51-0.75%) of CD4+ T cells and 0.47% (0.38-0.58%) of CD8+ T cells were SARS-CoV-2-specific terminally differentiated effector memory cells. Furthermore, age and interval between doses affected the magnitude of CoronaVac-induced immune responses. SARS-CoV-2 memory CD4+ T cells were strongly associated with both receptor binding domain (RBD)-specific memory B cells (r 0.87, p <0.0001) and SARS-CoV-2-specific memory CD8+ T cells (r 0.48, p <0.0001). CoronaVac induced robust circulating and memory B cell and T cell responses. Our study offers new insight into the underlying immunobiology of inactivated virus vaccines in humans and may have implications for vaccine strategies in the future.


Preloading, exit intoxication related to energy drink usage, and gender differences within night-time entertainment districts for young people.
Governments frequently introduce legislation to reduce drunkenness and violence in night-time entertainment districts (NEDs). However, there is no study which has looked at inebriation of a large sample of young people exiting a NED. We investigated Breath Approximated Blood Alcohol Concentration (BrAC; grams per decilitre, g/dl) levels as people left Brisbane (Australia) NEDs and measured the effects of preloading, energy drink usage, time of night and gender differences on exit intoxication. We systematically assessed patrons between November 2015 to March 2019 by administering surveys and breathalysing them as they exited the NEDs. We then analysed only those under the age of 26 years old (n = 3,211) as there was a natural break in the data on energy drink usage for those aged over 25 years old. This study found that young drinkers leave the NED with an average BrAC of 0.094 g/dl. Consistent with hypotheses, the exit BrAC was significantly and meaningfully higher in preloaders (medium effect size). These preloaders also came into the NEDs later but stayed for the same length of time as non-preloaders. BrAC levels did not significantly differ for those who did or did not use energy drinks during the night. As predicted, gender was not associated with a meaningful difference in alcohol intoxication and consumption. The time of night that patrons were interviewed was positively associated with inebriation levels, however, this association was small (r ≈ 0.1). With preloading being such a strong predictor for end of night intoxication, and length of time spent in the NED equal between those who do or do not preload, we suggest that to have people less inebriated, they should be encouraged into the NED earlier rather than focusing on their leaving time.


Nonvaccine human papillomavirus genotype common in women with HIV failing cervical precancer treatment.
The aim of this study was to assess failure after treatment of high-grade cervical intraepithelial neoplasia (CIN2+) by HIV status and human papillomavirus (HPV) type. A population-based register study. The Swedish National HIV Registry, the Swedish Population Registry and the Swedish National Cervical Screening Registry were linked to identify all women in Stockholm and Gothenburg counties (Sweden) living with HIV and diagnosed with CIN2+ sometime between 1983 and 2014 (n = 179). HIV-negative controls with CIN2+, were matched (2 : 1) for country of birth. CIN2+ biopsies were retrieved from biobanks and genotyped. Absolute risk and adjusted odds ratios (adjOR) of treatment failure by HIV status given HPV type (HPV16/18 vs. non-HPV16/18) were calculated. HPV16 (32%) and HPV35 (24%) dominated in women living with HIV (WLWH) with failure, HPV35 mainly in women born in sub-Saharan Africa (67%). The absolute risk of failure in women with HPV16/18 was 26% [95% confidence interval (95% CI) 14-44] in WLWH and 12% in HIV-negative (95% CI 7-19). The absolute risk of failure in women with non-HPV16/18 was 20% (95% CI 12-31) in WLWH and 5% in HIV-negative (95% CI 2-11). WLWH with non-HPV16/18 were six times more likely to fail than HIV-negative (adjOR 6.1, 95% CI 2.0-18.6). HPV35, not included in current HPV vaccines, was the second most common type in WLWH with failure. WLWH with non-HPV16/18 were six times more likely to fail than HIV-negative. This could have implications for surveillance and vaccination post CIN2+ treatment, particularly in WLWH from sub-Saharan Africa.


Genomic profiling of intestinal-type sinonasal adenocarcinoma reveals subgroups of patients with distinct clinical outcomes.
Patients with intestinal-type sinonasal adenocarcinoma (ITAC) have an unfavorable prognosis and new therapeutic approaches are needed to improve clinical management. Genetic analysis of 96 ITACs was performed by microarray comparative genomic hybridization and immunohistochemistry and correlated to previously obtained mutation, methylation, and protein expression data, and with pathological characteristics and clinical outcome. Seven copy number alterations (CNAs) were significantly associated with unfavorable clinical outcome: gains at 1q22-23, 3q28-29, 6p22, and 13q31-33, and losses at 4p15-16, 4q32-35, and 10q24. Unsupervised cluster analysis resulted in 5 subgroups of ITAC with significantly distinct genetic signatures and clinical outcomes, independently of disease stage or histological subtype. These data may guide studies to identify driver genes and signaling pathways involved in ITAC. In addition, the subclassification of genetic subgroups of patients with distinct clinical behavior can aid therapeutic decision making and may ultimately lead to personalized therapy with targeted inhibitors.


Longitudinal modifications of the MELD score have prognostic meaning in patients with liver cirrhosis.
The Model for End-Stage Liver Disease (MELD) score is an important and well established tool for assessing prognosis in patients with liver cirrhosis. It has been suggested that the longitudinal evaluation of the MELD score may reflect the progression of liver failure more reliably and therefore be more useful in prognostic assessment. To assess the prognostic meaning of MELD score modifications in a cohort of cirrhotic patients in whom clinical and biochemical workup was carried out at least twice during a minimum interval of 30 days. Forty-six cirrhotic patients were longitudinally evaluated for a median follow-up of 365 days. After initial assessment, all the patients had at least one clinical and biochemical reevaluation during follow-up, which was performed no less than 1 month after initial evaluation. MELD was calculated at entry and at second evaluation. DeltaMELD was calculated as MELD at second evaluation minus MELD at entry. DeltaMELD/time was calculated as DeltaMELD divided by time elapsed between initial assessment and second evaluation expressed in months. During follow-up, 13 patients died (28%). The median interval between clinical evaluations was 120 days. MELD scores at entry (13 +/- 4 vs 16 +/- 6, P = 0.0516) and DeltaMELD (0 +/- 4 vs 4 +/- 2, P = 0.0028) were significantly different between patients who died and those who survived during the 1-year follow-up. All the patients who died during follow-up showed an increase of at least 1 unit in DeltaMELD/time (sensitivity = 100%), and all the patients who survived showed a decrease of more than 1 unit in DeltaMELD/time (specificity = 100%). Longitudinal evaluation of the MELD score provides important prognostic information that seems to complete the prognostic definition provided by "static" MELD. Prospective studies in larger series are needed to validate the prognostic use of MELD modifications over time.


Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis.
Zinc finger protein 422 (Zfp422) is a widely expressed zinc finger protein that serves as a transcriptional factor to regulate downstream gene expression, but until now, little is known about its roles in myogenesis. We found here that Zfp422 plays a critical role in skeletal muscle development and regeneration. It highly expresses in mouse skeletal muscle during embryonic development. Specific knockout of Zfp422 in skeletal muscle impaired embryonic muscle formation. Satellite cell-specific Zfp422 deletion severely inhibited muscle regeneration. Myoblast differentiation and myotube formation were suppressed in Zfp422-deleted C2C12 cells, isolated primary myoblasts, and satellite cells. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) revealed that Zfp422 regulated ephrin type-A receptor 7 (EphA7) expression by binding an upstream 169-bp DNA sequence, which was proved to be an enhancer of EphA7. Knocking EphA7 down in C2C12 cells or deleting Zfp422 in myoblasts will inhibit cell apoptosis which is required for myoblast differentiation. These results indicate that Zfp422 is essential for skeletal muscle differentiation and fusion, through regulating EphA7 expression to maintain proper apoptosis.


Drug utilization review: mechanisms to improve its effectiveness and broaden its scope. The U.S. Pharmacopeia Drug Utilization Review Advisory Panel.
To address important problems and needed changes in online and retrospective drug utilization review (DUR) programs. Emphasis is placed on reliability of DUR criteria and the shift of traditional retrospective DUR programs toward disease management and health care outcomes. Published literature evaluating the role of online and retrospective DUR programs. Particular attention was given to studies assessing DUR criteria reliability and new interventions with retrospective DUR programs. A literature review was conducted along with an expert summary from the U.S. Pharmacopeia Drug Utilization Review Advisory Panel. Studies have revealed variations in DUR criteria that could be affecting clinical practice and patient care. Appropriate formal methodologies and use of consistent procedures in developing online prospective DUR programs and systems could help resolve these problems. Traditional retrospective DUR is also shifting to incorporate disease management and methodologies from health outcomes and pharmacoeconomics studies. Refinements are needed to improve the reliability and validity of online DUR criteria and to minimize false positive messages. Databases created as a result of DUR efforts have been used in new and innovative ways to incorporate health outcomes data and disease management interventions. Additional outcomes data, combined with quality assurance efforts, should increase the utility of DUR/disease management efforts in evaluating health systems while improving the effectiveness and efficiency of pharmacists' health care interventions.


Total body irradiation with a sweeping 60Cobalt beam.
This article describes the physical, technical, and dosimetric aspects of total body irradiation (TBI). The continuous head swivel motion of a standard 60Cobalt unit has been used to obtain a sweeping beam that encompasses the entire length of the patient in TBI. A perspex beam flattener designed to remove the inverse square fall-off in beam intensity along the sweep axis provides a 90% field length of 200 cm in air at a treatment source-to-skin distance of 160 cm. The anterior-posterior parallel pair setup permits accurate placement of customized lead compensators to limit the dose to lungs. Measured beam profiles, dose buildup curves, and percentage depth dose for the technique are presented. With compensators in place, the variation in lung dose is shown to be within +/- 5% of the prescribed tumor dose. A sweeping beam TBI technique has been devised using a standard 60Cobalt unit. The technique allows the patient to be treated in supine and prone positions, which facilitates the accurate placement of lung compensators to limit the dose to lung tissue.


Fate of concomitant tricuspid regurgitation in patients undergoing coronary artery bypass grafting.
Owing to a lack of supportive data, tricuspid regurgitation (TR) is usually not addressed in patients undergoing coronary artery bypass grafting (CABG). Here we evaluated changes in TR degrees over time and its impact on survival in patients undergoing CABG. We reviewed the data of 9726 patients who underwent isolated CABG between January 2000 and January 2021. According to preoperative TR severity, patients were stratified into nonsignificant (none to trivial, mild) and significant (moderate to severe) TR groups. We excluded patients who had undergone previous tricuspid valve surgery, pacemaker placement, and concomitant valve or ablative surgery. Propensity score matching and Cox proportional hazards models were used to identify associations between TR grade and the primary outcome of all-cause mortality. The secondary outcome was change in TR severity on the last echocardiogram. After propensity score matching, 380 patients in each group were identified. At baseline, 359 patients had moderate TR (94.5%) and 21 (5.5%) had severe TR. On the last follow-up echocardiogram, TR had improved in 40.5% of the patients in the significant TR group. Kaplan-Meier survival curves showed significantly lower survival in patients with significant preoperative TR compared to those with nonsignificant TR (P < .001). After adjusting for other confounders, survival was no worse in the patients with significant TR group (hazard ratio, 1.05; 95% confidence interval, 0.80-1.38; P = .70). Significant preoperative TR improved in 40.5% of patients after isolated CABG. After adjusting for other factors, significant TR did not affect long-term survival.


Locomotion of helical bodies in viscoelastic fluids: enhanced swimming at large helical amplitudes.
The motion of a rotating helical body in a viscoelastic fluid is considered. In the case of force-free swimming, the introduction of viscoelasticity can either enhance or retard the swimming speed and locomotive efficiency, depending on the body geometry, fluid properties, and the body rotation rate. Numerical solutions of the Oldroyd-B equations show how previous theoretical predictions break down with increasing helical radius or with decreasing filament thickness. Helices of large pitch angle show an increase in swimming speed to a local maximum at a Deborah number of order unity. The numerical results show how the small-amplitude theoretical calculations connect smoothly to the large-amplitude experimental measurements.


HomA and HomB, outer membrane proteins of Helicobacter pylori down-regulate activation-induced cytidine deaminase (AID) and Ig switch germline transcription and thereby affect class switch recombination (CSR) of Ig genes in human B-cells.
H. pylori is one of the major causes of chronic gastritis, peptic ulcer disease (PUD), gastric mucosa-associated lymphoid tissue lymphoma (MALT) and gastric carcinoma. H. pylori toxin VacA is responsible for host cell apoptosis, whereas CagA is known to aberrantly induce expression of activation-induced cytidine deaminase (AID) in gastric epithelial cells that causes mutations in oncogenes and tumour suppressor genes, leading to the transformation of normal cells into cancerous cells. Although, a significant amount of research has been conducted to understand the role of bacterial factors modulating deregulated host cell pathways, the interaction between H. pylori and immune cells of the marginal zone and its consequences are still not well understood. HomB and HomA, outer membrane proteins (OMPs) from H. pylori, which assist in the adhesion of bacteria to host cells, are found to be associated with H. pylori virulent strains and promote inflammation. Interestingly, we observed that the interaction of HomB/HomA OMPs with B-cells transiently downregulates AID expression and Ig switch germline transcription. Downregulation of AID leads to impairment of class switch recombination (CSR), resulting in significantly reduced switching to IgG and IgA antibodies. Besides, we examined the immune-suppressive response of B-cells and observed that the cells stimulated with HomA/B show upregulation in the levels of IL10, IL35, as well as PDL1, a T-cell inhibition marker. Our study suggests the potential role of OMPs in immune response modulation strategies used by the pathogen to evade the immune response. These results provide a better understanding of H. pylori pathogenesis and assist in identifying novel targets for therapy.


Combination antiemetic therapy in cisplatin-induced nausea and vomiting.
Twenty-seven consecutive patients with advanced gynecologic malignancies undergoing chemotherapy with cisplatin in combination with other agents were studied in a prospective, randomized fashion to compare the antiemetic efficacy of a combination regimen with high-dose metoclopramide. The combination regimen consisted of prochlorperazine, dexamethasone, and pentobarbital. Patients treated with the combination regimen had significantly less vomitus (P less than 0.01, Student's t test) and fewer vomiting episodes (P less than 0.001, test for homogeneity) than patients treated with metoclopramide. In addition, the sedative and sleep-inducing effect of the barbiturate made the experience of vomiting more tolerable, even in those instances where the combination regimen was not superior to metoclopramide in the control of vomiting.


Daytime sleep latency in medication-matched Parkinsonian patients with and without sudden onset of sleep.
Currently, it is unclear whether sleep attacks in Parkinson's disease (PD) represent a novel entity or just a phenomenon of daytime sleepiness. We investigated 10 PD patients with sleep attacks and compared them with 10 PD patients without any daytime sleepiness. The patients were matched according to their dopaminergic medication and subjected to a sleep medical investigation. The mean sleep latency on the multiple sleep latency test was in the normal range and not significantly different between the groups. These data suggest that sleep attacks can occur against a background of normal alertness.


Long term effects of early nutritional support with new enterotropic peptide-based formula vs. standard enteral formula in HIV-infected patients: randomised prospective trial Chlebowski R T, Beall G, Grovenor M, Lillington L, Weintraub N, Ambler C, Richards E W, Abbruzzese B C, McCamish M A and Cope F O Nutrition 1993; 9 (6): 507-512.
This paper describes a prospective trial of a new peptide based formula (NEF) compared with a standard enteral formula (SEF) in the management of weight loss in people with HIV infection. 80 largely asymptomatic patients were randomised to receive 2-3 8 oz cans of either the NEF or SEF supplement. Outcome measures included adherence, weight change, anthropometric measurements, serum biochemistry, gastrointestinal symptoms, physical performance and intercurrent health events and were assessed at baseline, 3 and 6 month intervals. For the 56 evaluable patients those receiving the NEF supplement maintained body weight better (p = 0.04), had more stable triceps skinfold measurements (p = 0.03), lower blood urea nitrogen (p = 0.04), and reduced hospitalisation during the 3-6 month evaluation period (p = 0.02) than those consuming the SEF supplement. The NEF supplement was well tolerated and did not result in untoward clinical effects. These data suggest that the supplemental use of a NEF provides superior nutritional management compared to an SEF for patients with early stage HIV infection.


Some monoclonal antibodies raised with a native protein bind preferentially to the denatured antigen.
Recent studies with monoclonal antibodies directed against different epitopes of the beta 2-subunit of Escherichia coli tryptophan synthase have shown that some of these antibodies bind rapidly in solution to the native protein; others bind very slowly to native beta 2 in solution while they recognize quite rapidly this antigen adsorbed on a microtitration plate. In the present work, an enzyme-linked immunosorbent assay competition test with either the native or a denatured form of the antigen has been developed. It allowed us to show that the rapidly binding antibodies recognize epitopes present on the native protein while those which react very slowly in solution bind preferentially to the denatured form of the protein. These results prompted us to emphasize how important it is, in the characterization of antibodies, to ascertain that the antigen they recognize remains native in the specificity test.


Freedon of inquiry and subjects' rights: an introduction.
The author introduces the Special Section papers to follow, pointing out that two new issues have attached themselves to the issue of the physical safety and civil dignity of human subjects. One new issue is an emphatically legal defense of the concept of subjects' rights; the other is the evolution of political characterizations and caricatures of many forms of research.


Massive integration of diverse protein quality assessment methods to improve template based modeling in CASP11.
Model evaluation and selection is an important step and a big challenge in template-based protein structure prediction. Individual model quality assessment methods designed for recognizing some specific properties of protein structures often fail to consistently select good models from a model pool because of their limitations. Therefore, combining multiple complimentary quality assessment methods is useful for improving model ranking and consequently tertiary structure prediction. Here, we report the performance and analysis of our human tertiary structure predictor (MULTICOM) based on the massive integration of 14 diverse complementary quality assessment methods that was successfully benchmarked in the 11th Critical Assessment of Techniques of Protein Structure prediction (CASP11). The predictions of MULTICOM for 39 template-based domains were rigorously assessed by six scoring metrics covering global topology of Cα trace, local all-atom fitness, side chain quality, and physical reasonableness of the model. The results show that the massive integration of complementary, diverse single-model and multi-model quality assessment methods can effectively leverage the strength of single-model methods in distinguishing quality variation among similar good models and the advantage of multi-model quality assessment methods of identifying reasonable average-quality models. The overall excellent performance of the MULTICOM predictor demonstrates that integrating a large number of model quality assessment methods in conjunction with model clustering is a useful approach to improve the accuracy, diversity, and consequently robustness of template-based protein structure prediction. Proteins 2016; 84(Suppl 1):247-259. © 2015 Wiley Periodicals, Inc.


Pain Recognition in Fish.
Empirical evidence has demonstrated that fish experience pain, and so to ensure their good welfare, it is vital that we can recognize and assess pain. A range of general, behavioral, and physiologic indicators can be used when assessing pain in fish. Many of these can be used at the tank side and are termed operational welfare indicators, whereas some require further computer or laboratory analysis. Behavioral indicators are valid and have been shown to profoundly differ between nonpainful and painful treatments in fish. However, these are not universal, and species-specific differences exist in behavioral responses to pain.


Optical coherence tomography of optic disk melanocytoma in 15 cases.
To describe the optical coherence tomography (OCT) features of optic disk melanocytoma. Case series including 15 patients. OCT characteristics of the tumor. The mean age of the patients was 42 years. By ophthalmoscopy, the mean basal diameter of the tumor was 2.7 mm, and by ultrasonography, the mean thickness was 1.8 mm. By OCT, the tumor showed a nodular appearance in 14 cases (93%). The tumor displayed a gradual sloping transition from normal retina into the mass, hyperreflectivity at its anterior tumor surface, and dense posterior shadowing with an optically empty appearance in all 15 cases (100%). Thicker tumors displayed thinner anterior hyperreflective borders and denser shadowing. There were no internal qualities of the tumor or disk visible by OCT due to dense shadowing. Other findings of OCT included vitreous seeds in 2 cases (13%) and adjacent retinal edema in 1 case (7%). There were no cases of retinal traction, subretinal fluid, macular edema, or epiretinal membrane in the macula. Optic disk melanocytoma shows characteristic features by OCT including a gradual transition from normal retina into nodular tumor, and the mass displays a bright anterior border layer with optically empty internal details.


(5R)-5-hydroxytriptolide inhibits the immune response of human peripheral blood mononuclear cells.
(5R)-5-hydroxytriptolide (LLDT-8) displayed immunosuppressive activities both in vitro and in autoimmune disease models. Here, we aim to further clarify the effect of LLDT-8 on the immune responses of human peripheral blood mononuclear cells (PBMC). Cell proliferation of human PBMC from healthy donors was evaluated by [3H]-thymidine uptake. NK cell cytotoxicity was assayed using K562 cells in a [3H] lysis assay. Cytokine production was determined by enzyme-linked immunosorbent assay. The expression of cell surface molecules was detected with flow cytometry. The mRNA expression and the protein phosphorylation levels were detected by RT-PCR and Western immunoblot assay. LLDT-8 at 25 and 50 nM significantly inhibited the PHA- and recall antigens-induced T cell proliferation, and suppressed mixed lymphocyte reaction. LLDT-8 reduced cytokines production (IFN-gamma, IL-2, TNF-alpha) in PHA- and Sac-activated PBMC. LLDT-8 did not alter the increased expression of MHC class I/II and B7.1, but reduced B7.2 by approximately 30%. No effect of LLDT-8 was observed for the expression of T cell activation markers (CD69, CD154). However, LLDT-8 significantly reduced IFN-gamma-expressing T cell percentages and IFN-gamma mRNA transcription in PHA-activated T cells. It also inhibited the phosphorylation levels of JNK and p38. LLDT-8 did not affect NK cytotoxic activity against K562 cells. LLDT-8 was a promising immunosuppressant for human immune-related diseases.


Experience of German Red Cross blood donor services with nucleic acid testing: results of screening more than 30 million blood donations for human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus.
The risk of transfusion-transmitted human immunodeficiency virus-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections is predominantly attributable to donations given during the early stage of infection when diagnostic tests may fail. In 1997, nucleic acid amplification technique (NAT)-testing was introduced at the German Red Cross (GRC) blood donor services to reduce this diagnostic window period (WP). A total of 31,524,571 blood donations collected from 1997 through 2005 were screened by minipool NAT, predominantly with pool sizes of 96 donations. These donations cover approximately 80 percent of all the blood collected in Germany during that period. Based on these data, the WP risk in the GRC blood donor population was estimated by using a state-of-the-art mathematic model. During the observation period, 23 HCV, 7 HIV-1, and 43 HBV NAT-only-positive donations were detected. On the basis of these data and estimated pre-NAT infectious WPs, the residual risk per unit transfused was estimated at 1 in 10.88 million for HCV (95% confidence interval [CI], 7.51-19.72 million), 1 in 4.30 million for HIV-1 (95% CI, 2.39-21.37 million), and 1 in 360,000 for HBV (95% CI, 0.19-3.36 million). Based on observed cases of breakthrough infections, the risk of transfusion-related infections may be even lower. The risk of a blood recipient becoming infected with HCV, HIV-1, or HBV has reached an extremely low level. Introduction of individual donation testing for HCV and HIV-1 would have a marginal effect on interception of WP donations.


Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice.
The Period 2 (Per2) gene is an important component of the circadian system and is thought to modulate many physiological and pathological processes in mammals. In the previous study, we have disclosed the protective role of Per2 against carbon tetrachloride induced liver injury and fibrosis. Here we further assess the effect of Per2 deficiency on cholestatic hepatic injury and fibrosis. Cholestasis was induced by bile duct ligation (BDL) for 10 days in wild-type (WT) and Per2(-/-) mice. Masson trichrome staining and analysis of α-SMA immunohistochemistry were performed to show the collagen accumulation and the HSC activation, respectively. The mRNA levels of fibrosis-related genes were monitored by quantitative real-time PCR. Following BDL, livers from Per2(-/-) mice exhibited markedly increased extent of bile infarct and extracellular matrix (ECM) deposition compared with WT mice. Furthermore, the expressions of fibrosis-related genes like TNF-α, TGF-β1, Col1α1 and TIMP-1 were dramatically elevated in Per2(-/-) cholestatic liver. Our observations indicated that clock gene Per2 plays a protective role in mediating liver injury and fibrosis during cholestasis.


The expression of stromal cell-derived factor 1 (SDF-1) in inflamed human dental pulp.
Although dental pulp progenitor/stem cells (DPSCs) are indispensable for repair after pulpal injury, the mechanisms regulating their recruitment and activation remain unknown. To address this issue, we evaluated whether DPSCs in inflamed dental pulp had an upregulation of the chemokine system, a system of proteins known to regulate cellular responses to inflammation. Stromal cell-derived factor 1 (SDF-1), a member of the CXC chemokine subfamily and its receptor CXC chemokine receptor 4 (CXCR4), were evaluated in inflamed dental pulps obtained from extracted human teeth that showed spontaneous pain and/or lingering pain in response to cold and/or heat stimulus and compared with control levels found in normal dental pulps obtained from healthy noncarious third molars. Using immunohistochemistry and real-time reverse-transcription polymerase chain reaction, the results indicated that in inflamed pulps the SDF-1/CXCR4 axis was mostly distributed in inflammatory cells and microvascular endothelial cells rather than in normal pulps. SDF-1 messenger RNA expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. These findings suggest that SDF-1 plays an important role in the process of pulpal inflammation via the recruitment of CXCR4-expressing inflammatory cells, and the SDF-1/CXCR4 axis may be involved in the recruitment of dental pulp stem cells at the injury site.


Studies of ciprofloxacin encapsulation on alginate/pectin matrixes and its relationship with biodisponibility.
Screening of ciprofloxacin (Cip) with selected biopolymers brings about 90% antibiotic interactions with a coacervate composed of alginate/high metoxylated pectin in 2:1 ratio. Fourier transform infrared spectroscopy analysis provides information about the nature of this interaction, revealing ionic and hydrophobic patterns among the molecules. Alginate/high methoxylated pectin gel microspheres developed by ionic gelation encapsulates 46.8 ± 5.0% Cip. The gel matrix can release Cip in a sustained manner, releasing 42.7 ± 0.2% in 2 h under simulated stomach pH conditions, and 83.3 ± 1.1% Cip release in 80 mM phosphate at pH = 7.40 (intestinal). The increase of sodium chloride from 50 to 200 mM implies a Cip release from 69.0 ± 1.5% to 95.1 ± 3.6% respectively in 2 h. Scanning electron microscopy revealed the cohesive effect of HM pectin over alginate molecules on the microsphere surface. Those results guarantee all Cip contained in the alginate/HM pectin microspheres could be released in an established kinetic profile along the gastrointestinal tract, avoiding the Cip undesirable side effects during absorption.


Exploiting heterogeneous sequence properties improves prediction of protein disorder.
During the past few years we have investigated methods to improve predictors of intrinsically disordered regions longer than 30 consecutive residues. Experimental evidence, however, showed that these predictors were less successful on short disordered regions, as observed two years ago during the fifth Critical Assessment of Techniques for Protein Structure Prediction (CASP5). To address this shortcoming, we developed a two-level model called VSL1 (CASP6 id: 193-1). At the first level, VSL1 consists of two specialized predictors, one of which was optimized for long disordered regions (>30 residues) and the other for short disordered regions (< or =30 residues). At the second level, a meta-predictor was built to assign weights for combining the two first-level predictors. As the results of the CASP6 experiment showed, this new predictor has achieved the highest accuracy yet and significantly improved performance on short disordered regions, while maintaining high performance on long disordered regions.


Ensemble: a web-based system for psychology survey and experiment management.
We provide a description of Ensemble, a suite of Web-integrated modules for managing and analyzing data associated with psychology experiments in a small research lab. The system delivers interfaces via a Web browser for creating and presenting simple surveys without the need to author Web pages and with little or no programming effort. The surveys may be extended by selecting and presenting auditory and/or visual stimuli with MATLAB and Flash to enable a wide range of psychophysical and cognitive experiments which do not require the recording of precise reaction times. Additionally, one is provided with the ability to administer and present experiments remotely. The software technologies employed by the various modules of Ensemble are MySQL, PHP, MATLAB, and Flash. The code for Ensemble is open source and available to the public, so that its functions can be readily extended by users. We describe the architecture of the system, the functionality of each module, and provide basic examples of the interfaces.


n-Butyl isocyanide oxidation at the [NiFe4S4OH(x)] cluster of CO dehydrogenase.
Carbon monoxide dehydrogenases (CODHs) catalyze the reversible oxidation of carbon monoxide by reaction with water to yield carbon dioxide, two protons, and two electrons. Two principal types of CODHs can be distinguished. Ni,Fe-containing CODHs contain a [NiFe(4)S(4)OH(x)] cluster within their active site, to which the direct binding of the substrates water and carbon dioxide has been revealed by protein X-ray crystallography. n-Butyl isocyanide is a slow-turnover substrate of CODHs, whose oxidation at the active site shows several parallels to the oxidation of carbon monoxide. Here, we report the crystal structure of CODH-II from Carboxydothermus hydrogenoformans resulting from the enzymatic oxidation of n-butyl isocyanide to n-butyl isocyanate at its active site cluster. The high resolution of the structure (d(min) = 1.28 Å) revealed n-butyl isocyanate bound to the active site cluster and identified a novel type of Ni-C bond in CODHs. The structure suggests the occurrence of tetrahedral in addition to square-planar nickel complexes in product-bound states of this enzyme. Furthermore, we discovered a molecule of n-butyl isocyanide in a hydrophobic channel leading to the active site, revealing a unique architecture for the substrate channel of CODH-II compared with the bifunctional CODHs.


Control of wild oat (Avena fatua) using some phenolic compounds I - Germination and some growth parameters.
The percentage of germination of wild oat was significantly inhibited by increasing the concentrations of phenolic compounds. Ferulic acid was the most effective compound which completely inhibited germination at a concentration of 3.0 mM. At the same time, wheat and barley were slightly affected with different concentrations of the four phenolic compounds. The percentage of germination of wheat significantly decreased with increasing of ferulic acid reaching a maximum inhibition at 3.0 mM concentration. On the other hand, the germination of wheat was not affected with the other three phenolic compounds. The percentage of germination of barley was not affected with all phenolic compounds except for hydroxy phenolic acetic acid which has significant effect at a concentration of 3.0 mM. Salicylic acid significantly inhibited the growth parameters gradually in wild oat, wheat and barley. The shoot/root ratio was decreased in wild oat and barley, while the ratio increased in wheat. The growth parameters were completely inhibited at 3.0 mM of ferulic acid for both wild oat and wheat but slightly inhibited for barley. The shoot/root ratio was increased in all concentrations of ferulic acid except at 3.0 mM which was completely inhibited for both wild oat and wheat, while the ratio was increased in all treatments of ferulic acid in the case of barley. The growth parameters were highly significant and decreased in wild oat, wheat and barley with increasing the concentrations of hydroxybenzoic acid and hydroxyphenyl acetic acid. The shoot/root ratio was not changed in all concentrations except at 3.0 mM in the case of wild oat, the ratio was decreased at 2.0 and 3.0 mM in the case of wheat, while the ratio increased in most of hydroxybenzoic acid concentrations in the case of barley. The shoot/root ratio was increased with increasing of the hydroxyphenyl acetic acid concentrations.


Hydrogen peroxide mediates defence responses induced by chitosans of different molecular weights in rice.
To investigate the mechanisms whereby treatment with chitosan (CHN) is observed to increase the capacity of plants to resist pathogens, CHNs of different molecular weights (MWs) prepared by enzyme hydrolysis were used to treat rice cells in suspension culture and also rice seedlings. The results obtained with cultured cells showed that in this material CHN treatment could trigger a set of defence responses, including the production of hydrogen peroxide (H2O2), increases in the activities of phenylalanine ammonialyase (PAL; EC 184.108.40.206) and chitinase (CHI; EC 188.8.131.52), increases in transcription of defence-related genes beta-1,3-glucanase (glu) and chitinase (chi) and accumulation of pathogen-related protein (PR1). Furthermore, CHNs of different MWs were observed to have different capacities to induce defence responses. CHNs of low MWs were more effective at inducing the described defence responses than those of higher MWs. Enhanced defence against rice blast pathogen Magnaporthe grisea 97-23-2D1 was observed in rice seedlings treated with low MW CHNs compared to seedlings treated with higher MW CHNs. In all cases, suppressing the production of H2O2 by adding scavengers dimethylthiourea (DMTU), 2,5-dihydroxycinnamic acid methyl ester (DHC), catalase (Cat) or ascorbate (As) blocked the defence responses. These results indicate that CHNs of low MWs have a greater capacity to induce the production of H2O2, thus resulting in stronger defence responses, than those with higher MWs.


Application of electrochemical impedance spectroscopy for monitoring allergen-antibody reactions using gold nanoparticle-based biomolecular immobilization method.
Gold nanoparticles were used to enhance the immobilization amount and retain the immunoactivity of recombinant dust mite allergen Der f2 immobilized on a glassy carbon electrode (GCE). The interaction between allergen and antibody was studied by electrochemical impedance spectroscopy (EIS). Self-assembled Au colloid layer (ø=16nm) deposited on (3-mercaptopropyl)trimethoxysilane (MPTS)-modified GCE offered a basis to control the immobilization of allergen Der f2. The impedance measurements were based on the charge transfer kinetics of the [Fe(CN)(6)](3-/4-) redox pair, compared with bare GCE, the immobilization of allergen Der f2 and the allergen-antibody interaction that occurred on the electrode surface altered the interfacial electron transfer resistance and thereby slowed down the charge transfer kinetics by reducing the active area of the electrode or by preventing the redox species in electrolyte solution from approaching the electrode. The interactions of allergen with various concentrations of monoclonal antibody were also monitored through the change of impedance response. The results showed that the electron transfer resistance increased with increasing concentrations of monoclonal antibody.


Copy number variations in the GATA4, NKX2-5, TBX5, BMP4 CRELD1, and 22q11.2 gene regions in Chinese children with sporadic congenital heart disease.
Congenital heart disease (CHD) is a common birth defect originating from both environmental and genetic factors. An overabundance of copy number variations (CNVs) affecting cardiac-related genes has previously been detected in individuals with CHD. To evaluate if the presence of CNVs in the 22q11.2 region, and to determine whether GATA4, NKX2-5, TBX5, BMP, and CRELD1 genes contributed toward the pathogenesis of isolated incidences of CHDs in southwest China. In total 167 patients from southwest China with sporadic CHD were studied, including 121 patients with ventricular septal defect (VSD), 24 with atrial septal defect (ASD), 12 with tetralogy of fallot (TOF), six VSD cases with TOF, two cases with patent ductus arteriosus (PDA), and two VSD cases with ASD. 22q11.2, GATA4, NKX2-5, TBX5, BMP4, and CRELD1 regions were screened using MLPA and copy number variation sequencing (CNV-Seq). A 2.5-2.8 Mb deletion in the 22q11.2 region was identified in 5 patients with CHD. Two of these patients were diagnosed with VSD, while two had VSD and ASD, and the other had TOF. 5 patients correspond to the same classical DiGeorge syndrome. A 0.86 Mb duplication in the 22q11.2 region was identified in a PDA patient, whom was without extracardiac symptoms. These data suggest that copy number variation in the 22q11.2 region is common in CHD patients in southwest China. Regardless of the presence or absence of extracardiac symptoms, results also indicate that it is necessary to perform prenatal screening for CHD.


Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner.
The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation. Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery. Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.


Hair cortisol levels in women with medically unexplained symptoms.
Stress has been demonstrated to be involved in the development of medically unexplained symptoms. A key underlying mechanism could be lower levels of cortisol, which can contribute to symptoms such as fatigue or pain. However, the literature is highly equivocal, which may be due to methodological limitations inherent in short-term cortisol assessment. The aim of this case-control study was to investigate, for the first time, whether individuals with different forms of medically unexplained symptoms show altered hair cortisol concentrations, a long-term marker of hypothalamic-pituitary-adrenal functioning. Two groups of women with medically unexplained symptoms were recruited. The first had a functional somatic syndrome, characterised by specific medically unexplained symptoms (i.e., chronic fatigue syndrome, fibromyalgia, or irritable bowel syndrome, n = 33). The second had somatic symptom disorder, characterised by excessive thoughts, feelings, and behaviours devoted to various medically unexplained symptoms (n = 23). These groups were contrasted with healthy controls (n = 30), and women with depression (n = 27). Cortisol representing the previous three months was extracted from hair. Chronic stress and childhood trauma were assessed (retrospectively). Women with somatic symptom disorder had lower hair cortisol than healthy controls and women with functional somatic syndromes. No differences in hair cortisol were found between healthy controls, functional somatic syndromes, and depression. Neither childhood trauma nor chronic stress was correlated with hair cortisol. Provided that our findings are replicated, they may suggest that hypocortisolism is found in a specific subgroup of individuals with medically unexplained symptoms, and potentially in those characterised by excessive thoughts, feelings, and behaviours about symptoms.


A quick and simple method for the routine determination of acetyl- and butyrylcholinesterase in blood.
The salient features of this method for biological monitoring of occupational exposure to organophosphorus insecticides are: (a) acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are determined separately in whole haemolysed blood using specific substrates at appropriate concentrations; (b) 20 microliter of blood drawn from the finger tip is sufficient for both determinations; (c) the blood sample is immediately diluted with a solution of saponin and may thereafter be frozen for storage; (d) diagnostic kits, commercially available for the determination of plasma BuChE, may be employed with modifications; (e) the kinetic procedure is avoided by blocking the enzyme reactions at the end of the incubation period. This paper describes attempts to achieve optimal conditions for the two reactions. Under the conditions finally chosen, the whole blood 'AChE' activity value still includes a small percentage of plasma BuChE activity (12.5% of the total), while the whole blood 'BuChE' activity includes a small percentage of erythrocyte AChE activity (7% of the total). Results of determinations performed with this procedure on 172 healthy subjects are reported.


Identification of a thrombin cleavage site and a short form of ADAMTS-18.
We previously reported that C-terminal fragment of ADAMTS-18 induces platelet fragmentation through ROS release. We have shown that thrombin cleaves ADAMTS-18 and that a short form of ADAMTS-18 in in vitro translational assay. However, the exact thrombin cleavage site and whether a short form ADAMTS-18 presents in vivo are not clear. In this study, we first identified that the thrombin cleavage site is between Arg775 and Ser776 by thrombin cleavage of ADAMTS-18 peptide following mass spectrum assay. We then showed that a short form ADAMTS-18 presents in brain, kidney, lung, and testicle from C57BL/6 mouse embryo. Since alternative form of ADAMTS-18 could be a mechanism to regulate its activity, we then investigated the mechanism involves in the generation of ADAMTS-18 short form. However, neither protease inhibitors nor mutations in catalytic domain of ADAMTS-18 have any significant effect on the generation of ADAMTS-18 short form. Thus, our data demonstrate a thrombin cleavage site and confirm a short form of ADAMTS-18 presents in vivo.


Resting heart rate in patients with ischemic heart disease in Saudi Arabia and Egypt.
To assess the level of resting heart rate (RHR) in an outpatient population presenting with stable coronary artery disease (CAD) as well as to measure its association with current therapeutic management strategies for cardiovascular events. A multi-center cross-sectional survey was carried out in Saudi Arabia and Egypt over a three month period (between January 2007 and April 2007). 2049 patients with CAD without clinical heart failure (HF) were included in this study through "cluster sampling". RHR was measured by manual palpitation. Mean age of CAD patients was 56.7 ± 10.4 and the mean RHR was 78.9 ± 13.9 b/m. 1686 patients (83.1%) were on β-blockers for whom the RHR was 78.5 ± 14.0 b/m (95.5% had RHR ⩾ 60 b/m, which is higher than recommended by the guidelines). 1094 (73.5%) of patients on β-blockers were on a lower dose, probably to avoid the complications associated with such a class. Among those not on β-blockers (16.9%), RHR was 80.9 ± 13.0 b/m. Moreover, 98 patients (4.8%) were on calcium channel blocker (diltiazem or verapamil) but not on β-blockers, for whom the RHR was 80.9 ± 12.0 b/m. Finally, 163 patients (8.0%) were on both β-blockers and the calcium channel blocker, and their RHR was 79.0 ± 14.4 b/m. Optimal target RHR has not been achieved in a significant number of screened patients. Achievements of such targets are known to decrease mortality and to improve survival.


[131I]Iodoazomycin arabinoside for low-dose-rate isotope radiotherapy: radiolabeling, stability, long-term whole-body clearance and radiation dosimetry estimates in mice.
The preliminary characterization of [(131)I]iodoazomycin arabinoside ([(131)I]IAZA) as a potential radiotherapeutic radiopharmaceutical is described. High-specific-activity [(131)I]IAZA was prepared in therapeutic doses (up to 3 GBq per batch) by isotope exchange in pivalic acid melt and was purified on Sep-Pak cartridges. Stability in 15% ethanol in saline at 4 degrees C was determined by high-performance liquid chromatography. IAZA cytotoxicity (IC(50), approximately 0.1 mM) against both murine (EMT-6) and human (143B, 143B-LTK) tumor cells determined by MTT test was in the range previously reported for EMT-6 cells using a clonogenic assay. Tissue radioactivity levels were measured in a murine tumor model for the 24- to 168-h postinjection period. Radiation dose estimates obtained from the tissue activity levels for this period were calculated from pharmacokinetic (WinNonlin) and dosimetry (MIRD and RAdiation Dose Assessment Resource) parameters. The radioiodination efficiency was >90%, but with systematic losses during Sep-Pak purification, the recovered yields of [(131)I]IAZA were approximately 75%. The product (specific activity, 4.6-6.4 GBq/micromol) was stable for at least 2 weeks, with only approximately 6% degradation over this storage period. Extended biodistribution studies in Balb/c mice bearing implanted EMT-6 tumors showed that the highest tumor/blood radioactivity ratio (T/B; 4.8) occurred 24 h after dosing; the T/B ratio was approximately 1.5 at the end of the 7-day study. The 24- to 168-h tissue radioactivity data fit a one-compartment model except for liver data, which best fit a two-compartment model. Dosimetry estimates showed a tumor self-dose of 7.4 mGy/MBq, which is several-fold higher than for the liver or the kidney. [(131)I]IAZA can be efficiently radiolabeled at high specific activity, purified by a simple Sep-Pak technique and stored with little radiolysis or chemical decomposition at these specific activities. Based on measured radioactivity burdens during the week following injection and on published animal ([(125)I]IAZA) and clinical ([(123)I]IAZA) dosimetry data, the current dose estimates point to selective tumor irradiation at low dose rates.


Characterization of BOLD-fMRI signal during a verbal fluency paradigm in patients with intracerebral tumors affecting the frontal lobe.
Previous studies have indicated that the BOLD-fMRI signal can be modified by tumor processes in close vicinity to functional brain areas. This effect has been investigated primarily for the perirolandic area but there is only a limited number of studies concerning frontal cortical regions. Therefore, the aim of the current study was to characterize BOLD-fMRI signal and activation patterns in patients with frontal brain tumors while performing a verbal fluency task. Six patients (ages 31-56 years) suffering from frontal (5 left sided and 1 right sided) intracerebral tumors were examined with fMRI while performing a verbal fluency task in a blocked paradigm design. Eight healthy volunteers served as the control group. The patients (5 right and 1 left handed) demonstrated left frontal activation which could be clearly located outside the tumor area and adjacent edema with varying degrees of additional right frontal activation. In the predominant left frontal activation cluster, the mean voxel based z-score and cluster size were not statistically different between patients and controls. The present fMRI study is indicating that language related BOLD signal changes in the frontal cortex of patients with tumors close to functional areas were comparable to the signal in normal controls. Additionally, the temporal hemodynamic response characteristic was comparable in both groups. This is an important finding consistent with PET results and corroborates the feasibility of functional mapping approaches in patients with tumors affecting the frontal lobe. Additional studies investigating alterations of the hemodynamic response depending on tumor location and histology are required in order to further elucidate the association between pathophysiology and BOLD fMRI signal.


A UK survey of psychiatric services for older people in general hospitals.
Psychiatric illness is common in older people in general hospitals, but little is known of the service models operating in the UK, or of the views of old age psychiatrists regarding service provision in this area. We set out to determine the range of UK old age psychiatry service models for older people in general hospital wards, and the opinions of clinicians on future service priorities and development. A postal questionnaire survey of old age psychiatrists providing psychiatric services to older people in general hospital wards. 73% of services were provided through a generic, sector-based, consultation psychiatry model. The remaining 27% employed a range of general hospital-based liaison psychiatry services for older people, involved in proactively seeking referrals and educating general hospital staff. Those providing a generic sector-based model were significantly slower at responding to referrals. 89% of respondents were unhappy with their service to older people in general hospital wards, with only 11% preferring the generic sector-based model. Organisational barriers to change identified included the management of mental health care and physical care by different organisations. Training, both of psychiatric staff in this specialist area, and of general hospital staff in the detection and basic management of common psychiatric conditions in the general hospital setting, was felt to be necessary. The management of co-morbid psychiatric and physical illness in older people is an important issue for health services. Old age psychiatrists are unhappy with the prevalent, reactive, consultation-based model, preferring a range of liaison psychiatry models based in the general hospital. The most important barriers to service development in this area were the separate managerial arrangements for psychiatric and physical care services, and a lack of evidence for effective old age psychiatry services in this setting.


[Use of a free antero-lateral thigh flap for two-stage reconstruction of a large thoracic defect].
In case of extremely large thoracic full-thickness defects where no pedicled flap is available, very large free flaps are sometimes the only options. Dealing with such full-thickness defects where failure of the flap could be lethal, Servant and al described the concept of "two stage free flap" using Latissimus Dorsi muscular or myocutaneous flap. We present a reconstruction of a wide right posterior trunk radionecrosis with exposure of an underlying infected prosthesis using this two-stage free flap strategy with a fasciocutaneous antero-lateral thigh flap.


In vivo degradation and bone reaction of long-term fixation with a magnesium alloy made by twin-roll casting in a rat femur model.
The effect of casting parameters on the microstructure and corrosion resistance of Mg alloys is still limited, especially in clinical animal experiments. We prepared a new magnesium rare earth alloy (Mg-Re, where Re is Ce or La) by vertical two-roll casting and Mg-A by further rolling. The microstructure characteristics, degradation behavior, and bone reaction of the two alloys were studied. Ti, Mg-Re, and Mg-A alloy plates were implanted in a rat femur model, and their degradation behavior was observed 48 weeks later. In vivo experiments showed no significant changes around the femur in the Ti group, excluding external factors that may cause bone remodeling and lead to new bone formation. Mg-A induces more new bone formation than Mg-Re, which meets the necessary conditions to prevent pathological fracture. The specimen staining and sectioning showed that the liver and heart of rats implanted with magnesium alloys had no pathological changes and the cell structure was normal, similar to that of rats without a magnesium alloy. Mg-A alloy has good healing potential as a biodegradable implant material.


Changes in transcription within the CA1 field of the hippocampus are associated with age-related spatial learning impairments.
Aged rats display a broad range of behavioral performance in spatial learning. The aim of this study was to identify candidate genes that are associated with learning and memory impairments. We first categorized aged-superior learners and age learning-impaired rats based on their performance in the Morris water maze (MWM) and then isolated messenger RNA from the CA1 hippocampal region of each animal to interrogate Affymetrix microarrays. Microarray analysis identified a set of 50 genes that was transcribed differently in aged-superior learners that had successfully learned the spatial strategy in the MWM compared to aged learning-impaired animals that were unable to learn and a variety of groups designed to control for all non-learning aspects of exposure to the water maze paradigm. A detailed analysis of the navigation patterns of the different groups of animals during acquisition and probe trials of the MWM task was performed. Young animals used predominantly an allocentric (spatial) search strategy and aged-superior learners appeared to use a combination of allocentric and egocentric (response) strategies, whereas aged-learning impaired animals displayed thigmotactic behavior. The significant 50 genes that we identified were tentatively classified into four groups based on their putative role in learning: transcription, synaptic morphology, ion conductivity and protein modification. Thus, this study has potentially identified a set of genes that are responsible for the learning impairments in aged rats. The role of these genes in the learning impairments associated with aging will ultimately have to be validated by manipulating gene expression in aged rats. Finally, these 50 genes were functioning in the context of an aging CA1 region where over 200 genes was found to be differentially expressed compared to a young CA1.


Cost-effective single-step synthesis of flower-like cerium-ruthenium-sulfide for the determination of antipsychotic drug trifluoperazine in human urine samples.
Nanostructured binary metal sulfides are considered as a promising electrode material because of their excellent electron transfer and good sensing behavior rather than metal oxides. As a result, the binary metal sulfides were applied in energy and electrochemical sensor applications. Herein, we propose the electrochemical sensor method based on flower-like cerium-ruthenium sulfide nanostructure (Ce-Ru-S NS) for the electrochemical sensing of trifluoperazine (TFPZ). The Ce-Ru-S NS prepared using the cost-effective one-pot hydrothermal synthesis technique. Then, the resultant materials were characterized through suitable spectrophotometric techniques and the electrocatalytic properties of the fabricated sensor were investigated by EIS, CV, and amperometric (i-t) techniques. The Ce-Ru-S material has good electrocatalytic activity towards the electrochemical oxidation of TFPZ. Significantly, the fabricated sensor demonstrates the distinct amperometric response with the lowest limit of detection (LOD) of 0.322 nM (S/N = 3), high sensitivity 2.682 μA μM-1 cm-2 and lowest oxidation potential of +0.64 V (Ag/AgCl). Furthermore, the Ce-Ru-S NS displays excellent selectivity, good reproducibility, and long-term stability. The practicability of the TFPZ sensor tested in a human urine sample.


[Uncommon manifestation of prostate cancer : Sister Mary Joseph's nodule].
We report on the case of an 81-year-old man suffering from prostate cancer for several years. In recent months, PSA levels increased, and 68Ga-PSMA-PET-CT (PSMA: prostate-specific membrane antigen) imaging demonstrated suspicious lesions in the paravesical area and an umbilical tumor mass. Local excision was performed. Histologically, the tumor mass was diagnosed as metastasis of the prostate cancer, which is also designated as Sister Mary Joseph's nodule. Umbilical metastases of primary prostate cancer are extremely rare; however, they are of clinical importance since they are commonly associated with tumor progress and with a particularly poor prognosis.


Therapeutic potential of melatonin in the intervertebral disc degeneration through inhibiting the ferroptosis of nucleus pulpous cells.
Ferroptosis, a novel type of cell death mediated by the iron-dependent lipid peroxidation, contributes to the pathogenesis of the intervertebral disc degeneration (IDD). Increasing evidence demonstrated that melatonin (MLT) displayed the therapeutic potential to prevent the development of IDD. Current mechanistic study aims to explore whether the downregulation of ferroptosis contributes to the therapeutic capability of MLT in IDD. Current studies demonstrated that conditioned medium (CM) from the lipopolysaccharide (LPS)-stimulated macrophages caused a series of changes about IDD, including increased intracellular oxidative stress (increased reactive oxygen species and malondialdehyde levels, but decreased glutathione levels), upregulated expression of inflammation-associated factors (IL-1β, COX-2 and iNOS), increased expression of key matrix catabolic molecules (MMP-13, ADAMTS4 and ADAMTS5), reduced the expression of major matrix anabolic molecules (COL2A1 and ACAN), and increased ferroptosis (downregulated GPX4 and SLC7A11 levels, but upregulated ACSL4 and LPCAT3 levels) in nucleus pulposus (NP) cells. MLT could alleviate CM-induced NP cell injury in a dose-dependent manner. Moreover, the data substantiated that intercellular iron overload was involved in CM-induced ferroptosis in NP cells, and MLT treatment alleviated intercellular iron overload and protected NP cells against ferroptosis, and those protective effects of MLT in NP cells further attenuated with erastin and enhanced with ferrostatin-1(Fer-1). This study demonstrated that CM from the LPS-stimulated RAW264.7 macrophages promoted the NP cell injury. MLT alleviated the CM-induced NP cell injury partly through inhibiting ferroptosis. The findings support the role of ferroptosis in the pathogenesis of IDD, and suggest that MLT may serve as a potential therapeutic approach for clinical treatment of IDD.


Investigations of the unimiracidial infection of Schistosoma intercalatum in snails and the infection of the final host using cercariae of one sex.
Infection with single miracidial doses of Schistosoma intercalatum from Cameroun in Bulinus forskalii and from Zaire in B.globosus resulted in an equal number of male and female infections. The cercarial production of both sexes started at the same time. The male infected snails produced a greater number of cercariae, because of the longer duration of infection. The recovery of schistosomes from infection with male and female cercariae was for S. intercalatum, Zaire, 38.8 +/- 10.6 and 18.7 +/- 14.0 respectively. For S. intercalatum from Cameroun, with single sex cercariae from two different populations of intermediate hosts from Zaire and Cameroun were 38.3 +/- 7.3 (male); 20.3 +/- 9.3 (female) and 35.0 +/- 8.7 (male); 12.2 +/- 4.5 (female), respectively.


[Infectious pneumonia favored by paraneoplastic Cushing syndrome in a pulmonary carcinoid tumor].
Ectopic Cushing's syndrome (CS) is a rare condition nevertheless well-known to endocrinologists. The pneumologist may be called upon to treat CS not only because bronchial carcinoid tumors are the most frequent source of ectopic ACTH secretion, but also due to the fact that the immunosuppression induced by hypercorticism favors lower respiratory tract infections. We report the case of a female patient presenting with acute respiratory failure secondary to Enterobacter cloacae pneumonia exacerbated by SC. Further investigations confirmed ectopic ACTH secretion and revealed a right upper lobe pulmonary nodule. After appropriate antibiotic therapy, the patient received preoperative adrenolytic treatment. Management by right upper lobectomy resulted in the extraction of a 12mm tumor. Pathological analysis was consistent with the diagnosis of a typical carcinoid tumor. Immunohistochemistry confirmed ACTH secretion by the tumor. Even though the postoperative course showed CS regression, the patient developed adrenal insufficiency. Ectopic CS induces immunosuppression, which aggravates lower respiratory tract infections. Search for a pulmonary neuroendocrine tumor should be systematic. Following control of the secretory syndrome by adrenolytic treatment, and if the diagnosis of carcinoid tumor is confirmed, surgical treatment is the preferred option.


Independent Vector Analysis for SSVEP Signal Enhancement, Detection, and Topographical Mapping.
Steady state visual evoked potentials (SSVEPs) have been identified as an effective solution for brain computer interface (BCI) systems as well as for neurocognitive investigations. SSVEPs can be observed in the scalp-based recordings of electroencephalogram signals, and are one component buried amongst the normal brain signals and complex noise. We present a novel method for enhancing and improving detection of SSVEPs by leveraging the rich joint blind source separation framework using independent vector analysis (IVA). IVA exploits the diversity within each dataset while preserving dependence across all the datasets. This approach is shown to enhance the detection of SSVEP signals across a range of frequencies and subjects for BCI systems. Furthermore, we show that IVA enables improved topographic mapping of the SSVEP propagation providing a promising new tool for neuroscience and neurocognitive research.


Left ventricular performance improves late after aortic valve replacement in patients with aortic stenosis and reduced ejection fraction.
EF in patients with aortic stenosis and reduced EF who underwent aortic valve replacement did not improve by 1 week postoperatively despite rectification of afterload mismatch. By 6 months, however, EF significantly improved without any further change in ventricular loading conditions. This implies that the benefit from aortic valve replacement (when measured by LV ejection performance) may not be evident until late postoperatively.


Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine.
Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer's disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 μg/μl), animals administered the 5 μg/μl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 μg/μl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 μg/μl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 μg/μl dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 μg/μl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or l-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 μg/μl) demonstrated compensatory changes of increased firing frequency, a more irregular firing pattern, and a higher percentage of cells firing in bursts. These results indicate that depressive-like behavior in mice is observed following the administration of 6-OHDA and the loss of LC noradrenergic neurons; however, the depressive-like behavior correlates positively with the number of surviving LC neurons with 6-OHDA administration. This data suggests the depression observed in MCI subjects and in the early stages of AD may due to the hypothesized early, minimal loss of LC neurons with remaining LC neurons being more active than normal.