Cellular Antioxidant Activity of Olive Pomace Extracts: Impact of Gastrointestinal Digestion and Cyclodextrin Encapsulation.
Olive pomace is a valuable secondary raw material rich in polyphenols, left behind after the production of olive oil. The present study investigated the protective effect of a polyphenolic extract from olive pomace (OPE) on cell viability and antioxidant defense of cultured human HepG2 cells submitted to oxidative stress induced by tert-butylhydroperoxide (tBOOH). The investigation considered possible matrix effects, impact of gastrointestinal digestion and cyclodextrin (CD) encapsulation. Pre-treatment of cells with OPE prevented cell damage and increased intracellular glutathione but did not affect the activity of glutathione peroxidase and superoxide dismutase. OPE matrix significantly enhanced cell protective effects of major antioxidants, such as hydroxytyrosol (HTS), while cyclodextrin encapsulation enhanced activity of OPE against intracellular reactive oxygen species (ROS) accumulation. The obtained results show that OPE is more potent antioxidant in comparison to equivalent dose of main polyphenols (HTS and TS) and that increasing solubility of OPE polyphenols by CD encapsulation or digestion enhances their potential to act as intracellular antioxidants. Antioxidative protection of cells by OPE was primarily achieved through direct radical-scavenging/reducing actions rather than activation of endogenous defense systems in the cell.


Female hydrocele of canal of nuck.
Hydrocele of the canal of Nuck is a very rare condition in females. The processus vaginalis within the inguinal canal forms "the canal of Nuck" in females, homologous to the processus vaginalis in males. Failure of obliteration of the processus vaginalis results in either a direct or an indirect inguinal hernia or if a sac of serous fluid is retained, it forms a hydrocele. Very little has been reported on this condition in the literature. We present a case of hydrocele of canal of Nuck in an 8-year-old female.


Losartan activates sirtuin 1 in rat reduced-size orthotopic liver transplantation.
To investigate a possible association between losartan and sirtuin 1 (SIRT1) in reduced-size orthotopic liver transplantation (ROLT) in rats. Livers of male Sprague-Dawley rats (200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 °C prior to ROLT. In an additional group, an antagonist of angiotensin II type 1 receptor (AT1R), losartan, was orally administered (5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients. Transaminase (as an indicator of liver injury), SIRT1 activity, and nicotinamide adenine dinucleotide (NAD(+), a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods. Protein expression of SIRT1, acetylated FoxO1 (ac-FoxO1), NAMPT (the precursor of NAD+), heat shock proteins (HSP70, HO-1) expression, endoplasmic reticulum stress (GRP78, IRE1α, p-eIF2) and apoptosis (caspase 12 and caspase 3) parameters were determined by Western blot. Possible alterations in protein expression of mitogen activated protein kinases (MAPK), such as p-p38 and p-ERK, were also evaluated. Furthermore, the SIRT3 protein expression and mRNA levels were examined. The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group, as evidenced by the significant decreases in alanine aminotransferase (358.3 ± 133.44 vs 206 ± 33.61, P < 0.05) and aspartate aminotransferase levels (893.57 ± 397.69 vs 500.85 ± 118.07, P < 0.05). The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity (5.27 ± 0.32 vs 6.08 ± 0.30, P < 0.05). This was concomitant with increased levels of NAD(+) (0.87 ± 0.22 vs 1.195 ± 0.144, P < 0.05) the co-factor necessary for SIRT1 activity, as well as with decreases in ac-FoxO1 expression. Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, IRE1α, p-eIF2) which was consistent with reduced levels of both caspase 12 and caspase 3. Furthermore, losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression. However, no changes were observed in protein or mRNA expression of SIRT3. Finally, the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration. The present study reports that losartan induces SIRT1 expression and activity, and that it reduces hepatic injury in a ROLT model.


Evaluation of lid speculum with a drape (LiDrape(®)) for preventing surgical-field contamination.
To compare the degree of surgical-field contamination in cataract surgeries between a new draping method using a lid speculum with a drape (LiDrape(®)) and a conventional draping method. Cataract surgery was performed on 21 eyes using LiDrape(®) (LiDrape(®) group) and on 22 eyes using a conventional draping method (conventional group). Contamination was evaluated by bacterial culture of conjunctival sac scrapings and ocular surface irrigation fluid. Conjunctival sac scrapings were collected before and after application of preoperative antibiotics. Ocular surface irrigation fluid was collected before incision placement and during surgery. Bacterial detection rate and types of organisms isolated at these four time points were examined. Bacterial detection rates were significantly decreased in the LiDrape(®) group at all time points after the application of antibiotics compared with preapplication. Regarding between-group comparisons, the bacterial detection rate in the LiDrape(®) group was only significantly lower than that in the conventional group in the intraoperative sample. Propionibacterium acnes was the most common organism isolated from ocular surface irrigation fluid. The number of P. acnes in the intraoperative sample was significantly lower in the LiDrape(®) group compared with the conventional group. There were no significant differences in detection rates for other bacteria between the groups. LiDrape(®) was as effective as conventional draping for preventing surgical-field contamination. The number of P. acnes during surgery was significantly lower in the LiDrape(®) group compared with the conventional group, suggesting that LiDrape(®) may contribute to the prevention of postoperative infection.


Bioaccumulation, antioxidative response, and metallothionein expression in Lupinus luteus L. exposed to heavy metals and silver nanoparticles.
Yellow-lupin (Lupinus luteus L.) was grown on soils contaminated with heavy metals during two parallel studies. In the first one, the soil was contaminated by industrial activities whereas, in the second one, the soil was artificially contaminated with a single metal including Cd, Pb, Zn, Ni (in nitrate form), and Ag (in nitrate and nanoparticles form). The study was performed to assess a plant's response to contamination including its antioxidative response and molecular mechanisms involved in metal detoxification through the expression level of metallothioneins (MTs). Overall, the study provided insights into identification and validation of housekeeping genes (HKG) in L. luteus under exposure to metal stress and showed the effects of selected heavy metals and silver nanoparticles on the expression of metallothioneins, the activity of guaiacol peroxidase (GPX) and bioaccumulation of metals in leaves of L. luteus. As such, HKG validation using BestKeeper, NormFinder, and geNorm software allowed for the selection of four most stable reference genes in a context metal contamination for the selected plant. Moreover, a significant increase in the expression levels of MT was observed in plants grown under heavy metal stress and none on plants grown on 25 mg kg-1 of silver nanoparticles. Also, the GPX activity and MT expression showed statistically significant changes between different conditions and doses which means that they can be used as highly sensitive stress markers for planning the phytoremediation process on a large scale.


[Childbirth and live newborns of adolescent and young adult mothers in the municipality of Feira de Santana, Bahia State, Brazil, 1998].
Data from the Brazilian Ministry of Health and the literature indicate that adolescents may be overrepresented in the prevalence of maternal morbidity and mortality and neonatal complications. This study focused on childbirth and live newborns among adolescent and young adult mothers in the municipality of Feira de Santana, Bahia, identifying risk factors for morbidity and mortality. A cross-sectional cohort study was conducted based on data from the Information System on Live Births (SINASC) in the municipality in 1998, totaling 5,279 live births among adolescent (10 to 19 years) and young adult mothers (20 to 24 years). Variables were age, schooling, prenatal care, gestational care, form of delivery, and birthweight. The authors measured the association between maternal age and the child's birthweight, while controlling potential confounders. Some 21.6% of live births were to adolescent mothers, 51.2% of whom had not finished primary school; there was an association between the 10 to 16-year age bracket and incomplete primary schooling, lack of prenatal care, and low and insufficient birthweight as compared to the other age brackets; there was also a high rate of underrecording in the SINASC. The results suggest the need for specific measures focusing on the reproductive health of adolescents in the municipality.


Adolescent risk behaviors and religion: findings from a national study.
Too few studies have assessed the relationship between youth risk behaviors and religiosity using measures which captured the varied extent to which youth are engaged in religion. This study applied three measures of religiosity and risk behaviors. In addition, this study ascertained information about youths' participation in religious activities from a parent or caretaker. Based on a national random sample of 2004 teens (ages 11-18), this study indicates that youth perceive religion as important, are active in religious worship and activities, and further shows that perceived importance of religion as well as participation in religious activities are associated with decreased risk behaviors. Looking at ten risk behaviors, religiosity variables were consistently associated with reduced risk behaviors in the areas of: smoking, alcohol use, truancy, sexual activity, marijuana use, and depression. In the case of these six risk variables, religiosity variables were significantly associated with reduced risk behaviors when controlling for family background variables and self-esteem. The study highlights the importance of further understanding the relationship between religious variables, background variables, self-esteem, and youth risk behaviors.


Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol.
Inhaled corticosteroids (ICSs) and long-acting inhaled beta(2)-agonists (LABAs) are recommended treatment options for asthma. This review compares the clinical effectiveness and tolerability of the ICSs fluticasone propionate and budesonide and the LABAs formoterol fumarate and salmeterol xinafoate administered alone or in combination. A systematic review of the clinical studies available on MEDLINE (database period, 1950-September 2009) was conducted to assess English-language randomized controlled trials in children and adults with asthma. Treatment outcomes included lung function, symptom-free days (SFDs), use of rescue/reliever medications, asthma exacerbations, and tolerability profile. Use of fluticasone was associated with significantly greater improvement in lung function and better asthma symptom control than budesonide. Similarly, formoterol was associated with significantly greater improvement in lung function and better asthma symptom control (as measured by less rescue medication use and more SFDs) compared with salmeterol. Single inhaler combination regimens (budesonide/ formoterol and fluticasone/salmeterol) were frequently more effective in improving all treatment outcomes than either monotherapy alone. Across all comparisons, a review of studies in adults and children did not find statistically significant differences in outcomes between the ICS and LABA therapies considered in this research. In general, no differences in tolerability profiles were reported between the ICS and LABA options, although the risk for growth retardation was lower with fluticasone than budesonide and with budesonide/formoterol than with budesonide monotherapy. In this systematic review, fluticasone and formoterol appear to provide improved therapeutic benefits versus budesonide and salmeterol, respectively. Both fluticasone/salmeterol and budesonide/ formoterol combination therapies appeared to be associated with greater improvements in outcomes measures than the corresponding ICS and LABA monotherapies.


A switch in disulfide linkage during minicollagen assembly in Hydra nematocysts.
The smallest known collagens with only 14 Gly-X-Y repeats referred to as minicollagens are the main constituents of the capsule wall of nematocysts. These are explosive organelles found in Hydra, jellyfish, corals and other Cnidaria. Minicollagen-1 of Hydra recombinantly expressed in mammalian 293 cells contains disulfide bonds within its N- and C-terminal Cys-rich domains but no interchain cross-links. It is soluble and self-associates through non-covalent interactions to form 25-nm-long trimeric helical rod-like molecules. We have used a polyclonal antibody prepared against the recombinant protein to follow the maturation of minicollagens from soluble precursors present in the endoplasmic reticulum and post-Golgi vacuoles to the disulfide-linked insoluble assembly form of the wall. The switch from intra- to intermolecular disulfide bonds is associated with 'hardening' of the capsule wall and provides an explanation for its high tensile strength and elasticity. The process is comparable to disulfide reshuffling between the NC1 domains of collagen IV in mammalian basement membranes.


Pitfalls in using sodium hypochlorite as a seed disinfectant in C incorporation studies.
Seeds sterilized with sodium hypochlorite (NaOCl) retained sufficient amounts to interfere with studies of amino acid metabolism of the sterilized seeds during germination. Repeated washing in water did not remove NaOCl completely. However, soaking the seeds for 10 min in 0.01 n HCl removed NaOCl completely, without reducing germinability.Residual NaOCl reacted with the amino acids and reduced their concentrations in the incubation media. This reaction resulted in high production of CO(2) and low uptake of amino acids by the seeds. Decarboxylation of the amino acids occurred in the incubation medium outside the seed, was independent of the presence of seeds in the reaction, and therefore was not related to amino acid metabolism by the seeds. Effects of NaOCl on uptake, incorporation, and CO(2) production from indoleacetic acid were similar to those of the amino acids studied.


Muller's ratchet and the pattern of variation at a neutral locus.
The levels and patterns of variation at a neutral locus are analyzed in a haploid asexual population undergoing accumulation of deleterious mutations due to Muller's ratchet. We find that the movement of Muller's ratchet can be associated with a considerable reduction in genetic diversity below classical neutral expectation. The extent to which variability is reduced is a function of the deleterious mutation rate, the fitness effects of the mutations, and the population size. Approximate analytical expressions for the expected genetic diversity are compared with simulation results under two different models of deleterious mutations: a model where all deleterious mutations have equal effects and a model where there are two classes of deleterious mutations. We also find that Muller's ratchet can produce a considerable distortion in the neutral frequency spectrum toward an excess of rare variants.


Enhancing the development of infants and toddlers with dual diagnosis of autism spectrum disorder and deafness.
Children diagnosed with autism spectrum disorder (ASD) are often referred for audiological diagnostic evaluation. This article provides some strategies for preparing children for a successful diagnostic evaluation. Children who are deaf or hard of hearing with a dual diagnosis of ASD may have difficulty learning to demonstrate detection or imitation of the Ling 6 sounds. The Ling 6 sounds are used to determine what a child with a dual diagnosis can hear and discriminate with amplification (hearing aids or cochlear implants). Because children with ASD may not look at the conversational partner and may have difficulty with imitation, adaptive strategies may be necessary to teach these children with dual diagnosis their first words. Strategies for teaching children with dual diagnosis through sign language will also be discussed.


A model of irritant-induced bronchoconstriction in the spontaneously breathing guinea-pig.
1 Inhalation of an aqueous aerosol of citric acid caused bronchoconstriction in anaesthetized guinea-pigs which was abolished by bilateral vagal section. 2 Conscious guinea-pigs developed slow, laboured breathing within 90 s of exposure to citric acid aerosol. The onset of this pattern of breathing was delayed by prior aerosol administration of atropine, ipratropium bromide, isoprenaline and tetracaine. 3 The data suggest that exposure of guinea-pigs to citric acid may be a useful model of reflex bronchoconstriction.


Diabetic ketoacidosis: update on management.
Diabetic ketoacidosis (DKA) is not a rare presentation to hospital, despite being an entirely preventable condition. A concerning number of people also develop DKA while already in hospital. Management of DKA has changed in the last decade, and national guidelines introduced, to help standardise care, spread best practice, and reduce mortality and morbidity.


Proline affects oligomerization of a coiled coil by inducing a kink in a long helix.
The structural effect of a proline in a helix in trifluoroethanol (TFE)/water medium was examined on a 29-mer peptide and its proline analog derived from the leucine zipper (LZ)-like motif of gp41 (the transmembrane glycoprotein of HIV-1) by NMR and circular dichroism (CD) spectroscopies. Lower helical content was found for the proline mutant from the CD study. NMR data show that distortion of the helix by proline is local and occurs mainly on the N-terminal side of the substitution site. Molecular dynamics computation exhibits a bending of the helical axis of 30 degrees +/- 10 degrees, in agreement with X-ray diffraction results. Light-scattering experiments indicated that the average aggregation number of the proline-substituted mutant is substantially lower than that of the wild-type peptide. From the ratio of dissociation constants of the wild-type and the proline mutant peptides, the difference in free energy of trimeric formation is calculated to be 2.1 kcal/mol. Thermal stability, helicity, and the average aggregation number for the helix oligomers were found to be correlated. The structural alteration and the reduced coiled coil stability may account for the deficiency in the biological functions of the proline mutants of gp41 and in the inhibitory action of proline-substituted peptides. These effects may also be important in unraveling the roles played by proline in transmembrane proteins.


Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems.
Injectable controlled-release systems based on biodegradable copolymers of lactic and glycolic acids (PLGAs) have become widely used for delivery of protein therapeutics and vaccine antigens. Over the last five years, great strides have been made toward overcoming the difficulty of stabilizing PLGA-encapsulated proteins. In addition to stabilizing proteins during encapsulation with anhydrous methods, two approaches have proven highly effective to stabilize proteins during 1-month release incubation under physiological conditions: protein complexation with zinc and control of PLGA microclimate pH with antacid excipients. Described here are recent advances in the stabilization of proteins encapsulated in PLGA delivery systems.


Separation and identification of N4-(guanosin-7-yl)-4-aminoquinoline 1-oxide, a novel nucleic acid adduct of carcinogen 4-nitroquinoline 1-oxide.
A novel nucleic acid adduct of the carcinogen 4-nitroquinoline 1-oxide, N4-(guanosin-7-yl)-4-aminoquinoline 1-oxide, was separated and identified after RNA was treated with activated 4-hydroxyaminoquinoline 1-oxide. This is the first report of a 7-arylaminated guanine adduct produced by arylaminating carcinogens.


Investigation of a brief teaching encounter using standardized patients: teaching residents alcohol screening and intervention.
To investigate a brief teaching intervention using standardized patients (SPs) trained to improve residents' detection and advising of problem drinkers. Pretest-posttest design assessing resident behavior and skills. Nineteen internal medicine residents in a University Hospital General Internal Medicine Clinic. Announced SPs were interviewed by residents and presented to faculty who provided brief instruction on the National Institute on Alcohol Abuse and Alcoholism guidelines for screening and brief counseling of problem drinkers. Unannounced SPs assessed resident behavior and skills. Following the teaching intervention, 2 times more residents screened for alcohol use and nearly 3 times more residents did brief counseling. Residents reported that the intervention was informative and valuable. A single, 1-hour teaching intervention lead to a 2- to 3-fold increase in resident detection and advising of problem drinkers. SPs provide effective teaching encounters and a useful measure of resident behavior.


Light/Dark modulation of enzyme activity in developing barley leaves.
Light/dark modulation of the ribulose-5-phosphate kinase, NADP(+)-glyceraldehyde-3-phosphate dehydrogenase, and fructose- 1,6-bisphosphatase activity was measured in the developing primary leaf of barley (Hordeum vulgare L.) seedlings. Ribulose-5-phosphate kinase and NADP(+) -glyceraldehyde-3-phosphate dehydrogenase were fully light activated even at the earliest developmental stage sampled. In contrast, light modulation of fructose- 1,6-bisphosphatase exhibited a complex response to leaf developmental status. Light stimulation of fructose- 1,6-bisphosphatase activity (measured at pH 8.0) increased progressively during leaf development. On the other hand, acid fructose- 1,6-bisphosphatase activity (measured at pH 6.0) was inhibited by light, and this light inhibition was greater in the base of the leaf than in the tip of the leaf.


Contribution of extravascular compression to reduction of maximal coronary blood flow.
Effects of ventricular compression on maximally dilated left circumflex coronary blood flow were investigated in seven mongrel dogs under pentobarbital anesthesia. The left circumflex artery was perfused with the animals' own blood at a constant pressure (63 mmHg) while left ventricular pressure was experimentally altered. Adenosine was infused to produce maximal vasodilation, verified by the hyperemic response to coronary occlusion. Alterations of peak left ventricular pressure from 50 to 250 mmHg resulted in a linear decrease in total circumflex flow of 1.10 ml.min-1 x 100 g heart wt-1 for each 10 mmHg of peak ventricular to coronary perfusion pressure gradient; a 2.6% decrease from control levels. Similar slopes were obtained for systolic and diastolic flows as for total mean flow, implying equal compressive forces in systole as in diastole. Increases in left ventricular end-diastolic pressure accounted for 29% of the flow changes associated with an increase in peak ventricular pressure. Doubling circumferential wall tension had a minimal effect on total circumflex flow. When the slopes were extrapolated to zero, assuming linearity, a peak left ventricular pressure of 385 mmHg greater than coronary perfusion pressure would be required to reduce coronary flow to zero. The experiments were repeated in five additional animals but at different perfusion pressures from 40 to 160 mmHg. Higher perfusion pressures gave similar results but with even less effect of ventricular pressure on coronary flow or coronary conductance. These results argue for an active storage site for systolic arterial flow in the dilated coronary system.


The relationship between baseline EEG spectra power and memory performance in older African Americans endorsing cognitive concerns in a community setting.
The finding that some older individuals report declines in aspects of cognitive functioning is becoming a frequently used criteria to identify elderly at risk for mild cognitive impairment (MCI) and dementia. Once concerns are identified in a community setting, however, effective means are necessary to pinpoint those individuals who should go on to more complex and costly diagnostic evaluations (e.g., functional imaging). We tested 44 African American volunteers endorsing cognitive concerns (37 females, 7 males) age≥65years with CogState battery subtests and recorded resting-state EEG, with eyes closed. After current source density (CSD) transformations of EEG recordings we obtained spectral power for delta, theta, alpha, and beta frequency bands. We characterized CogState One Card Back Learning (OCL, memory) with diffusion model parameters drift rate, boundary and non-decision time (NDT). Forward regression models showed that lower OCL drift rate, slower accumulation of information needed for decision making was linked to increased absolute and relative delta at occipital region. Lower drift rate was also linked to decrease in OCL theta power at parietal region, with no findings for ONB. Results show that cortical resting, eyes closed EEG rhythms are related to memory in African American seniors endorsing cognitive concerns. This study further supports the use of EEG as an easily accessible, cost-effective, culture-fair, and noninvasive clinical measurement that could provide potentially reliable diagnostic (and perhaps prognostic) information to differentiate at-risk from stable African American seniors.


Characterization of cAMP-dependent protein kinase and its endogenous substrate proteins in ram testicular, cauda epididymal, and ejaculated spermatozoa.
Mammalian spermatozoa have been shown to possess cAMP-dependent protein kinase (A-PK) and endogenous substrate proteins for this enzyme. A study of the kinase system was undertaken to determine changes that may be associated with sperm maturation by comparing immature testicular with mature cauda epididymal and ejaculated spermatozoa. Absolute activity levels of A-PK, stimulated over a concentration range of 10(-9) to 10(-5) M, was significantly greater in testicular than ejaculated spermatozoa. At an optimal cAMP concentration (10(-6) M), testicular spermatozoa had significantly greater amounts of cAMP-dependent protein kinase activity than did cauda or ejaculated spermatozoa. Electrophoretic analysis and autoradiography of NP-40-soluble protein extracts revealed the presence of two substrate proteins (Mr = 62,000 and 44,000) in all three types of spermatozoa. In addition, a phosphoprotein (Mr = 20,000) was detected in mature cauda and ejaculated but not immature testicular spermatozoa. The phosphorylation of these substrate proteins was both dose and time dependent. Examination of cyclic AMP phosphodiesterase activity revealed significantly higher levels in testicular than ejaculated spermatozoa. These results indicate marked alterations in cAMP-modulated protein phosphorylation and dephosphorylation systems in ram spermatozoa during epididymal maturation.


Anti-inflammatory actions of (-)-epicatechin in the adipose tissue of obese mice.
Obesity and type 2 diabetes (T2D) are major public health concerns. Visceral adipose tissue inflammation is considered a significant contributor to obesity-associated T2D development. We previously showed that the flavan-3-ol (-)-epicatechin (EC) can mitigate insulin resistance in mice fed a high fat diet (HFD). This study investigated the capacity of EC to inhibit visceral adipose tissue inflammation occurring as a consequence of HFD consumption in C57BL/6J mice, and characterized the underlying mechanisms. In association with the development of obesity and insulin resistance, HFD consumption caused inflammation in the visceral adipose tissue as evidenced by activation of the pro-inflammatory transcription factor NF-κB and increased tissue levels of the macrophage marker F4/80, tumor necrosis factor alpha (TNFα), and the chemokine MCP-1. EC supplementation mitigated all these events. In addition, we observed activation of the three branches of the unfolded protein response (UPR), and upregulation of NADPH oxidases NOX4 and NOX2 in visceral fat of mice fed HFD. These can account, at least in part, for the associated oxidative stress and activation of the redox sensitive NF-κB. Notably, EC supplementation mitigated this and the release of pro-inflammatory proteins from metabolically stressed adipocytes. Attenuation of adipocyte endoplasmic reticulum (ER) and oxidative stress by EC could contribute to decreased inflammation and improved visceral adipose tissue insulin sensitivity. Our results support the concept that consumption of EC-rich foods could mitigate obesity-associated insulin resistance through attenuation of adipose tissue inflammation.


Mind and matter: The neurological complications of thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear stress, including the brain. The acute neurological complications have historically been those most feared by clinicians and synonymous with a poor prognosis. TTP, however, is no longer perceived as two extremes of acute presentation and remission, rather once diagnosed a chronic condition with the potential for a long-term symptom burden. Optimal neuroimaging timing and modality lacks consensus and as we learn more about the changes seen during the acute and chronic stages of TTP, there is scope for neuroimaging to play a greater role in guiding management and the secondary prevention of vascular disease. Reduced ADAMTS13 activity levels have been associated with increased thrombotic risk and novel therapies including caplacizumab and recombinant ADAMTS13 may offer a neuroprotective role. Given the increasing evidence of the neurocognitive and psychological disease in TTP, the importance of screening and timely intervention should not be underestimated. As more patients are surviving their initial TTP presentation, it is crucial for us to develop a greater understanding of the longer-term morbidity affecting these patients.


Performance of compressive sensing for the reconstruction of different QRS pulses in ECG signals.
Compressive sensing (CS) is studied for the acquisition of different QRS complexes in ECG signals. By applying sparse binary measurement matrix and by applying regularization for promoting temporal correlation, performance of CS techniques for the reconstruction of ECG segments containing different QRS complexes, such as, normal QRS, paced QRS, right bundle branch block beat, left bundle branch block beat, and ventricular flutter beat, has been studied. Simulation results demonstrate that performance of CS differs with the types of beats, and ECG segments with well-known beats can be reconstructed with signal-to-noise ratio (SNR) approximately equal to 25dB for the realization of CS systems with compression ratio as high as 95%; for lower compression ratio much higher SNR can be attained.


[Metabolomic profiling in culture media of day-5 human embryos].
The aim of this study was to determine the changes of metabolomic profiles in embryonic culture media (ECM) for the evaluation of quality and implantation potential of human embryos. ECM (n=163) were collected on day 5 before transfer or cryopreservation. Some embryos were used in preimplantation genetic screening for detection of aneuploidy karyotypes. Samples were subdivided into groups according to embryo morphological classification (by Gardner), genetic analysis and implantation data. ECM were extracted with methanol, precipitates were separated by centrifugation and metabolite production of individual embryo was analysed by LC-MS (the positive ion mode). After peak detection and retention time alignment, data were analysed using the PCA algorithm. MS fingerprinting analysis of embryo culture medium showed significant differences between morphologically divided groups. Intragroup comparisons did not reveal differences between subclasses. Genetic screening of embryos revealed 33 aneuploid karyotypes. It was shown that chromosome number did not affect the metabolite profiles comparing with the normal group. The culture media of embryos that were positive or negative for successful implantation showed specific signatures that allowed to distinguish embryos with different outcomes.The characterization of ECMs by LC-MS may facilitate more accurate selection of the best embryo for the implantation, improving single-embryo transfer and thus eliminating the risk and undesirable effects of multiple pregnancies.


[Huntington's disease--advances in gene mapping].
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. It is inherited in an autosomal dominant fashion. The genetic defect causing HD was assigned to chromosome 4 in 1983 using polymorphic DNA markers in humans. Thereafter, a location cloning approach was pursued to isolate and characterize the HD gene. Recently, the Huntington's disease collaborative research group has isolated a new gene, IT 15, in 4p 16.3. IT 15 contains a polymorphic trinucleotide repeat that is expanded and unstable on HD chromosomes. A (CAG)n repeat longer than the normal range was observed on HD chromosomes from disease families. The (CAG)n repeat appears to be located within the coding sequence of a predicted 348 kd protein that is unrelated to any known gene.


Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy.
Diabetic retinopathy (DR) is a vascular insult that accompanies the hyperglycemic state. Retinal vasculature holds a pivotal role in maintaining the integrity of the retina, and any alteration to retinal vasculature affects retinal functions. The blood retinal barrier, a prerequisite to vision acuity, is most susceptible to damage during the progression of DR. This is a consequence of impaired biochemical pathways such as the polyol, advanced end glycation products (AGE), hexosamine, protein kinase C (PKC), and tissue renin-angiotensin system (RAS) pathways. Moreover, the role of histone modification and altered miRNA expression is also emerging as a major contributor. Epigenetic changes create a link between altered protein function and redox status of retinal cells, creating a state of metabolic memory. Although various biochemical pathways underlie the etiology of DR, the major insult to the retina is due to oxidative stress, a unifying factor of altered biochemical pathways. This review primarily focuses on the critical biochemical pathways altered in DR leading to vascular dysfunctions and discusses antioxidants as plausible treatment strategies.


The effects of beta-aminopropionitrile on colonic anastomosis in rats.
Wound contraction is a clinically important biological process because it frequently results in contractures, strictures, and stenosis. If collagen synthesis could be altered to minimize the contracture, then the outcome could be improved. Lathyrism produces poorly cross-linked collagen in healing anastomosis, keeping a larger portion of the synthesized collagen soluble. Ultimately, the amount of contracting collagen is reduced, lowering the bulk and lessening the contracture. The aim of this study was to observe the effects of a lathyrogen, beta-aminopropionitrile (BAPN), on the healing of colonic anastomosis. Thirty rats were divided into three groups. Colostomy and anastomosis were performed on all rats. Intraperitoneal saline solution (control) and either intraperitoneal (ip) or oral (po) BAPN were administered. The rats were killed 1 week later. Anastomotic healing was assessed by bursting pressure and the hydroxyproline content of the anastomotic tissues. Granulation tissue thickness, number of fibroblasts, inflammatory cells, and growing capillaries in granulation tissue per unit area were determined. Collagen fibril diameters were estimated, and spatial arrangements of fibrils were examined by an electron microscope. All results were evaluated by Mann-Whitney U-test. The analyses of anastomotic tissues from BAPN-treated rats showed a significantly reduced mean bursting pressure (158.9 +/- 12.3, 171.3 +/- 13.9, ip and po, respectively), hydroxyproline content (8.9 +/- 2.6, 10.1 +/- 2.7), granulation tissue thickness (24.3 +/- 2.6, 16.1 +/- 5.2), number of inflammatory cells (37.8 +/- 4.3, 25 +/- 4.3), fibroblasts (3.2 +/- 1.1, 2.8 +/- 0.7), and a significantly reduced collagen fiber diameter (15 +/- 2, 20 +/- 3) compared with those of control group (236.9 +/- 9, 14 +/- 4.4, 26.8 +/- 4.8, 39 +/- 2.6, 6.9 +/- 1.1, and 35 +/- 5, respectively). As a result, collagen fibers were flimsy, and lost their regular parallel alignment in the BAPN groups. On the other hand, a number of growing capillaries were found to be significantly increased in these groups (16.5 +/- 1.1, 18.2 +/- 0.7) compared to the control (6.7 +/- 1.3). Thus, it is suggested that BAPN may be useful in the prevention of gastrointestinal stricture formation.


Effects of intensive urbanization on the intrusion of shallow groundwater into deep groundwater: examples from Bangkok and Jakarta.
Asian megacities have severe pollution problems in both coastal and urban areas. In addition, the groundwater potential has decreased and land subsidence has occurred because of intensive groundwater pumping in urban areas. To prevent the adverse effects of urbanization on groundwater quality, it is necessary to confirm the changes in groundwater flow and contaminant transport caused by urbanization. We examined the effects of urbanization on contaminant transport in groundwater. The research areas were located around Bangkok, Thailand, and Jakarta, Indonesia, cities with populations of approximately 8 and 12 million, respectively. Each metropolitan city is located on a river delta and is adjacent to a bay. We measured the water level and collected water samples at boreholes at multiple depths (100 to 200 m) in 2004 and 2006 in Bangkok and Jakarta, respectively. The current hydraulic potential is below sea level in both cities because of prior excess abstraction of groundwater. As a result, the direction of groundwater flow is now downward in the coastal area. The Cl(-) concentration and delta(18)O distributions in groundwater suggest that the decline in hydraulic potential has caused the intrusion of seawater and shallow groundwater into deep groundwater. Concentrations of Mn and NO3(-)-N in groundwater suggest the intrusion of these contaminants from shallow to deep aquifers with downward groundwater flow and implies an accumulation of contaminants in deep aquifers. Therefore, it is important to recognize the possibility of future contaminant transport with the discharge of deep groundwater into the sea after the recovery of groundwater potential in the coastal areas.


SNARE complex regulation by phosphorylation.
SNAREs (soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptors) are ubiquitous proteins that direct vesicular trafficking and exocytosis. In neurons, SNAREs act to mediate release of neurotransmitters, which is a carefully regulated process. Calcium influx has long been shown to be the key trigger of release. However, calcium alone cannot regulate the degree of vesicle content release. For example, only a limited number of docked vesicles releases neurotransmitters when calcium entry occurs; this suggests that exocytosis is regulated by other factors besides calcium influx. Regulation of the degree of release is best explained by looking at the many enzymatic proteins that interact with the SNARE complex. These proteins have been hypothesized to regulate the formation, stability, or disassembly of the SNARE complex and therefore may regulate neurotransmitter release. One group of enzymatic regulators is the protein kinases. These proteins phosphorylate sites on both SNARE proteins and proteins that interact with SNARE proteins. Recent research has identified some of the specific effects that phosphorylation (or dephosphorylation) at these sites can produce. Additionally, palmitoylation of SNAP-25, regulates the localization, and hence activity of this key SNARE protein. This review focuses on the location and effects of phosphorylation on SNARE regulation.


Combined use of GC-TOF MS and UHPLC-(Q)TOF MS to investigate the presence of nontarget pollutants and their metabolites in a case of honeybee poisoning.
The combined use of gas chromatography (GC) and ultrahigh-pressure liquid chromatography (UHPLC), both coupled to time-of-flight mass spectrometry (TOF MS), has been explored in this work for the investigation of several cases of honeybee poisoning. The procedure applied involves a previous extraction with acetone followed by liquid-liquid extraction with dichloromethane. Both techniques, GC-TOF MS and UHPLC-(Q)TOF MS, have been applied to discover the presence of compounds that might be responsible of honeybee deaths. The application of a nontarget methodological approach to a first case of poisoning allowed the detection of the insecticide coumaphos at high concentration levels in the samples. The presence of possible metabolites of this organophosphorus insecticide was investigated by using both techniques. UHPLC-(Q)TOF MS showed its higher applicability in this case, as most of the metabolites were more polar than the parent compound. Four metabolites were identified by UHPLC-(Q)TOF MS, whereas only two of them were found by GC-TOF MS. The developed methodology was applied to other subsequent poisoning cases in which insecticides such as coumaphos, thiamethoxam, pyriproxyfen, and chlorfenvinphos were identified by both techniques, whereas GC-TOF MS also allowed the detection of fenitrothion and methiocarb. In all positive cases, the confirmation of the presence of the compound detected was feasible by means of accurate mass measurements of up to five ions together with their ion ratio evaluation.


Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux.
Type IIB hyperlipidemia is associated with premature vascular disease, an atherogenic lipoprotein phenotype characterised by elevated levels of triglyceride-rich VLDL and small dense LDL, together with subnormal levels of HDL. The dose-dependent and independent effects of a potent HMGCoA reductase inhibitor, Atorvastatin, at daily doses of 10 and 40 mg, were evaluated on triglyceride-rich lipoprotein subclasses (VLDL-1, VLDL-2 and IDL), on the major LDL subclasses (light LDL, LDL-1+LDL-2, D: 1.019-1.029 g/ml; intermediate LDL, LDL-3, D: 1.029-1.039 g/ml and small dense LDL, LDL-4+LDL+5, D: 1.039-1.063 g/ml), on CETP-mediated cholesteryl ester transfer from HDL to apoB-containing lipoproteins, on phospholipid transfer protein activity and on plasma-mediated cellular cholesterol efflux in patients (n=10) displaying type IIB hyperlipidemia. Plasma concentrations of triglyceride-rich lipoprotein subclasses (TRL: VLDL-1, Sf 60-400; VLDL-2, Sf 20-60 and IDL, Sf 12-20) and of LDL (D: 1.019-1.063 g/ml) were markedly diminished after 6 weeks of statin treatment at 10 mg per day (-31 and -36%, respectively; P<0.002) and by 42 and 51%, respectively at the 40 mg per day dose. Increasing doses of atorvastatin progressively normalised both the quantitative and qualitative features of the LDL subclass profile, in which dense LDL predominated at baseline. Indeed, dense LDL levels were reduced by up to 57% at the 40-mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles typical of normolipidemic subjects. In addition, marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (P<0.02) in CETP-mediated CE transfer from HDL. Finally, a significant dose-dependent statin-mediated elevation (+15% at 10 mg; P=0.0003 and +35% at 40 mg; P<0.0001 compared to baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Moreover, atorvastatin (40 mg per day) significantly increased plasma apoAI levels (+24%; P<0.05), thereby suggesting that this statin enhances production of apoAI and with it, formation of nascent pre-beta HDL particles. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing the dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in type IIB dyslipidemia, thereby diminishing the atherosclerotic burden in subjects characterised by high cardiovascular risk.


[Abdominal wall endometriosis: case report].
Endometriosis is defined as the presence of endometrial glands and stroma outside uterus. This ectopic finding occur in the abdominal wall among 0,03% to 1% of women with prior gynecologic surgery, particularly after cesarean section. Most frequently, endometriosis is present as a palpable mass, painfull during menstrual period, near surgical scar. It could mimic other pathologies such as hematomas, granulomas, inicisional hernias, abscesses and tumors. We report the case of a 35 years old woman with a painful mass during menstruation nearly cesarean scar. The tumor was completely removed and a polipropylen mesh was placed to repair the abdominal wall defect. It was identified as endometriosis in the anatomo-patologic examination.


Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families.
Two high-risk genes have been implicated in the development of CM (cutaneous melanoma). Germline mutations of the CDKN2A gene are found in < 25% of melanoma-prone families and there are only seven families with mutation of the CDK4 gene reported to date. Beside those high penetrance genes, certain allelic variants of the MC1R gene modify the risk of developing the disease. to determine the prevalence of germline CDKN2A mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible CDK4 mutations, and to determine the frequency of variations in the MC1R gene. From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing. Seven families with CDKN2A mutations were discovered (7/25 or 28.0%). The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54). One p14ARF variant was discovered in the control group and no mutations of the CDK4 gene were found. Most frequently found variants of the MC1R gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant. The present study has shown high prevalence of p16INK4A mutations in Slovenian population of familial melanoma patients (37%) and an absence of p14ARF or CDK4 mutations.


[Clinical analysis on 368 children cases with tracheobronchial foreign body].
To investigate the clinical pathological features of children tracheobronchial foreign bodies and to improve diagnosis and treatment. A retrospective study 368 children cases with tracheobronchial foreign bodies in our hospital. Each patient was analyzed for age, sex, nature,complication and location of the foreign body, results of bronchoscopic removal and presence of foreign bodies in the airways. Among this cases, three of them coughed out the foreign body before operation; two of them failed to be operated for serious complication, others were conducted by rigid bronchoscopy and bronchoscopic removal with general anaesthesia. Three children of 368 coughed out the foreign body before operation; 4 children of them were dead for the long heartbeat respiratory arrest and deep coma; 2 children of them suffered form hypoxic ischemic encephalopathy and epilepsy; others were successfully taken out by operation. For the diagnosis of children cases with tracheobronchial foreign bodies, it is very important to collect the detailed history of foreign body inhalation, physical examination and careful analysis on the findings from chest radiographs or CT scan.


Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major.
To examine the relationship between hepatic iron stores and plasma ferritin concentration in individuals treated with red cell transfusion and iron chelation therapy, 37 patients with sickle cell anemia and 74 patients with thalassemia major were studied. In each patient, hepatic iron stores were measured by an independently validated noninvasive magnetic method, and plasma ferritin was determined by immunoassay. The correlation between hepatic iron and plasma ferritin was significant both in patients with sickle cell anemia (R = 0.75, P < 0.0001) and in those with thalassemia major (R = 0.76, P < 0.0001). Regression analysis showed no significant difference between the two groups in the linear relationships between hepatic iron stores and plasma ferritin. Considering all 111 transfused patients as a group, the coefficient of correlation between hepatic iron stores and plasma ferritin was highly significant (R = 0.76, P < 0.0001). Regression analysis found that variation in body iron stores, as assessed by magnetic determinations of hepatic iron, accounted for only approximately 57% of the variation in plasma ferritin, suggesting that the remainder was the result of other factors, such as hemolysis, ineffective erythropoiesis, ascorbate deficiency, inflammation, and liver disease. The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores. Variability resulting from factors other than iron status limits the clinical usefulness of the plasma ferritin concentration as a predictor of body iron stores.


CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.
CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.


A cross-cultural comparison of high school students' responses to a science centre show on the physics of sound in South Africa.
We report on the attitudes and ideas developed by students from three distinct school groups to a science show about sound. We addressed two research questions: (1) How do the students compare with respect to their (a) attitudes to the sound show and to science in general and (b) changes in conceptual understanding as a result of the show and (2) what changes could be made to the show, and to science shows in general, that would be sensitive to the cultural and language differences of the groups? These were addressed by multiple-choice, pre- and post-tests comprising both attitudinal and conceptual questions. Our results pointed to a common enjoyment of the show but a different understanding of concepts and consequent learning, which suggest that science shows (and science teaching) need to be adjusted to accommodate different cultural groups for maximum impact.


Topographic organization of connections between the main olfactory bulb and pars externa of the anterior olfactory nucleus in the hamster.
The organization of connections between the main olfactory bulb (MOB) and pars externa (pE) of the anterior olfactory nucleus was studied in hamsters by using wheat germ agglutinin-horseradish peroxidase as both an anterograde and a retrograde neuronal tracer. Bulbar efferents of pE project exclusively to the contralateral MOB. A topographic organization is evident in these efferents, such that distinct sectors of pE project predominantly to certain sectors of the contralateral MOB and lightly to other sectors. The predominant projection to any bulbar sector in the coronal plane is repeated at nearly all rostral-caudal levels, i.e., the pE efferents to the contralateral MOB terminate within long strips or wedges that show a sector-to-sector topographic organization with respect to the medial-lateral and dorsal-ventral axes but not the rostral-caudal axis of the MOB. Afferents to pE arising in the ipsilateral MOB also show a sector-to-sector topographic organization. Injections into restricted sectors along the circumference of pE label all classes of output neurons (mitral cells and internal, middle, and external tufted cells) in restricted sectors of the ipsilateral MOB, and the sectors that have retrograde neuronal labeling are homotopic to those in the contralateral MOB that have dense anterograde terminal labeling. External tufted cells are not labeled and the other classes of MOB output neurons do not have prominent topographic patterns of labeling in cases with injections caudal to pE. The somata of external tufted cell that project to pE are predominantly in the deep part of the glomerular layer; most of the external tufted cells that lie more superficially in the glomerular layer do not appear to have projections extrinsic to the MOB. These results indicate that both the afferent and efferent connections of pE with the MOB are topographically organized and provide a short synaptic pathway between homotopic sectors of the two main olfactory bulbs.


An integrated cooperation model for long-term mentally ill in the community.
1. This article describes a Swedish model of community support for patients with a long-term mental illness. 2. The result confirms that the staff-psychiatric practical nurses and aids are important in the care with support and coping as essential elements. 3. The staff members do require supervision from a nurse with knowledge about society and psychiatric care.


A model for integration and continuous development of standards for tumour documentation using relational database techniques and extensible markup language.
In oncology various international and national standards exist for different aspects of a disease. These standards, maintained by different organisations, have multiple relationships with each other. A common data dictionary like UMLS would facilitate the reorganisation of such relationships when a new version of a standard is published. While the modelling of relationships usually is restricted to types having a relevant frequency, there are often relationships which are expressed in texts like definitions or explanations. Such texts are a very important supplement for the acceptance and the safe use of coding systems, but often are neglected when implementing coding systems in computerised systems, because they are costly to implement. This paper discusses potentials when integrating various sources in a common, database based dictionary enhanced by XML (Extensible Markup Language) techniques.


Induced sputum for the investigation of airway inflammation: evidence for its clinical application.
Airway inflammation is considered to be the primary cause of airway diseases. Its prevention and reversal are the primary aims of treatment. Measurement of the inflammation is now possible relatively noninvasively and reliably by using induced sputum cell counts. The differential count indicates the presence and type of the inflammation (eosinophilic or neutrophilic) and the total cell count the intensity. Sputum eosinophilia responds to treatment with corticosteroid, while there is increasing evidence that an isolated neutrophilia does not. Clinical judgement of airway inflammation is made difficult because of the different types of inflammation and their inconsistent correlation with the clinical features. Hence, reliable measurement of induced sputum cell counts may be useful to guide treatment in clinical practice. Consideration should now be given as to how to make it more available.


Next-generation nanomedicines and nanosimilars: EU regulators' initiatives relating to the development and evaluation of nanomedicines.
Over the last three decades many first-generation nanomedicines have successfully entered routine clinical use and it is now important for medicines regulatory agencies to consider the mechanisms needed to ensure safe introduction of 'follow-on' nanomedicine products, 'nanosimilars'. Moreover, drug regulators need to ensure that 'next'-generation nanomedicines enter clinical development and consequently the market in a safe and timely way for the benefit of public health. Here we review recent European Medicines Agency activities that relate to the effective development and evaluation of nanomedicine products while keeping patient and consumer safety at the forefront.


Do biological activities of selective histone deacetylase 6 (HDAC6) inhibitors rely on the modification of cap group?
Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding-free energies and conformational rearrangements after 1 μs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.


First-line chemotherapy for NSCLC: an overview of relevant trials.
In advanced non-small cell lung cancer (NSCLC), monotherapy with gemcitabine improves quality of life when compared to best supportive care alone, while single-agent taxanes and vinorelbine also improve survival. Platinum-based combinations achieve benefits in response rate, time to progression and survival compared to single-agent cisplatin. With the introduction of combinations of newer agents, 2-year survival rates of 10-20% are being seen in co-operative group trials. Until recently, the various doublets that have been subjected to randomized comparison appear to have achieved similar rates of response and survival, though toxicities differ considerably depending on the choice of drugs used. However, study TAX 326, the largest trial yet conducted in advanced NSCLC, has now demonstrated that the combination of docetaxel with cisplatin is superior to that of vinorelbine and cisplatin. Controlled trials of platinum-containing vs. non-platinum combinations have yet to demonstrate any superiority of one over the other. Hopes for further improvement in survival are focused on the combination of cytotoxic agents with novel molecularly-targeted drugs such as the anti-angiogenics and EGFR inhibitors.


Acoustic, piezoelectric, and dielectric nonlinearities of AlN in coupled resonator filters for high RF power levels.
Coupled resonator filters (CRFs) are the new generation of BAW filters recently designed for the front-end modules of mobile transmission systems. Looking for designers' requirements, CRF devices have been characterized and modeled. The model based on equivalent circuits relies on material constants such as stiffness and electro-coupling coefficients, and works only for linear-mode propagation. Because of their positions between antennas and power amplifiers, they often work under high RF power, inducing nonlinear response in the AlN piezoelectric layer. In this work, we analyze for the first time the nonlinear behavior of AlN material particularly for coupled BAW resonators. To characterize the nonlinear effects in CRFs, we measure the 1-dB gain compression point (P1dB) and the intercept point (IP(3)). Then, we develop a nonlinear model of CRFs using harmonic balance (HB) simulation in commercially available software. The HB environment allows fitting simulations to measurements in terms of P(1dB) and IP(3). We find that a high RF power induces nonlinear changes in the material constants' real parts: elastic stiffness c(33) (4.9%), piezoelectric e(33) (17.4%), and permittivity ϵ(33) (5.2%). These nonlinear variations of material constants describe the nonlinear behavior of CRF devices using the same deposit process for AlN material.


Impact of COVID-19 pandemic on TB prevention and care in Addis Ababa, Ethiopia: a retrospective database study.
The current COVID-19 pandemic in Ethiopia could cause severe dysfunction in tuberculosis (TB) treatment, diagnostic services, and prevention and control efforts. In this study, we evaluated the effect of COVID-19 on TB service indicators in Addis Ababa, where more than two-thirds of the country's COVID-19 morbidity was recorded. We performed a comparative retrospective study to evaluate the impact of COVID-19 on TB services during the pre-COVID-19 era (from April 2019 to March 2020) and the COVID-19 era (from April 2020 to March 2021) in Addis Ababa, Ethiopia. We extracted data on total TB detection rate, TB treatment success rate, isoniazid prophylaxis therapy, and drug susceptibility tests and others from the health information system. Using Poisson regression, we estimated the incidence rate ratios and the absolute number difference of the indicators (number per quarter and year) in the COVID-19 and pre-COVID-19 eras. Compared with the pre-COVID-19 era, the total TB detection, bacteriologically confirmed TB, TB treatment success rate, latent TB infection treatment and community health workers' engagement in TB detection decreased, respectively, by 11%, 11.8%, 17%, 44.7% and 77.2% during the COVID-19 period. Rifampicin resistance increased by 27.7% during the same period. Comparative analysis showed a significant decline in these TB service indicators (p<0.001) CONCLUSION: The COVID-19 pandemic has had a negative impact on TB service indicators in Addis Ababa. This highlights the importance of reinforcing TB services, including adopting alternative digital health technology to screen for TB and integrating TB and COVID-19 services to mitigate COVID-19's challenges to TB prevention and care.


[Ethanol induced increase of fibroblast growth factor 2 mRNA content in emotiogenic brain structures of rats].
We studied the effects of acute, subacute, and chronic alcohol treatment of rats on the content of fibroblast growth factor 2 (FGF2) mRNA in various brain structures. Results suggest a possible role of FGF2 in the functioning of dopaminergic neurons in the midbrain. In our experiment, ethanol treatment of rats was accompanied by an increase in the FGF2 mRNA level in the emotiogenic structures of the brain. This effect was blocked by pretreatment of animals with chlorpromazine. This suggests FGF2 involvement in the mechanisms of alcohol dependence and can be considered as a possible diagnostic and therapeutic target in alcoholism.


The predictive prognostic values of serum TNF-α in comparison to SOFA score monitoring in critically ill patients.
The use of inflammatory markers to follow up critically ill patients is controversial. The short time frame, the need for frequent and serial measurement of biomarkers, the presence of soluble receptor and their relatively high cost are the major drawbacks. Our study's objective is to compare the prognostic values of serum TNF-α and SOFA score monitoring in critically ill patients. A total of ninety patients were included in the study. Forty-five patients developed septic complication (sepsis group). Forty-five patients were critically ill without evidence of infectious organism (SIRS group). Patients' data include clinical status, central venous pressure, and laboratory analysis were measured. A serum level of TNF-α and SOFA score were monitored. Monitoring of TNF-α revealed significant elevation of TNF-α at 3rd and 5th days of ICU admission in both groups. Monitoring of SOFA score revealed significant elevation of SOFA scores in both groups throughout their ICU stay, particularly in nonsurvivors. Positive predictive ability of SOFA score was demonstrated in critically ill patients. Transient significant increase in serum levels of TNF-α were detected in septic patients. Persistent elevation of SOFA score was detected in nonsurvivor septic patients. SOFA score is an independent prognostic value in critically ill patients.


Axiographic findings in patients undergoing orthodontic treatment with and without premolar extractions.
Mechanical axiography was performed on 49 (37 female, 12 male) patients prior to orthodontic treatment, after removal of the fixed appliance, and at the end of retention. Twenty-five subjects (mean age 12.8 years) underwent orthodontic treatment without premolar extractions (group 1) and 24 subjects (mean age 13.5 years) with premolar extractions (group 2). The axiographic tracings of the protrusive movements were analysed using a digitizer and specially designed software. A statistically significant increase (P < 0.05) in the values for horizontal condylar inclination (HCI) was found for both groups over the entire observation period. Group 1 showed a higher increase (P < 0.05) between the beginning of treatment and removal of the brackets, and group 2 between bracket removal and the end of retention. At the end of retention, a similar increase in HCI values was found for both groups. Over the observation period, the frequency of pathological axiographic findings decreased, which seems to be a positive effect of orthodontic treatment.


Catechin isolated from cashew nut shell exhibits antibacterial activity against clinical isolates of MRSA through ROS-mediated oxidative stress.
Staphylococcus aureus causes severe infections and among all methicillin-resistant S. aureus (MRSA) remains a great challenge in spite of decade research of antibacterial compounds. Even though some synthetic antibiotics have been developed, they are not effective against MRSA, and hence, there is a search for natural, alternative and plant-based antibacterial compound. In this connection, catechin isolated from cashew nut shell was investigated for its antibacterial potential against MRSA. Catechin exhibited zone of inhibition (ZOI) and minimum inhibitory concentration (MIC) in a range of 15.1-19.5 mm and 78.1-156.2 μg/ml, respectively, against ATCC and clinical isolates of MRSA. Among all clinical isolates, clinical isolate-3 exhibited highest sensitivity to catechin. Catechin has arrested the growth of MRSA strains and also caused toxicity by membrane disruption which was illustrated by AO/EB fluorescence staining. Increased nucleic acid leakage (1.58-28.6-fold) and protein leakage (1.40-23.50-fold) was noticed in MRSA due to catechin treatment when compared to methicillin. Bacteria treated with catechin at its MIC showed 1.52-, 1.87- and 1.74-fold increase of ROS production in methicillin susceptible S. aureus (MSSA), MRSA and clinical isolate-3 strains, respectively, as compared to control. Superoxide dismutase (5.31-9.63 U/mg protein) and catalase (1573-3930 U/mg protein) were significantly decreased as compared to control in catechin-treated S. aureus. Thus, catechin exhibited antibacterial activity through oxidative stress by increased production of ROS and decreased antioxidant enzymes. Altogether results suggest that catechin is a promising lead compound with antibacterial potential against MRSA. KEY POINTS: • Catechin was isolated and identified as active compound in cashew nut shell. • Catechin exhibited antimicrobial activity against clinical isolates of MRSA. • Bacterial cell wall damage was caused by catechin in MRSA strains. • Catechin increased the oxidative stress in MRSA by intracellular ROS production.


[Relationship between Myopia and Light Exposure].
Epidemiological studies found that the incidence of myopia was increasing year by year and the age of onset of myopia was showing a trend of affecting increasingly younger children. Reducing the occurrence of myopia and controlling the increase of myopia diopter have always been the focus of research on the prevention and control of myopia. Large randomized controlled clinical trials have found that outdoor activities can effectively reduce the incidence of myopia and delay the progression of myopia. Basic experiments also revealed that there were certain connections between light exposure and myopia. We herein review the research progress, limitations and future directions of research on light exposure and myopia. From the perspective of light properties, increasing the intensity of light can slow the progression of myopia and reduce the occurrence of experimentally induced myopia. However, the actual mechanism of action is still unclear. The rhythmic changes of light exposure caused by the light/dark cycle may cause abnormalities in the secretion of melatonin and dopamine, and changes in the circadian rhythm of intraocular pressure and choroidal thickness, thus affecting myopia. The red light, with relatively longer wavelength and forming images behind the retina, tends to induce myopia more easily, while the blue light, with medium and short wavelength and forming images before the retina, tends to delay myopia progression. However, different species respond differently to lights of different wavelengths, and the relationship between light wavelength and myopia needs further investigation. Future research can be done to further explore the mechanism of action of how light exposure changes the progression of myopia, including the following aspects: how light changes dopamine levels, causing changes in downstream signal pathways, and thus controlling the growth of the axial length of the eye; how retinal photoreceptor cells receive light signals of different wavelengths in order to adjust the refractive power of the eyes; and how to design artificial lighting of reasonable intensity, composition and properties, and apply the design in myopia prevention and control.


[Reducible meniscal luxation of the temporomandibular joint].
Normal and pathologic functioning of the temporomandibular joint are summarized and clinical and arthrographic signs of reducible meniscal luxation described. The latter is distinguished clinically and radiologically from irreducible meniscal luxation and the myofacial syndrome. Etiological features are discussed and therapeutic solutions proposed in relation to three clinical cases reported.


Growth characteristics of murine tumors: neuroblastoma, renal cell adenocarcinoma, Wistar/Furth Wilms' after storage in a cryopreservation system.
Three murine tumor models, neuroblastoma CL 300, renal cell adenocarcinoma, and Wistar/Furth Wilms' tumor were evaluated for long-term storage in a cryopreservation system. Several transfer generations were observed in all tumor groups. Percent of tumor take poststorage, rate of tumor growth postimplantation and percent of metastatic development were calculated. Tumor take ranged from 5 to 100% poststorage and implant. Tumor growth was noted to require more days with stored tumor than with tumors implanted directly from donor to recipient. Tumor weights were comparable. Metastatic growth was observed in all transfer groups implanted with renal cell adenocarcinoma. Metastatic growth was not observed in all Wistar/Furth Wilms' transfer groups nor in all the neuroblastoma CL 300 transfer groups. This cryopreservation system can be utilized for storing tumor cells with up to 100% recovery of the tumor cell growth.


Cancer and mortality risks of patients with scoliosis from radiation exposure: a systematic review and meta-analysis.
The study aimed for unraveling the long-term health impact of cumulative radiation exposure from full-spine radiographs on children/adolescents with scoliosis. All cohort, case-control or cross-sectional studies about radiation exposure to scoliosis patients with follow-up period as 20 years or more were included. Meta-analyses were performed for outcomes reported in two or more studies. A total of 9 eligible studies involving 35,641 participants between 1912 and 1990 fulfilled the inclusion criteria, including 18,873 patients with scoliosis and 16,768 controls as regional matched general population. The average number of full-spine radiographs was 23.13 (range: 0-618) according to 14,512 patients between 1912 and 1990 in five studies. The estimated mean cumulated radiation dose of breast was 11.35 cGy. In comparison with controls, pooled incidence rates of cancer, breast cancer and cancer mortality of patients with scoliosis were statistically significant higher [rate of cancer, odds risk (OR) = 1.46, p < 0.00001; breast cancer, OR = 1.20, p = 0.02; cancer mortality, OR = 1.50, p < 0.00001]. No statistically significant differences were found in terms of reproductive events for scoliosis patients, pulmonary function and physical activity for adolescent idiopathic scoliosis patients. Based on 35,641 participants with over 20 years' observations from 1912 to 1990, repeated radiographs and pertaining cumulative radiation dose resulted in elevated rates of cancer, breast cancer and cancer mortality for children/adolescents with scoliosis in comparison with matched general population. It is recommended that low-radiation or radiation-free and efficient methods should be used to monitor the evolution of children/adolescents with scoliosis.


The conservative management of first trimester miscarriages and the use of colour Doppler sonography for patient selection.
This study of patients with first trimester miscarriage evaluates whether conservative management is a feasible strategy and assesses the value of colour Doppler ultrasonography for patient selection. After confirmation of the diagnosis by transvaginal sonography all patients were offered the choice of immediate dilatation and curettage or conservative management. The presence of a gestational sac, the occurrence of spontaneous complete miscarriage within 28 days, detectable pulsatile blood flow within the placenta in the presumed region of the intervillous space and post-treatment complications were the main end-points. Out of a total of 108 women recruited, 23 (21.3%) elected to undergo immediate dilatation and curettage and 85 (78.7%) chose conservative management. The treatment groups were similar in age, gestational age, gestational sac diameter, serum concentrations of human chorionic gonadotrophin (HCG) and progesterone, and proportion of patients who had post-treatment complications (12-13%). Of patients in the conservative management group, 71 out of 85 (84%) had a spontaneous, complete abortion, while 37 out of 46 cases (80%) with detectable presumed intervillous pulsatile blood flow had a complete, spontaneous abortion within 1 week; this occurred in 23% of cases with no detectable flow. This suggests that conservative management is a successful approach for many patients with first trimester miscarriage; colour Doppler ultrasonography can be used to select the most suitable patients for this strategy, and thus reduce the need for hospital admission and surgery.


[Surgical treatment of mature extracephalic vascular malformations (excluding portwine hemangioma). Experience of this department].
The department's experience of mature extracephalic vascular malformations shows that, regardless of the site and the type of the lesion, only surgical excision is able to ensure a good result for vascular malformations of the limbs. The results were almost always excellent and only the diffuse forms benefitted from preoperative sclerosant injections. Palliative treatments such as elastic compression still have a place in these indications. Arterial embolisations are only of limited value, particularly when they are selective, as a complement to surgery (risk of necrosis in peripheral lesions). All sites may be observed, but the authors particularly emphasise perineoscrotal lymphangiomatous lesions. Recurrences do occur, but are rare when the lesion is widely resected and a good quality reconstruction is performed.


Surveillance recommendations based on an exploratory analysis of respiratory syncytial virus reports derived from the European Influenza Surveillance System.
Respiratory syncytial virus (RSV) is an important pathogen that can cause severe illness in infants and young children. In this study, we assessed whether data on RSV collected by the European Influenza Surveillance Scheme (EISS) could be used to build an RSV surveillance system in Europe. Influenza and RSV data for the 2002-2003 winter season were analysed for England, France, the Netherlands and Scotland. Data from sentinel physician networks and other sources, mainly hospitals, were collected. Respiratory specimens were tested for influenza and RSV mainly by virus culture and polymerase chain reaction amplification. Data on RSV were entered timely into the EISS database. RSV contributed noticeably to influenza-like illness: in England sentinel RSV detections were common in all age groups, but particularly in young children with 20 (40.8%) of the total number of sentinel swabs testing positive for RSV. Scotland and France also reported the highest percentages of RSV detections in the 0-4 year age group, respectively 10.3% (N = 29) and 12.2% (N = 426). In the Netherlands, RSV was detected in one person aged over 65 years. We recommend that respiratory specimens collected in influenza surveillance are also tested systematically for RSV and emphasize the use of both community derived data and data from hospitals for RSV surveillance. RSV data from the EISS have been entered in a timely manner and we consider that the EISS model can be used to develop an RSV surveillance system equivalent to the influenza surveillance in Europe.


The SRCR/SID region of DMBT1 defines a complex multi-allele system representing the major basis for its variability in cancer.
Deleted in malignant brain tumors 1 (DMBT1) at 10q25.3-q26.1 has been proposed as a candidate tumor-suppressor gene for brain and epithelial cancer. DMBT1 encodes a multifunctional mucin-like protein presumably involved in epithelial differentiation and protection. The gene consists of highly homologous and repeating exon and intron sequences. This specifically applies to the region coding for the repetitive scavenger receptor cysteine-rich (SRCR) domains and SRCR-interspersed domains (SIDs) that constitutes the major part of the gene. This particular structure may previously have interfered with the delineation of DMBT1 alterations in cancer. Uncovering these, however, is of mechanistic importance. By a combined approach, we conducted a detailed mutational analysis, starting from a panel of 51 tumors, including 46 tumor cell lines and five primary tumors. Alterations in the repetitive region were present in 22/31 (71%) tumors that were investigated in detail. Six tumors showed presumably de novo mutations, among these three with point mutations in combination with a loss of heterozygosity. However, none of the alterations unambiguously would be predicted to lead to an inactivation of DMBT1. We define seven distinct DMBT1 alleles based on variable numbers of tandem repeats (VNTRs). At least 11 tumors exclusively harbored these VNTRs. The data suggest that the SRCR/SID region defines a complex multi-allele system that has escaped previous analyses and that represents the major basis for the variability of DMBT1 in cancer. DMBT1 thus compares to mucins rather than to conventional tumor suppressors.


Temporal fluctuation and reproduction of Thermocyclops decipiens (Copepoda, Cyclopoida) in an eutrophic lake of central Brazil.
Lake Paranoá is an eutrophic reservoir situated in the urban region of Brasília. This study was carried out in a fixed collection station located in the Riacho Fundo branch of the reservoir. Zooplankton samples were collected at intervals of 3-5 d at 9:00 a.m. during two months in the dry and rainy seasons for two years (dry-1996, rainy-1997, dry-1997 and rainy-1998), using a 64 microns-mesh plankton net. The most predominant species was Thermocyclops decipiens (about 50% of the total zooplankton community), which during the whole period had a high reproductive rate. The highest densities were found in the dry-1996 season (1700 ind/l for nauplii), and also fluctuated widely overtime. Nauplii stages dominated during the four periods, comprising 50-75% of the total population density. Ovigerous females peaked in the dry-1996 and rainy-1997 seasons, with 20-30% of the total females. The largest peak in egg production occurred during the dry-1996 season, and the total egg production was 2.0 x 10(3) eggs/l. Mesocyclops longisetus is a first record for Lake Paranoá. The ecological factors that determine the success of T. decipiens in eutrophic systems are related to omnivorous feeding habits and prey-predator interactions.


Does radiographic emphysema correlate with low bone mineral density?
Several large epidemiologic studies have shown an association between chronic obstructive pulmonary disease (COPD) and osteoporosis. Recent studies have further implied an emphysema-specific association with low bone mineral density independent of obstruction severity. This review will outline the studies demonstrating an independent association between radiographic emphysema and decreased bone mineral density and will discuss potential disease mechanisms, including systemic inflammation and immune-mediated factors, linking these disease processes. Radiographic emphysema should be considered an independent risk factor in studies examining the mechanisms underlying COPD-related bone loss. Future research focused on the relationship between emphysema and low bone mineral density could provide mechanistic insight and result in the development of targeted therapies designed to halt progression of both disease processes.


Pre-diagnosis urine exosomal RNA (ExoDx EPI score) is associated with post-prostatectomy pathology outcome.
ExoDx Prostate IntelliScore (EPI) is a non-invasive urine exosome RNA-based test for risk assessment of high-grade prostate cancer. We evaluated the association of pre-biopsy test results with post-radical prostatectomy (RP) outcomes to understand the potential utility of EPI to inform invasive treatment vs active surveillance (AS) decisions. Urine samples were collected from 2066 men scheduled for initial biopsy with PSA between 2 and 10 ng/mL, no history of prostate cancer, and ≥ 50 years across multiple clinical studies. 310 men proceeded to RP, of which 111 patients had Gleason group grade 1 (GG1) at biopsy and would have been potential candidates for AS. We compared pre-biopsy urine scores with ERSPC and PCPT multivariate risk calculator scores for men with GG1 at biopsy to post-RP pathology. Urine EPI scores were significantly lower in men with GG1 at biopsy than in men with > GG1 (p = 0.04), while there were no differences in multivariate risk scores used in standard clinical practice (p > 0.05). Further, EPI scores were significantly lower in men with GG1 at biopsy who remained GG1 post-RP compared to men upgraded to ≥ GG3 post-RP (p < 0.001). In contrast, none of the multiparametric risk calculators showed significant differences (p > 0.05). Men with GG1 at biopsy and EPI score < 15.6 had zero rate of upgrading to ≥ GG3 post-RP compared to 16.0% for EPI scores ≥ 15.6. The EPI urine biomarker outperformed the multivariate risk calculators in a homogenous risk group of pre-biopsy men. The EPI score was associated with low-risk pathology post-RP, with potential implications on informing AS decisions. NCT02702856, NCT03031418, NCT03235687, NCT04720599.


Cryopreservation and xenotransplantation studies of microencapsulated rat pancreatic islets.
Islets of Langerhans were isolated from the Sprague Dawley rat pancreas digested by injected collagenase, and purified by Ficoll density gradient centrifugation. In order to make smaller and more uniform microencapsulated islets, we designed a special high-voltage electrostatic microcapsule generator. The effects of operational parameters of the generator on the size and the uniformity of microcapsules were analyzed, such as the voltage, the plunger speed of suspension delivery to the needle tip, the distance between needle tip and solution surface. The optimal parameter combinations for making microcapsules are: 5 kV of voltage, 50 mm/h of the plunger speed, and 20 mm distance. The high-voltage electric system can produce uniform microcapsules with diameters ranging from 0.3 to approximately 0.5 mm, which are smaller and more uniform than those produced by air-jet system. A comparison of the cryopreservation effects between microencapsulated islets and unencapsulated islets showed that the microcapsules can protect the fragile islets from freezing damage, and increase the retrieval rate from 68.5% to 92.6%. Xenotransplantation of the cryopreserved rat islets resulted in the normalization of the metabolic blood glucose of the diabetic mice for 90 days, whereas the unencapsulated islets were easily fragmented and lost during the freezing process. They only reversed hyperglycemia for less than 3-5 days.


Ammonia Oxidizers in a Grazing Land with a History of Poultry Litter Application.
Poultry litter (PL) is widely applied on grazing lands in Georgia. However, it is not clear how its long-term use affects soil microorganisms and their function. We examined changes in activity and community structure of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in a grazing land with a history of PL application and compared it to treatment with urea ammonium nitrate (UAN). Soil samples (0-15 cm) were collected in 2009 (after 15 yr of PL application) and in 2013 (after 2 yr of no application). The abundance and community composition of ammonia oxidizers (AO) were determined with molecular techniques that targeted Nitrification potential (NP) was used for measuring their activity. Abundance of AO was significantly higher in PL (7.41 and 7.10 log copies g soil for AOB and AOA, respectively) than in UAN plots (6.82 and 6.50 log copies g soil for AOB and AOA, respectively) in 2009. This is consistent with NP, which was higher in PL (0.78 mg NO -N kg h) than in UAN (0.50 mg NO-N kg h) plots in 2009. The abundance of AO and NP decreased in 2013. There was no treatment effect on the composition of AO. Correlation analysis suggested that AOB were functionally more important than AOA, indicating the need to target AOB for efficient management of N in PL-receiving soils. Overall, the difference in nitrification between PL and UAN was mainly caused by the change in AO abundance rather than composition, and AO were not negatively affected by an increase in PL-derived trace metal concentrations.


Lifetime Health and Economic Outcomes of Active Surveillance, Radical Prostatectomy, and Radiotherapy for Favorable-Risk Localized Prostate Cancer.
To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer. A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Costs were included from a public payer perspective in Australian dollars. Outcomes were discounted at 5% over a lifetime horizon. Probabilistic and scenario analyses quantified parameter and structural uncertainty. A total of 60% of patients in the AS arm eventually received radical treatment (surgery or radiotherapy) compared with 90% for RP and 91% for RT. Although AS resulted in fewer treatment-related complications, it led to increased clinical progression (AS 40.7%, RP 17.6%, RT 19.9%) and metastatic disease (AS 13.4%, RP 6.1%, RT 7.0%). QALYs were 10.88 for AS, 11.10 for RP, and 11.13 for RT. Total costs were A$17 912 for AS, A$15 609 for RP, and A$15 118 for RT. At a willingness to pay of A$20 000/QALY, RT had a 61.4% chance of being cost-effective compared to 38.5% for RP and 0.1% for AS. Although AS resulted in fewer and delayed treatment-related complications, it was not found to be a cost-effective strategy for favorable-risk localized prostate cancer over a lifetime horizon because of an increase in the number of patients developing metastatic disease. RT was the dominant strategy yielding higher QALYs at lower cost although differences compared with RP were small.


Surgical correction of spastic equinovarus deformity in the adult head trauma patient.
The results of 59 surgical procedures for correction of spastic equinovarus deformity of the foot using the split anterior tibial tendon (SPLATT) were reviewed in 54 adults with traumatic head injury. The mean time of follow-up was 49.7 months. Thirty-nine individuals had hemiplegic involvement, three had triplegic involvement, and 12 were quadriplegic. Evaluation of the patterns of lower extremity muscle activity preoperatively by dynamic electromyography in 33 patients showed no significant difference from that seen in the hemiplegic stroke population, namely, spastic calf muscles with overactive toe flexors and anterior tibial muscle. At follow-up all feet were in a plantigrade position. The only complication was a superficial skin slough on the dorsum of the foot which healed uneventfully. Postoperatively, 18 extremities (31%) were brace-free. Forty-one extremities required support because of calf weakness, ataxia, or proprioceptive deficits. Of the 15 patients who were nonambulatory prior to surgery, nine (60%) became ambulatory. At follow-up 36 patients (67%) were independent ambulators, four (7%) required supervision assistance, two (4%) required standby assistance, and six (11%) required minimal assistance. The six individuals (11%) who remained maximally assisted or nonambulatory had improved wheelchair positioning and shoe wear. These results show that the split anterior tibial tendon transfer is a safe and effective procedure for the head trauma patient since it corrects the equinovarus deformity, allowing for improved shoe wear and wheelchair positioning in the nonambulatory individual and improved ambulation with decreased brace wear in the more functional patient.


Inactivation of creatine kinase induced by stilbene derivatives.
Compounds acting as antioxidants to lipids often have a prooxidant effect on DNA or protein. In this study, inactivation of creatine kinase was examined as an indicator of protein damage induced by antioxidative stilbene derivatives, including diethylstilboestrol, resveratrol and tamoxifen, with horseradish peroxidase and hydrogen peroxide (horseradish peroxidase-H2O2). Diethylstilboestrol and resveratrol, but not tamoxifen, rapidly inactivated creatine kinase. Also, creatine kinase in heart homogenate was inactivated by diethylstilboestrol and resveratrol. Tamoxifen, which has no phenolic hydroxyl groups in its structure, was about 10 times less active in protecting lipids and creatine kinase than diethylstilboestrol and resveratrol, suggesting that phenolic hydroxyl groups in diethylstilboestrol and resveratrol of stilbene derivatives are anti- and pro-oxidative. Absorption spectra of these stilbene derivatives rapidly changed during the reaction with horseradish peroxidase-H202. Diethylstilboestrol and resveratrol free radicals emitted electron spin resonance signals and creatine kinase effectively diminished the electron spin resonance signals. These results suggest that free radicals of diethylstilboestrol and resveratrol formed through reaction with horseradish peroxidase-H202 inactivated creatine kinase. Presumably, oxidation of essential cysteine and tryptophan residues lead to inactivation of creatine kinase. Other enzymes, including alcohol dehydrogenase and cholinesterase, were also sharply inhibited by diethylstilboestrol and resveratrol with horseradish peroxidase-H202. Free radicals of diethylstilboestrol and resveratrol seem to mediate between anti- and prooxidative actions.


The Effects of Religiosity on Depression Trajectories After Widowhood.
This longitudinal study analyzed data from the 2006-2016 waves of the nationally representative Health and Retirement Study (HRS). Trajectories of depression among older adults ≥ 50 years (N = 1254) were examined over time to explore patterns of depression among those entering widowhood and the potential impact of religiosity on depressive symptoms during various stages of widowhood. Ordinary least squares (OLS) regression analysis was used to examine the association between widowhood and depression and the role of religiosity as a moderator of this association. Older adults experienced a statistically significant increase in depressive symptomology after the onset of widowhood, and depressive symptomology decreased post widowhood, but did not return to pre-widowhood levels. Additionally, high religious service attendance and higher intrinsic religiosity were both associated with lower depressive symptomology. High religious service attendance moderated the relationship between widowhood and depression among widowed older adults living alone.