New bysspectin A derivatives as potent inhibitors of human carboxylesterase 2A.
Human carboxylesterase 2A (hCES2A), the most abundant carboxylesterase in the human gut, plays a crucial role in the metabolic clearance and activation of various ester-bearing drugs, environmental toxins and carcinogens. Inhibition of intestinal hCES2A can alleviate irinotecan-induced gut toxicity and modulate the oral bioavailability of hCES2A-substrate drugs. Bysspectin A, a natural product isolated from the endophytic fungus Byssochlamys spectabilis, has been identified as a highly selective hCES2A inhibitor. Herein, two sets of bysspectin A derivatives have been designed and synthesized, utilizing a Cu-catalyzed domino Sonogashira-cyclization as the key step. Following two rounds of structure activity relationship (SAR) studies and structural optimizations, compound 20w was identified as the most potent hCES2A inhibitor, with an IC50 value of 1.6 nM, an approximately 1000-fold improvement over bysspectin A. Further investigation showed that 20w potently inhibited hCES2A in a mixed inhibition manner, while this agent could also potently inhibit intracellular hCES2A in living cells and exhibited suitable metabolic stability. In summary, our findings demonstrate that a new bysspectin A derivative (20w) is a promising candidate for the development of clinically used hCES2A inhibitor.


Patterns of sexual behaviour associated with repeated chlamydia testing and infection in men and women: a latent class analysis.
Adolescents and young adults are at higher risk of acquiring Chlamydia trachomatis infection (chlamydia), so testing is promoted in these populations. Studies have shown that re-testing for chlamydia is common amongst them. We investigated how sexual risk behaviour profiles are associated with repeated testing for chlamydia. We used baseline data from a cohort of 2814 individuals recruited at an urban STI -clinic. We applied latent class (LC) analysis using 9 manifest variables on sexual behaviour and substance use self-reported by the study participants. We fitted ordered logistic regression to investigate the association of LC membership with the outcomes repeated testing during the past 12 months and lifetime repeated testing for chlamydia. Models were fit separately for men and women. We identified four LCs for men and three LCs for women with increasing gradient of risky sexual behaviour. The two classes with the highest risk among men were associated with lifetime repeated testing for chlamydia: adjOR = 2.26 (95%CI: 1.50-3.40) and adjOR = 3.03 (95%CI: 1.93-4.74) as compared with the class with lowest risk. In women, the class with the highest risk was associated with increased odds of repeated lifetime testing (adjOR =1.85 (95%CI: 1.24-2.76)) and repeated testing during past 12 months (adjOR = 1.72 (95%CI: 1.16-2.54)). An association with chlamydia positive test at the time of the study and during the participant's lifetime was only found in the male highest risk classes. Prevention messages with regard to testing for chlamydia after unprotected sexual contact with new/casual partners seem to reach individuals in highest risk behaviour classes who are more likely to test repeatedly. Further prevention efforts should involve potentially more tailored sex-specific interventions taking into consideration risk behaviour patterns.


Disgust and political attitudes Guest Editors' Introduction to the Special Issue.
We introduce the Politics and the Life Sciences Special Issue on Disgust and Political Attitudes discussing the importance of understanding state and trait disgust, the innovative and transparent process by which registered reports and preregistered studies were chosen and funded, and the manuscripts that make up this special issue. This essay concludes by discussing future research directions in disgust and political attitudes, as well as the benefits of a transparent review process that avoids the "file drawer problem" of unpublished null findings.


Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14.
To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate β-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; β=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; β=-0.31) and worst β-cell function (p=0.023; β=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.


JNK: a new therapeutic target for diabetes.
Jun N-terminal kinase (JNK) regulates the transcription factor AP-1, which is implicated in the controlled expression of many genes involved in the immune response. For this reason, drug discovery efforts have focused on the development of JNK inhibitors for chronic inflammatory diseases. However, recent genetic evidence and emerging pharmacological data indicate that activated JNK could be critical in causing diabetes, insulin resistance and obesity. Indeed, if JNK is considered as a stress-activated protein kinase, there appear to be multiple mechanisms through which it might promote diabetes.


Fractional differentiation by neocortical pyramidal neurons.
Neural systems adapt to changes in stimulus statistics. However, it is not known how stimuli with complex temporal dynamics drive the dynamics of adaptation and the resulting firing rate. For single neurons, it has often been assumed that adaptation has a single time scale. We found that single rat neocortical pyramidal neurons adapt with a time scale that depends on the time scale of changes in stimulus statistics. This multiple time scale adaptation is consistent with fractional order differentiation, such that the neuron's firing rate is a fractional derivative of slowly varying stimulus parameters. Biophysically, even though neuronal fractional differentiation effectively yields adaptation with many time scales, we found that its implementation required only a few properly balanced known adaptive mechanisms. Fractional differentiation provides single neurons with a fundamental and general computation that can contribute to efficient information processing, stimulus anticipation and frequency-independent phase shifts of oscillatory neuronal firing.


Multifunctional nanomedicine strategies to manage brain diseases.
Brain diseases represent a substantial social and economic burden, currently affecting one in six individuals worldwide. Brain research has been focus of great attention in order to unravel the pathogenesis and complexity of brain diseases at the cellular, molecular, and microenvironmental levels. Due to the intrinsic nature of the brain, the presence of the highly restrictive blood-brain barrier (BBB), and the pathophysiology of most diseases, therapies can hardly be considered successful purely by the administration of one drug to a patient. Apart from improving pharmacokinetic parameters, tailoring biodistribution, and reducing the number of side effects, nanomedicines are able to actively co-target the therapeutics to the brain parenchyma and brain lesions, as well as to achieve the delivery of multiple cargos with therapeutic, diagnostic, and theranostic properties. Among other multivalent effects that can be personalized according to the disease needs, this represents a promising class of novel nanosystems, termed multifunctional nanomedicines. Herein, we review the principal mechanisms of therapeutic resistance of the most prevalent brain diseases, how to overcome this therapeutic resistance through the use of multifunctional nanomedicines that tackle multiple fronts of the disease microenvironment, and the promising therapeutic responses achieved by some of the most cutting-edge multifunctional nanomedicines reported in literature.


cis-{1-Butyl-3-[2-(phenyl-sulfan-yl)eth-yl]-4-imidazolin-2-yl-κ2 C 2,S'}di-chlorido-platinum(II).
The asymmetric unit of the title compound, [PtCl2(C15H20N2S)], comprises one PtII ion, one N-heterocyclic carbene(NHC)-thio-ether ligand and two chloride ions. The PtII ion is four-coordinated by one C atom and one S atom of the NHC-thio-ether ligand, and by two chloride ions, forming an approximately square-planar geometry. In the crystal, the mol-ecules are linked via C-H⋯Cl and C-H⋯π inter-actions, forming a layer parallel to the ab plane.


Change in nitric oxide in humans due to application of a pneumatic tourniquet.
The nitric oxide profile produced by application of a pneumatic tourniquet was investigated in the plasma of 15 patients. Nitrite (NO2-) and nitrate (NO3-) plasma concentrations were measured simultaneously by high-performance liquid chromatography (HPLC). UV detection using the Griess reaction was done after the reduction of nitrate to nitrite. The plasma nitrate concentration 5 min after reperfusion was significantly higher than the concentrations before ischemia, immediately before reperfusion, and the next day. In contrast, there was no significant difference in the plasma nitrite concentrations before ischemia, immediately before reperfusion, 5 min after reperfusion, and the next day. These findings suggest that the generation of NO is important in ischemic reperfusion injury.


Hybrid organic-inorganic structures trigger the formation of primitive cell-like compartments.
Alkaline hydrothermal vents have become a candidate setting for the origins of life on Earth and beyond. This is due to several key features including the presence of gradients of temperature, redox potential, pH, the availability of inorganic minerals, and the existence of a network of inorganic pore spaces that could have served as primitive compartments. Chemical gardens have long been used as experimental proxies for hydrothermal vents. This paper investigates-10pc]Please note that the spelling of the following author name in the manuscript differs from the spelling provided in the article metadata: Richard J. G. Löffler. The spelling provided in the manuscript has been retained; please confirm. a set of prebiotic interactions between such inorganic structures and fatty alcohols. The integration of a medium-chain fatty alcohol, decanol, within these inorganic minerals, produced a range of emergent 3 dimensions structures at both macroscopic and microscopic scales. Fatty alcohols can be considered plausible prebiotic amphiphiles that might have assisted the formation of protocellular structures such as vesicles. The experiments presented herein show that neither chemical gardens nor decanol alone promote vesicle formation, but chemical gardens grown in the presence of decanol, which is then integrated into inorganic mineral structures, support vesicle formation. These observations suggest that the interaction of fatty alcohols and inorganic mineral structures could have played an important role in the emergence of protocells, yielding support for the evolution of living cells.


Epidemiology of Fear, Sadness, and Anger Expression in Palliative Care Conversations.
Advancing the science of serious illness communication requires methods for measuring characteristics of conversations in large studies. Understanding which characteristics predict clinically important outcomes can help prioritize attention to scalable measure development. To understand whether audibly recognizable expressions of distressing emotion during palliative care serious illness conversations are associated with ratings of patient experience or six-month enrollment in hospice. We audiorecorded initial palliative care consultations involving 231 hospitalized people with advanced cancer at two large academic medical centers. We coded conversations for expressions of fear, anger, and sadness. We examined the distribution of these expressions and their association with pre/post ratings of feeling heard and understood and six-month hospice enrollment after the consultation. Nearly six in 10 conversations included at least one audible expression of distressing emotion (59%; 137 of 231). Among conversations with such an expression, fear was the most prevalent (72%; 98 of 137) followed by sadness (50%; 69 of 137) and anger (45%; 62 of 137). Anger expression was associated with more disease-focused end-of-life treatment preferences, pre/post consultation improvement in feeling heard and understood and lower six-month hospice enrollment. Fear was strongly associated with preconsultation patient ratings of shorter survival expectations. Sadness did not exhibit strong association with patient descriptors or outcomes. Fear, anger, and sadness are commonly expressed in hospital-based palliative care consultations with people who have advanced cancer. Anger is an epidemiologically useful predictor of important clinical outcomes.


Effect of a novel podophage AB7-IBB2 on Acinetobacter baumannii biofilm.
Biofilm formation in Acinetobacter baumannii is a common cause of nosocomial infections in humans. Clinical devices and abiotic surfaces are important sites of colonization leading to formation of biofilms. Such infections are often resistant to multiple antibiotic therapies, and hence there is need for an effective mode of control. Herein, we describe the isolation, characterization of a new lytic bacteriophage of A. baumannii and its effect on biofilm. The phage AB7-IBB2, with a genome size of about 170 kb was identified to be of family Podoviridae as revealed by transmission electron microscopy. It had an isometric head (35 nm) and a short tail (7 nm). It lysed 19/39 (49 %) clinical isolates of A. baumannii. Rapid adsorption (>99 % adsorbed in 4 min), a latency period of 25 min and a burst size 22 PFU/infected cell was observed. The phage could inhibit A. baumannii biofilm formation and disrupt preformed biofilm as well. The phage has promising potential to be considered as a candidate biocontrol agent for A. baumannii infections.


Chemical cleavage of fucoxanthin from Undaria pinnatifida and formation of apo-fucoxanthinones and apo-fucoxanthinals identified using LC-DAD-APCI-MS/MS.
As the most abundant carotenoid in nature, fucoxanthin is susceptible to oxidation under some conditions, forming cleavage products that possibly exhibit both positive and negative health effects in vitro and in vivo. Thus, to produce relatively high amounts of cleavage products, chemical oxidation of fucoxanthin was performed. Kinetic models for oxidation were probed and reaction products were identified. The results indicated that both potassium permanganate (KMnO4) and hypochlorous acid/hypochlorite (HClO/ClO(-)) treatment fitted a first-order kinetic model, while oxidation promoted by hydroxyl radical (OH) followed second-order kinetics. With the help of liquid chromatography-tandem mass spectrometry, a total of 14 apo-fucoxanthins were detected as predominant cleavage products, with structural and geometric isomers identified among them. Three apo-fucoxanthinones and eleven apo-fucoxanthinals, of which five were cis-apo-fucoxanthinals, were detected upon oxidation by the three oxidizing agents (KMnO4, HClO/ClO(-), and OH).


Restoring an elliptical chamber during rebuilding a wrap around anterior infarction.
Left ventricular geometry is distorted after anterior infarction caused by occlusion of a wrap around left anterior descending artery. Loss of the apex creates a spherical left ventricular (LV) chamber, whose rebuilding requires reconstruction techniques that exclude the non-functional inferior wall. The described technique of tailoring the apex defines a way to create an oblique elliptical rim for subsequent patch placement to complete the restoration procedure. This method of ventricular rebuilding differs from methods that follow the inferior wall scar, which result in a restoration procedure that leaves a spherical or box-like apical region.


Molecular links between mitochondrial dysfunctions and schizophrenia.
Schizophrenia is a complex neuropsychiatric disorder with both neurochemical and neurodevelopmental components in the pathogenesis. Growing pieces of evidence indicate that schizophrenia has pathological components that can be attributable to the abnormalities of mitochondrial function, which is supported by the recent finding suggesting mitochondrial roles for Disrupted-in-Schizophrenia 1 (DISC1). In this minireview, we briefly summarize the current understanding of the molecular links between mitochondrial dysfunctions and the pathogenesis of schizophrenia, covering recent findings from human genetics, functional genomics, proteomics, and molecular and cell biological approaches.


Microbial quality of wastewater: detection of hepatitis A virus by reverse transcriptase-polymerase chain reaction.
The persistent circulation of hepatitis A virus (HAV) in the Mediterranean area suggests the need for monitoring its presence in the environment. A reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the presence of HAV in several consecutive raw sewage and final effluent samples, collected over an 8-month period from an activated sludge treatment plant in southern Italy. Two distinct purification protocols, either based on antigen-capture with monoclonal antibody (AC) or RNA extraction, were compared. The possible influence of the antibody used in the AC phase was evaluated in preliminary experiments on HAV-spiked samples, using two different monoclonal antibodies. Hepatitis A virus RNA was detected in all but one sewage environmental sample examined. The contemporary presence of enteroviruses, reoviruses and phages was observed, while HAV growth in cell culture was hampered. The RT-PCR technique was confirmed to be a valuable tool for the rapid monitoring of HAV in sewage samples. In addition, this study demonstrated that application of different sample purification methods can result in different levels of sensitivity of the assay and that, in the antigen-capture method, the choice of antibody can have a crucial role. This work underlines the need for technical uniformity in environmental studies from different laboratories for a correct and useful comparison of the results.


A new approach to the vascular-nervous correlations of the superior mediastinum in man.
The relationship between the superior mediastinal organs has been investigated in the adult and the newborn. It was found that this region could be represented by a geometrical schematization based on the correlations that exist among the vascular and nervous elements that lie on the right mediastinal wall. A vascular triangle, a vascular-nervous triangle and a retro-vagal square are described. The size of these forms and their relations with the organs they enclose varies depending on the build of the subject being examined in this area, particularly from a teaching point of view.


The cruciferous phytoalexins brassinin and cyclobrassinin are intermediates in the biosynthesis of brassilexin.
Following feeding experiments with the tetradeuterated cruciferous phytoalexins brassinin (5b) and cyclobrassinin (6b), leaves of Brassica carinata were elicited with the blackleg causing fungus Phoma lingam and incubated. Spectroscopic and HPLC analyses indicated that both brassinin (5a) and cyclobrassinin (6a) were incorporated into the cruciferous phytoalexin brassilexin (7a).


Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease.
Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500). These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.


[Endoscopic diagnosis and therapy of benign stenosis of Vater's papilla].
Out of 921 endoscopic papillotomies (EPT) 110 (12%) were performed in patients with benign stenosis of the papilla of Vater. Among these patients were 96 after cholecystectomy and 14 with gallbladder in situ. The diagnostic aspects of the stenosis of papilla and the complications of EPT were investigated on the basis of these patients. The dilation of the bile ducts is not a specific criteria for the diagnosis of papilla-stenosis. Dilatation could develop after cholecystectomy despite the normal sphincter pressure. The complication rate in patients with stenosis of papilla of Vater is increased (13.6%) in comparison with the patients with biliary stones (8.8%). This can be account for the increased number of haemorrhage and cholangitis.


Diminished Disease-Free Survival After Lobectomy: Screening Implications.
The aim of this study was to estimate the effect of lobectomy on life expectancy in healthy smokers and consider the implications for lung cancer screening. In a retrospective cohort study that provided a minimum of 15 years of follow-up, we analyzed lung cancer survival, all-cause survival, and fatality (1-survival) of 261 persons with stage I non-small-cell lung cancer who underwent lobectomy at Portland Providence Medical Center between 1978 and 1994. We: (1) compared 5-year disease-free fatality (non-lung-cancer fatality) with lung cancer fatality; and (2) based on actuarial data that demonstrated life expectancy equivalence of the healthiest smokers (whom we assumed would be comparable with subjects judged eligible for lobectomy) in the US population, we compared their long-term, disease-free survival (our primary end point) with actuarial expectations by computing the Kaplan-Meier survival function of the differences between lifetimes since surgery in disease-free persons versus matched, expected remaining lifetimes in the US population. (1) Five-year disease-free fatality (16.1%) was 58% as high as 5-year lung cancer fatality (27.6%); (2) disease-free survival was reduced by 6.9-years (95% confidence interval, 5.5-8.3), 41% of actuarial life expectancy (17 years). The divergence from expected survival took place largely after 6 years of follow-up. Lobectomy materially diminishes long-term disease-free survival in the healthiest smokers--persons judged healthy enough to tolerate major surgery and to have sufficient pulmonary reserve to sustain loss of one-fifth of their lung tissue. In screened populations, diminished survival in overdiagnosed persons will offset, to an undetermined extent, the mortality benefit imparted by preemption of advanced lung cancer.


Smart and eco-friendly N-isopropylacrylamide and cellulose hydrogels as a safe dual-drug local cancer therapy approach.
Local cancer treatment by in situ injections of thermo-responsive hydrogels (HG) offers several advantages over conventional systemic anti-cancer treatments. In this work, a biodegradable and multicompartmental HG composed of N-isopropylacrylamide, cellulose, citric acid, and ceric ammonium nitrate was developed for the controlled release of hydrophilic (doxorubicin) and hydrophobic (niclosamide) drugs. The formulation presented ideal properties regarding thermo-responsiveness, rheological behavior, drug release profile, biocompatibility, and biological activity in colon and ovarian cancer cells. Cellulose was found to retard drugs release rate, being only 4 % of doxorubicin and 30 % of niclosamide released after 1 week. This low release was sufficient to cause cell death in both cell lines. Moreover, HG demonstrated a proper injectability, in situ prevalence, and safety profile in vivo. Overall, the HG properties, together with its natural and eco-friendly composition, create a safe and efficient platform for the local treatment of non-resectable tumors or tumors requiring pre-surgical adjuvant therapy.


Dopaminergic effects on simple and choice reaction time performance in Parkinson's disease.
The present study examined whether premovement central neural processing in Parkinson's disease was related to functional motor disability and plasma L-dopa concentration. Reaction time (RT) performance in simple and choice RT tasks was assessed while plasma L-dopa levels were controlled by continuous IV L-dopa infusion in five parkinsonian patients. Five age-matched controls performed the same RT tasks for comparison. Simple RT for the patients was longer than the normal control RT at all infusion levels (p less than or equal to 0.005). However, choice RT was normal when the patients were "on," but became prolonged as plasma L-dopa levels decreased (p less than or equal to 0.01). The results show that there are abnormalities of premovement central neural processing in Parkinson's disease, and that simple and choice RTs are differentially affected by L-dopa replacement. This suggests that different neural mechanisms may be involved in the processing of these tasks.


Gastric mucosal barrier in the rats fed with protein deficient diet or treated with carbon tetrachloride.
The effects of protein deficient diet and liver damage on the gastric mucosal barrier were studied in 32 Sprague-Dawley rats. The animals were divided into 4 groups according to their dietary regimens, CCl4 induced liver damage and/or serotonin administration. Group 1 (control) was fed standard rat chow. Group II was fed a nonprotein diet for 2 weeks. Group III and IV were fed standard rat chow and given 1 ml of CCl4 per/Kg body weight intraperitoneally twice weekly for 12 weeks. Rats in Group IV were also injected with 20mg per/Kg of serotonin intraperitoneally 30 minutes prior to surgery. After pyloric ligation, an acid test solution composed of 100 mM HCl, 10mM NaCl, 5mM KCl and 5g per litre of PEG was instilled into the stomach and fluxes of Na +, K +, H + and Cl-ions across the gastric mucosa were measured. Compared to Group I, rats in Group II, III and IV demonstrated an increased net negative hydrogen flux (p less than 0.05). An increased net negative chloride flux (p less than 0.05) was also demonstrated in Group II and IV, but no increase was noted in Group III. There were no significant differences in fluxes of sodium and potassium ions. As mentioned above, a lack of protein in the diet, liver damage or both, renders the gastric mucosa of the rat more susceptible to injury. In the gastric mucosa of these rats, there have occurred more increase in the negative net fluxes of hydrogen and chloride ion, which may indicate the reduction of defence mechanism against a mucosal damage.


Genome-wide survey of D/E repeats in human proteins uncovers their instability and aids in identifying their role in the chromatin regulator ATAD2.
D/E repeats are stretches of aspartic and/or glutamic acid residues found in over 150 human proteins. We examined genomic stability of D/E repeats and functional characteristics of D/E repeat-containing proteins vis-à-vis the proteins with poly-Q or poly-A repeats, which are known to undergo pathologic expansions. Mining of tumor sequencing data revealed that D/E repeat-coding regions are similar to those coding poly-Qs and poly-As in increased incidence of trinucleotide insertions/deletions but differ in types and incidence of substitutions. D/E repeat-containing proteins preferentially function in chromatin metabolism and are the more likely to be nuclear and interact with core histones, the longer their repeats are. One of the longest D/E repeats of unknown function is in ATAD2, a bromodomain family ATPase frequently overexpressed in tumors. We demonstrate that D/E repeat deletion in ATAD2 suppresses its binding to nascent and mature chromatin and to the constitutive pericentromeric heterochromatin, where ATAD2 represses satellite transcription.


From silos to systems: an integrated approach to neuroscience innovation.
The Ontario Brain Institute manages a network of partnerships among researchers, clinicians, industry representatives and patients to maximize their collective impact on developing better treatment and care for those living with brain disorders.


[Differential diagnosis of ischemia of the lower extremities in young adults].
Lower-extremity arterial occlusive disease in individuals younger than 50 years is rare. We report on 4 young adults with lower limb ischemia, each of them with a different cause. According to literature premature atherosclerosis is the most common cause and is followed by thromboangiitis obliterans, coagulation abnormalities and popliteal artery entrapment syndrome. We suggest a diagnostic concept which could help to avoid undue delay.


Associations between discrimination experiences and symptoms of depression and anxiety among transgender adults: a nationwide cohort study of 269 transgender adults in South Korea.
Recently, there has been an increase in awareness of social stigma and mental health issues experienced by transgender individuals in South Korea. To provide quantitative evidence, we conducted a nationwide cohort study of transgender adults, first of its kind in Asia. The aim of the study is to assess the prevalence of depressive and anxiety symptoms and examine their associations with discrimination experiences among transgender adults. We conducted a two-wave longitudinal survey of 269 Korean transgender adults, where the baseline was collected in October 2020 and the follow-up in October 2021. Experiences of discrimination in the past 12 months at follow-up were categorized accordingly: those who experienced (1) none, (2) only anti-transgender discrimination, (3) only other types of discrimination, and (4) both anti-transgender and other types of discrimination. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale at both waves and anxiety symptoms were measured using the Generalized Anxiety Disorder 7 only at follow-up. We used modified Poisson regression to examine the association between experiences of discrimination and mental health outcomes at follow-up and adjusted for sociodemographic characteristics and baseline depressive symptoms. A total of 63.9% had depressive symptoms and 47.2% had anxiety symptoms. Participants who experienced both anti-transgender and other types of discrimination had 1.38-times (95% CI 1.06-1.81) and 1.77-times (95% CI 1.16-2.70) higher prevalence of depressive and anxiety symptoms, respectively, compared to those without any experiences of discrimination. Interventions to lessen discrimination towards transgender individuals are needed for the promotion of mental health among transgender individuals.


Pulsed electromagnetic field at 9.71 GHz increase free radical production in yeast (Saccharomyces cerevisiae).
Potential human health hazards have been reported after exposure to electromagnetic fields at low power density. Increased oxidative stress has been suggested as a potential mechanism involved in long-term effect of such exposure. In the present work, yeast cultures were exposed for 20 min to a 9.71 GHz pulsed electromagnetic field at specific absorption rates (SAR) from 0.5 W/kg to 16 W/kg. Oxidative perturbations were investigated using ESR spin trapping experiments and their impacts on membrane fluidity were assessed using spin label five nitroxide stearate. The experiments using the water-soluble spin trap alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone and the lipid-soluble N-tert-butyl-alpha-phenylnitrone showed an increase of spin adduct production both in low power density exposure (SAR<4 W/kg) and in thermal conditions (SAR>4 W/kg). The membrane fluidity diminutions after exposure in all the conditions were consistent with lipid peroxidation. The overall results suggest an increase of the free radical production in the intra cellular compartment; however no effect on the yeast vitality was found.


Brain grafts can restore irradiation-damaged neuronal connections in newborn rats.
Immature rat brain tissue grafted to the brain of other immature and adult rats can survive and establish nerve connections with the host brains. In addition to facilitating the study of factors involved in the formation of central neural connections, brain grafts may also be used to substitute damaged or maldeveloped neurones. With exceptions in the visual system, the restoration of specific central neural connections has to date involved grafts of cholinergic and monoaminergic neurones, which have good regenerative capacity. In the present study, rat hippocampal neurones were damaged by neonatal X-ray irradiation and replaced by transplantation of normal, developing neurones of the same type. The grafted neurones (dentate granule cells) are not cholinergic or monoaminergic, but when appropriately located in the host hippocampal region they established specific and highly ordered afferent and efferent connections with the damaged host brain. Moreover, simultaneous demonstration of afferent and efferent transplant pathways showed that serial host-transplant-host connections had formed, restoring the normal neuronal circuitry initially disrupted by the irradiation.


The role of MRI in spinal stab wounds compared with intraoperative findings.
Spinal stab wound injuries are quite rare and only few patients have been reported on the basis of MRI scan. A 25-year-old man was stabbed at C1/2 and had an incomplete Brown-Sequard syndrome. He underwent surgical exploration because of CSF leakage on the fourth day. After a follow-up period of 32 months, he was left with a remaining loss of the proprioception of the right foot. We show detailed CT and MR images with the focus on the lesions of the dura and myelon and compared them with intraoperative images. In addition, we contrast our findings with a review of literature published over the last three decades. MRI gives the most detailed view of soft tissue lesions in SSWs and is in accordance with our intraoperative findings.


Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).
To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.


Protein turnover in patients before and after elective orthopaedic operations.
Whole body protein turnover was measured in 11 patients before and after elective orthopaedic operations be giving 15N-glycine orally every 4 hours for 32 hours. The patients were maintained throughout on a constant protein intake. In 2 control subjects a comparison was made between intermittent dosage and continuous infusion of 15N-glycine for the estimation of total protein turnover. With intermittent dosage the 15N abundance in urinary urea reached a constant level after about 24 hours. Rates of total protein synthesis and breakdown were calculated from the 15N abundance at the plateau level. After surgery there was a moderate increase in urinary N output. The apparent N balance (intake--urinary N) was -0-52 +/- 1-31 g/d (mean +/- s.d.) before operation and -7-51 +/- 4-5 g/d after operation. The rate of protein synthesis fell from 3-83 +/- 0-73 g kg-1 d-1 before operation to 2-94 +/- 0-83 g kg-1 d-1 after operation. This difference is statistically significant (0-05 greater than P greater than 0-01). There was no significant change in the rate of protein breakdown. The possibility remains that a block in protein synthesis, probably mainly in muscle, may be partly responsible for the so-called 'catabolic' loss of nitrogen after injury, but this has not been proved.


Regular wine consumption in chronic heart failure: impact on outcomes, quality of life, and circulating biomarkers.
Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P<0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P=0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P<0.0001, and pentraxin-3, P=0.01) after adjusting for possible confounders. We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. URL: http://www.clinicaltrials.gov. Unique identifier: NCT0033633.


Adenylyl Cyclase 9 Polymorphisms Reveal Potential Link to HDL Function and Cardiovascular Events in Multiple Pathologies: Potential Implications in Sickle Cell Disease.
Adenylyl cyclase 9 (ADCY9) mediates β2-adrenoceptor (β2-AR) signalling. Both proteins are associated with caveolae, specialized cholesterol-rich membrane substructures. Apolipoprotein A1 (ApoA1), the major protein component of high-density lipoprotein (HDL), removes cholesterol from cell membrane and caveolae and may thereby influence β2-AR signalling, shown in vitro to be modulated by cholesterol. Patients with Sickle Cell Disease (SCD) typically have low HDL and ApoA1 levels. In patients, mainly of African origin, with SCD, β2-AR activation may trigger adhesion of red blood cells to endothelial cells, leading to vascular occlusive events. Moreover, ADCY9 polymorphism is associated with risk of stroke in SCD. In recent clinical trials, ADCY9 polymorphism was found to be a discriminant factor associated with the risk of cardiovascular (CV) events in Caucasian patients treated with the HDL-raising compound dalcetrapib. We hypothesize that these seemingly disparate observations share a common mechanism related to interaction of HDL/ApoA1 and ADCY9 on β2-AR signalling. This review also raises the importance of characterizing polymorphisms that determine the response to HDL-raising and -mimicking agents in the non-Caucasian population at high risk of CV diseases and suffering from SCD. This may facilitate personalized CV treatments.


[Study of a series of 158 parotidectomies and histological problems in mixed tumors of salivary glands (author's transl)].
About a homogeneous statististic of 158 parotidectomies, authors study repartition parameters of parotid gland tumors. They insist on particular surgical and evolutive problems in relation to histology sometimes very difficult.


Optimization of region of interest luminances may enhance radiologists' light adaptation.
Radiologic image details are best discriminated at luminance levels to which the eye is adapted. Recommendations that ambient light conditions are matched to overall monitor luminance to encourage appropriate adaptation are based on an assumption that clinically significant regions within the image match average monitor luminance. The current work examines this assumption. Three image types were considered: posteroanterior (PA) chest; PA wrist; and computed tomography (CT) head. Luminance at clinically significant regions was measured at hilar region and peripheral lung (chest), distal radius (wrist), and supraventricular white matter (head). Average monitor luminances were calculated from measurements at 16 regions of the display face plate. Three ambient light levels-30, 100 and 400 lux-were employed. Thirty samples of each image type were used. Statistically significant differences were noted between average monitor luminances and clinically important regions of interest of up to a factor of 3.8, 2, and 6.3 for chest, wrist, and CT head images respectively (P < .0001). Values for the hilum of the chest and distal radius were higher than average monitor levels, whereas the reverse was observed for the peripheral lung and CT brain. Increasing ambient light had no impact on results. Clinically important radiologic information for common radiologic examinations is not being presented to observers in a way that facilitates optimized adaptation. This may have a significant impact on the ability of the observer to identify details with low contrast discriminability. The importance of image-processing algorithms focussing on clinically significant abnormalities rather than anatomic regions is highlighted.


Precision of different fatigue methods for predicting glass-ceramic failure.
This study aimed to characterize the fatigue behavior using two fatigue methods, boundary and staircase, and to predict the probability of failure (Pf) of zirconia-reinforced lithium silicate glass-ceramic (ZLS). Bar-shaped specimens of ZLS (18 ×4 ×1.2 mm) were fabricated. Thirty specimens were subjected to a three-point flexural strength test using a universal testing machine with 0.5 mm/min crosshead speed, in 37 °C distilled water. Flexural strength data were analyzed with Weibull statistics. Eighty-six bars were subjected to cyclic fatigue using boundary and staircase methods. Fatigue tests were performed in a pneumatic cycling machine (2 Hz, 37 °C distilled water) for 10 ³ and 104 cycles. Fatigue data were analyzed using an inverse power law relationship and log normal-lifetime distribution. Fracture toughness (KIc) was determined using V-notched specimens (18 ×4 ×3 mm) and the short beam toughness method (n = 7). Vickers hardness (VH) was evaluated (4.9 N, 20 s). Fractographic and EDS analyses were also performed. ZLS showed a characteristic strength of 197 MPa, Weibull modulus of 4, VH of 6.67 GPa and KIc of 1.93 MPa m1/2. After 103 cycles, for both methods, there was a degradation of 78% of the initial strength. There was no significant degradation when the number of cycles increased from 103 to 104. Both methods resulted in similar Pf and precision at 40 MPa (~50% Pf). Yet, staircase shows good accuracy and precision in predicting the stress amplitude for a Pf near 50%; while boundary is also effective for Pf lower than 50%. The fatigue methods evaluated show similar accuracy and precision for predicting the Pf of a glass-ceramic when simulations were made in the range of stress levels and lifetimes used in the fatigue tests.


Potential effects of Ag ion on the host by changing the structure of its gut microbiota.
Silver (Ag) can change the structure of the gut microbiota (GM), but how such change may affect host health is unknown. In this study, mice were exposed to silver acetate daily for 120 days. During this period, Ag accumulation in the liver was measured, its effects on GM structure were analyzed, and potential metabolic changes in liver and serum were examined. Although Ag accumulation remained unchanged in most treatments, the ratio of Firmicutes to Bacteroidetes at the phylum level increased and changes in the relative abundance of 33 genera were detected, suggesting that Ag altered the energy metabolism of mice via changes in the gut GM. In serum and liver, 34 and 72 differentially expressed metabolites were identified, respectively. The KEGG pathways thus enriched mainly included those involving the metabolism of amino acids, organic acids, lipids, and purine. Strong correlations were found between 33 % of the microorganisms with altered relative abundances and 46 % of the differentially expressed metabolites. The resulting clusters yielded two communities responsible for host inflammation and energy metabolism. Overall, these results demonstrate potential effects of Ag on the host, by changing its GM structure, and the need to consider them when evaluating the health risk of Ag.


[Etiopathogentic aspects, clinical picture and differential diagnostic view of first and second branchial arch syndromes].
The AA. examine in the present work the main syndrome of I and II branchial arch, valuing the hetiopathogenetic and clinic aspects and determining a diagnostic-differential scheme between the same. It is underlined the importance of the echografic exam for the prenative diagnosis and the clinic exam for the after native diagnosis.


Evolution of cyclic amidohydrolases: a highly diversified superfamily.
Dihydroorotases are universal proteins catalyzing the third step of pyrimidine biosynthesis. These zinc metalloenzymes belong to the superfamily of cyclic amidohydrolases, comprising also other enzymes that are involved in degradation of either purines (allantoinases), pyrimidines (dihydropyrimidinases) or hydantoins (hydantoinases). The evolutionary relationships between these mechanistically related enzymes were estimated after designing a method to build an accurate multiple sequence alignment. The amino acid sequences that have been crystallized were used to build a seed alignment. All the remaining homologues were progressively added by aligning their HMM profiles to the seed HMM profile, allowing to obtain a reliable phylogeny of the superfamily. This helped us to propose a new evolutionary classification of dihydroorotases into three major types, while at the same time disentangling an important part of the history of their complex structure-function relationships. Although differing in their substrate specificity, allantoinases, hydantoinases and dihydropyrimidinases are found to be phylogenetically closer to DHOase Type I than the proximity of the three DHOase types to each other. This suggests that the primordial cyclic amidohydrolase was a multifunctional, highly evolvable generalist, with high conformational diversity allowing for promiscuous activities. Then, successive gene duplications allowed resolving the primordial substrate ambiguity in various substrate specificities. The present-day superfamily of cyclic amidohydrolases is the result of the progressive divergence of these ancestral paralogous copies by descent with modification.


Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia.
Parathyroid hormone-related peptide (PTHrP) is the predominant cause of malignancy-associated hypercalcemia. However, its prognostic utility is unclear. We aimed to determine the prognostic value of serum PTHrP levels in patients who had hypercalcemia associated with malignancy. In this prospective case series, we evaluated 76 patients with a diagnosis of cancer and hypercalcemia (serum calcium level >/=10.3 mg/dL on at least two occasions). PTHrP levels >/=1 pmol/L were considered elevated. We used multivariate Cox regression analysis to identify factors associated with mortality. Fifty patients (66%) died during follow-up. In a multivariate analysis, higher pretreatment calcium levels and elevated PTHrP levels were associated with increased mortality, with effects of PTHrP varying by age (P = 0.03). Survival was associated with pretreatment calcium levels both in patients over 65 years of age (hazard ratio [HR] per mg/dL = 1.5; 95% confidence interval [CI]: 1.2 to 1.8; P <0.001) and in patients aged 65 years or less (HR = 1.3; 95% CI: 1.1 to 1.5; P = 0.003). Adjusted for pretreatment calcium levels, elevated PTHrP levels were associated with increased mortality in patients aged </=65 years (HR = 3.8; 95% CI: 1.6 to 8.8; P = 0.002), but not in older patients (HR = 0.7; 95% CI: 0.3 to 1.9; P = 0.51). PTHrP is a useful prognostic factor in malignancy-associated hypercalcemia, at least in patients aged </=65 years.


Behavioral indices of neurotoxicity: what can be measured?
The ability to identify and characterize the potential neurotoxicity of chemicals is an important and necessary function of various regulatory agencies. Behavioral assessments of toxicity may be important because of their relative sensitivity to some chemicals, their generally noninvasive characteristics, and their ability to measure toxicity in organ systems other than the nervous system. Behavioral tests can be classified by several criteria including traditional experimental definitions, their desired experimental usage, the neurobehavioral functions they are designed to assess, and the strategy chosen for their use in the evaluation of chemicals. Examples of neurobehavioral tests used to evaluate the effects of chemicals for toxicity include those that evaluate motor (spontaneous motor activity, motor coordination, weakness, abnormal movement or posture, tremor, and on-going performance), sensory (screening, reflex modification, and instrumental conditioning), learning/memory (nonassociative and associative), instrumental performance (schedules of reinforcement), and naturally occurring responses (consummatory behaviors). Behavioral procedures have also been utilized in select ways in toxicological research to detect latent damage, to study mechanisms of action, and to screen for functional dysfunction following exposure during development. Many considerations, such as the behavioral mechanism of action, definition of an adverse effect, problem of functional reserve, and several statistical questions, should be taken into account in the use and interpretation of data obtained from behavioral tests. During the last decade, there have been numerous recommendations from groups within the United States and, most recently, the World Health Organization, suggesting that systematic observational assessments may be appropriate when carried out within already existing toxicological protocols.


Na(+)-Ca2+ exchange modulates Ca2+ handling of human platelets by altering intracellular Ca2+ store size.
In order to elucidate the role of Na(+)-Ca2+ exchange in regulating cytosolic free Ca2+ concentration in human platelets, we investigated the relationship between cytosolic free Na+ and Ca2+ concentrations in human platelets. Sodium-binding benzofuran isophthalate and fura-2 were used to monitor cytosolic free Na+ and Ca2+ concentrations, respectively. Ouabain at a concentration of 100 mumol/l induced an increase in cytosolic free Na+ concentration within 5 min, followed by increases in resting cytosolic free Ca2+ concentration and intracellular Ca2+ store. These three parameters were increased in a time-dependent manner significantly above the timed control over a period of 60 min. Pre-incubation of platelets with 100 mumol/l ouabain for 30 min significantly enhanced the cytosolic free Ca2+ response to thrombin and arginine vasopressin in the absence of extracellular Ca2+. The decrease from peak cytosolic free Ca2+ concentration in response to ionomycin in the absence of extracellular Ca2+ was significantly slower in low-Na+ buffer than in standard buffer. In addition, 5 mumol/ionomycin increased the cytosolic free Na+ concentration markedly in the presence of 0.1 mmol/l extracellular Ca2+, but the rise in cytosolic free Na+ concentration was suppressed by 2 mmol/l Ni2+ (NiCl2) or by removal of extracellular Ca2+. These results suggest that Na(+)-Ca2+ exchange is important in extruding Ca2+ from the cytosol in human platelets, and inhibition of this exchange leads to the accumulation of intracellular Ca2+ store, which may be responsible for the enhanced responsiveness of cytosolic free Ca2+ to agonists.


The Genetic Basis of Anthocyanin Acylation in North American Grapes (Vitis spp.).
Hydroxycinnamylated anthocyanins (or simply 'acylated anthocyanins') increase color stability in grape products, such as wine. Several genes that are relevant for anthocyanin acylation in grapes have been previously described; however, control of the degree of acylation in grapes is complicated by the lack of genetic markers quantitatively associated with this trait. To characterize the genetic basis of anthocyanin acylation in grapevine, we analyzed the acylation ratio in two closely related biparental families, Vitis rupestris B38 × 'Horizon' and 'Horizon' × Illinois 547-1, for 2 and 3 years, respectively. The acylation ratio followed a bimodal and skewed distribution in both families, with repeatability estimates larger than 0.84. Quantitative trait locus (QTL) mapping with amplicon-based markers (rhAmpSeq) identified a strong QTL from 'Horizon' on chromosome 3, near 15.85 Mb in both families and across years, explaining up to 85.2% of the phenotypic variance. Multiple candidate genes were identified in the 14.85-17.95 Mb interval, in particular, three copies of a gene encoding an acetyl-CoA-benzylalcohol acetyltransferase-like protein within the two most strongly associated markers. Additional population-specific QTLs were found in chromosomes 9, 10, 15, and 16; however, no candidate genes were described. The rhAmpSeq markers reported here, which were previously shown to be highly transferable among the Vitis genus, could be immediately implemented in current grapevine breeding efforts to control the degree of anthocyanin acylation and improve the quality of grapes and their products.


Redox-Sensitive multifunctional hyaluronic acid-based nanomicelles with Fine-controlled anticancer drug release.
A significant contributor to cancer-related death globally is metastatic breast cancer. To reduce death rates, tumor-specific penetration and triggered drug release are crucial. Herein, targeted intracellular doxorubicin (Dox) delivery system was effectively prepared based on redox-sensitive hyaluronic acid-palmitoyl (HA-ss-PA) copolymers. The amphiphilic copolymers self-assembled into nano and showed outstanding drug-loading capacities and encapsulation efficiency for Dox. Micelles were stable under physiological conditions, but they quickly disintegrated in the presence of a reducing agent. The intracellular location of the fluorescent probe rhodamine b demonstrated that HA-ss-PA micelles are an efficient approach for drug delivery in breast cancer cells. Based on flow cytometry and live/dead assay, observations indicated that micelles induce apoptosis in both MCF-7 and MDA-MB-231 cells. In vivo evaluation in tumor-bearing mice confirmed that HA-ss-PA micelles exhibited excellent tumor-targeting activity. These findings imply that redox-sensitive HA-ss-PA micelles are promising candidates for use as intracellular delivery systems for hydrophobic anti-cancer drugs.


Population attributable fraction estimates for factors associated with different types of anaemia among women in Ethiopia: multilevel multinomial analysis.
This study aimed to identify factors for different levels of anaemia among Ethiopian women and to estimate the population attributable fraction (PAF). This study was a detailed analysis of data of the 2016 Ethiopian Demographic and Health Survey data. Adjusted OR (AOR) with 95 % CI was computed using multilevel multinomial regression models, and the PAF were estimated using these AOR. This study was conducted in Ethiopia. Women of reproductive age. The PAF showed that the proportion of mild anaemia cases attributable to having no formal education was 14·6 % (95 % CI 3·4, 24·5), high gravidity (≥4) was 11·2 % (95 % CI 1·2, 19·9) and currently breast-feeding was 5·2 % (95 % CI 0·0, 10·7). Similarly, the proportion of moderate-severe anaemia cases attributable to being in a rural residence was 38·1 % (95 % CI 15·9, 54·8); poorest wealth quantile, 12·6 % (95 % CI 2·9, 24·6); giving birth in the last 5 years, 10·5 % (95 % CI 2·9, 18·2) and unimproved latrine facilities, 17 % (95 % CI 0, 32·5). The PAF suggest that rural residency, low education, low wealth status, high parity, pregnancy and breast-feeding contribute substantially to the occurrence of anaemia among women in Ethiopia. Mild anaemia could be reduced by setting intervention strategies targeting women with low education, multigravida women and breast-feeding women, while preventing moderate-severe anaemia may require increasing income and improving living environments through the accessibility of hygienic latrines.


Diagnostic laparoscopy and adhesiolysis: does it help with complex abdominal and pelvic pain syndrome (CAPPS) in general surgery?
Abdominal pains secondary to adhesions are a common complaint, but most surgeons do not perform surgery for this complaint unless the patient suffers from a bowel obstruction. The purpose of this evaluation was to determine if lysis of bowel adhesions has a role in the surgical management of adhesions for helping treat abdominal pain. The database of our patients with complex abdominal and pelvic pain syndrome (CAPPS) was reviewed to identify patients who underwent a laparoscopic lysis of adhesion without any organ removal and observe if they had a decrease in the amount of abdominal pain after this procedure. Thirty-one patients completed follow-up at 3, 6, 9, and 12 months. At 6, 9, and 12 months postoperation, there were statistically significant decreases in patients' analog pain scores. We concluded that laparoscopic lysis of adhesions can help decrease adhesion-related pain. The pain from adhesions may involve a more complex pathway toward pain resolution than a simple cutting of scar tissue, such as "phantom pain" following amputation, which takes time to resolve after this type of surgery.


In closed wedge distal femur osteotomies for correction of valgus malalignment overcorrection of mLDFA should be avoided.
The purpose of the study was to investigate the influence of the mLDFA (mechanical lateral distal femur angle) as a parameter in varus realignment osteotomies for valgus deformities of the knee. We hypothesized that joint line obliquity with mLDFA > 90° after distal femur osteotomy (DFO) is associated with inferior clinical outcome. In a retrospective study, a total of 52 patients with isolated femoral valgus deformities were included in the study. The mean postoperative follow-up was 70.5 (SD 33.3) months (standard deviation SD±33.3). In all patients, a distal femur osteotomy was performed. A clinical examination and survey of questionnaires was conducted with the HSS (Hospital for Special Surgery), LG (Lysholm-Gilquist), and KOOS (Knee Injury and Osteoarthritis Outcome Score) scores. Several radiological parameters were assessed on long-standing x-rays: mechanical tibio-femoral angle (mTFA), mLDFA, mechanical medial proximal tibia angle (mMPTA), joint-line convergence angle (JLCA). The t test was used for normally distributed data. The Mann-Whitney U test was performed in non-normally distributed data. The mLDFA was 84.9° (SD±2.3) preop and changed to 91.9° (SD±3, 22.9) postop. The mTFA (mechanical tibio-femoral angle) was 5.2° (SD±2.9°) preop and - 1.8° (SD±2.9) postop demonstrating a difference of 6.7°. For analysis, the data was divided into two groups based on postop mLDFA. Group 1: mLDFA ≤ 90°; Group 2: > 90°. Postoperatively, a mean mLDFA of 88.6° (SD±1.4°) was measured in group 1 and 93.9° (SD±2.1) in group 2. The change in mLDFA was 4.7° (SD±1.6) in group 1 and 8.4° (SD±2.8) in group 2. Preoperatively, the mTFA was 4.8° (SD±1.9) in group 1 and 5.5° (SD±3.3) in group 2. Postoperatively, the mTFA decreased in group 1 by 4.8° (SD±2.3) to - 0.1° (SD±2.1). In group 2, the mTFA decreased by 8.2° (SD±3.8) to - 2.8° (SD±2.9). Regarding the HSS, group 1 showed a 10.4 points better score than group 2 (p<0.01). Also, regarding the Lysholm, a significant difference of 16.9 points was found (p<0.01). Correction of valgus knees using closed wedge DFO leads to good clinical results. A postoperative mLDFA of 85-90° results in superior clinical outcome compared to mLDFA > 90°. Joint-line obliquity should be avoided using double level osteotomy, if needed. III.


A methodological basis for SEM autoradiography: biosynthesis and radioligand binding.
A method is described for scanning electron microscope (SEM) autoradiography whereby preservation of high resolution cell surface details is retained together with degelatination of the emulsion without gross loss or redistribution of silver grains. This method should provide a convenient medium-sized marker for SEM (using secondary, backscattered electron and X-ray imaging) topographic studies of biosynthesized molecules, and of cell surface receptors and antigens, using indirect or direct labelling procedures with radio-labelled ligands.


NMR studies of hemoproteins. VI. Acid-base transitions of ferric myoglobin and its imidazole complex.
220 MHz proton NMR was applied to the acid-base transition of ferric myoglobin and its imidazole complex. In horse and sperm whale ferric myoglobins: (1) pH-dependent shift of heme-ring methyl signals above p2H 10 was analyzed on the basis of rapid exchange between alkaline and acidic forms by the use of pK value 9.1 of acid-base transition in 1H20 solution; (2) limiting shifts of three methyl signals were reasonably determined for purely alkaline form. For the imidazole complex: (3) a drastic high field shift of each signal was observed above p2H 9.0, whereas N0methyl imidazole complex did not exhibit such a shift, which suggests the 2H+ dissociation from liganded imidazole greater than N2H. It is concluded thns.


Identification of subgingival periodontal pathogens and association with the severity of periodontitis in patients with chronic kidney diseases: a cross-sectional study.
The aim of our study was to assess the subgingival profile of 9 periodontal pathogens, by means of real-time PCR, in a group of predialysis chronic kidney disease patients with and without periodontal disease and to identify the risk factors associated with periodontal disease in these patients. This is a single centre cross-sectional cohort study performed on 70 CKD patients. Patients received a full-mouth periodontal examination and the following parameters were assessed: periodontal pocket depth (PPD), clinical attachment level, bleeding on probing, and plaque index; subgingival biofilm samples were collected from the deepest periodontal pocket of each quadrant and were pooled in one transporting unit. Clinical data were drawn from the medical file of the patients. T. denticola (P = 0.001), T. forsythia (P < 0.001), and P. micros (P = 0.003) are significantly associated with periodontal disease in CKD subjects but in a multivariate model only age and T. forsythia remain independent risk factors for periodontal disease in patients with CKD. In our cohort, age and T. forsythia are independently associated with periodontitis in CKD patients. Within the limits of this study, CKD was not significantly associated with a particular subgingival periodontal pathogens profile in periodontitis patients.


[Management of critical severe acute respiratory syndrome and risk factors for death].
To investigate the management of critical severe acute respiratory syndrome (SARS) and possible risk factors for death. Thirty-three patients with SARS referred to Guangzhou Institute of Respiratory Disease (GIRD) between December 2002 and March 2003 were studied retrospectively. Paired t-test using statistical software SPSS 10.0 was employed to compare the respiratory frequency and pulse O(2) saturation (SpO(2)) before and after noninvasive ventilation with continuous positive airway pressure (CPAP) on the 33 patients. Among them, 18 patients who presented with SpO(2) of 90% - 93% at rest under O(2) inhalation 5 L/min were further recorded for their SpO(2) during slight physical movement and CPAP. The possible death-related risk factors including age, underlying diseases, leucocytosis, thrombocytopenia, and lymphopenia were analyzed by the Mantel-Haenszel chi(2) test. The respiratory frequencies were significantly decreased and SpO(2) was improved in the 33 patients after one hour of noninvasive ventilation. The SpO(2) in the latter 18 patients fell during slight physical movement and improved one hour after CPAP (p < 0.01). The RRs of the five death predictors concerning thrombocytopenia, age (> 50 yrs, underlying diseases, leucocytosis, and lymphopenia were 25.83, 8.57, 6.40, 1.64, and 1.17, respectively, with the 95% CI of 3.64 - 183.59, 1.94 - 37.83, 1.75 - 23.33, 0.38 - 7.05 and 0.16 - 8.48, respectively. Management with corticosteroids effectively ameliorated and suppressed the development of pulmonary fibrosis. Noninvasive ventilation relieves dyspnea and SpO(2) in patients with critical SARS, and should also be employed in those with SpO(2) of 90% - 93% at rest under O(2) inhalation 5 L/min. Noninvasive as an add-on management may probably cut down on the dosage and duration of corticosteriod therapy. Among 5 possible risk factors, 3 were recognized as death-related, turning out to be thrombocytopenia, age (> 50 yrs) and underlying diseases.


Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity.
The effect of chronic opioid antagonist treatment on the analgesic potency of six opioid agonists was compared to changes in opioid receptor density and the selectivity of each agonist for mu (DAMGO), delta (DPDPE) and kappa (U69,593) opioid receptors. Mice were implanted SC with a 15-mg naltrexone or placebo pellet for 8 days. The pellets were removed and 24 h later, mice were sacrificed and binding studies were conducted, or mice were tested in analgesia (tail-flick) dose-response studies. All six analgesics acted as full agonists for both placebo and naltrexone-treated mice. Naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9-3.2-fold. The analgesic potency of propoxyphene was not increased significantly (1.3-fold). In saturation binding studies in brain homogenate, naltrexone increased the Bmax of mu, delta, and kappa opioid receptors by 86, 43, and 33%, respectively, without altering Kd. Competition binding studies for each receptor type were conducted in brains from untreated mice, and KIs were determined for each agonist. All agonists had greatest selectivity toward mu compared with delta and kappa receptors. There did not appear to be an obvious relationship between receptor selectivity and the magnitude of supersensitivity. These studies indicate that supersensitivity occurs for a broad range of opioid analgesics following chronic opioid antagonist treatment in the mouse. However, the selectivity of these agonists for mu, delta, and kappa receptors does not appear to correlate with differences in supersensitivity.


A computer based handbook and atlas of pathology.
The Diagnostic Encyclopaedia Workstation (DEW) is a computerized handbook of pathology intended for use in diagnostic practice. It consists of a combination of a personal computer (PC), a video disc player (VDP), for which a specially developed disc is used, two monitors, a mouse and software. The hard disc of the computer contains textual information on diagnoses in categories such as macroscopy, common histology, immunopathology, clinical observations and prognosis and case histories. This information is frequently illustrated by pictures on a video disc which is automatically addressed by the computer software. All pictures, at present some 3000, pertain to case histories which are included in the system. Also integrated are classification aids in two categories: diagnostic criteria and differential diagnosis. Advantages of DEW over the use of conventional manuals are 1) the extensive volume of text, 2) the large number of high quality illustrations, 3) the immediate access to cross references and 4) the potential for continuous revision.


Risk factors for multidrug-resistant bacterial infection among patients with tuberculosis.
Given that anti-tuberculosis medication itself has antibacterial activity and that broad-spectrum antibiotics are frequently used, the emergence of multidrug-resistant (MDR) bacteria among patients being treated for tuberculosis (TB) is likely. We used a case-control design to study the clinical predictors of MDR bacterial infection among TB patients. Both cases and controls were selected from among patients who were diagnosed and treated as having TB between 1 January 1996 and 31 August 2006. TB patients with MDR bacterial infection were included as cases and those with non-MDR bacterial infection were included as controls. Multiple logistic regression analysis was performed to elucidate the risk factors for MDR bacterial infection. During the study period 3667 patients were diagnosed with, and treated for, TB. A total of 123 experienced episodes of bacterial infection, of whom 59 (48.0%) were infected by an MDR strain at least once. The presence of chronic renal failure [adjusted odds ratio (OR): 4.96; 95% confidence interval (CI): 1.37-18.01] and the use of antimicrobials other than typical anti-TB drugs within three months (adjusted OR: 4.37; 95% CI: 1.74-10.95) were independent risk factors for MDR bacterial infection. Bacterial infection in TB patients is commonly multidrug resistant. Clinicians should be aware of the possibility of MDR bacterial infection among TB patients with chronic renal failure or recent use of other antimicrobials.


HIAYA CHAT study protocol: a randomized controlled trial of a health insurance education intervention for newly diagnosed adolescent and young adult cancer patients.
For adolescent and young adult (AYA) cancer patients aged 18 to 39 years, health insurance literacy is crucial for an effective use of the health care system. AYAs often face high out-of-pocket costs or have unmet health care needs due to costs. Improving health insurance literacy could help AYAs obtain appropriate and affordable health care. This protocol illustrates a randomized controlled trial testing a virtual health insurance education intervention among AYA patients. This is a two-arm multisite randomized controlled trial. A total of 80 AYAs diagnosed with cancer in the Mountain West region will be allocated to either usual navigation care or tailored health insurance education intervention with a patient navigator that includes usual care. All participants will complete a baseline and follow-up survey 5 months apart. The primary outcomes are feasibility (number enrolled and number of sessions completed) and acceptability (5-point scale on survey measuring satisfaction of the intervention). The secondary outcomes are preliminary efficacy measured by the Health Insurance Literacy Measure and the COmprehensive Score for financial Toxicity. This trial makes a timely contribution to test the feasibility and acceptability of a virtual AYA-centered health insurance education program. ClinicalTrials.gov NCT04448678. Registered on June 26, 2020.


Toward a molecular understanding of metal transport by P(1B)-type ATPases.
The P(1B) family of P-type ATPases couples the transport of cytoplasmic transition metals across biological membranes to the hydrolysis of ATP. These ubiquitous transporters function in maintaining cytoplasmic metal quotas and in the assembly of metalloproteins, and have been classified into subfamilies (P(1B-1)-P(1B-5)) on the basis of their transported substrates (Cu(+), Zn(2+), Cu(2+), and Co(2+)) and signature sequences in their transmembrane segments. In addition, each subgroup presents a characteristic membrane topology and specific regulatory cytoplasmic metal-binding domains. In recent years, significant major aspects of their transport mechanism have been described, including the stoichiometry of transport and the delivery of substrates to transport sites by metallochaperones. Toward understanding their structure, the metal coordination by transport sites has been characterized for Cu(+) and Zn(2+)-ATPases. In addition, atomic resolution structures have been determined, providing key insight into the elements that enable transition metal transport. Because the Cu(+)-transporting ATPases are found in humans and are linked to disease, this subfamily has been the focus of intense study. As a result, significant progress has been made toward understanding Cu(+)-ATPase function on the molecular level, using both the human proteins and the bacterial homologs, most notably the CopA proteins from Archaeoglobus fulgidus, Bacillus subtilis, and Thermotoga maritima. This chapter thus focuses on the mechanistic and structural information obtained by studying these latter Cu(+)-ATPases, with some consideration of how these aspects might differ for the other subfamilies of P(1B)-ATPases.


Glomerular capillary endotheliosis in sow kidney.
A high incidence of proliferative renal glomerular lesions was found in sows from a breeding herd. All the sows had a very similar lesion, which was characterised by swelling of endothelial cells, with varying degrees of obstruction of the capillary lumina, and an increase in the number of mesangial cells. By differential diagnosis the condition was found to conform most closely with the renal lesion of human pregnancy toxaemia (pre-eclampsia syndrome). It is suggested that this nephropathy may play a part in limiting the useful breeding life of affected sows.


Functional Regurgitation of Atrioventricular Valves and Atrial Fibrillation: An Elusive Pathophysiological Link Deserving Further Attention.
In patients with structurally normal atrioventricular valvular apparatus, functional regurgitation of the mitral or tricuspid valves has been attributed mainly to ventricular dilation and/or dysfunction, through a combination of annulus dilation and tethering of the valve leaflets. The occurrence of functional regurgitation of atrioventricular valves in patients with long-standing persistent atrial fibrillation and atrial dilation but normal ventricular size and function has received much less attention, and its peculiar mechanisms still remain to be understood. This distinct form of functional regurgitation (i.e., "atrial functional regurgitation") may require different treatment and interventional repair approaches than the classical functional regurgitation due to ventricular dilatation and dysfunction ("ventricular functional regurgitation"), and current guideline recommendations do not yet address this distinction. Clarifying the differences in the pathophysiology of atrial functional regurgitation and its management implications is of paramount importance. This review describes briefly the comparative anatomy of mitral and tricuspid apparatus and the pathophysiology and typical echocardiographic features of atrial functional regurgitation compared with ventricular functional regurgitation, as well as the added value of three-dimensional echocardiography as an essential imaging tool to clarify the mechanisms involved in its development.


Semicarbazide-sensitive amine oxidase (SSAO) in the brain.
Semicarbazide-sensitive amine oxidase (SSAO) is widely distributed in almost tissues. However, its presence in brain microvessels is still controversial. The affinity of SSAO towards benzylamine (Bz) is considerably higher than that of monoamine oxidase (MAO). SSAO plays a role in the toxicity of several environmental and endogenous amines. SSAO-mediated production of toxic aldehydes has been proposed to be related to pathophysiological conditions. The most potent of inhibition of SSAO in monkey brain was observed by tricyclic antidepressant drug imipramine, as compared to tetracyclic drug maprotiline or non-cyclic drug nomifensine. An endogenous SSAO modulator in rat brain cytosol after immobilization stress (IMMO) was found and that this inhibitor could be induced by IMMO. SSAO activity in rat brain might be regulated by the level of this inhibitor. Semicarbazide, a SSAO inhibitor, enhances the formation of .OH products of efflux/oxidation due to 1-methyl-4-phenylpyridinium ion (MPP+). The precise physiological functions of SSAO could play an important role in the control of energy balance in adipose tissue. SSAO could play an important role in the regulation of adipocyte homeostasis.


Significant frequency of allelic imbalance in 3p region covering RARβ and MLH1 loci seems to be essential in molecular non-small cell lung cancer diagnosis.
The aim of the study was to investigate the influence of allelic imbalance (AI) in several loci of tumor suppressor genes in 3p region on the non-small cell lung cancer (NSCLC) development. We evaluated the frequency of loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) and assessed their association with patients' characteristics (age, gender, tobacco addiction) and NSCLC classification according to TNM/AJCC staging. To analyze the potential role of AI involved in NSCLC pathogenesis, we allelotyped a group of 74 NSCLC patients using 7 microsatellite markers. The highest frequency of LOH/MSI, however, not statistically significant, was observed in RARβ and MLH1 (p = 0.104 and p = 0.216, respectively) loci. The association between high LOH/MSI frequency in 3p region with male gender (p = 0.041) as well as with age (especially >60 years) for RARβ and MLH1 genes (p = 0.0001 and p = 0.020, respectively) was documented. Statistically significant increased frequency of MLH1 allelic loss in squamous cell carcinoma (SCC) versus non-squamous cell carcinoma (non-SCC) was observed (p = 0.01). Significant increase in LOH/MSI frequency in 3p region (mainly in FHIT and MLH1 loci) in correlation with cigarette addiction in a lifetime (≥40 years and ≥40 Pack Years) was also documented (p < 0.05). The highest LOH/MSI was revealed in RARβ locus in IA tumors (p = 0.0001), while the similarly high allelic loss of MLH1 correlated with III A/B tumors (p = 0.0002), according to AJCC staging. The obtained results demonstrate that AI is influenced by tobacco smoking and seems to be vital in the molecular diagnosis of NSCLC, especially of SCC subtype.


Sp1 Inhibits PGC-1α via HDAC2-Catalyzed Histone Deacetylation in Chronic Constriction Injury-Induced Neuropathic Pain.
Our previous study has illuminated that PGC-1α downregulation promoted chronification of pain after burn injury. RNA-seq analysis predicted association between Sp1 and chronic constriction injury (CCI)-provoked neuropathic pain. Further ChIP-Atlas data investigation suggested the binding to Sp1 to PGC-1α. Thereby, we performed this study to illustrate the functional relevance of the Sp1/PGC-1α axis in neuropathic pain. Neuropathic pain was induced by CCI in vivo in rats, followed by assessment of neuropathic pain-like behaviors. The expression of Sp1 and correlated genes was determined in CCI rat spinal cord tissues. Furthermore, microglia were exposed to lipopolysaccharide (LPS) to mimic inflammation and then cocultured with neurons. Knockdown and ectopic expression methods were used in vivo and in vitro to define the role the Sp1/HDAC2/PGC-1α axis. Sp1 expression was upregulated in spinal cord tissues of CCI rats. Silencing Sp1 ameliorated CCI-induced neuropathic pain, as reflected by elevated paw withdrawal threshold and paw withdrawal latency, as well as alleviated microglia activation, neuronal dysfunction, inflammatory responses, mitochondrial dysfunction, and oxidative stress in spinal cord tissues. Sp1 knockdown also reversed LPS-induced microglial inflammation and neuronal dysfunction. Sp1 promoted histone deacetylation in the PGC-1α promoter and inhibited PGC-1α expression via recruiting HDAC2. PGC-1α overexpression diminished CCI-induced neuropathic pain and LPS-induced inflammation and mitochondrial dysfunction, based on which Sp1 aggravated microglial inflammation and neuronal dysfunction in neuropathic pain. This study elucidated the promoting effects of Sp1 on CCI-induced neuropathic pain via the HDAC2/PGC-1α axis.


Identification of N-degrons and N-recognins using peptide pull-downs combined with quantitative mass spectrometry.
Regulated protein degradation controls protein levels of all short-lived proteins to ensure cellular homeostasis and also protects cells from misfolded or other abnormal proteins. The most important players in the degradation system are E3 ubiquitin ligases which recognize exposed sequence motifs, so-called degrons, of target proteins and mark them through the attachment of ubiquitin for degradation. N-terminal (Nt) sequences are extensively used as degrons (N-degrons) and all 20 amino acids are able to feed proteins in 1 of the 5 known N-degron pathways. Studies have mainly focused on characterizing systematically the role of the starting amino acid on protein stability and less on the identification of the E3 ligases involved. Recent data from our lab and literature suggest that there is an extensive interplay of N-recognins and Nt-modifying enzymes like Nt-acetyltransferases (NATs) or N-myristoyltransferases which only starts to be elucidated. It suggests that improperly modified or unexpectedly unmodified proteins become rapidly removed after synthesis ensuring protein maturation and quality control of specific subsets of proteins. Here, we describe a peptide pull-down and down-stream bioinformatics workflow conducted in the MaxQuant and Perseus computational environment to identify N-recognin candidates in an unbiased way using quantitative mass spectrometry (MS)-based proteomics. Our workflow allows the identification of N-recognin candidates for specific N-degrons, to determine their sequence specificity and it can be applied as well more general to identify binding partners of N-terminal modifications. This method paves the way to identify pathways involved in protein quality control and stability acting at the N-terminus.


Role of brain monoamines in the anorectic activity of mazindol and d-amphetamine in the rat.
The interaction of mazindol and d-amphetamine with brain monoamines was studied in rats. At each dose used, both compounds markedly counteracted the decrease of brain noradrenaline induced by 6-hydroxydopamine while only at high doses they did significantly reduce the effect of 6-hydroxydopamine on brain dopamine. Unlike d-amphetamine, mazindol significantly counteracted the decrease of brain serotonin induced by fenfluramine. The anorectic effect of mazindol and of d-amphetamine was markedly reduced by an electrolytic lesion at the level of the ventral noradrenergic bundle but not by an electrolytic lesion of the nucleus raphe medianus. An intrastriatal injection of 6-hydroxydopamine significantly reduced the effect of mazindol but not that of d-amphetamine. The results indicate that both compounds may block noradrenaline uptake in the brain while their effect on dopamine uptake is less evident. Ulike d-amphetamine, mazindol appears to inhibit serotonin uptake also. In addition, the integrity of the noradrenergic neurons in the brain appears to be an important condition for these drugs to exert their anorectic effect.


Compound natural and human disasters: Managing drought and COVID-19 to sustain global agriculture and food sectors.
Individually, both droughts and pandemics cause disruptions to global food supply chains. The 21st century has seen the frequent occurrence of both natural and human disasters, including droughts and pandemics. Together their impacts can be compounded, leading to severe economic stress and malnutrition, particularly in developing countries. Understanding how droughts and pandemics interact, and identifying appropriate policies to address them together and separately, is important for maintaining a robust global food supply. Herein we assess the impacts of each of these disasters in the context of food and agriculture, and then discuss their compounded effect. We discuss the implications for policy, and suggest opportunities for future research.


Anti-Inflammatory Activity of Lauraceae Plant Species and Prediction Models Based on Their Metabolomics Profiling Data.
The Lauraceae is a botanical family known for its anti-inflammatory potential. However, several species have not yet been studied. Thus, this work aimed to screen the anti-inflammatory activity of this plant family and to build statistical prediction models. The methodology was based on the statistical analysis of high-resolution liquid chromatography coupled with mass spectrometry data and the ex vivo anti-inflammatory activity of plant extracts. The ex vivo results demonstrated significant anti-inflammatory activity for several of these plants for the first time. The sample data were applied to build anti-inflammatory activity prediction models, including the partial least square acquired, artificial neural network, and stochastic gradient descent, which showed adequate fitting and predictive performance. Key anti-inflammatory markers, such as aporphine and benzylisoquinoline alkaloids were annotated with confidence level 2. Additionally, the validated prediction models proved to be useful for predicting active extracts using metabolomics data and studying their most bioactive metabolites.


Prevalence of genes encoding exfoliative toxins, leucotoxins and superantigens among high and low virulence rabbit Staphylococcus aureus strains.
Staphylococcus aureus is an important cause of pododermatitis, subcutaneous abscesses and mastitis in rabbits. On rabbitry level, two types of S. aureus infections can be distinguished. In the first type, caused by low virulence strains, the infection affects only a small number of animals. The second type of infection is caused by high virulence strains and spreads throughout the rabbit flock. The pathogenic capacity of a particular S. aureus strain is attributed to a combination of invasive properties and extracellular factors such as toxin production. Therefore, 22 high virulence and 37 low virulence S. aureus isolates were compared regarding the prevalence of genes encoding exfoliative toxins, leucotoxins and superantigens. This study revealed a clearly significant difference between HV and LV rabbit S. aureus strains. All typical HV isolates were positive for the egc cluster, containing the enterotoxin(like) genes seg, sei, selm, seln, selo and selu, whereas these genes were not detected in any of the LV isolates. Further research is necessary to clarify the importance of the egc cluster in the pathogenesis of infections with high virulence S. aureus strains in rabbits.


[Conclusions from shifts in morbidity patterns of hospitalized children with neuropsychiatric diseases].
The decrease of neurological illnesses and the corresponding increase of psychogenic disturbances by patients belonging to clinical departments of neuropsychiatry of child and youth are described. This conversion leads to a frequently longer staying of the patients within the clinics. Furthermore, changes of the behaviours of the whole team for treatment may be observed.


Viability and fate of Cryptosporidium parvum and Giardia lamblia in tubular anaerobic digesters.
In many developing countries where pathogenic diseases of animal waste origin, such as giardiasis and cryptosporidiosis, are often prevalent, facilities are limited to treat livestock waste. However, household-scale anaerobic digesters are currently being promoted for bioenergy production from livestock manure. Since the effluent is often used as a fertilizer for food crops, it is critical to understand the effect of environmental conditions within household-scale digesters on the viability of Cryptosporidium parvum oocysts and Giardia lamblia cysts. In this study, key environmental parameters affecting (oo)cyst inactivation were measured in four tubular anaerobic digesters, which are a type of household-scale digester promoted for treatment of swine waste in rural Costa Rica. Interviews and participant observations were used to understand digester operation and maintenance procedures. Ambient temperatures (21-24°C), near-neutral pH, total ammonia nitrogen (TAN) concentrations<250 mg/L and hydraulic retention times (HRTs) between 23 and 180 days were observed. Laboratory (oo)cysts inactivation studies were performed in bench-scale digesters, which were maintained under conditions similar to those observed in the field. Apparent first-order inactivation rate coefficients for Giardia lamblia and Cryptosporidium parvum were 0.155 ± 0.041 and 0.054 ± 0.006 day(-1), respectively. Temperature and volatile fatty acids were the main factors contributing to Cryptosporidium parvum and Giardia lamblia inactivation. A mathematical model was developed that predicts the concentration of (oo)cysts in the liquid effluent of tubular digesters like those observed in Costa Rica. A mathematical model was developed that predicts the concentration of (oo)cysts in the liquid effluent of tubular digesters like those observed in Costa Rica. Two dimensionless groups can be used to predict the performance of the digesters for inactivating pathogens; both dimensionless groups depend upon the average HRT in the digester. This is the first study to combine mathematical modeling with qualitative analysis, field and laboratory studies to predict the concentrations of (oo)cysts in tubular digester effluents.


CD48 expression on leukocytes in infectious diseases: flow cytometric analysis of surface antigen.
The function of CD48, one of the pan leukocyte cell surface antigens, is not yet well understood. CD48 was recently shown to enhance the CD40-mediated activating signal to B lymphocytes. As CD48 is one of the activation antigens of monocytes, neutrophils and lymphocytes, a change of its expression on the cells could be expected in infectious diseases. Leukocytes from 27 healthy controls and 97 patients with various infectious diseases were stained with anti CD48 antibody and analyzed by flow cytometry. On monocytes and neutrophils, the CD48 expression was increased in all of the patients with varicella, measles, rubella, infectious mononucleosis, streptococcus tonsillitis, sepsis and appendicitis. On lymphocytes, a significant increase of CD48 was also detected in the patients with the same diseases, except those with sepsis or appendicitis. The normalization of increased CD48 expression was confirmed on monocytes at the convalescent phase. These data suggest that CD48 expression on leukocytes reflects the disease activity of infectious diseases, especially of viral infections.


Genetic polymorphisms of Fas (CD95) and Fas ligand (CD178) influence the rise in CD4+ T cell count after antiretroviral therapy in drug-naïve HIV-positive patients.
Fas and Fas ligand (FasL) are the main genes that control cell death in the immune system. Indeed, they are crucial for the regulation of T lymphocyte homeostasis because they can influence cell proliferation. A strong debate exists on the importance of Fas/FasL system during HIV infection, which is characterized by the loss of CD4+ T cells directly, or indirectly, caused by the virus. To investigate whether the genetic background of the host plays a role in the immunoreconstitution, we studied the influence of different Fas and FasL polymorphisms on CD4+ T lymphocyte count and plasma viral load following initiation of highly active antiretroviral therapy (HAART) in drug-naïve HIV+ patients. We studied 131 individuals, who were compared to 136 healthy donors. Statistical analysis was performed by using Chi2 test, Fischer's Exact Test, and analysis for repeated measurements. The group of HIV+ patients had an unexpected lower frequency of FasLnt169 polymorphism (delT allele) than healthy controls (p = 0.039). We then observed no significant differences in the immune reconstitution, in terms of CD4+ T cell increase, when the influence of single alleles of the gene Fas or FasL was considered. However, the combination of some polymorphisms of Fas or FasL significantly influenced CD4+ T cell production and viral load decrease, showing that these genes can play a role in the immunoreconstitution triggered by antiretroviral therapy.


[Older patients in abdominal surgery].
The aging society imposes special challenges on operative medicine. Characteristics in the perioperative treatment of older patients. Consequences for the daily practice. Evaluation and summary of existing literature including recommendations for the (peri)operative management of older patients. Despite the growing relevance there are only few studies focusing on older patients. The altered (patho)physiology and comorbidities are challenging and can lead to complications. The evaluation of the indications for surgery should meticulously take the improvement to be expected into account by weighing up the individual wishes of patients and special risks. The adequate perioperative care including early mobilization and sufficient analgesia are decisive.