Conjugate of Enkephalin and Temporin Peptides as a Novel Therapeutic Agent for Sepsis.

Antimicrobial peptides (AMPs) exhibit a wide spectrum of actions, ranging from a direct bactericidal effect to multifunctional activities as immune effector molecules. The aim of this study was to examine the anti-inflammatory properties of a DAL-PEG-DK5 conjugate composed of a lysine-rich derivative of amphibian temporin-1CEb (DK5) and dalargin (DAL), the synthetic Leu-enkephalin analogue. Detailed study of the endotoxin-neutralizing activity of the peptide revealed that DAL-PEG-DK5 interacts with LPS and the LPS binding protein (LBP). Moreover, DAL-PEG-DK5 prevented dimerization of TLR4 at the macrophage surface upon LPS stimulation. This inhibited activation of the NF-κB signaling pathway and markedly reduced pro-inflammatory cytokine production. Finally, we showed that aggregation of DAL-PEG-DK5 into amyloid-like structures induced by LPS neutralized the endotoxin proinflammatory activity. Consequently, DAL-PEG-DK5 reduced morbidity and mortality in vivo, in a mouse model of endotoxin-induced septic shock. Collectively, the data suggest that DAL-PEG-DK5 is a promising therapeutic compound for sepsis.

Flexibility of foraging strategies of the great skua Stercorarius skua breeding in the largest colony in the Barents Sea region.

BACKGROUND: Foraging strategies of seabird species often vary considerably between and within individuals. This variability is influenced by a multitude of factors including age, sex, stage of annual life cycle, reproductive status, individual specialization and environmental conditions. RESULTS: Using GPS-loggers, we investigated factors affecting foraging flight characteristics (total duration, maximal range, total distance covered) of great skuas Stercorarius skua of known sex breeding on Bjørnøya, Svalbard, the largest colony in the Barents Sea region. We examined influence of sex (females are larger than males), phase of breeding (incubation, chick-rearing), reproductive status (breeders, failed breeders) and bird ID (they are known for individual foraging specialization). Our analyses revealed that only bird ID affected foraging flight characteristics significantly, indicating a high degree of plasticity regardless of sex, reproductive status or phase of breeding. We recognized three main groups of individuals: 1) those preying mainly on other seabirds in the breeding colonies (6%), 2) those foraging at sea (76%) and kleptoparasiting other seabirds and/or foraging on fish and/or offal discarded by fishing vessels, and 3) those alternating between preying on other seabirds in breeding colonies and foraging at sea (18%). Despite marked size sexual dimorphism, we found no apparent sex differences in flight characteristics. Birds after egg- or chick-loss and thus not constrained as central foragers did not modify their foraging flights. CONCLUSIONS: Great skuas breeding on Bjørnøya displayed a high degree of plasticity regardless of sex, reproductive status or phase of breeding. We recognized groups of individuals regularly preying in the seabird colonies, foraging at sea, and alternating between both strategies. This suggests foraging specialization of some individuals.

ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives.

Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare.

Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation.

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

Repeated co-treatment with mirtazapine and aripiprazole reversed the schizophrenia-like behaviors and increased the brain-derived neurotrophic factor mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal brain development.

Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.

Application of optimization algorithms to adaptive motion control for repetitive process.

The application of optimization algorithms to adaptive motion control is proposed in this paper. In order to provide optimal system response, optimization algorithm is used as adjustment mechanism of controller coefficients. Most of optimization algorithms are not able to work in continuous optimization mode and with non-constant search space (i.e. dataset). For this reason, the introduction of a novel approach, Adaptive Procedure for Optimization Algorithms (APOA), that allows to apply most of optimization algorithms to adaptation process seems to be necessary. Such an algorithm is innovative, due to its universality in terms of applied optimization algorithm. Its application allows to obtain optimal motion control in modern electric drives. The proposed APOA is presented together with the novel desired-response adaptive system (DRAS) approach for repetitive processes. This solution provides unchanged system response regardless of plant parameters variation or external disturbances. The developed adaptive approach based on optimization algorithm is implemented in permanent magnet synchronous motor (PMSM) drive to adapt state feedback speed controller during moment of inertia variations. Since the proposed DRAS is model-free approach, the adaptation procedure is immune to issues related to plant parameters mismatch. The obtained results prove that proposed adaptive speed controller for PMSM assures desired system response regardless of the moment of inertia variation.

High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

[Hormonal (levonorgestrel) emergency contraception--effectiveness and mechanism of action]. / Antykoncepcja dorazna z uyciem lewonorgestrelu--skutecznosc i mechanizm dzialania.

Periodic abstinence and coitus interruptus are the most popular methods of contraception in Poland. Recent studies have provided us with evidence that the so-called "menstrual calendar" may be much less effective than it was believed. In these circumstances, promotion and use of safe and truly effective contraceptives is very important for Polish women. Emergency contraception (EC) is a method which could be used even in cases when other contraception methods have failed. Mechanism of action of levonorgestrel used for EC and possible disturbances in the process of implantation of the blastocyst in the endometrium, remain the source of heated discussion among medical professionals. The latest publications provide us with evidence that the use of levonorgestrel in EC neither alters endometrial receptivity nor impedes implantation. Hormonal EC effectiveness is another hot topic of gynecological endocrinology and statistics. There is, however, no better, safer, and more ethically accepted method of preventing unwanted pregnancy for patients in need of postcoital contraception.

Flexibility of little auks foraging in various oceanographic features in a changing Arctic.

Using GPS-tracked individuals, we compared foraging ecology and reproductive output of a High-Arctic zooplanktivorous seabird, the little auk Alle alle, between three years differing in environmental conditions (sea surface temperature). Despite contrasting environmental conditions, average foraging fights distance and duration were generally similar in all studied years. Also, in all years foraging locations visited by the little auk parents during short trips (ST, for chick provisioning) were significantly closer to the colony compared to those visited during long trips (LTs, mainly for adults' self-maintenance). Nevertheless, we also found some differences in the little auk foraging behaviour: duration of LTs was the longest in the coldest year suggesting more time for resting for adults compared to warmer years. Besides, birds foraged closer to the colony and in significantly colder water in the coldest year. Interestingly, these differences did not affect chick diet: in all the years, the energy content of food loads was similar, with the Arctic copepod, Calanus glacialis copepodite stage V being the most preferred prey item (>73% of items by number and >67% by energy content). Also chick survival was similar in all the study years. However, when examining chicks growth rate we found that their peak body mass was lower in warmer years suggesting that overall conditions in the two warm years were less favourable. While our results, demonstrate a great foraging flexibility by little auks, they also point out their vulnerability to changing environmental conditions.

To add or not to add probiotics to infant formulae? An updated systematic review.

We updated evidence on the effects of the administration of probiotic-supplemented infant formulae (IF) compared with unsupplemented IF. Five databases were searched up to September 2016 for randomised controlled trials. Twenty publications were identified, including five new RCTs. Supplementation of IF with Bifidobacterium lactis Bb12, either alone or with Streptococcus thermophilus, had no effect on growth, respiratory illness, antibiotic use, stool frequency or consistency. However, there was a significant reduction in the number of episodes of gastrointestinal infections (Bb12) and a lower frequency of colic or irritability (when both strains were used). Lactobacillus johnsonii La1 had no effect on growth, gastrointestinal infections, or respiratory illness episodes. There were no effects of supplementation of IF with Bifidobacterium longum BL999, alone or with Lactobacillus rhamnosus LPR. L. rhamnosus GG was associated with better growth; it had no effect on colic/crying, or irritability, and it was associated with greater indexes of loose stools and a higher defecation frequency. Lactobacillus reuteri ATCC 55730 had no effect on growth, colic, crying, irritability, respiratory illness, antibiotic use, stool frequency, or stool consistency; however, it reduced the number of episodes of diarrhoea. L. reuteri DSM 17938 had no effect on growth, night-time sleeping, or flatulence, but it reduced the number of spitting episodes. Lactobacillus salivarius CEC5713 had no effect on growth, colic, crying, or irritability; however, it resulted in a significant reduction in the rate of diarrhoea and the number of episodes of respiratory symptoms. In conclusion, the administration of probiotic-supplemented formulae to healthy infants does not raise safety concerns with regard to growth and adverse effects. Some beneficial clinical effects are possible; however, there is no existing robust evidence to recommend their routine use. The latter conclusion may reflect the small amount of data on a specific probiotic strain(s) and outcomes, rather than a genuine lack of an effect.

Habitat foraging niche of a High Arctic zooplanktivorous seabird in a changing environment.

Here, we model current and future distribution of a foraging Arctic endemic species, the little auk (Alle alle), a small zooplanktivorous Arctic seabird. We characterized environmental conditions [sea depth, sea surface temperature (SST), marginal sea ice zone (MIZ)] at foraging positions of GPS-tracked individuals from three breeding colonies in Svalbard: one located at the southern rim of the Arctic zone (hereafter 'boreo-Arctic') and two in the high-Arctic zone on Spitsbergen ('high-Arctic'). The birds from one 'high-Arctic' colony, influenced by cold Arctic water, foraged in the shallow shelf zone near the colony. The birds from remaining colonies foraged in a wider range of depths, in a higher SST zone ('boreo-Arctic') or in the productive but distant MIZ (second 'high-Arctic' colony). Given this flexible foraging behaviour, little auks may be temporarily resilient to moderate climate changes. However, our fuzzy logic models of future distribution under scenarios of 1 °C and 2 °C SST increase predict losses of suitable foraging habitat for the majority of little auk colonies studied. Over longer time scales negative consequences of global warming are inevitable. The actual response of little auks to future environmental conditions will depend on the range of their plasticity and pace of ecosystem changes.

Swaziland's Traditional Birth Attendants Survey.

The Traditional Birth Attendants (TBAs) Survey in Swaziland was undertaken between March 27th 1996 and April 8th 1996. The objective of the survey was to generate reliable information regarding activities of TBAs in Swaziland. The survey was conducted in 25 Chiefdoms sampled out of a total of 206 Chiefdoms registered in Swaziland. The total number of sampled respondents in the 25 Chiefdoms was 721. From the survey, it is estimated that there were probably 3000 TBAs in the country, and in the majority of cases such TBAs would be a 51-year old woman who herself had delivered six children and had worked as a TBA for at least 10 years. Between 9,000 and 12,000 deliveries are estimated to take place out of health facilities. Of these many, nearly 43.5% are assisted by "TBAs"; 16.3% of woman interviewed deliver relative/family member and 15.1% are assisted by friends/neighbours, etc. Some of TBAs carry out procedures which are considered to be potentially harmful. Nearly 30% of TBAs have administered herbs; 45% attend to abnormal deliveries (breech and multiple pregnancies); 26.7% re-use their cord cutting tools and in the case of haemorrhage 23.4% do manual procedures within reproductive tract of delivering women.

The effectiveness of a body mass reduction program in obese women in perimenopausal and menopausal age compared with the effectiveness of such a program in younger (18-44 years of age) women living in Poland.

OBJECTIVE: The aim of the work was: to compare the effectiveness of body mass reducing program in women of perimenopausal (and menopausal) age with the effectiveness of such a program when it was applied to women aged 18-44 years. METHODS: The paper deals with observation study of the group of obese patients recruited and treated in Bialystok's Clinical Center for Cardiology and Body Mass Reduction. The authors summarize 12 months of clinical observation (as it was initially planned) of the two groups of obese women, taking part in the special body mass reduction program; Group I - 81 women in perimenopausal and menopausal age, Group II - 107 women in 18-44 years of age. The proposed treatment contained diet, physical exercises, psychological support and pharmacotherapy. RESULTS: The positive reaction for the treatment of obesity was less visible in obese women in perimenopausal and menopausal age, than in the group of obese women in 18-44 years of age (change of BMI in the group of younger women was -3.44 kg/m2 vs. -2.65 kg/m2 in older women). As it was observed, the weaker reaction for the proposed treatment in the group of older women, was not related to lower BMR, than in the group of younger obese women. Provisional result shows that use of HRT (Hormonal Replace Therapy) may probably result in better response of body mass reduction in perimenopausal and menopausal women. CONCLUSION: The high dropout of the patients included into the study does not allow to formulate unequivocal conclusions but it seems that body mass reduction program for women in perimenopausal and menopausal age should concentrate on building the motivation of the patients, HRT may play some role in improvement of effectiveness of such program but this should be confirmed by further studies.

Systematic review with meta-analysis: early infant feeding and coeliac disease--update 2015.

BACKGROUND: New evidence emerged on early feeding practices and the risk of coeliac disease. AIM: To systematically update evidence on these practices to find out whether there is a need to revise current recommendations. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from July 2012 (end of last search) to February 2015 for studies of any design that assessed the effect of gluten consumption and breastfeeding on the development of coeliac disease and/or coeliac disease-related autoimmunity. RESULTS: We identified 21 publications, including two, new, large, randomised controlled trials performed in high-risk infants. Exclusive or any breastfeeding, as well as breastfeeding at the time of gluten introduction, did not reduce the risk of developing coeliac disease during childhood. For infants at high risk of developing coeliac disease, gluten introduction at 4 months of age in very small amounts, or at 6 or 12 months of age, resulted in similar rates of coeliac disease diagnosis in early childhood. Later gluten introduction was associated with later development of coeliac specific autoimmunity and coeliac disease during childhood, but not total risk reduction. Observational studies indicate that consumption of a higher amount of gluten at weaning may increase the risk for coeliac disease development. CONCLUSIONS: Infant feeding practices (breastfeeding, time of gluten introduction) have no effect on the risk of developing coeliac disease during childhood (at least at specific timeframes evaluated in the included studies), necessitating an update of current European recommendations.

Delayed upregulation of GABA(A) alpha1 receptor subunit mRNA in somatosensory cortex of mice following learning-dependent plasticity of cortical representations.

Experience-dependent modifications of cortical representational maps are accompanied by changes in several components of GABAergic inhibitory neurotransmission system. We examined with in situ hybridization to 35S-labeled oligoprobe changes of expression of GABA(A) receptor alpha1 subunit mRNA in the barrel cortex of mice after sensory conditioning training. One day and 5 days after the end of short lasting (3 daily sessions) training an increased expression of GABA(A) alpha1 mRNA was observed at the cortical site where the plastic changes were previously found. Learning associated activation of the cerebral cortex increases expression of GABA(A) receptor mRNA after a short post-training delays.

PSD95 protein level rises in murine somatosensory cortex after sensory training.

Proteins of the postsynaptic density are implicated in mechanisms of synaptic plasticity. We examined involvement of PSD95 and alphaCaMkII in learning-dependent plastic changes of representational maps in somatosensory cortex of mice. The barrel cortex of mice was examined following a 3 day long classical conditioning training, in which activation of facial vibrissae was linked to an aversive stimulus. This procedure produced expansion of cortical representations of vibrissae involved in the training. In subcellular fraction enriched in postsynaptic densities from the barrel cortex, it was estimated by Western blotting that the level of PSD95 increased after the training by about 50%, while the level of CaMkII remained unchanged. The results indicate involvement of PSD95 in learning-dependent cortical plasticity.

[Non-clinical factors in decision making about cesarean section]. / Pozakliniczne uwarunkowania w podejmowaniu decyzji o cieciu cesarskim.

Increasing cesarean-section rates have focused attention on variation in the use of this procedure that appear to be not only dependent of medical indication. This suggestion has been checked on the basis of newly implemented special forms in hospitals located in some areas of Poland in 1990. Documentation of 11.813 live births (almost 100% of live births in described area) has been analysed. It has been found 13.2% cesarean-section rate and 2.0% rate of other operative deliveries. Majority of cesarean sections have been medically indicated. But it has been also found that highest level of mothers education has been directly linked with higher rates of cesarean section. This linkage has been stronger than any other association (with age, parity etc.). Poland as a country, is divided for several regions subordinated to particular hospitals. It has been found that some of the patients have been admitted not to regional hospitals. We conclude that cesarean section rate among these patients was higher than this same ratio among all other patients admitted for deliveries in these hospitals. This association cannot be accounted for by differences in maternal age, parity, birth weight etc.

[Territorial distribution of neural tube defects in Poland]. / Zróznicowanie terytorialne wystepowania wad cewy nerwowej w Polsce.

Neural tube defects (ntd) remain unresolved therapeutic problems, even for contemporary health services. Prophylactic measures are the best methods for limitation of the problem. In many countries, the number of children born with ntd has been reduced significantly, even in 4-5 folds. Authors found that the situation in Poland remains stable since last 20 years. Epidemiological evaluation of the ntd morbidity in Poland is very difficult. There is no National Register of Inherited Defects. Authors observed and analysed mortality and hospitalisation due to ntd in Poland, in early ninetees, and compared these data with information originated from Regional (Wielkopolska) Inherited Defects Register. It was found that ntd mortality and hospitalisation in Wielkopolska was similar to average in Poland. It has been estimated that the rate of children born with ntd in Poland, in 1995 was 2.68 per 1000 live and stillbriths (in 1972-1974 was 2.04). Especially high rates of ntd's have been found in north-eastern part of Country. Incidence of ntd's was higher in rural, than in urban population of the Country.

[Large-scale screening for early diagnosis of gestational diabetes mellitus (GDM)]. / Wczesne rozpoznawanie cukrzycy ciazowej w populacyjnych badaniach przesiewowych.

The aim of study was to evaluate incidence of GDM in Poland. All 1500 pregnant women between 24-28 week's gestation consulted in 4 centers were offered a 50 g oral glucose test (screening test). Capillary blood glucose was measured at 60 min after glucose ingestion. When blood glucose > 140 mg/dl, 75 g OGTT according to WHO criteria was performed. 241 women have abnormal screening test and in 181 cases blood glucose were at range 140-160 mg/dl, in 39 at range 160-180 and 21 were > 180 mg/dl. Only 14 women in the first group (140-160 mg/dl) have diagnosed GDM (7.7%). In second group 24 pregnant women have GDM (61.5%). Overall GDM incidence is shown to be 3.7% (57 women). The mean age for the GDM was 28.8 +/- 0.9 years compared with 26.4 +/- 0.4 years (p < 0.05) uncomplicated pregnancy.

[The value of skin densitometry in diagnosis of decreased bone mass in the spine of women during the period around and post-menopause]. / Wartosc densytometrii skórnej w diagnostyce zmniejszenia masy kostnej kregoslupa u kobiet w okresie okolo i pomenopauzalnym.

OBJECTIVE: In peri- and postmenopausal women, the association of skin thickness with bone mass is well described, and a low skin thickness is a useful predictor of osteoporosis. In this study the association between skin thickness and bone mass of lumbar spine in peri- and postmenopausal women was assessed; and the potential for skin thickness as a screening test for osteoporosis evaluated. DESIGN/METHODS: Skin thickness was measured at the arm by ultrasonography (probe 22 MHz). Bone mass was measured at lumbar spine by dual-energy X-ray absorptiometry. One hundred and three peri- and postmenopausal women were studied. RESULT: Successive decrease of skin thickness going along with the loss of lumbar spine bone mass was found. There was a statistically significant difference (p < 0.05) in skin thickness between group of females with normal bone mass and group with osteoporosis. CONCLUSIONS: Ultrasound skin measurement is a very simple method which can be used in the diagnostics of osteoporosis of the lumbar spine in peri- and postmenopausal women.