The occurrence of Mycobacterium bovis infection in cattle in and around an area subject to extensive badger (Meles meles) control.
The occurrence of Mycobacterium bovis infection in cattle herds during the period 1966-92 in two geographically related areas in South-West England is compared. In one area comprising 104 km2 all badgers were systematically destroyed from 1975-81, after which recolonization was allowed; in the other, comprising 116 km2, small scale, statutory badger removal operations were undertaken from 1975 onwards where specific herds were detected with M. bovis infection. In the area with total clearance, no further incidents with M. bovis isolation occurred from 1982-92. Survival analysis and proportional hazards regression indicated that the risk of herds being identified with infection was less once badgers had been cleared from their neighbourhood, whereas it was greater in herds with 50 or more animals, and once cattle in a herd had responded positively to the tuberculin skin test, even though infection with M. bovis was not confirmed subsequently. The study provides further evidence that badgers represent an important reservoir of M. bovis infection for cattle and that badger control is effective in reducing incidents of cattle infection with M. bovis if action is thorough and recolonization is prevented.


Mol-CycleGAN: a generative model for molecular optimization.
Designing a molecule with desired properties is one of the biggest challenges in drug development, as it requires optimization of chemical compound structures with respect to many complex properties. To improve the compound design process, we introduce Mol-CycleGAN-a CycleGAN-based model that generates optimized compounds with high structural similarity to the original ones. Namely, given a molecule our model generates a structurally similar one with an optimized value of the considered property. We evaluate the performance of the model on selected optimization objectives related to structural properties (presence of halogen groups, number of aromatic rings) and to a physicochemical property (penalized logP). In the task of optimization of penalized logP of drug-like molecules our model significantly outperforms previous results.


Dual mode of energy coupling by the oxyanion-translocating ArsB protein.
The arsA and arsB genes of the ars operon of R-factor R773 confer arsenite resistance in Escherichia coli by coding for an anion-translocating ATPase. Arsenite resistance and the in vivo energetics of arsenite transport were compared in cells expressing the arsA and arsB genes and those expressing just the arsB gene. Cells expressing the arsB gene exhibited intermediate arsenite resistance compared with cells expressing both the arsA and arsB genes. Both types of cells exhibited energy-dependent arsenite exclusion. Exclusion of 73AsO2- from cells expressing only the arsB gene was coupled to electrochemical energy, while in cells expressing both genes, transport was coupled to chemical energy, most likely ATP. These results suggest that the Ars anion transport system can be either an obligatory ATP-coupled primary pump or a secondary carrier coupled to the proton motive force, depending on the subunit composition of the transport complex.


Protective effect of placenta extracts against nitrite-induced oxidative stress in human erythrocytes.
Aqueous-saline human placenta extract (HPE) is known to possess antioxidant activity due to the high concentration of bioactive substances. This fact allows its application in clinical practice in order to treat oxidation-induced diseases. Extract antioxidant activity is mainly conditioned by proteins. Freezing of extracts has been shown to lead to their antioxidant activity increasing due to protein conformation changes.Different biological models are widely used in order to evaluate efficacy of novel antioxidants and mechanisms of their action. One such model appears to be erythrocytes under nitrite-induced oxidative stress. Nitrite is known to be able to penetrate erythrocyte membrane and to oxidize hemoglobin. In order to investigate whether HPE is able to decrease nitrite-induced oxidative injuries and to evaluate the protein contribution to this process, spectrophotometric and electron spin resonance (ESR) assays were used.Experimental data have revealed that antioxidant activity of extracts and of some of their fractions correlates with methemoglobin concentration lowering. Preliminary erythrocyte incubation with an extract fraction of 12 kDa allows preservation of the structural-dynamic cytosol state the closest to the control.


The outcomes of renin-angiotensin-aldosterone system inhibition and immunosuppressive therapy in children with X-linked Alport syndrome.
Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy. Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively. Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased < 60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003). RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD.


Transdermal iontophoresis: modulation of electroosmosis by polypeptide.
The objective of this research was to further evaluate the relative importance of electrorepulsion and electroosmosis to the mechanism of enhanced transport across the skin during iontophoresis. Specifically, the impact of iontophoresing into the skin positively and negatively charged polypeptides (poly-L-lysines and poly-L-glutamic acids, respectively) on the membrane's permselectivity and hence on the quantity and direction of electroosmotic flow, was examined. Experiments were performed in vitro at pH 7.4 using conventional methodology; electroosmosis during the iontophoresis of the polypeptides into and across the skin was tracked in the usual way via the movement of the polar, uncharged, non-metabolizable marker, D-mannitol. Electrotransport of the cationic polypeptides attenuated electroosmotic flow in the normal anode-to-cathode direction; the degree of inhibition was correlated both with the initial concentration of poly-L-lysine in the anodal chamber and with the molecular weight of the polypeptide employed (from 1 to 25 kilodaltons). Iontophoresis of the anionic poly-L-glutamic acids from the cathode provoked a slight increase in electroosmotic flow in the 'reverse' direction (i.e. from the receptor phase beneath the skin towards the cathode chamber located on the epidermal side of the membrane); this effect, however, was much less dramatic than that produced in the opposite sense by the cationic polypeptides. The results suggest that driving large positively-charged polypeptide molecules into the skin leads to neutralization of the membrane's negativity, a subsequent loss of permselectivity and a concomitant attenuation of electroosmosis in the conventional anode-to-cathode direction. Presumably, the relatively poor iontophoretic permeability of these species (which becomes more and more evident with increasing molecular weight) results in a sufficiently important association of the polypeptide with the skin during the period of current passage. Much less significant effects are realized by the cathodal iontophoresis of poly-anions due to the difficulty of 'pushing' negative ions into an already negatively-charged membrane.


A warrant for violence? An analysis of Donald Trump's speech before the US Capitol attack.
On January 6th, 2021, Donald Trump's speech during a 'Save America' rally was followed by mass violence, with Trump's supporters storming the U.S. Capitol to prevent the certification of Joe Biden's victory in the presidential election. In its wake, there was a great deal of debate around whether the speech contained direct instructions for the subsequent violence. In this paper, we use a social identity perspective on leadership (and more specifically, on toxic leadership) to analyse the speech and see how its overall argument relates to violence. We show that Trump's argument rests on the populist distinction between the American people and elites. He moralises these groups as good and evil respectively and proposes that the very existence of America is under threat if the election result stands. On this basis he proposes that all true Americans are obligated to act in order prevent Biden's certification and to ensure that the good prevails over evil. While Trump does not explicitly say what such action entails, he also removes normative and moral impediments to extreme action. In this way, taken as a whole, Trump's speech enables rather than demands violence and ultimately it provides a warrant for the violence that ensued.


Unwanted childbearing and household food insecurity in the United States.
Household food insecurity is a population health concern disproportionately affecting families with children in the United States. Unwanted childbearing may place unanticipated strain on families to meet basic needs, heightening the risk for household food insecurity. We investigated the association between mother's and father's report of unwanted childbearing and exposure to household food insecurity among children residing in two-parent households in the United States. Data from the Early Childhood Longitudinal Study - Birth Cohort, a nationally representative cohort of US children (n ∼ 6150), were used to estimate the odds of household food insecurity when children were aged 9 months and 2 years, separately, based on parental report of unwanted childbearing. The majority of children were reported as wanted by both parents (74.4%). Of the sample, report of unwanted childbearing by father-only was 20.0%, mother-only was 3.4% and joint mother and father was 2.2%. Household food insecurity was higher when children were 9 months compared with 2 years. In adjusted models accounting for confounders, children born to mothers and fathers who jointly reported unwanted childbearing were at higher odds of exposure to household food insecurity at 9 months [adjusted odds ratio (AOR) = 3.31; 95% confidence interval (CI): 1.97, 5.57] and 2 years (AOR = 2.52; 95% CI: 1.12, 5.68). In two-parent households, we found that children raised by parents reporting unwanted childbearing were more likely to be exposed to food insecurity and potentially related stressors. Further studies that prospectively measure wantedness before the child's birth will aid in confirming the direction of this association.


The bystander effect in rats.
To investigate whether the classic bystander effect is unique to humans, the effect of bystanders on rat helping was studied. In the presence of rats rendered incompetent to help through pharmacological treatment, rats were less likely to help due to a reduction in reinforcement rather than to a lack of initial interest. Only incompetent helpers of a strain familiar to the helper rat exerted a detrimental effect on helping; rats helped at near control levels in the presence of incompetent helpers from an unfamiliar strain. Duos and trios of potential helper rats helped at superadditive rates, demonstrating that rats act nonindependently with helping facilitated by the presence of competent-to-help bystanders. Furthermore, helping was facilitated in rats that had previously observed other rats' helping and were then tested individually. In sum, the influence of bystanders on helping behavior in rats features characteristics that closely resemble those observed in humans.


Prevalence of antibodies to herpes simplex virus types 1 and 2 in pregnant women, and estimated rates of infection.
There has been a recent increase in notifications of genital herpes but it is not known whether this has been reflected in the pregnant population. We have therefore carried out a study to determine the prevalence of herpes simplex antibodies in pregnant women and to estimate the incidence of primary infection. Sera were collected from 3533 women at antenatal clinics and tested for total antibodies to herpes simples virus (HSV), and if positive, for specific antibodies to HSV-2. Estimates of HSV-1 seroprevalence were derived from the HSV-2 seronegative population. HSV-1 seroprevalence was nearly 100% in black women born in Africa or the Caribbean and 60-80% in white, Asian and UK born black women. It was lower in women in non-manual employment. HSV-2 seroprevalence was related to age, rising from 0 at age 16 to 40% at age 35 in black women, and to about 10% in Asian and white women. The estimated incidence of primary HSV-2 infection during pregnancy, per 1000 pregnancies, was about 2.4 in Asian women, 5 in white women, and 20 in black women. Estimates of the incidence of neonatal infection were derived from these figures and compared to the nationally reported rates.


Nitrogen gas produces less behavioural and neurophysiological excitation than carbon dioxide in mice undergoing euthanasia.
Carbon dioxide (CO2) is one of the most commonly used gas euthanasia agents in mice, despite reports of aversion and nociception. Inert gases such as nitrogen (N2) may be a viable alternative to carbon dioxide. Here we compared behavioural and electrophysiological reactions to CO2 or N2 at either slow fill or rapid fill in C57Bl/6 mice undergoing gas euthanasia. We found that mice euthanised with CO2 increased locomotor activity compared to baseline, whereas mice exposed to N2 decreased locomotion. Furthermore, mice exposed to CO2 showed significantly more vertical jumps and freezing episodes than mice exposed to N2. We further found that CO2 exposure resulted in increased theta:delta of the EEG, a measure of excitation, whereas the N2 decreased theta:delta. Differences in responses were not oxygen-concentration dependent. Taken together, these results demonstrate that CO2 increases both behavioural and electrophysiological excitation as well as producing a fear response, whereas N2 reduces behavioural activity and central neurological depression and may be less aversive although still produces a fear response. Further studies are required to evaluate N2 as a suitable euthanasia agent for mice.


Coronary spasm-related acute myocardial infarction in a patient with essential thrombocythemia.
We report a case of essential thrombocythemia (ET) in a 30-year-old female who exhibited inferior wall ST-elevation acute myocardial infarction (AMI) without significant obstructive coronary artery disease. Right coronary vasospasm was observed after intra-coronary methylergonovine administration and she received verapamil 120 mg/dthereafter and hydroxyurea 1500 mg/d for thrombocythemia. After discontinuation of the hydroxyurea for 9 mo based on the impression of coronary spasm-related instead of coronary thrombosis-related AMI, her platelet count rose but no chest pain was observed. It is suggested that coronary spasm potentially plays a role in patients with ET, AMI and no significant coronary artery stenosis.


Evaluating the effectiveness of a multi-component intervention on early childhood development in paediatric HIV care and treatment programmes: a randomised controlled trial.
HIV infection in a family may affect optimum child development. Our hypothesis is that child development outcomes among HIV-exposed infants will be improved through a complex early childhood stimulation (ECS) programme, and income and loans saving programme for HIV positive parents. The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe. Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a group ECS parenting programme, an internal savings and lending scheme (ISALS) and case-management home visits by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0-24 months) where the infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process evaluation was conducted. The results of this cluster-randomised trial will provide important information regarding the effects of multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited environments. This trial is registered with the Pan African Clinical Trials Registry ( www.pactr.org ), registration number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered).


Former chronic methylenedioxymethamphetamine (MDMA or ecstasy) users report mild depressive symptoms.
Previous work has indicated recreational use of methylenedioxymethamphetamine (MDMA or ecstasy) is associated with elevated scores on self-report measures of depression. We sought to examine the long-term effects of consumption on depression in a group of individuals who had consumed large quantities of the drug in the past, but were now leading relatively drug free lives. Respondents to this study (n = 29) had consumed an average of 1.5 ecstasy tablets in the last month, 8.4 in the last 6 months and 23.3 in the last 12 months. The estimated total consumed was 527 tablets, indicating that these respondents were indeed former chronic users of the drug. None of the respondents had consumed ecstasy in the last 14 days. Levels of depression (Beck's Depression Inventory) were significantly (p < 0.01) elevated compared to a matched non-drug using control group. Within the group of former chronic users, these levels of depression were not significantly affected by current use of alcohol, cannabis or amphetamine, but were positively correlated with an external locus of control (p < 0.05), infrequent but severe- (p < 0.05) and frequent but mild- (p < 0.005) self-report measures of life stress. Multiple regression indicated that levels of frequent but mild life stress (p < 0.005) and the quantity of ecstasy tablets respondents consumed over a 12-h period (p < 0.05) were the only variables that were significant predictors of self-reported levels of depression. The results of this study indicate that former chronic ecstasy users report higher levels of depression than their matched controls.


Incidence of Adverse Effects of Propofol for Procedural Sedation/Anesthesia in the Pediatric Emergency Population: A Systematic Review and Meta-Analysis.
To investigate the incidence of adverse effects of propofol among pediatric population for sedation or anesthesia. We performed Cochrane Library, PubMed, CNKI, VIP, and Wanfang databases to research relevant literature. We did sensitivity analysis to assess the incidence of adverse effects of propofol among pediatric population for sedation or anesthesia. In 132 studies, eight RCTs were included in this analysis. The result showed that adverse events (bradypnea, hypotension, hypertension, and apnea) were significantly improved in the pediatric emergency population in the propofol group, but it had no effect on the incidence of cough attacks, desaturation, agitation, stridor, and laryngospasm. Furthermore, the subgroup analysis showed that those who received propofol for had decreased adverse effects compared with the patients who received ketamine treatment (SMD = 0.44, 95%CI = [0.28, 0.67], I 2 = 0%, and P = 0.0002), which demonstrated that propofol could decrease the incidence of adverse effects compared with ketamine and ketofol. The study demonstrated that propofol may decrease the incidence of bradypnea, hypotension, hypertension, and apnea, but it had no effect on the incidence of cough attacks, desaturation, agitation, stridor, and laryngospasm. Furthermore, more large RCTs are needed to assess incidence of adverse effects of propofol among pediatric population.


Impaired fetal growth: definition and clinical diagnosis.
Intrauterine growth retardation (IUGR) may affect up to 10% of pregnancies and results in substantially increased perinatal morbidity and mortality. Although many infants are small on a constitutional basis and not as a result of disease, many others suffer malnutrition from chronic progressive uteroplacental insufficiency. Genetic disease, embryonic infection, and various drug exposures may also result in IUGR. Inconsistency of diagnostic criteria has seriously hampered clinical research aimed at clarification of both the short- and long-term implications of IUGR. This part of the report examines both the significance and clinical definition of IUGR and reviews the diagnostic tests used for the detection of the problem of impaired fetal growth. The clinical approach to the management of IUGR is presented in the subsequent part of the report, which includes the ultrasonic evaluation and management of this entity.


Umbilical cord blood transplantation: current state of the art.
Human leukocyte antigen-matched sibling donor umbilical cord blood transplantation, or 0-2 human leukocyte antigen mismatched unrelated donor umbilical cord blood, is now considered an acceptable alternative to the use of bone marrow as a source for hematopoietic stem cells for pediatric hematopoietic stem cell transplantation, and is being investigated in adults. Major advantages of umbilical cord blood include the speed of availability compared with unrelated donor bone marrow, and tolerance of 1-2 human leukocyte antigen mismatch, which offers the opportunity to extend the donor pool. Umbilical cord blood transplantation is associated with durable engraftment and low incidence of severe graft-versus-host disease, even in the 1-2 human leukocyte antigen mismatched setting. Clinical experience has established the importance of graft cell dose in determining engraftment and survival in unrelated donor umbilical cord blood transplantation. More recently, the influence of human leukocyte antigen on outcome has become apparent. This review outlines the state of the art of umbilical cord blood transplantation, with emphasis on practical considerations in umbilical cord blood selection, and describes current research directions for this hematopoietic stem cell source.


Association of angiokeratoma of the vulva with angioma serpiginosum.
Angioma serpiginosum is a rare benign vascular disorder usually beginning in childhood. It is characterized clinically by multiple minute, bright red to purple, grouped macules and histopathologically by an ectatic dilatation of capillaries. Angiokeratoma of the vulva is an uncommon lesion occurring in older women. It consists of purple papular lesions measuring less than 1 cm in diameter and characterizing histopathologically by hyperkeratosis, papillomatosis, acanthosis, and dilated vasculature in the papillary dermis.


The dachshund gene is required for the proper guidance and branching of mushroom body axons in Drosophila melanogaster.
The dachshund gene encodes a transcription factor required for the proper development of Drosophila eyes, legs, and mushroom bodies. The mushroom bodies of dachshund mutants exhibit a marked reduction in the size of the vertical lobes and disorganization of the horizontal lobes. In mosaic animals, mutant axons fail to contribute significantly to the mushroom body alpha lobe. Here we show that this defect is due to the misrouting of alphabeta axons to the region normally occupied by alpha'beta' axons. This defect is pronounced for clones generated in larval stages but not clones generated after pupariation, indicating that dachshund function is particularly important around the time of puparium formation. In addition, mushroom body axons exhibit excessive branching in dachshund mutant clones. Thus, dachshund is required in mushroom body neurons for proper axon guidance and branching.


The development of national quality performance standards for disposable absorbent products for adult incontinence.
Disposable absorbent products are widely used in inpatient care settings and in the community to manage adult urinary and fecal incontinence, but few product standards exist to help guide their production or optimal use. Increasing costs and reduced revenues have caused a number of states to evaluate absorbent product use among persons who receive care at home with the assistance of the Medicaid Waiver Program, further increasing concerns about the lack of product performance standards. To address these issues, the National Association For Continence (NAFC) formed a council of experts and key stakeholders with the objective of establishing national, independent quality performance standards for disposable absorbent products provided by states to Waiver Program recipients. The Council consisted of representatives from five purposefully selected states, technical directors from six nonwoven product manufacturers, an officer of the nonwoven manufactures trade association, a delegate from an academic nursing program and professional societies, a family caregiver, and a patient representative. Following a consensus method and guidelines for use, nine specific recommendations were developed, posted for public comment, and further refined. Final recommendations for product performance assessment include: rewet rate (a measure of a product's ability to withstand multiple incontinent episodes between changes), rate of acquisition (a measure of the speed at which urine is drawn away from the skin by a product, product retention capacity (a measure of a product's capacity to hold fluid without rewetting the skin), sizing options, absorbency levels, product safety, closure technology, breathable zones (a measure of the air permeability across a textile-like fabric at a controlled differential pressure), and elasticity. The Council also set values for and recommended four quantifiable parameters, and the testing methodology associated with each, to help consumers and states evaluate absorbent products (medium adult size): Maximum Rewet Rate: <1.0-2.0 g for briefs and <0.5-1.0 g for underwear; Maximum Rate of Acquisition: <50-60 seconds for briefs and <35-45 seconds for underwear; Minimum Retention Capacity: >250 g for standard briefs or underwear and >400 g for premium briefs or underwear; and Breathability of Zones: Minimum of >100 cubic feet per minute. As these recommendations are implemented, research is needed to evaluate the impact on both cost and quality of care for further refinement and modifications, particularly as technology and knowledge is advanced.


Evaluation of Pain Mitigation Strategies in Goat Kids after Cautery Disbudding.
Nowadays, most of the goat milk production in developed countries is done in intensive indoors production systems. In these systems, procedures such as disbudding are performed routinely. Disbudding is done in young goat kids and is a recognised as a painful procedure. Pain mitigation strategies have been extensively researched, but a method that is effective in mitigating pain as well as being safe and practical has not yet been found. In this paper we used three treatment groups: one control and two groups with pain mitigation strategies for cautery disbudding, one using local anaesthesia (lidocaine) and a second one using local anaesthesia (lidocaine) plus an analgesic (flunixin meglumine). The behaviour of twenty-seven goat kids was recorded for three hours after disbudding. Overall, the goat kids that received both pain mitigation treatments dedicated more time performing active and positive behaviours. Nevertheless, the incidence of behaviours related to pain and discomfort was not consistently reduced. Research is still needed to find a practical and effective pain mitigation strategy for disbudding. A solution to this challenge would improve animal welfare as well as address societal concerns linked to the suffering of farm animals.


[Toxicological effects induced by the chronic intake of brominated vegetable oils].
Several biochemical parameters of male Wistar rats fed during 15 weeks with standard laboratory chow, supplemented with 0.1 g of brominated vegetable oil (olive, sunflower) per 100 g of diet, were compared to those of a control group fed a normal diet during the same period of time. The former group showed a significant increase of triglyceride content in both heart and soleus muscle, as well as of total and sterified cholesterol in heart muscle. This increase was accompanied by decreased plasma levels of total and HDL-cholesterol. Some of these abnormalities were similar to those observed in rats fed the same standard laboratory chow, supplemented with 0.5 g of brominated oil per 100 g of diet. The hepatic levels of triglycerides, total proteins and glycogen, as well as the weight gain and caloric intake of the animals which were fed 0.1 g of brominated oil per 100 g diet, were similar to those of the control group. In summary, the toxicologic effects observed during the chronic intake of diets supplemented with relatively low doses of brominated oils, suggest the need to undertake wider and deeper biochemical studies. The authors consider that these are necessary in order to ascertain the maximum tolerance levels for the use of these compounds, to minimize the risk of inducing important biological alterations.


[Neuropeptides in atopic dermatitis in children].
Radioimmunoassay was used to measure the blood plasma content of endogenous opioid peptides (beta-andorphine, methionin- and leucine-enkephalins), R substance, calcium-regulating hormones (parathyroid hormone and carcitonin), ionized calcium and cortisol in 152 children aged 6 months to 12 years with atopic dermatitis. The data obtained were compared to those obtained in healthy children. The stress-activating and stress-limiting systems were established to be activated in all the patients. It is concluded that the intensity of the adaptation compensatory process depends on the clinical form, disease standing, and spreading of skin impairment.


Impact of elexacaftor-tezacaftor-ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis.
Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls. Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils, interleukin (IL)-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition. In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.


Raman spectroscopic study, DFT calculations and MD simulations on the conformational isomerism of N-alkyl-N-methylpyrrolidinium bis-(trifluoromethanesulfonyl) amide ionic liquids.
The conformational behaviors of N-alkyl-N-methylpyrrolidinium bis-(trifluoromethanesulfonyl) amide ionic liquids (alkyl; propyl and butyl, [P(1n)][TFSA]; n = 3 and 4) were studied by Raman spectroscopy in the frequency range of 200-1700 cm(-1) at different temperatures. Observed Raman spectra in the frequency range 870-960 cm(-1) for [P(13)][TFSA] and at 860-950 cm(-1) for [P(14)][TFSA] depend on the temperature, indicating that pseudo rotational isomerization of the pyrrolidinium ring exists in the ionic liquids. DFT calculations revealed that the pseudo rotational potential energy surfaces for P(13)(+) and P(14)(+) ions were similar to each other, i.e., the e6 isomer is the global minimum, whereas the three other isomers e1, e4, and e5 are ca. 3 kJ mol(-1) higher in energy. Optimized geometries with no imaginary frequency were successfully obtained for the e6, e1, and e4 isomers. For both cations, the theoretical Raman spectra of the e6 isomers reproduce well the observed data. To explain their observed Raman spectra in a reasonable way, it is necessary to consider one or more species as predicted by DFT calculations, i.e., the e4 isomer of P(13)(+) rather than the e1, or the e1 isomer of P(14)(+) rather than the e4. In addition, the torsion energy potentials of the alkyl chains of the cations were scanned by DFT calculations. It turns out that the alkyl chains of the cations prefer all trans conformations. It should be emphasized that the alkyl chains of the pyrrolidinium cations show remarkably different conformational behaviors comparing with those of the imidazolium. The isomerization enthalpies Delta(iso)H degrees from the e6 to the e4 isomer of P(13)(+) and to e1 of P(14)(+) were reasonably estimated from the temperature dependence of Raman spectra based on our proposed assignments to be 2.9 kJ mol(-1) for P(13)(+) and 4.2 kJ mol(-1) for P(14)(+), respectively. Thus evaluated experimental Delta(iso)H degrees values, which may contain some uncertainties, are in agreement with those predicted by DFT calculations and MD simulations suggesting that pseudo rotational isomerization equilibria are established in the examined N-alkyl-N-methylpyrrolidinium ionic liquids. The conformational behavior of TFSA(-) was also investigated. The Delta(iso)H degrees from the trans (trifluoromethyl groups on opposite sides of the S-N-S plane) to the cis isomer were evaluated to be 4.2 kJ mol(-1) for [P(13)][TFSA] and 3.5 kJ mol(-1) for [P(14)][TFSA], respectively, which are similar to that for the 1-ethyl-3methylimidazolium ionic liquid.


Cognitive and neurologic findings in subjects with diffuse white matter lucencies on computed tomographic scan (leuko-araiosis).
As part of a prospective clinicopathologic study, a cohort of 105 "normal" elderly volunteers was investigated with computed tomographic scans, psychometric testing (Extended Scale for Dementia [ESD]) and neurologic examination. Computed tomographic scans were evaluated for the presence or absence of white matter lucencies, termed leuko-araiosis. These are defined as patchy or diffuse areas of decreased attenuation involving only white matter and with no change in adjacent ventricles or sulci. The nine controls with leuko-araiosis had lower scores on the ESD than the 96 controls without leuko-araiosis (mean ESD with leuko-araiosis, 227.1 +/- 14; without leuko-araiosis, 237.1 +/- 8), and the difference remains significant even after adjusting for the possible confounding effects of age, sex, education, and infarct detected on computed tomography. Significant differences were also found comparing subjects with leuko-araiosis and those without in respect to abnormal gait, limb power, plantar response, and the rooting and palmomental reflexes. Leuko-araiosis may represent a marker for early dementia. The pathophysiology of this finding remains uncertain. Our results suggest that white matter abnormalities play a role in the development of intellectual impairment in the elderly.


The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease.
Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.


Numerical study of exact Purcell factors in finite-size planar photonic crystal waveguides.
The waveguide-length sensitivity on modified spontaneous emission in finite-size planar photonic crystal (PC) waveguides is investigated by numerically computing the exact Purcell (enhanced emission) factor. An unusual dependence on the number of waveguide unit cells and on the waveguide facet truncation is found, allowing one to nanoengineer large Purcell factors in excess of several hundred. Besides having important applications for single-photon sources, these results offer physical insight into the nature of light-matter interactions in miniaturized finite-size PC waveguides, where periodic Bloch-wave analysis breaks down.


Local tetra patterns: a new feature descriptor for content-based image retrieval.
In this paper, we propose a novel image indexing and retrieval algorithm using local tetra patterns (LTrPs) for content-based image retrieval (CBIR). The standard local binary pattern (LBP) and local ternary pattern (LTP) encode the relationship between the referenced pixel and its surrounding neighbors by computing gray-level difference. The proposed method encodes the relationship between the referenced pixel and its neighbors, based on the directions that are calculated using the first-order derivatives in vertical and horizontal directions. In addition, we propose a generic strategy to compute nth-order LTrP using (n - 1)th-order horizontal and vertical derivatives for efficient CBIR and analyze the effectiveness of our proposed algorithm by combining it with the Gabor transform. The performance of the proposed method is compared with the LBP, the local derivative patterns, and the LTP based on the results obtained using benchmark image databases viz., Corel 1000 database (DB1), Brodatz texture database (DB2), and MIT VisTex database (DB3). Performance analysis shows that the proposed method improves the retrieval result from 70.34%/44.9% to 75.9%/48.7% in terms of average precision/average recall on database DB1, and from 79.97% to 85.30% and 82.23% to 90.02% in terms of average retrieval rate on databases DB2 and DB3, respectively, as compared with the standard LBP.


Lack of the expression of EBNA-2 and LMP-1 in T-cell neoplasms possessing Epstein-Barr virus.
We investigated 34 cases of T-cell neoplasm [15 cases of T-cell granular lymphocytic leukemia (T-GLL), 10 cases of T-cell non-Hodgkin's lymphoma (T-NHL), six cases of T-cell chronic lymphocytic leukemia (T-CLL), and three cases of cutaneous T-cell lymphoma] to study their association with Epstein-Barr virus (EBV). In 4 (three T-NHL and one T-GLL) of 34 cases, EBV genome was detected in a single episomal form, while polyclonal EBV-DNA was detected in one (T-NHL) of the remaining cases. All three cases of T-NHL having monoclonal EBV episome showed histologically diffuse large-cell lymphoma and developed leukemic conversion. Phenotypic analysis showed that two of these four cases were CD4+, CD8-, and the remaining two cases were CD4-, CD8+. The cells from all four cases were confirmed to be in T-cell lineage by detecting the rearrangement of T-cell receptor (TCR) beta or gamma chain gene. By reverse transcription-polymerase chain reaction (RT-PCR), EBNA-1 was detected at low levels, and neither EBNA-2 nor LMP-1 were found in any of the three cases examined. Lack of the expression of EBNA-2 and LMP-1 was also confirmed by immunocytochemical staining. The cells of these four cases did not show rearrangement or overexpression of c-myc and bcl-2 genes by Southern and Northern blots, and the mutation of p53 gene was detected in only one patient. These results suggest that other latent gene products of EBV or other cellular oncogenes are involved in the development of Japanese T-cell neoplasm after EBV infection.


Overexpression of phospholipase C-gamma 1 in familial adenomatous polyposis.
Phosphoinositide-specific phospholipase C (PLC) isozymes occupy a central role in the signal transduction system by regulating various cellular processes including proliferation and differentiation. In the present study, we examined the contents of PLCs in colorectal adenomas, carcinomas, and normal mucosa obtained from 4 familial adenomatous polyposis patients to find out whether this enzyme plays any role in the pathogenesis of adenomas and/or carcinomas in familial adenomatous polyposis. Radioimmunoassay and immunoblot analysis revealed that in contrast to little difference in PLC-beta 1 and PLC-delta 1 content, a considerably higher level of PLC-gamma 1 was detected in 3 of 4 cases for adenoma and in all cases for carcinoma as compared to normal mucosa. The level of PLC-gamma 1 expression increased from normal mucosa to adenoma, and finally to carcinoma progressively. Immunohistochemical findings also confirmed this observation. Likewise, activity of PLC-gamma 1 was considerably higher in adenomas and carcinomas than in normal mucosa. These results suggest that PLC-gamma 1-mediated signal transduction may play a significant role in the progression of colorectal tumors in patients with familial adenomatous polyposis.


Anti-inflammatory effect of Ishige okamurae ethanolic extract via inhibition of NF-kappaB transcription factor in RAW 264.7 cells.
Nowadays, much attention has been paid to the development of anti-inflammatory agents from marine natural resources. As a result of screening anti-inflammatory agents from marine algae using immunoassay, we found for the first time that ethanolic extract of Ishige okamurae (IO) classified into brown algae was effective in inhibiting the production of inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and prostaglandin E(2), in RAW264.7 cells stimulated by lipopolysaccharide, compared with dexamethasone and aspirin used as positive control in this study. Moreover, transcriptional activation of NF-kappaB transcription factor that regulates the expression of these inflammatory mediators was also examined using reporter gene assay and western blot analysis. It was observed that IO extract exerted anti-inflammatory effect via inactivation of NF-kappaB transcription factor in macrophages. In addition, the expression and activity of matrix metalloproteinase-2 and 9 that play an important role in chronic inflammation were decreased in dose-dependent manner in the presence of IO extract in HT1080 cells. The above results suggest that IO extract can inhibit inflammation through inactivation of NF-kappaB transcription factor in macrophage.


Asthma control in Kazakhstan: need for urgent action.
Asthma control, patients' awareness level and adherence to treatment in Kazakhstan have never been studied. The aim of this study was to verify the prevalence of controlled, poorly controlled and uncontrolled asthma in a large sample of three largest cities of Kazakhstan. We recruited 600 (median age 54 (interquartile range (IQR) 22) years, 64% females) patients with diagnosis confirmed earlier in the outpatient facilities in Almaty, Astana and Shymkent in 2020-2021. We offered a structured questionnaire on asthma control and risk factors as of GINA and performed spirometry. We report the prevalence of asthma control, knowledge and skills and pharmacological treatment with 95% confidence interval (CI) and the association of selected predictors with asthma control. With the median of 9 (IQR 13) years of diagnosis, 40% of patients had comorbid COPD and 42% had allergic rhinitis, whereas 32% lived with pets. Asthma was well-controlled in only 12.3% (95% CI 9.7-15.0), partly controlled in 29.8% (95% CI 26.2-33.5) and uncontrolled in 57.8% (95% CI 53.9-61.8) patients. ACQ-5 score (range 0-5.8, median 2) equaled 0.2 (IQR 0.85) in well-controlled asthma patients, 1.4 (IQR 1) in partly controlled and 2.8 (IQR 1.4) in uncontrolled asthma patients. Knowledge and skills levels were very low. Only 54% were on inhaled corticosteroids (52.2% of them used budesonide/formoterol and 39.5% used fluticasone/salmeterol). 39% used steroids per os or parenterally within a period of 12 months (51% of patients with uncontrolled asthma). Asthma control, knowledge and skills levels of asthma patients in the largest cities of Kazakhstan remain unacceptably low, whereas pharmacological treatment is far from optimal. Urgent action should be taken to support doctors' training, and we call to launch a national asthma program to coordinate asthma care in Kazakhstan.


Dysplastic bone marrow changes during maintenance therapy for acute leukemia.
We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.


Natural Products-Based Nanoformulations: A New Approach Targeting CSCs to Cancer Therapy.
Cancer stem cells (CSCs) lead to the occurrence and progression of cancer due to their strong tumorigenic, self-renewal, and multidirectional differentiation abilities. Existing cancer treatment methods cannot effectively kill or inhibit CSCs but instead enrich them and produce stronger proliferation, invasion, and metastasis capabilities, resulting in cancer recurrence and treatment resistance, which has become a difficult problem in clinical treatment. Therefore, targeting CSCs may be the most promising approach for comprehensive cancer therapy in the future. A variety of natural products (NP) have significant antitumor effects and have been identified to target and inhibit CSCs. However, pharmacokinetic defects and off-target effects have greatly hindered their clinical translation. NP-based nanoformulations (NPNs) have tremendous potential to overcome the disadvantages of NP against CSCs through site-specific delivery and by improving their pharmacokinetic parameters. In this review, we summarize the recent progress of NPNs targeting CSCs in cancer therapy, looking forward to transforming preclinical research results into clinical applications and bringing new prospects for cancer treatment.


A local fast marching-based diffusion tensor image registration algorithm by simultaneously considering spatial deformation and tensor orientation.
It is a key step to spatially align diffusion tensor images (DTI) to quantitatively compare neural images obtained from different subjects or the same subject at different timepoints. Different from traditional scalar or multi-channel image registration methods, tensor orientation should be considered in DTI registration. Recently, several DTI registration methods have been proposed in the literature, but deformation fields are purely dependent on the tensor features not the whole tensor information. Other methods, such as the piece-wise affine transformation and the diffeomorphic non-linear registration algorithms, use analytical gradients of the registration objective functions by simultaneously considering the reorientation and deformation of tensors during the registration. However, only relatively local tensor information such as voxel-wise tensor-similarity is utilized. This paper proposes a new DTI image registration algorithm, called local fast marching (FM)-based simultaneous registration. The algorithm not only considers the orientation of tensors during registration but also utilizes the neighborhood tensor information of each voxel to drive the deformation, and such neighborhood tensor information is extracted from a local fast marching algorithm around the voxels of interest. These local fast marching-based tensor features efficiently reflect the diffusion patterns around each voxel within a spherical neighborhood and can capture relatively distinctive features of the anatomical structures. Using simulated and real DTI human brain data the experimental results show that the proposed algorithm is more accurate compared with the FA-based registration and is more efficient than its counterpart, the neighborhood tensor similarity-based registration.


Clogging of soft particles in two-dimensional hoppers.
Using experiments and simulations, we study the flow of soft particles through quasi-two-dimensional hoppers. The first experiment uses oil-in-water emulsion droplets in a thin sample chamber. Due to surfactants coating the droplets, they easily slide past each other, approximating soft frictionless disks. For these droplets, clogging at the hopper exit requires a narrow hopper opening only slightly larger than the droplet diameter. The second experiment uses soft hydrogel particles in a thin sample chamber, where we vary gravity by changing the tilt angle of the chamber. For reduced gravity, clogging becomes easier and can occur for larger hopper openings. Our simulations mimic the emulsion experiments and demonstrate that softness is a key factor controlling clogging: with stiffer particles or a weaker gravitational force, clogging is easier. The fractional amount a single particle is deformed under its own weight is a useful parameter measuring particle softness. Data from the simulation and hydrogel experiments collapse when compared using this parameter. Our results suggest that prior studies using hard particles were in a limit where the role of softness is negligible, which causes clogging to occur with significantly larger openings.


TeleAudiology in the Veterans Health Administration.
To assess effectiveness of TeleAudiology for hearing aid services. Retrospective case-control. Ambulatory Veterans Health Administration and Community-Based Outpatient Clinics (CBOCs). 42,697 veterans who received hearing aids from January through September, 2014. TeleAudiology (TA) and conventional in-person (IP) audiology care. International Outcome Inventory for Hearing Aids (IOI-HA) outcomes data. The IOI-HA is a 7-item survey used to assess hearing aid effectiveness. Scored from 7 to 35 points, higher scores are more favorable. Among veterans nationwide who received hearing aids and completed the IOI-HA survey, 1,009 received TA and 41,688 received IP care. TA and IP groups have comparable mean IOI-HA values (TA = 29.6, SD = 3.9; IP = 28.7, SD = 4.2). Although comparison showed a statistically significant difference (p < 0.0001, t test), principally because of large sample size, the distinction is not clinically meaningful.Subgroup analysis of veterans from San Francisco and six affiliated CBOCs showed 169 received TA and 338 received IP care. TA and IP groups have similar mean age (TA = 74, SD = 9.8; IP = 76, SD = 10.3) and sex distribution (TA male = 100%; IP male = 96%) with statistically significant (p < 0.01, t test) but clinically insignificant differences. Mean IOI-HA scores (TA = 30.7, SD = 3.6; IP = 30.5, SD = 3.1) are not different between groups (p > 0.05, t test). TA and IP encounters to provide hearing aid services to veterans are comparable, as both are highly effective based on IOI-HA results. The noninferiority of TA suggests its adoption to non-veterans may improve access while preserving high satisfaction. Financial impact of migration to TA will require future econometric analysis.


In vivo measures of cochlear length and insertion depth of nucleus cochlear implant electrode arrays.
Three-dimensional cochlear canal lengths, electrode array intracochlear insertion depths, and characteristic frequency ranges were estimated for 20 Nucleus implant recipients on the basis of in vivo computed tomography (CT) scans. Ultra-high resolution images were reconstructed from spiral CT data with 0.1-mm slicing and expanded attenuation scales. Canal length estimates (mean 33.01 mm; SD 2.31) were consistent with previous findings for normal human temporal bones. Intracochlear array insertion depths estimated by 3-dimensional (3-D) spiral calculations (mean 20.19 mm; SD 2.86) and by a computerized array tracking algorithm (mean 20.36 mm; SD 2.66) were not significantly different. Estimates from surgical observations were significantly longer (mean 21.03 mm; SD 2.31) because array compressions were not detectable. Characteristic frequencies at apical electrodes estimated from Greenwood's equations ranged from 387 Hz to 2,596 Hz. The results show that significant variations in cochlear anatomy and array distribution among implant patients that may impact implant performance can be reliably detected and quantified by using in vivo high-resolution CT and 3-D reconstructions.


Understanding topical fluoride hesitancy and refusal behaviors through the extended parallel process model and health belief model.
Topical fluoride helps prevent dental caries. However, many caregivers are hesitant about topical fluoride for their children and may refuse it during clinic visits. In this qualitative study, we assessed the relevance of the extended parallel process model (EPPM) and health belief model (HBM) in caregivers' decision-making about topical fluoride. We interviewed 56 fluoride-hesitant or fluoride-refusing caregivers using a semi-structured interview script that included questions based on select constructs from the EPPM (perceived severity, susceptibility, response efficacy) and HBM (perceived benefits and consequences). Two team members conducted a thematic analysis of the interview data. Most caregivers acknowledged the severity of cavities but did not believe their child was susceptible. Caregivers also understood the general benefits of fluoride in preventing tooth decay, but reported low response efficacy of fluoride for their children especially compared to the other ways of reducing caries risk like reducing sugar intake and toothbrushing. Many caregivers had concerns about topical fluoride, especially regarding safety, with the potential consequences of fluoride outweighing its benefits. Our findings were generally consistent with the EPPM and HBM, which appear to be relevant in understanding fluoride hesitancy behaviors. Additional research is needed on ways to improve provider communications about topical fluoride with caregivers.


[Evaluation of the efficiency of preventive medical examinations of railway transport workers].
The paper reflects the priority role of preliminary and periodic medical examinations in the system of measures implemented by therapeutic-and-prophylactic institutions of the Ministry of Railway of Russia. It gives a comprehensive assessment of the medical, social, and economic aspects of the efficiency of preventive medical examinations. Emphasis is laid on the necessity of elaborating methods to evaluate the economic efficiency of medical measures under the conditions of market economy. At the same time, light is shed on the difficulties available when a full-scale, within the whole industry, economic evaluation of periodic medical examinations is made. The role of a cost-effect analysis is shown as the most flexible existing principle in the evaluation of the efficiency of medical preventive measures.


Pathology and Biobanking.
Biobanks are units where high quality and long-term protection of biomaterials is maintained. This system, in which biological materials and data are systematically recorded and stored, is a unique resource for the study of the pathophysiology of disease, the development of diagnostic biomarkers, and working with human tissues for the potential discovery of targeted therapeutic agents. At this point, the pathology unit plays a unifying and complementary role between the clinical and core disciplines and offers optimal management of the patients' biomaterials for diagnostic and research projects. The aim of this article is to present general information with regard to a biobank constructed for the storage of tumor tissue and blood biospecimens. Ethical issues (informed consent, protection of confidentiality and privacy, and secondary use of biospecimens) and the information technology system (collection, systematic recording, backup and protection of clinical information) are important issues in biobanking. The selection of freezers to be used in storage (mechanical freezers, liquid-vapor nitrogen tanks), and if mechanical freezers are preferred the establishment of the relevant infrastructure and support team (such as additional power units for protection from power outages), the preservation of materials by aliquoting in different freezers, ensuring financing so as to afford the cost of the infrastructure, and implementation of all these dynamics while adhering to international guidelines are of the utmost importance.


Space-dependent aspects of electron degradation.
Space- and energy-dependent flux densities were computed by a Monte Carlo method of electron degradation for 0.1-3.0 keV incident electrons in argon. These flux densities contain the basic information about the electron degradation process and can be used to calculate a yield for any inelastic state at any spatial position. Numerical results were analytically represented in terms of the recently introduced phenomenological model. It was found that flux densities multiplied by an absorption cross section in argon are approximately the same as flux densities multiplied by an absorption cross section in nitrogen. This feature provides a basis to use an analytical approximation of flux densities from this study for any gas.


In Vitro Assessment of Homeopathic Potencies of Hydrastis canadensis on Hormone-Dependent and Independent Breast Cancer.
Breast cancer is the second leading cause of cancer-related deaths in women. Conventional treatment such as chemotherapy, hormonal therapy and radiotherapy has decreased the mortality rate among cancer patients but has also revealed long-term side effects. Drug resistance and toxicity to normal cells compound the problems associated with the use of modern medicines. Hence, complementary or alternative treatment options are being explored. The current study, using different homeopathic potencies of Hydrastis canadensis, was conducted to distinguish between any effects they might have on hormone-dependent and independent breast cancer. The cytotoxic effect of homeopathic medicine Hydrastis on hormone-dependent (MCF 7) and hormone-independent (MDA-MB-468) breast cancer cells was assessed using viability and colony-forming assays after 48 or 72 hours of treatment. Flow cytometry-based Annexin V-PI (propidium iodide), caspase 3 and cell cycle analysis was performed following treatment of cells with mother tincture or various potencies of Hydrastis (1C, 2C, 30C, 200C). Different potencies of Hydrastis displayed selective cytotoxic effects against MCF 7 cells, but only marginal effects against MDA-MB-468. The maximum cytotoxicity was established in the case of 1C following 72 hours of treatment. Treatment of breast cancer cells revealed an increase in the G0/G1 cell population, along with an increase in the caspase 3 levels and induction of apoptosis. Hydrastis may have a selective cytotoxic effect against hormone-dependent breast cancer MCF 7 cells, leading to cell cycle arrest in the G0/G1 phase, which could be the plausible reason for the induction of apoptosis. The results need to be validated in vivo.


[Topical immunosuppressors: new therapeutic approach in atopic dermatitis].
The efficiency of topical immunosuppressors in the treatment of atopic dermatitis is undebatable. These agents induce immunosuppression by inhibiting T cell activation and cytokine production. An intermittent treatment, with two applications per day, and photoprotection is recommended in adults and children aged more than two years. The precise position of the topical immunosuppressors in the treatment strategy of atopic dermatitis remains to be defined. Main side effects are irritative or allergic cutaneous reactions and cutaneous infections, no systemic side effects have been recorded. The consequence of long-term topical immunosuppression and specially the possible development of skin cancers in UV exposed skin, is not well known and necessitates careful monitoring of patients. These treatments are contra-indicated during pregnancy, breast feeding, in erythrodermic states and with any alterations of the cutaneous barrier.


1,2,4-Triazolo[4,3-a]quinoxalin-1-one: a versatile tool for the synthesis of potent and selective adenosine receptor antagonists.
4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4, 3-a]quinoxalin-1-one (1) has been found to be an A(2A) versus A(1) selective antagonist (Colotta et al. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 39-41). In this paper some novel triazoloquinoxalin-1-ones 4-25 bearing different substituents on the 2-phenyl and/or 4-amino moiety of the parent 4-amino-1, 2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (3) have been synthesized and tested in radioligand binding assays at bovine A(1) and A(2A) and cloned human A(3) adenosine receptors (AR). Moreover, the binding activities at the above-mentioned AR subtypes of the 1,4-dione parent compounds 26-31 and their 5-N-alkyl derivatives 33-37 were also evaluated. The substituent on the 2-phenyl ring exerted a different effect on AR subtypes, while replacement of a hydrogen atom of the 4-amino group with suitable substituents yielded selective A(1) or A(3) antagonists. Replacement of a hydrogen atom of the 4-NH(2) with an acyl group, or replacement of the whole 4-NH(2) with a 4-oxo moiety, shifted the binding activity toward the A(3) AR. The binding results allowed elucidation of the structural requirements for the binding of these novel tricyclic derivatives at each receptor subtype. In particular, A(1) and A(2A) binding required the presence of a proton donor group at position-4, while for A(3) affinity the presence of a proton acceptor in this same region was of paramount importance.


Non-alcoholic fatty liver disease and childhood obesity.
Non-alcoholic fatty liver disease (NAFLD) in children and adolescents has an estimated prevalence of 36.1% in the context of obesity. This figure is anticipated to increase in conjunction with the global obesity epidemic. Worryingly, NAFLD in childhood persisting into adulthood is likely to be harmful, contributing to significant hepatic and extrahepatic morbidities. Early disease detection is required, although the optimum timing, frequency and mode of screening remains undetermined. While the efficacy of several medications, antioxidants, fatty acid supplements and probiotics has been investigated in children, healthy eating and physical activity remain the only prevention and treatment strategies for paediatric NAFLD. This short review discusses the epidemiology, diagnosis, pathogenesis and management of NAFLD in childhood obesity.


A long-term metabolic study to assess the nutritional value of and immunological tolerance to two soy-protein concentrates in adult humans.
Seventeen healthy young adult men participated in a long-term metabolic study (11 wk) to evaluate the tolerance to and protein nutritional value of two commercially produced soy-protein concentrates. Danpro-S (nine subjects) and Danprotex-H 40 (eight subjects) (Aarhus Oliefabrik A/S, Aarhus, Denmark). Each test protein (0.8 g.kg-1.d-1) served as the sole source of dietary nitrogen. Subjects remained healthy, no problems of clinical or metabolic significance appeared, body weight remained constant, and body composition indices (lean body mass by H2(18)O dilution and creatinine excretion) and basal metabolic rate did not change. N balances fluctuated around body N equilibrium. Immunological studies confirmed the absence of any allergic responses in these subjects. It is concluded that these protein concentrates can be consumed as the sole source of dietary protein for protein nutritional maintenance and with excellent tolerance.


Remission in rheumatoid arthritis: a comparison of the 2 newly proposed ACR/EULAR remission criteria with the rheumatoid arthritis disease activity index-5, a patient self-report disease activity index.
We analyzed whether a patient self-report remission criterion, such as that according to the Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), meets the criteria of the 2011 proposed American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) definition of remission. The 2 approaches of the ACR/EULAR proposal [Boolean- and Simplified Disease Activity Index (SDAI)-based] as well as the RADAI-5 were used to assess whether patients with RA are in remission. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and kappa analyses were performed to illustrate the relationship among the different approaches defining remission at a group level. In total, 705 patients' assessments were included. Eighty-nine patients were classified as being in remission according to the Boolean-based and 169 according to the SDAI-based definition of the ACR/EULAR proposals, and 154 according to the RADAI-5. Sixty-eight assessments were classified as being in remission according to all 3 definitions. In the case of RADAI-5 remission, sensitivity was 78%, specificity 86%, PPV 45%, and NPV 96%, indicating remission according to the Boolean-based definition; and 60%, 92%, 66%, and 90%, respectively, indicating remission according to the SDAI-based definition. In the case of remission according to the SDAI-based ACR/EULAR definition, sensitivity was 52%, specificity 100%, PPV 98%, and NPV 87%, also indicating remission according to the Boolean definition; while according to the Boolean definition the values were 98%, 87%, 52%, and 100%, respectively. Kappa statistics showed fair to good agreement for all 3 definitions. Nearly twice as many assessments were classified as being in remission using the SDAI-based or the RADAI-5 definitions when compared to the Boolean-based definition. Remission according to the RADAI-5 also was highly specific for both ACR/EULAR criteria. Sensitivity for the RADAI-5 criterion was even better for the Boolean-based definition than that for the SDAI-based definition.


[Drug-induced (probably allopurinol) agranulocytosis. Case report and discussion].
Agranulocytosis is a rare but sometimes extremely dangerous adverse drug reaction which can be induced by almost any drug. We report the case of a 89-year-old man with a well-documented granulocyte chart, who received allopurinol in addition to preexisting therapy with cardiovascular drugs. Three weeks later agranulocytosis was found which bone-marrow biopsy indicated was drug-induced. After cessation of all drugs, isolation and antibiotic therapy, the leukocyte count returned to normal but the patient died four weeks later from progressive renal failure. A relation between allopurinol therapy and agranulocytosis was presumed. The drugs which might have caused this adverse reaction are discussed. The incidence, signs, symptoms and treatment are summarized and proposals are made concerning the action to be taken in the event of drug-induced agranulocytosis.


Survival after conservative (palliative) management of pleural malignant mesothelioma.
Malignant mesothelioma is a lethal disease. Aggressive multimodality treatment protocols are reportedly associated with improved survival, but the apparent survival benefits may simply reflect patient selection and the variable natural history of this malignancy. Before embarking on our own protocol of experimental treatment for mesothelioma, we sought to identify important prognostic factors and document the survival of patients treated conservatively (with palliative intent only) in our region. We performed a retrospective review of all patients with a diagnosis of malignant mesothelioma seen at our center between 1987 and 1999. Since curative intent treatment had not been given, we assumed that measured survival would largely reflect the natural history of the malignancy. There were 101 patients (80 males and 21 females). Mean age was 65 +/- 9.2 years. Symptoms of disease were present for a median time of 5 months before the diagnosis was established. The most common presenting symptoms were dyspnea (46 patients), chest pain (30 patients), and weight loss (22 patients). Sixty-eight patients (68%) had a history of asbestos exposure. Mesothelioma subtypes included epithelial (43 patients), sarcomatous (26 patients), mixed (19 patients), desmoplastic (4 patients), and unspecified (9 patients). All 101 patients were treated with palliative intent. Talc pleurodesis was performed in 70 patients. At the time of analysis, 90 patients had died and 11 remained alive. Median survival was 213 (95% CI 137-289) days. Survival for the three major histological subtypes was significantly different (log rank, P = 0.0016). Histological subtype (epithelial favorable) was the only significant independent prognostic factor (Cox proportional hazard regression, P = 0.0009). Patients with epithelial mesothelioma survive longer than those with other histological subtypes. Conservatively managed patients with pleural malignant mesothelioma have a median survival of approximately 7 months. These data from conservatively treated patients can serve as baseline information for future studies of experimental treatments.


Family mealtime emotions and food parenting practices among mothers of young children: Development of the Mealtime Emotions Measure for Parents (MEM-P).
Family mealtimes can be important for supporting children's healthy development, yet the emotional context of mealtimes can vary considerably, likely impacting their overall success and enjoyment. Yet, despite having an important role, little is known about how parents emotionally experience mealtimes with their family. The first aim of the current study was to assess the factor structure of a novel self-report measure to assess parents' emotional responses experienced during family mealtimes (Mealtime Emotions Measure for Parents; MEM-P). The second aim was to examine relationships between maternal mealtime emotions and their food parenting practices. Mothers of children aged between 1.5 and 6 years participated in this study. Mothers were invited to complete an online questionnaire measuring family mealtime emotions, anxiety, depression and food parenting practices. Exploratory factor analysis produced a three-factor solution comprising both positive and negative emotion subscales: MEM-P Efficacy; MEM-P Anxiety; MEM-P Stress and Anger. Mothers' positive mealtime emotions (mealtime efficacy) were related to greater use of practices promoting autonomy, providing a healthy home food environment, and modelling healthy eating. Higher anxiety about mealtimes was related to greater reports of child control over eating, and mealtime stress and anger was associated with greater use of food to regulate emotions. These findings highlight novel relationships between how mothers emotionally experience family mealtimes and the food parenting practices they use with their children. It is important to develop resources to help promote positive maternal experiences of family mealtimes and food-based interactions.


A single-surgeon randomized trial comparing sutures, N-butyl-2-cyanoacrylate and human fibrin glue for mesh fixation during primary inguinal hernia repair.
We sought to determine the efficacy of sutures, human fibrin glue and N-butyl-2-cyanoacrylate for mesh fixation in patients undergoing the plug and mesh procedure for groin hernia. A total of 156 patients with 167 inguinal hernias (11 bilateral) underwent a plug and mesh procedure and were randomly assigned to received either sutures (n = 59 hernias), human fibrin glue (n = 52) or N-butyl-2-cyanoacrylate (n = 56) for mesh fixation. The overall morbidity rate was 38.98% in the suture group, 9.62% in the fibrin glue group and 10.71% in the N-butyl-2-cyanoacrylate group (suture v. fibrin glue, p < 0.001; suture v. N-butyl-2-cyanoacrylate, p < 0.001). There was no significant difference in morbidity between the fibrin glue and N-butyl-2-cyanoacrylate groups. Overall, short-term morbidity was significantly higher in the suture group (27.12%) than in the fibrin glue (9.62%, p = 0.01) or N-butyl-2-cyanoacrylate (8.93%, p = 0.004) groups, but there was no significant difference between the fibrin glue and N-butyl-2-cyanoacrylate groups. There was no significant difference between the groups in terms of mean postoperative stay (32.6 h in the suture group v. 30.8 h in the fibrin glue group v. 32.0 h in the N-butyl-2-cyanoacrylate group) or mean time to return to work (20.4 d in the suture group v. 20.3 d in the fibrin glue group v. 19.8 d in the N-butyl-2-cyanoacrylate group). Overall, long-term morbidity was significantly higher in the suture group (11.86%) than in the fibrin glue (0%, p = 0.001) or N-butyl-2-cyanoacrylate (1.78%, p = 0.03) groups. There was no recurrence in any of the groups. Two cases (3.39%) of chronic groin pain were reported in patients in the suture group. A sensation of extraneous body was reported in 5 (8.47%) patients who received sutures and in 1 (1.78%) patient in the N-butyl-2-cyanoacrylate group; there were no reported cases in the fibrin glue group (suture v. fibrin glue, p = 0.01; suture v. N-butyl-2-cyanoacrylate, p = 0.03; fibrin glue v. N-butyl-2-cyanoacrylate, p = 0.30). The use of human fibrin glue or N-butyl-2-cyanoacrylate is better tolerated than sutures in tension-free inguinal open repair using the plug and mesh technique in terms of overall immediate results, and there is a better trend in the long-term data.


PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC(1)) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC(1) and VPAC(2))] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of efferent sympathetic activity. Increases in sympathetic activity are observed in most types of hypertension and heart failure. PACAP delivered intrathecally also causes massive sympathoexcitation. We aimed to determine the presence and abundance of the three PACAP receptors in the RVLM, the role, in vivo, of PACAP in the RVLM on tonic and reflex cardiovascular control, and the contribution of PACAP to hypertension in the spontaneously hypertensive rat (SHR). Data were obtained using quantitative PCR and microinjection of PACAP and its antagonist, PACAP(6-38), into the RVLM of anesthetized artificially ventilated normotensive rats or SHRs. All three receptors were present in the RVLM. PACAP microinjection into the RVLM caused sustained sympathoexcitation and tachycardia with a transient hypertension but did not affect homeostatic reflexes. The responses were partially mediated through PAC(1)/VPAC(2) receptors since the effect of PACAP was attenuated (∼50%) by PACAP(6-38). PACAP was not tonically active in the RVLM in this preparation because PACAP(6-38) on its own had no inhibitory effect. PACAP has long-lasting cardiovascular effects, but altered PACAP signaling within the RVLM is not a cause of hypertension in the SHR.


Why the immorality of consuming alcohol during pregnancy cannot tell us that abortion is immoral: A reply to Hendricks.
Recently, Perry Hendricks argued that abortion is immoral even if the fetus is not a person. He did so by arguing that causing a future child to suffer from fetal alcohol syndrome is wrong because it is an impairment, and an abortion would be an even more substantial impairment. Here I reply that the argument depends on ignoring relevant facts that are essential for moral decision-making. Moreover, if we adapt the argument to consider these essential facts, then the argument fails because it no longer applies to the case under consideration.


Effect of recovery-based interventions on recovery knowledge and attitudes of mental health professionals, regarding recovery-oriented practice: A quantitative narrative review.
Mental health recovery is an enabling process encouraging consumers to live a productive life, notwithstanding the presence of debilitating symptoms of illness. The recovery model has been integrated into all areas of mental health. However, literature shows that mental health professionals are not equipped to provide recovery-oriented care to consumers. Researchers have recommended recovery-based interventions to develop knowledge, attitudes, and skills to promote recovery-oriented practice in mental health, yet there is a paucity of research regarding the effect of recovery-oriented interventions on the knowledge and attitudes of mental health professionals to improve recovery-oriented practice. Therefore, the purpose of the current review is to understand the effectiveness of interventions on recovery knowledge and attitudes of mental health professionals regarding recovery-oriented practice. The papers were identified through the Population Intervention Comparison and Outcome strategy. The heterogeneity of the selected papers led to a narrative review instead of a systematic review with meta-analysis. The analysis suggested that recovery-based interventions are effective in enhancing the recovery knowledge and attitudes of mental health professionals. Recovery-based interventions have the potential to reduce the use of physical restraints and improve work satisfaction among mental health professionals. The limitations of the studies were the heterogeneity of the selected populations and the absence of strong methodologies to assess the effect of the interventions. Therefore, future investigations should be focused on the effect of interventions on a homogeneous group using randomized controlled trials.


Faults in the mojave desert, california, as revealed on enhanced landsat images.
Previously unknown strike-slip and normal faults in the central and eastern Mojave Desert have been revealed on Landsat Thematic Mapper images enhanced by four-component processing. This method provides color images on which lithologies are discriminated by their contrasting absorption and reflection, primarily at infrared wavelengths and particularly with regard to their ferric iron, ferrous iron, and hydroxyl contents, while retaining landform depiction. These discriminants represent a new type of geophysical display for geologic mapping in regions of well-exposed bedrock. Faults are revealed on the images by abrupt spectral and textural contrasts that coincide with aligned topographic features. The newly discovered faults form part of an extensive regional network of right shear that connects faults in the Death Valley region with the San Andreas fault system. They support a heterogeneous strain model for late Cenozoic tectonic evolution of the region. Regional structural relations indicate a westward migration of the locus of strain through time. Some of the newly identified faults bound blocks that have experienced contrasting rotational histories since early Miocene time.


α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitory Activity of Plastoquinones from Marine Brown Alga Sargassum serratifolium.
Sargassum serratifolium C. Agardh (Phaeophyceae, Fucales) is a marine brown alga that belongs to the family Sargassaceae. It is widely distributed throughout coastal areas of Korea and Japan. S. serratifolium has been found to contain high concentrations of plastoquinones, which have strong anti-cancer, anti-inflammatory, antioxidant, and neuroprotective activity. This study aims to investigate the anti-diabetic activity of S. serratifolium and its major constituents through inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO--mediated albumin nitration. S. serratifolium ethanolic extract and fractions exhibited broad PTP1B and α-glucosidase inhibitory activity (IC50, 1.83~7.04 and 3.16~24.16 µg/mL for PTP1B and α-glucosidase, respectively). In an attempt to identify bioactive compounds, three plastoquinones (sargahydroquinoic acid, sargachromenol and sargaquinoic acid) were isolated from the active n-hexane fraction of S. serratifolium. All three plastoquinones exhibited dose-dependent inhibitory activity against PTP1B in the IC50 range of 5.14-14.15 µM, while sargachromenol and sargaquinoic acid showed dose-dependent inhibitory activity against α-glucosidase (IC50 42.41 ± 3.09 and 96.17 ± 3.48 µM, respectively). In the kinetic study of PTP1B enzyme inhibition, sargahydroquinoic acid and sargaquinoic acid led to mixed-type inhibition, whereas sargachromenol displayed noncompetitive-type inhibition. Moreover, plastoquinones dose-dependently inhibited ONOO--mediated albumin nitration. Docking simulations of these plastoquinones demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B and α-glucosidase, indicating that these plastoquinones have high affinity and tight binding capacity towards the active site of the enzymes. These results demonstrate that S. serratifolium and its major plastoquinones may have the potential as functional food ingredients for the prevention and treatment of type 2 diabetes.


Effects of COVID-19 lockdown in Milan urban and Rome suburban acoustic environments: Anomalous noise events and intermittency ratio.
The COVID-19 pandemic affected the acoustic environment worldwide, entailing relevant reductions of equivalent noise levels (LAeq) during this exceptional period. In the context of the LIFE+ DYNAMAP project, two wireless acoustic sensor networks were deployed in Milan and Rome. Taking advantage of the built-in identification of anomalous noise events (ANE) in the sensors, this work analyses the effects of the COVID-19 lockdown in both urban and suburban acoustic environments from January to June 2020, considering the distribution of ANEs and the intermittency ratio (IR) as an indicator of the impact of noise on population. The results show statistically significant increments of ANEs in Rome during the lockdown, mainly on weekends, and especially at night, despite the significant decrease in salient events. Differently, ANEs decrease during the lockdown in Milan, mostly at daytime, as a result of population confinement. Although the IR increases in several urban locations, most sensed locations show a relevant decrease in IR during the confinement, which represents a noteworthy reduction of the negative impact of noise in the population of both cities. During the post-lockdown period, all the scores start to return to those observed in the pre-lockdown, but still remaining higher than in 2019.


Low Threshold for Cutaneous Allergen Sensitization but No Spontaneous Dermatitis or Atopy in FLG-Deficient Mice.
Loss of FLG causes ichthyosis vulgaris. Reduced FLG expression compromises epidermal barrier function and is associated with atopic dermatitis, allergy, and asthma. The flaky tail mouse harbors two mutations that affect the skin barrier, Flgft, resulting in hypomorphic FLG expression, and Tmem79ma, inactivating TMEM79. Mice defective only for TMEM79 featured dermatitis and systemic atopy, but also Flgft/ft BALB/c congenic mice developed eczema, high IgE, and spontaneous asthma, suggesting that FLG protects from atopy. In contrast, a targeted Flg-knockout mutation backcrossed to BALB/c did not result in dermatitis or atopy. To resolve this discrepancy, we generated FLG-deficient mice on pure BALB/c background by inactivating Flg in BALB/c embryos. These mice feature an ichthyosis phenotype, barrier defect, and facilitated percutaneous sensitization. However, they do not develop dermatitis or atopy. Whole-genome sequencing of the atopic Flgft BALB/c congenics revealed that they were homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that FLG deficiency does not cause atopy in mice, in line with lack of atopic disease in a fraction of patients with ichthyosis vulgaris carrying two Flg null alleles. However, the absence of FLG likely promotes and modulates dermatitis caused by other genetic barrier defects.


The utility of surveillance biopsies in pediatric kidney transplantation.
Surveillance biopsies (SBs) are performed in some pediatric kidney transplant programs, based on data obtained in earlier immunosuppressive eras that the treatment of subclinical acute rejection results in better graft survival. The benefit of SBs for patients on modern immunosuppression regimens is unclear. We have therefore evaluated the clinical utility of SBs in a population of children receiving a kidney transplant. We have performed SBs at 3, 6 and 12 months post-transplantation as standard of care at our institution since 2013 in patients on a regimen of rabbit anti-thymocyte globulin, tacrolimus, mycophenolate and rapid steroid taper (RST; steroids maintained in some exceptions). We reviewed pathology reports of 82 SBs from 34 transplants in 34 children for all abnormal findings and adequacy of specimens. Clinical records were reviewed for changes in management resulting from SB findings and for significant procedure complications. Of the 82 biopsies, 41 (50%) had abnormal findings separate from fibrosis, including five Banff Grade I rejections, ten borderline rejections, six calcineurin-inhibitor nephrotoxicity, four BK-virus nephropathy, five recurrent disease and three acute pyelonephritis. Moderate or more fibrosis was present in nine of the 82 (11%) biopsies. Management changes due to SB findings occurred in nine cases (11.0%). The proportion of abnormal findings or management changes did not differ between the RST or steroid-based groups. Patients performing clean intermittent catheterization showed inflammatory changes often read as rejection, but were managed differently. Three biopsies were deemed inadequate. No significant complications occurred. A high percentage of the SBs performed under modern immunosuppression showed abnormal findings even when fibrosis was excluded. However, management changes due to the SB findings were less frequent, although they occurred in a clinically meaningful percentage of cases. Complications or inadequate specimens were rare.


Inhibitors of inositol monophosphatase.
Inositol monophosphatase (IMPase) catalyses the hydrolysis of myo-inositol monophosphates to myo-inositol, which is required in the phosphatidyl inositol cell signalling pathway. Here the enzyme structure, mechanism and inhibition of IMPase are reviewed. Lithium, an effective therapy for manic depression, is an uncompetitive inhibitor. In the search for alternative inhibitors to lithium, substrate-based inhibitors, bisphosphonates, terpenoid and tropolone analogues are described.


Cumulative sum failure analysis of a policy change from on-pump to off-pump coronary artery bypass grafting.
Use of the sequential probability cumulative sum (CUSUM) technique may be more sensitive than standard statistical analyses in detecting a cluster of surgical failures. We applied CUSUM methods to evaluate the learning curve after a policy change by a single surgeon from routine on-pump (cardiopulmonary bypass [CPB]) to off-pump coronary artery bypass grafting (OPCAB). Fifty-five consecutive first-time coronary artery bypass patients (CPB group) were compared with the next 55 patients undergoing an attempt at routine OPCAB using the same coronary stabilizer. The goal in OPCAB patients was to obtain complete revascularization, albeit with a low threshold for conversion to CPB to maximize patient safety during the learning curve. Preoperative patient risk was calculated using previously validated models of the Cardiac Care Network of Ontario. The occurrence of operative mortality and nine predefined major complications (myocardial infarction, bleeding, stroke, renal failure, balloon pump use, mediastinitis, respiratory failure, life-threatening arrhythmia, and sepsis) was compared between the CPB and OPCAB groups using Wilcoxon, Fisher exact, and two-tailed t tests, as well as CUSUM methodology. An intention to treat analysis was performed. The CPB and OPCAB groups had similar predicted mortality and length of stays (2.2% +/- 2.5%, 8.1 +/- 2.5 days versus 2.4% +/- 3.5%, 8.1 +/- 2.4 days, respectively). The mean number of grafts per patient was 3.1 +/- 0.7 in the CPB group versus 3.0 +/- 0.7 in the OPCAB group (p = 0.45). Two of 55 (3.6%) CPB patients died, as opposed to 1 of 55 (1.8%) OPCAB patients (p = 0.99). Eight of 55 CPB patients (14.5%) incurred major complications, as opposed to 4 of 55 (7.3%) OPCAB patients (p = 0.36). Median hospital length of stay was 6.0 days in the CPB group versus 5.0 days in the OPCAB group (p = 0.28). On CUSUM analysis, the failure curve in CPB patients approached the upper 80% alert line after eight cases, whereas the curve in OPCAB patients reached below the lower 80% (reassurance) boundary 28 cases after the policy change, indicating superior results in the OPCAB group despite the learning curve. A policy change from coronary artery bypass on CPB to routinely attempting OPCAB can be accomplished safely despite the learning curve. CUSUM analysis was more sensitive than standard statistical methods in detecting a cluster of surgical failures and successes.


Impact of obesity on gynecology.
Rising obesity rates around the world have had a profound impact on female reproductive health. Childhood obesity is associated with early onset of puberty, menstrual irregularities during adolescence and polycystic ovary syndrome. Women of reproductive age with high BMIs have a higher risk of ovulatory problems and tend to respond poorly to fertility treatment. Strategies for fertility control can also be complex since the efficacy and safety of hormonal contraceptives can be compromised by increased body weight. Obesity can aggravate symptoms of pelvic organ prolapse, stress urinary incontinence and increase the risk of endometrial polyps and symptomatic fibroids. Weight reduction enhances reproductive outcomes, diminishes symptoms of urinary incontinence and reduces morbidity following gynecological surgery. Sustained and substantial weight loss is difficult to achieve with the lifestyle and dietary measures that are currently available. A number of pharmacological treatment options are available, and there are emerging data on reproductive outcomes following surgical treatment for obesity.


Electroporation, an alternative to biolistics for transfection of Bombyx mori embryos and larval tissues.
There are few powerful techniques available to transfect insect tissues. We previously used biolistics to transfect Bombyx mori embryos, and larval and pupal tissues (Thomas J-L et al. 2001. Journal of Insect Science 1/9, Kravariti L et al. 2001. Insect Biochemistry and Molecular Biology 31: 473-479). As the main limitation was the irregularity in results we explored electroporation as an alternative technique by adapting techniques used for chicken embryos to B. mori embryos. By injecting the DNA solution into the hemocoel of late embryos that were finishing organogenesis, we expressed marker genes in numerous tissues following electroporation. With some adaptation of the method this was also achieved for early embryos lacking a hemocoel. Some larval tissues were also transfected. During these technical studies we found that optimizing parameters such as electrical voltage, number of pulses and their frequency, and conductivity of the buffer was important. These results confirmed that electroporation is a reliable technique for transfecting B. mori tissues.


Estradiol Valerate Enhances Cardiac Function via the Nrf2 Signaling Pathway to Protect Against Oxidative Stress by the Nrf2 Signaling Pathway in an Ovariectomized Rat Model.
The increased risk of cardiovascular disease (CVD) in postmenopausal women and ovariectomized patients suggests that estrogen has a protective effect on cardiac function. Oxidative stress is the main cause of CVD, and the cellular defensive Nrf2 antioxidant pathway plays a protective role in various pathologies. However, the regulation of Nrf2 by estrogen has received little attention. The present study aimed to investigate the role of Nrf2 in the effect of estrogen on cardiac function. In the present study, female SD rats were divided into three groups as follows: sham operation (SHAM), bilateral ovariectomy (OVX) and bilateral ovariectomy with estradiol valerate (EV) supplementation (OVX+EV). Vaginal smears and E2 concentrations were used to confirm the success of the model. We compared cardiac morphology and function by echocardiography and HE staining. The levels of oxidative stress markers and antioxidant enzymes as well as protein expression of antioxidant genes were evaluated by Western blotting and immunohistochemistry. Our results showed that supplementation with estrogen restored the parameters to some extent. Left ventricular end diastolic diameter at diastolic (LVID;d) and left ventricular volume at diastolic (LV vol;d) increased but MV E wave/A wave (E/A) significantly decreased. The oxidative stress indicators (malondialdehyde) increased, and the antioxidant activity indicators, such as superoxide dismutase (SOD) and catalase (CAT), decreased. Further, the expression of most Nrf2 antioxidant pathway-related proteins in the heart decreased after ovariectomy. The present study demonstrated that estrogen may protect cardiac function by regulating antioxidant capacity through the Nrf2 pathway.


Enzymic degradation of sorghum glucuronoarabinoxylans leading to tentative structures.
Three glucuronoarabinoxylan (GAX) populations, obtained from water-unextractable cell wall material from sorghum by different alkali extractants, were digested by combinations of endo-xylanases (Xyl I, Xyl III and GXH), arabinofuranosidases (AXH and AraB) and an alpha-glucuronidase (GlcAase). All three GAX populations were shown to be rather poorly degradable, due to the very high degree of substitution, as well as the substitution pattern. The barium hydroxide-extracted GAX showed a maximum degree of degradation of almost 12%, using Xyl I combined with GXH and AXH. The GAX population extracted by 4 M KOH was hardly degraded by any of the tested combinations. In all cases, Xyl III showed lowest activity upon the three extracts. Synergistic effects were observed between Xyl I and AXH. Both neutral and acidic arabinoxylan oligomers were formed. The GlcAase acted only upon oligomeric material released by Xyl I. No synergistic effects were observed between the GXH and AXH. Combining the patterns of degradation with the modes of action of the enzymes, structures were proposed for the different populations of sorghum GAX. Evidence was obtained that the xylan backbone of especially the GAX extracted by 4 M KOH, is substituted by arabinose and glucuronic acid according to a strict pattern, which hinders the enzymes to act.


Phillip V. Tobias as an anatomist.
The article outlines the career of the renowned South African scientist Phillip Vallentine Tobias. While he made substantial contributions to a number of scientific disciplines, Tobias spent most of his career teaching anatomy at his alma mater, University of the Witwatersrand, Johannesburg, and saw himself primarily as an anatomist. The first part of this article presents Tobias' major contributions to science and demonstrates that his profound knowledge of anatomy was the basis of many of his groundbreaking research accomplishments. The second part of the article focuses on Tobias' career in anatomy and his significant contribution to anatomy teaching and administration, particularly in establishing and organizing the Anatomical Society of Southern Africa. The article also demonstrates how Tobias' academic career was constrained by the oppressive system of apartheid South Africa and how social engagement was an integral part of his intellectual activities.