Statement on gender-affirmative approach to care from the pediatric endocrine society special interest group on transgender health.
The purpose of this Position Statement is to emphasize the importance of an affirmative approach to the health care of transgender individuals, as well as to improve the understanding of the rights of transgender youth. Transgender youth have optimal outcomes when affirmed in their gender identity, through support by their families and their environment, as well as appropriate mental health and medical care. The Pediatric Endocrine Society Special Interest Group on Transgender Health joins other academic societies involved in the care of children and adolescents in supporting policies that promote a safe and accepting environment for gender nonconforming/transgender youth, as well as adequate mental health and medical care. This document provides a summary of relevant definitions, information and current literature on which the medical management and affirmative approach to care of transgender youth are based.


Procedural text structure and reader perceptions and performance.
This research tested the relationship between text structural variables (on vs. off the causal chain, active vs. static information, and hierarchical structure) and reader perceptions, reading time, and true-false performance for procedural texts. Twenty-four college-age participants each read 3 procedural texts. As predicted, sentences that were (a) on the causal chain, (b) active, and (c) associated with task steps were read more slowly and judged to be more important (p < .05). The results were similar to those previously found with narratives, except for the hierarchical structure variable. Also as predicted, text differences were found such that as the variation in the type of information contained in the text increased, relationships with the structural variables increased.


Generation of the Becker muscular dystrophy patient derived induced pluripotent stem cell line carrying the DMD splicing mutation c.1705-8 T>C.
Becker Muscular dystrophy (BMD) is an X-linked syndrome characterized by progressive muscle weakness. BMD is generally less severe than Duchenne Muscular Dystrophy. BMD is caused by mutations in the dystrophin gene that normally give rise to the production of a truncated but partially functional dystrophin protein. We generated an induced pluripotent cell line from dermal fibroblasts of a BMD patient carrying a splice mutation in the dystrophin gene (c.1705-8 T>C). The iPSC cell-line displayed the characteristic pluripotent-like morphology, expressed pluripotency markers, differentiated into cells of the three germ layers and had a normal karyotype.


The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels following erector spinae plane block (ESPB) in posterior lumbar decompression: a randomized, controlled trial.
Neutrophile-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are the inflammatory biomarkers of the stress response. In this study, we aimed to evaluate the effects of erector spinae plane block (ESPB) on posterior lumbar decompression and stabilization by comparing NLR, PLR, postoperative pain, opioid consumption, and functional recovery between sham block and ESPB. This was a prospective, double-blinded, randomized controlled trial in a tertiary referral hospital. Sixty patients were randomized into two equal groups, each receiving either a sham block or ESPB. The primary outcome was the NLR and PLR 12 h and 24 h after lumbar posterior decompression and stabilization. The secondary outcomes were total opioid consumption and pain score 24 h postoperatively. Also, functional recovery determined by getting out of bed, verticalization, and walking by the balcony were reviewed as secondary outcomes. Significant differences existed between the sham block and ESPB group in NLR (29.08 ± 12.29 vs. 16.97 ± 10.38; p < 0.0001) and PLR (556.77 ± 110.32 vs. 346.43 ± 117.34; p < 0.0001) 12 h after surgery. Also, there was a significant difference in NLR (p = 0.0466) and PLR (p < 0.0001) 24 h after surgery. In addition, there was a substantial difference in pain score, total opioid consumption, and functional recovery. ESPB performance during spinal surgery lowers NRL and PLR ratios 12 h and 24 h after surgery. In addition, ESPB provides better analgesia and improves functional recovery compared to sham block following posterior lumbar decompression and stabilization.


Reciprocal relationships between blood lactate and hemorheology in athletes: another hemorheologic paradox?
Blood lactate increases during exercise. Although this increase was classically interpreted as a "Pasteur-like effect" resulting from anaerobiosis, it is now clear that it mostly results from a shift in the balance of oxidation of substrates in the muscle, with carbohydrate becoming the predominant fuel. However, we have repeatedly observed that the rise in blood lactate during exercise is correlated to blood viscosity and red cell aggregation. More recently we investigated this issue with the modelling of postexercise lactate kinetics, that allows a fair evaluation of lactate production by muscles (gamma1) and lactate disappearance (gamma2). Postexercise red cell aggregation (Myrenne M1) appears to be correlated to gamma2. Thus microcirculatory adaptations influenced by red cell aggregation may influence lactate disposal, adding its effect to that of the balance between carbohydrates and fat. On the other hand, the rise in blood lactate seems to induce some alterations in erythrocyte rheology at exercise. Correlations between its concentrations during exercise and erythrocyte rigidity support the concept that lactate, at least when it rises above the 4 mmol.l(-1) threshold impairs red cell deformability. Moreover, it seems that endurance training influences erythrocyte response to lactate. While lactate did not in vitro affect erythrocyte aggregation, it impaired (as expected) erythrocyte deformability in sedentary subjects but it (unexpectedly) improved it in trained subjects. This difference may be due to training-induced adaptations in erythrocyte metabolism, including transmembrane transfer via monocarboxylate transporters which show marked alterations in this context. This specific training-induced pattern of response to lactate may provide an alternative explanation to the exercise-induced arterial hypoxemia that occurs in such athletes.


Changes in food bolus texture during mastication.
The purpose of this study was to survey the changes that occur in bolus texture from intake to swallowing during the mastication process for four types of food materials and to identify how texture is related to the number of chews. We recruited 15 young Japanese participants for this study. The subjects were asked to spit the food bolus just before swallowing when eating four different foods: cracker, boiled rice, hard gelatine gel, and soft gelatine gel. Three physical properties (hardness, adhesiveness, and cohesiveness) were measured in the bolus after being chewed for 25, 50, 75, 100, and 125% of the normal number of chews. Occlusal force and pressure as well as stimulated whole saliva volume were also measured. Extensive variation in the number of chews existed between subjects, but minimal intra-subject variation was observed. Hardness was observed to decrease, whereas cohesiveness and adhesiveness increased in a chew-dependent manner for the cracker, soft gelatine gel, and hard gelatine gel, but not boiled rice. Bolus texture appears to be largely related to the number of chews. Hardness also tended to be influenced by occlusion. The adhesiveness and hardness of the boiled rice were also greatly influenced by saliva volume and occlusal force, respectively. Hardness is an important rheological factor in food bolus texture and likely plays a significant role in determining the appropriate number of chews. Adhesiveness and cohesiveness appear to be secondary factors in this process. We propose a model of oral processing for application in determining the appropriate number of chews for an individual. Hardness appears to be an important rheological factor in food bolus texture, with adhesiveness and cohesiveness being secondary aspects. When food is hard or difficult to swallow, chewing behavior will likely be more influenced by the perception of bolus texture.


[Prevention of pertussis and high expectations concerning vaccines].
The basic vaccine used in the prevention of pertussis is the combined vaccine including a whole cell pertussis component and tetanus and diphtheria toxoids. Although this type of vaccine has been used more than 50 years in USA and more than 40 years in Poland it is still effective what can be evidenced by the decreased number of pertussis cases since the vaccine has been implemented. There are however some evidences that the whole cell vaccine may lead to the acute encephalopathy, fever seizures, hypotonic-hyporeactive episodes, inconsolable crying or anaphylactic reactions. But still is a lack of convincing evidences that the vaccine may be a cause of persistent brain damage. It was also shown that the longer is the period after the last dose of the vaccine the lower effectiveness was observed. Improving the safety of the pertussis vaccine was the reason of introducing the acellular vaccines in the eightieth. All these products contain pertussis toxoid and some of them contain also filamentous hemagglutinin, pertactin and fimbrial agglutinogens. Some published studies have shown that the effectiveness of these vaccines is similar to the whole cells vaccines and that the incidence of some adverse events especially seizures, hypotonic-hyporeactive episodes and inconsolable crying is lower.


Sensitivity enhancement in structural measurements by solid state NMR through pulsed spin locking.
Free induction decay (FID) signals in solid state NMR measurements performed with magic angle spinning can often be extended in time by factors on the order of 10 by a simple pulsed spin locking technique. The sensitivity of a structural measurement in which the structural information is contained in the dependence of the integrated FID amplitude on a preceding evolution period can therefore be enhanced substantially by pulsed spin locking in the signal detection period. We demonstrate sensitivity enhancements in a variety of solid state NMR techniques that are applicable to selectively isotopically labeled samples, including 13C-15N rotational echo double resonance (REDOR), 13C-13C dipolar recoupling measurements using the constant-time finite-pulse radio-frequency-driven recoupling (fpRFDR-CT) and constant-time double-quantum-filtered dipolar recoupling (CTDQFD) techniques, and torsion angle measurements using the double quantum chemical shift anisotropy (DQCSA) technique. Further, we demonstrate that the structural information in the solid state NMR data is not distorted by pulsed spin locking in the detection period.


Non-synaptic cholinergic modulation of neurogenic twitches of the guinea-pig ileum.
The effect of cholinergic and anticholinergic compounds on conduction of neuronal excitation has been studied in myenteric plexus-longitudinal muscle strips from the guinea-pig ileum. A preparation in a special triple bath was drawn through two rubber membranes dividing the strip into three segments. Neurogenic stimulation of the oral segment set up nerve action potentials propagating aborally across the middle segment (10 mm) so that the aboral segment might be also invaded, eventually. Drugs were added to the middle segment to affect neuronal propagation (non-synaptic effects) which was monitored by twitch height of the aboral segment. The application of acetylcholine to the middle segment augmented aboral twitches. The effects of nicotine, pilocarpine and oxotremorine were selectively blocked by (+)-tubocurarine, pirenzepine and atropine, respectively. The effect of acetylcholine was suppressed by pirenzepine and atropine and mimicked by doubling of KCl concentration. The effect of acetylcholine may be thus explained by the facilitated propagation of nerve action potentials in partially depolarized cholinergic terminals via stimulation of muscarinic receptors. The adenylate cyclase system is not directly involved in the mechanism of muscarinic facilitation of neuronal propagation in the terminals; however, it may participate in the modulation of a final common effector mechanism.


Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer.
Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index ≥ 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link.


Efficacy and safety of cefprozil versus other beta-lactam antibiotics in the treatment of lower respiratory tract infections.
Cefprozil was evaluated in four multicentre comparative studies in the treatment of acute respiratory tract infections. In two studies, cefprozil 500 mg q. 12 hours was compared to cefaclor 500 mg q. eight hours for ten days of therapy. Randomization was on a 2:1 (cefprozil:cefaclor) basis in the European centres and 1:1 in North America. The clinical efficacy in acute bronchitis was 88% (284 out of 324 patients) for cefprozil and 88% (183 out of 208) for cefaclor, with successful bacteriological eradication of the causative pathogen in 86% and 82% of the patients, respectively. Amongst the patients with acute exacerbations of chronic bronchitis, the clinical response rate of 80% (59 out of 74) for cefprozil appeared superior to that of cefaclor at 62% (p = 0.067), whilst the bacteriological response rates were 62% (36 out of 58) for cefprozil and 74% (20 out of 27) for cefaclor. In pneumonia, the clinical response rates for cefprozil and cefaclor therapy were similar, 82% vs. 79%, although bacteriological eradication rates were better for cefprozil at 82% than for cefaclor at 71%. In the comparison of cefprozil with cefuroxime axetil, a total of 170 patients were evaluable. The clinical and bacteriological response rates for cefprozil of 95% and 100% were better than those for cefuroxime axetil 500 mg q. 12 hours of 84% and 75%, respectively. In the cefprozil vs. amoxicillin-clavulanate, 500 mg q. eight hours comparative study, the two antibiotics displayed no significant difference in clinical or bacteriological responses.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis of the first rNHC (remote N-heterocyclic carbene) complexes with no heteroatom in the carbene carbon-containing ring.
Two cationic carbene complexes with no heteroatom in the ring containing the carbene carbon, trans-bromo(2-methyl-2,6-dihydroisoquinolin-6-ylidene)bis(triphenylphosphine)palladium(II) triflate (3) and trans-chloro(1,2-dimethyl-1,7-dihydroquinolin-7-ylidene)bis(triphenylphosphine)palladium(II) triflate (4), were synthesized by oxidative substitution of Pd(PPh3)4 with N-methylated 6-bromoisoquinolinium and 7-chloro-2-methylquinolinium cations, respectively. Compound 3 was also prepared by methylation of neutral trans-bromo(2-methylisoquinolin-6-yl)bis(triphenylphosphine)palladium(II) (5). All complexes were unambiguously characterized by NMR and X-ray crystallographic studies.


Functional classification of peripheral T-cell lymphomas as an approach to improve outcome prediction and therapy selection.
Many types of peripheral T-cell lymphoma (PTCL) are currently classified by the World Health Organization (WHO) based on their predominant site of organ involvement (eg, intestinal or cutaneous types). However, this approach and traditional staging scores such as the IPI can provide limited prognostic information, especially in those PTCL types where morbidity and mortality are primarily related to immune dysregulation and cytokine syndromes driven by the lymphoma cells. These "immune participatory" PTCLs (including, commonly, angioimmunoblastic T-cell lymphoma and many extranodal types) can therefore have poor outcomes even at low tumor burdens. For these reasons, a classification that includes functional profiling of the lymphoma cells may add valuable prognostic information. Such data, including cytokine expression patterns and T-cell receptor signaling pathway activation status, whether normal or abnormal, need to be considered in future classification systems, especially when incorpating targeted therapy.


Prohexadione-calcium alleviates the leaf and root damage caused by salt stress in rice (Oryza sativa L.) at the tillering stage.
Salt stress, as a principal abiotic stress, harms the growth and metabolism of rice, thus affecting its yield and quality. The tillering stage is the key growth period that controls rice yield. Prohexadione-calcium (Pro-Ca) can increase the lodging resistance of plants by reducing plant height, but its effects on rice leaves and roots at the tillering stage under salt stress are still unclear. This study aimed to evaluate the ability of foliar spraying of Pro-Ca to regulate growth quality at the rice tillering stage under salt stress. The results showed that salt stress reduced the tillering ability of the rice and the antioxidant enzyme activity in the roots. Salt stress also reduced the net photosynthetic rate (Pn), stomatal conductance (Gs) and intercellular CO2 concentration (Ci) of the rice leaves and increased the contents of osmotic regulatory substances in the leaves and roots. The application of exogenous Pro-Ca onto the leaves increased the tiller number of the rice under salt stress and significantly increased the photosynthetic capacity of the leaves. Additionally, it increased the activities of antioxidant enzymes and the AsA content. The contents of an osmotic regulation substance, malondialdehyde (MDA), and H2O2 in the leaves and roots also decreased. These results suggested that Pro-Ca can increase the tillering ability, photosynthetic capacity, osmotic adjustment substance content levels and antioxidant enzyme activity levels in rice and reduce membrane lipid peroxidation, thus improving the salt tolerance of rice at the tillering stage.


Generation of constitutively active recombinant caspases-3 and -6 by rearrangement of their subunits.
Caspases play a major role in the transduction of the apoptotic signal and execution of apoptosis in mammalian cells. Ectopic overexpression of the short prodomain caspases-3 and -6 precursors in mammalian cells does not induce apoptosis. This is due to their inability to undergo autocatalytic processing/activation and suggests that they depend on the long prodomain caspases for activation. To investigate directly the apoptotic activity of these two caspases in vivo, we engineered constitutively active recombinant caspases-3 and -6 precursors. This was achieved by making contiguous precursor caspases-3 and -6 molecules, which have their small subunits preceding their large subunits. Unlike their wild type counterparts, these recombinant molecules were capable of autocatalytic processing in an in vitro translation reaction, suggesting that they are catalytically active. They were also capable of autoprocessing and inducing apoptosis in vivo independent of the upstream caspases. Furthermore, their autocatalytic and apoptotic activities were inhibited by the pancaspase inhibitor z-VAD-fluoromethylketone, but not by CrmA or Bcl-2, thus directly demonstrating that the targets of inhibition of apoptosis by CrmA and Bcl-2 are upstream of caspases-3 and -6. Since caspases-3 and -6 are the most downstream executioners of apoptosis, the constitutively active versions of these caspases could be used at very low concentrations in gene therapy model systems to induce apoptosis in target tissues or tumors.


Increasing the Use of Earth Science Data and Models in Air Quality Management.
In 2010, the U.S. National Aeronautics and Space Administration (NASA) initiated the Air Quality Applied Science Team (AQAST) as a 5-year, $17.5-million award with 19 principal investigators. AQAST aims to increase the use of Earth science products in air quality-related research and to help meet air quality managers' information needs. We conducted a Web-based survey and a limited number of follow-up interviews to investigate federal, state, tribal, and local air quality managers' perspectives on usefulness of Earth science data and models, and on the impact AQAST has had. The air quality managers we surveyed identified meeting the National Ambient Air Quality Standards for ozone and particulate matter, emissions from mobile sources, and interstate air pollution transport as top challenges in need of improved information. Most survey respondents viewed inadequate coverage or frequency of satellite observations, data uncertainty, and lack of staff time or resources as barriers to increased use of satellite data by their organizations. Managers who have been involved with AQAST indicated that the program has helped build awareness of NASA Earth science products, and assisted their organizations with retrieval and interpretation of satellite data and with application of global chemistry and climate models. AQAST has also helped build a network between researchers and air quality managers with potential for further collaborations. NASA's Air Quality Applied Science Team (AQAST) aims to increase the use of satellite data and global chemistry and climate models for air quality management purposes, by supporting research and tool development projects of interest to both groups. Our survey and interviews of air quality managers indicate they found value in many AQAST projects and particularly appreciated the connections to the research community that the program facilitated. Managers expressed interest in receiving continued support for their organizations' use of satellite data, including assistance in retrieving and interpreting data from future geostationary platforms meant to provide more frequent coverage for air quality and other applications.


Renovascular hypertension: a non-invasive Duplex scanning screening.
A Duplex-Scanner was used to screen 62 patients with severe hypertension, queried renovascular. Ten results were technically unsatisfactory and in the remaining 52 highlighted flow alterations in the renal arteries of 29 patients were found. Control angiographies confirmed renal artery stenosis in 27 cases. Comparative statistical analyses proved the test to be both highly sensitive and specific, considering other screening methods currently used in diagnosing renovascular hypertension--which include endovenous digital subtraction angiography. Results confirmed the Duplex-Scanner as a reliable renovascular hypertension screener as well as being a non-invasive method with no potentially toxic effects.


Skeletal muscle-derived cell cultures as potent models in regenerative medicine research.
Cell cultures have been used extensively by many scientists in recent decades to study various cell and tissue mechanisms. The use of cell cultures has many advantages over use of in vivo experimental models, but there are also limitations. As skeletal muscle-derived cell cultures become more commonly utilized in studies of muscle regeneration processes the question of their relevance in experimentation is highlighted with regard to in vivo experimental models. This article reviews studies that have been performed simultaneously in in vivo and in vitro experiments on skeletal muscle and assesses the correlation of results. Although they seem to correlate, no such studies on humans have been performed so far.


Why is quinidine an inhibitor of cytochrome P450 2D6? The role of key active-site residues in quinidine binding.
We have previously shown that Phe(120), Glu(216), and Asp(301) in the active site of cytochrome P450 2D6 (CYP2D6) play a key role in substrate recognition by this important drug-metabolizing enzyme (Paine, M. J., McLaughlin, L. A., Flanagan, J. U., Kemp, C. A., Sutcliffe, M. J., Roberts, G. C., and Wolf, C. R. (2003) J. Biol. Chem. 278, 4021-4027 and Flanagan, J. U., Maréchal, J.-D., Ward, R., Kemp, C. A., McLaughlin, L. A., Sutcliffe, M. J., Roberts, G. C., Paine, M. J., and Wolf, C. R. (2004) Biochem. J. 380, 353-360). We have now examined the effect of mutations of these residues on interactions of the enzyme with the prototypical CYP2D6 inhibitor, quinidine. Abolition of the negative charge at either or both residues 216 and 301 decreased quinidine inhibition of bufuralol 1'-hydroxylation and dextromethorphan O-demethylation by at least 100-fold. The apparent dissociation constants (K(d)) for quinidine binding to the wild-type enzyme and the E216D and D301E mutants were 0.25-0.50 microm. The amide substitution of Glu(216) or Asp(301) resulted in 30-64-fold increases in the K(d) for quinidine. The double mutant E216Q/D301Q showed the largest decrease in quinidine affinity, with a K(d) of 65 microm. Alanine substitution of Phe(120), Phe(481),or Phe(483) had only a minor effect on the inhibition of bufuralol 1'-hydroxylation and dextromethorphan O-demethylation and on binding. In contrast to the wild-type enzyme, a number of the mutants studied were found to be able to metabolize quinidine. E216F produced O-demethylated quinidine, and F120A and E216Q/D301Q produced both O-demethylated quinidine and 3-hydroxyquinidine metabolites. Homology modeling and molecular docking were used to predict the modes of quinidine binding to the wild-type and mutant enzymes; these were able to rationalize the experimental observations.


Ageing in fishes.
Fishes show three types of senescence. Lampreys, eels and pacific salmon exhibit rapid senescence and sudden death at first spawning. The guppy, red panchax, medaka, platyfish, Indian murrel and many other teleosts undergo gradual senescence, as observed in most of the vertebrates. A number of fishes (e.g. sturgeons, paddlefish, female plaice, flatfish, rockfish) show indeterminate growth, the occurrence of senescence in them is supposed to be very slow or negligible. Neuroendocrine mechanisms are involved in rapid senescence. Most of the evidences in favour of the occurrence of senescence in fishes have been derived from studies in species showing gradual senescence. Age-related increases in mortality rate, accumulation of lipofuscin, lipid peroxidation, collagen cross-linking and decreases in growth rate, reproductive capacity and protein utilisation are clearly marked in such species. Anatomical changes in various organs during ageing also confirm increases in degenerative changes and pathological symptoms. Dietary restriction and lower environmental temperature retard the ageing processes in a few species showing gradual senescence. These results tentatively support the contention of commonality in mechanism of ageing processes in vertebrates. At present, anatomical, cellular, biochemical and genetic evidences in support or against the occurrence of slow senescence or negligible senescence in long-lived fish species are almost nonexistent. Extensive studies on ageing in fishes are needed to explain the multiple mechanisms which are not unexpected considering the number and variety of the existing species.


An Update Evolving View of Copy Number Variations in Autoimmune Diseases.
Autoimmune diseases (AIDs) usually share possible common mechanisms, i.e., a defect in the immune tolerance exists due to diverse causes from central and peripheral tolerance mechanisms. Some genetic variations including copy number variations (CNVs) are known to link to several AIDs and are of importance in the susceptibility to AIDs and the potential therapeutic responses to medicines. As an important source of genetic variants, DNA CNVs have been shown to be very common in AIDs, implying these AIDs may possess possible common mechanisms. In addition, some CNVs are differently distributed in various diseases in different ethnic populations, suggesting that AIDs may have their own different phenotypes and different genetic and/or environmental backgrounds among diverse populations. Due to the continuous advancement in genotyping technology, such as high-throughput whole-genome sequencing method, more susceptible variants have been found. Moreover, further replication studies should be conducted to confirm the results of studies with different ethnic cohorts and independent populations. In this review, we aim to summarize the most relevant data that emerged in the past few decades on the relationship of CNVs and AIDs and gain some new insights into the issue.


Familial ovarian dysgerminomas (Swyer syndrome) in females associated with 46 XY-karyotype.
An asymptomatic woman (age 38 years) with a family history of ovarian malignancies was referred for presymptomatic genetic testing of mutations in the BRCA genes. A familial Swyer syndrome with the occurrence of dysgerminomas is the most likely diagnosis. However, in our case, all known causes of this heterogeneous disorder have been excluded pointing to the existence of another yet unknown genetic locus. The family history revealed three affected paternal aunts. Two of them developed ovarian malignancies at 13 and 15 years of age, and died at ages 19 and 20. The third aunt, 82 years old, was affected by this disease at the age of 35. She underwent hormonal treatment for 3 years starting at the age of 15 because of primary amenorrhea. Under this treatment she developed nearly complete secondary sexual characteristics. Karyotype analysis revealed a normal male karyotype (46 XY, QFQ). Pelvic ultrasound showed an uterus of normal size, incompatible with an androgen resistance syndrome or a defect in testosterone biosynthesis. We excluded a mutation in the sex-determining region on chromosome Y (SRY) by direct sequencing of the SRY gene. An involvement of the subtelomeric region of chromosome 9p (9p 24.3) recently reported to be involved in XY-sex reversal phenotypes was excluded by molecular testing for loss of heterozygosity as well as fluorescence in situ hybridization studies. Analyses of the DAX1 gene in the dosage sensitive sex reversal locus on chromosome Xp21 by Southern blot analysis showed no duplications.


Redistribution of pulmonary blood flow induced by positive end-expiratory pressure and dopamine infusion in acute respiratory failure.
The mechanism by which mechanical ventilation (MV) with positive end-expiratory pressure (PEEP) improves hypoxemia in patients with acute respiratory failure (ARF) is unclear, and may be attributed in part to a decrease in cardiac output inducing by itself a reduction of the shunt. Using the multiple inert gas elimination technique we evaluated the effects of PEEP on ventilation-perfusion (VA/Q) distribution in 8 patients while cardiac output was maintained at control value by means of a dopamine infusion. In each patient, evaluation was performed during MV without PEEP (control) then with PEEP (17 +/- 2 cm H2O) and dopamine. After application of PEEP, PaO2, PvO2, and oxygen transport (TO2) increased significantly, whereas venous admixture decreased from 37.5 +/- 5 to 17 +/- 2% (p less than 0.01). Comparison of VA/Q distribution during PEEP and zero end-expiratory pressure documented a redistribution of pulmonary blood flow; the shunt decreased markedly from 30 +/- 4 to 13 +/- 2% (p less than 0.001), whereas the fraction of cardiac output distributed to "normal" VA/Q ratio units (0.1 to 10) increased from 62 to 78.5% (p less than 0.001). Dead space increased slightly with PEEP, from 44 to 49% (p less than 0.01) of total ventilation. The pattern of ventilation distribution was essentially unaltered; specifically, no additional high VA/Q mode was observed during PEEP. It is concluded that cardiac output maintenance with dopamine infusion during PEEP does not suppress the beneficial effects of PEEP on gas exchange, but induces a redistribution of pulmonary blood toward the main VA/Q ratio.


GREM1 and POLE variants in hereditary colorectal cancer syndromes.
Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.


Glucocorticoid metabolism and reproduction: a tale of two enzymes.
Within potential target cells, the actions of physiological glucocorticoids (cortisol and corticosterone) are modulated by isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). To date, two isoforms of 11 beta HSD have been cloned: 11 beta HSD1 acts predominantly as an NADP(H)-dependent reductase to generate active cortisol or corticosterone, and 11 beta HSD2 is a high affinity NAD(+)-dependent enzyme that catalyses the enzymatic inactivation of glucocorticoids. Whereas the regeneration of active glucocorticoids by 11 beta HSD1 has been implicated in the cellular mechanisms of pituitary function, ovulation and parturition, the enzymatic inactivation of cortisol and corticosterone by 11 beta HSD enzymes appears to be central to the protection of gonadal steroidogenesis, prevention of intra-uterine growth retardation, and lactation. Recent evidence indicates that follicular fluid contains endogenous modulators of cortisol metabolism by 11 beta HSD1, the concentrations of which are associated with the clinical outcome of assisted conception cycles and are altered in cystic ovarian disease. In conclusion, the two cloned isoforms of 11 beta HSD fulfil diverse roles in a wide range of reproductive processes from conception to lactation.


Nanocomposite three-dimensional solar cells obtained by chemical spray deposition.
The present study is focused on low-cost preparation of thin film TiO2/CuInS2 nanocomposite three-dimensional (3D) solar cells. With the aid of a simple spray deposition method, we have been able to obtain 3D solar cells, with a remarkable energy conversion efficiency of 5%. The new 3D solar cell design has the potential to breakdown the price barrier and to open up new production technologies for low-cost photovoltaic solar cells.


Sense of Coherence and Burnout in Healthcare Professionals in the COVID-19 Era.
Emotional exhaustion in the context of vulnerability to burnout is a part of the universal narrative of high stress and systematically reported in healthcare professionals. The sense of coherence (SOC) is a salutogenic construct, operationalized by A. Antonovsky as a generalized resistance resource (GRR) to stress in three dimensions: meaningfulness (Me), the desire of a person to be motivated to cope; comprehensibility (C), the belief that the challenge is understood; and manageability (Ma), the belief that coping resources are available. The relation between SOC and the dimensions of burnout-Emotional Exhaustion (EE), Depersonalization (D), and Personal Accomplishment (PA)-is a part of salutogenic functioning, which reveals the inner motivation and self-organization of the psycho-emotional energetic resource. This study traces the salutogenic functioning of Bulgarian healthcare professionals during the pandemic. A general psychological background of coherence and exhaustion has been identified. All components of the SOC were positively correlated to Personal Accomplishment. Emotional Exhaustion and Depersonalization correlated negatively with coherence. SOC was validated as a possible determinant to predict the reduction of exhaustion and depersonalization as well as high levels of professional performance. The dimension of Meaningfulness in the coherence phenomenon was demonstrated to have the highest predictive value for professional burnout.


The role of prediction error and memory destabilization in extinction of cued-fear within the reconsolidation window.
Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This 'retrieval-extinction' procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the 'retrieval-extinction' effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.


Sensitivity to Antimicrobial Drugs of Pseudomonas Aeruginosa Extreme-Resistant Strains Isolated in the Major Hospitals of Central Kazakhstan.
The article presents the current data on the sensitivity of the main 37 strains of eXtremaly Drugs Resistance (XDR) category to anti-pseudomonas drugs. The strains were collected during the prospective multicenter study in large multidisciplinary hospitals of Central Kazakhstan. Susceptibility to antimicrobial drugs was carried out by disk method and the serial dilution method with the interpretation of the results according to EUCAST criteria. Detection of carbapenemases gene of VIM, IMP, NDM and GES classes was carried out by PCR method using the commercial kits. All identified carbapenemases were sorted to VIM class and accounted for 63.64%. Resistance to aminoglycoside drugs exceeded 80%. All the strains were susceptible to polymyxin. Thus, at the present stage the circulation of P. aeruginosa strains of XDR category continues in major hospitals in Kazakhstan. The strains remain sensitiveness only to polymyxin.


Conserved sequence and functional domains in satellite 2 from three families of salamanders.
Thirteen satellite 2 elements from Ambystoma talpoideum and 16 from Amphiuma tridactylum were cloned, sequenced, and compared with the satellite 2 consensus from Notophthalmus viridescens. These elements have maintained a high degree of similarity during the 65-200 Myr that the salamander families, represented by the three species, have been separated. The DNA sequences of the consensus elements from A. talpoideum and A. tridactylum are 81% similar, and both are approximately 65% similar to the N. viridescens consensus. In addition to its DNA sequence, the functional properties of satellite 2 have also been conserved. By selecting and analyzing clones that closely mimicked the consensus of each species, we were able to demonstrate that satellite 2 from each species was capable of promoting transcription after injection into Xenopus laevis oocytes and that synthetic transcripts of satellite 2 from each species were capable of catalyzing their own site-specific cleavage. These properties may be related to the process of retroposition, which was previously proposed to be responsible for the genomic proliferation of satellite 2. Each of these functional properties also has general biological interest.


Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment.
The main protease of SARS-CoV-2 virus, Mpro, is an essential element for viral replication, and inhibitors targeting Mpro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for Mpro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC50 value of 20.7 μM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys145 residue of Mpro. Our results highlight the challenges of targeting Mpro protease and pave the way toward the discovery of potent lead molecules.


[Submaximal spiroergometric stress study in patients with mixed dust pneumoconiosis].
Disabilities of patients with coal-workers' pneumoconiosis (CWP) are currently estimated by changes in lung function at rest and the degree of dust equivalents in chest x-ray (ILO-classification 1980). Functional disturbances during exercise are not taken into consideration on a regular basis. We assumed that standardised sub-maximal exercise tests might be useful even in disabled patients to give additional information on functional disabilities of patients with CWP. The impact of low-grade anthracosilicosis on ventilation and gas exchange during exercise was assessed in 20 patients (all male, age 64.55 +/- 3.78 years) and 24 healthy volunteers (all male, age 58.13 +/- 4.68 years, never dust exposed). Data were also analysed according to ILO classification subgroups (group 1: ILO-classification 1/0 to 1/2, n = 11; group 2: ILO-classification 2/1 to 2/2, n = 9). Heart rate (HR), minute ventilation (VE), ventilatory equivalent for O2 (VE/VO2), ventilatory equivalent for CO2 (VE/VCO2), O2 uptake (VO2)CO2 output (VCO2), end-tidal oxygen partial pressure (PetO2), end-tidal carbon dioxide partial pressure (petCO2) and estimated dead space to tidal volume ratio (VD/VT) were determined breath-by-breath during a 50 watts constant work load protocol on an exercise bicycle. The VE/VO2 (patients: 32.9 +/- 4.2; controls: 25.7 +/- 2.9; p < 0.001), the VE/CO2 (patients: 39.4 +/- 4.6; controls; 31.0 +/- 3.9), the VE (patients: 30.1 +/- 5.6, controls: 23.5 +/- 3.0; p < 0.001) and the PetO2 (patients 115.6 +/- 4.8; controls: 99.1 +/- 27.4; p < 0.05) at an exercise of 50 watts were significantly higher in the patients' group, the PetCO2 (patients: 38.4 +/- 4.5; controls: 44.0 +/- 4.1) were significantly lower in the patients' group. The comparison of patients subgroups did not reveal any significant differences between group 1 and group 2. A higher VE/VO2 during 50 watts of exercise is attributable to an increased ventilation/perfusion mismatch. There was no correlation between the radiological grade of the CWP (ILO classification) and the ventilation and gas exchange during exercise. We conclude that a sub-maximal spiroergometry with a 50 watts constant work load might serve as a sensitive and easy to apply procedure add information about the functional impairment in CWP. The exercise test should be included in the evaluation for disability benefits.


The variable influence of an alpha component in pregnancy plasma on four different assay systems for the measurement of pregnancy-specific beta1 glycoprotein.
Four methods (radioimmunoassay, electroimmunoassay, laser nephelometry and kinetic immunoturbidimetry) have been evaluated for the measurement of proteins with pregnancy-specific beta1 glycoprotein immunoreactivity. The influence of two maternal plasma proteins with different electrophoretic mobilities (alpha2 and beta1) but with similar antigenic determinants has been assessed in each assay system. The radioimmunoassay method, which utilises a homogeneous preparation of pregnancy-specific beta1 glycoprotein for the preparation of iodinated tracer, and the kinetic immunoturbidimetric assay which measures antigen-antibody complex formation over the first minute of the reaction, were both considerably more specific for the beta1 component of pregnancy specific beta1 glycoprotein immunoreactivity than the laser nephelometric or electroimmunoassay methods.


A practical, modular hyperthermia phantom.
A catheterized, three-component slab phantom has been fabricated for use in mapping specific absorption rate (SAR) distributions from hyperthermia applicators. A planar array of 21 closely spaced catheters, located at one surface of the 1-cm-thick slab, can be positioned at depths of 0-7 cm below the phantom surface, in 1-cm steps, through appropriate placement and orientation of this slab within the three-slab set. Owing to its modular design, the phantom can be prepared, and also purged of degraded material rapidly and without damage to the catheter tracks.


Genetic ancestry and prostate cancer susceptibility SNPs in Puerto Rican and African American men.
The Puerto Rican (PR) population is a racially admixed population that has a high prostate cancer (PCa) mortality rate. We hypothesized in this pilot study that West African Ancestry (WAA) was associated with PCa in this heterogeneous (PR) population. A case/case and case/control study was performed. Controls, 207 African American (AA) and 133 PR were defined as men with no PCa, a serum PSA < 2.5 ng/mL and a negative rectal examination. Cases were patients with pathological specimens from radical prostatectomies (RP) (291 PR and 200 AA). DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPs. We assessed the association of PCa and aggressiveness with genetic ancestry using an ancestry informative marker panel (AIMs) and Wilcoxon rank-sum test and the association of PCa and aggressiveness with 15 previously PCa associated SNPs using Chi square test. Gleason Score (GS) and tumor stage (TS) were used to define low risk (GS ≤ 7[3 + 4]), TS ≤ pT2) and high risk (GS≥ 7[4 + 3], TS > pT2) PCa. Statistical analyses were done using SAS. No difference in overall percent WAA was found between PR cases and controls. Among PR or AA cases WAA was not associated with disease severity based upon risk group, Gleason score or stage. Among AA controls WAA was significantly higher than in cases. The SNP rs7824364 (chromosome 8q24) PCa risk allele was significantly increased among cases versus controls for both AA (P < 0.0001) and PR (P = 0.0001) men. PR men with ≥1 risk allele exhibited a higher percent of WAA (39% vs 29%, P = 0.034). The SNP rs7824364, a local marker of WAA in the 8q24 region was associated with PCa among both AA and PR men and with increased WAA among PR men. This novel relationship of PCA risk loci, WAA with PCa and its phenotype among PR men deserves further study.


Effect of antifungal agents on biological fitness of Lygus hesperus (Heteroptera: Miridae).
Artificial diets have become important components of rearing systems for insects that are used for research purposes and in commercial production. Because the rearing conditions for insects also provide ideal settings for mold growth, antifungal additives are often used to reduce diet contamination. However, the antifungal agents must not only be effective in mold suppression, they must also be safe to the target insects of the rearing programs. The toxicity of five commonly used antifungal agents (benzoic acid, formalin, methyl paraben, propionic acid, and sorbic acid) was tested using diet bioassays on Lygus hesperus Knight, and the effect on biological fitness was measured. Biological fitness was defined as total number of survivors, mean biomass (dry weight) accumulated per cage over the total treatment period, egg production, time to adult emergence, and time to start of egg laying. Methyl paraben and formalin were found to have significant negative effects on these measurements of biological fitness. Challenge tests to determine the ability of the antifungal agents to suppress mold growth when inoculated into the diet medium are currently in progress.


A retrospective study of predictive factors for unexpectedly prolonged or shortened progression-free survival and overall survival among patients with metastatic renal cell carcinoma who received first-line targeted therapy.
To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies. This retrospective study included 146 patients with mRCC who were treated during 2007-2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models. The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05). We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.


A phase II study of weekly paclitaxel, cisplatin and concurrent radiation therapy for locally-advanced unresectable non-small cell lung cancer: early closure due to lack of efficacy.
In this phase II study, the efficacy and safety of weekly paclitaxel concomitant with cisplatin and thoracic radiotherapy (TRT) was evaluated in patients with locally-advanced unresectable non-small cell lung cancer (NSCLC). Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) received TRT (63 Gy in 35 fractions over 7 weeks) with concurrent weekly cisplatin 20 mg/m(2) and paclitaxel 40 mg/m(2)/week infused over 3 hours. In patients without evidence of disease progression, the administration of a further 2 cycles of consolidation chemotherapy, consisting of paclitaxel 175 mg/m(2) and cisplatin 75 mg/m(2), were planned after completion of the TRT. Between Feb 2000 and Dec 2002, 20 patients were entered into the study; 13 completed all 7 weeks of treatment (median 7.6 weeks; range 3.3 to 9.4). Seven out of 16 (43.8%) objective responses were observed, with 15 (75%) patients experiencing at least one episode of grade 3/4 toxicity. The main toxicities were moderate to severe neutropenia and gastrointestinal toxicity. The unsatisfactory response rate and the high incidence of grade 3/4 hematologic and non-hematologic toxicities, including 7 early discontinuations of treatment and exceeding the study stopping rules, prompted the early closure of the study. In view of the activity observed, the protocol was amended to protracted continuous infusion paclitaxel, cisplatin and concurrent TRT.


Recent advances in understanding mechanisms and natural history of diabetic renal disease.
A large subset of individuals with insulin-dependent diabetes mellitus (IDDM) develops clinical nephropathy that progresses to end-stage renal failure. Identification of clinically proteinuric patients has limited impact on management of the condition. No treatment strategy has succeeded in permanently arresting the evolution of clinical nephropathy. However, important advances have been made in slowing its progress, and these are reviewed in this study. Treatment of raised blood pressure early in the course of diabetic renal disease has emerged as the most effective therapeutic measure. Susceptible individuals can be detected before persistent proteinuria becomes manifest by screening IDDM patients for microalbuminuria, which has proved predictive of persistent proteinuria in approximately 80% of cases. Microalbuminuria can be associated with a raised glomerular filtration rate and is often accompanied by subclinical increases in arterial blood pressure. The independent predictive significance of the two latter variables remains to be established in humans. Unfortunately, microalbuminuria is not apparent until 5 yr after stabilization of newly diagnosed diabetes, suggesting that it is a marker of early disease rather than an indicator of susceptibility. However, many therapeutic interventions, ranging from blood glucose control to low-protein diet and angiotensin-converting enzyme inhibition, are effective in reducing or even normalizing microalbuminuria. If current controlled trials show that treatment of microalbuminuric patients prevents progression to clinical nephropathy, the diagnostic criteria for diabetic renal disease will require radical revision.


Delta-thalassemia in Cyprus.
To help clarify the hematological picture of patients who may be positive for beta- and delta-globin gene mutations, the following study was carried out. Our aim was to identify the delta-globin gene mutations found in the Greek Cypriot population, their frequencies and the Hb A2 values associated with them. Seventy-four samples were selected from a random sample of 5,030 individuals, and the database of the Molecular Genetics Thalassaemia Department containing diagnostic analyses data was also mined for relevant information. Four novel for Cyprus delta-globin gene mutations: -30 (T-->C), Hb A2-Wrens [delta98(FG5)Val-->Met, GTG-->ATG], IVS-I-2 (T-->C) and Hb A2-Yokoshima [delta25(B7)Gly-->Asp (GGT-->GAT)] were identified. Hb A2-Yialousa [delta27(B9)Ala-->Ser, GCC-->TCC], Hb A2-Yokoshima, Hb A2-Troodos [delta116(G18)Arg-->Cys, CGC-->TGC], Hb A2-Pelendri [delta141(H19)Leu-->Pro, CTG-->CCG], codon 4 [delta4(A1)Thr-->Ile], codon 59 (-A), Hb A2-Wrens, IVS-II-897 (A-->G), IVS-I-2, -55 (T-->C) and -30 bring the total to 11 delta-globin alleles found in the Greek Cypriot population. Hb A2-Yialousa is the most common mutation followed by codon 4, with frequencies of 60.7 and 17.8%, respectively.Hb A2 levels above 1.9% have been found to indicate a significantly reduced possibility for the presence of a delta-globin gene mutation in this population. For Hb A2 levels of 1.7 and 1.8% the possibility of a delta-globin gene mutation rises to 90.9% and reaches 100% for lower Hb A2 levels. The frequency of all the mutant delta-globin chromosomes in the sample is 0.0067 and the carrier frequency is 1.26%.


Eggshell Membrane Based Turmeric Extract Loaded Orally Disintegrating Films.
The increasing interest in using natural bioactive compounds as new drug candidates due to their low solubility led to designing and developing novel drug delivery systems. Out of those, orally disintegrating films (ODFs) are a very eminent drug delivery system among pediatrics and geriatrics. In our study, the solvent casting method was used to prepare eggshell membrane-based and turmeric extract loaded orally disintegrating films. Characterization of the prepared films was done with FTIR, AFM, and SEM analysis. The release profile of the turmeric extract was determined and fitted to the mathematical models. AFM results showed that the best interaction between components was achieved in Film 2. The highest cumulative release percentage was obtained for the film with 7.5% (w/w) turmeric extract (Film-2) as 41.98%, based on the HPLC measurements. The Higuchi model was the best-- fitted model for Film 2. In this study, SEP and CMCH were used for the first time as biopolymers to prepare the orally disintegrating film. Turmeric extract was successfully integrated into films prepared from SEP and CMCH.


Effect of strontium ions on calcification of preosteoblasts cultured on porous calcium- and phosphate-containing titanium oxide layers formed by micro-arc oxidation.
Strontium (Sr) ions were added to calcium- and phosphate-containing porous titanium oxide layers formed by micro-arc oxidation (MAO) of titanium (Ti) substrates to improve their osseointegration. An MC3T3-E1 preosteoblast was used to evaluate the effect of the incorporated Sr species on cell calcification. Similar surface microporous morphologies of the oxide layers were observed for all specimens produced by MAO, while the contents of the incorporated Sr ions increased with increasing Sr concentrations in MAO electrolytes. The calcium- and phosphate-containing porous layers promoted the cell alkaline phosphatase (ALP) activity, while cell calcification was promoted by the Sr addition. In particular, the ALP activity significantly increased after 10 days of culture, and larger areas of calcified deposits were observed for the specimens treated with MAO electrolytes containing 0.15 mol L(-1) of Sr species. The effect of Sr addition on the calcification of the MAO-treated Ti oxide layers was established in this study.


Effects of Eleutherococcus senticosus extracts on hexobarbital metabolism in vivo and in vitro.
Eleutherococcus senticosus (Siberian Ginseng) is widely exported from China as a health food. Pharmacologically it has been classified as an adaptogen and enzyme induction has been proposed as its mechanism of action. To evaluate this hypothesis E. senticosus was administered to mice on an acute (40-320 mg/kg i.p., X 1 day) or chronic (80-320 mg/kg i.p., X 4-5 days) basis. Sleep latency and duration, in response to hexobarbital sodium (100 mg/kg i.p.), were determined either 1 h (acute and chronic) or 24 h (chronic) following the last E. senticosus injection. E. senticosus produced a sedative effect which decreased the sleep latency (47%) and increased sleep duration (45-228%) following acute administration. A similar effect was seen following chronic administration (125-202% increase in sleep duration). E. senticosus was also shown to produce an inhibition (66%) of hexobarbital metabolism, in vitro, as compared to controls. These data support enzyme inhibition rather than enzyme induction as a mechanism for the actions of Siberian Ginseng.


Biochemical studies of mammalian oogenesis: kinetics of accumulation of total and poly(A)-containing RNA during growth of the mouse oocyte.
Kinetics of accumulation of total and poly(A)-containing RNA have been measured during growth of the mouse oocyte. Total RNA from oocytes isolated at discrete stages of growth was determined by two independent microassays. The full-grown oocyte contained about 0.60 ng of RNA. Kinetics of accumulation of total RNA with respect to oocyte volume were biphasic. Small, growing oocytes (about 30 pl) contained about 0.20 ng of RNA/oocyte. The amount of RNA increased in a quasi-linear fashion until oocyte volume was about 160 pl, at which point there was about 0.57 ng of RNA/oocyte. Thus oocytes about 65% of their final volume had accumulated about 95% of the total amount of RNA present in the fully-grown oocyte. The relative amount of poly (A)-containing RNA in oocytes of various size was determined by in situ hybridization of [3H] poly (U) to ovarian sections from juvenile mice of known age, followed by autoradiography. The kinetics of accumulation of poly (A)-containing RNA were similar to those of total RNA; oocytes about 70% of their final volume had accumulated about 95% of the amount of poly (A)-containing RNA present in the fully-grown oocyte. The poly(A)-containing RNA resided predominantly in the cytoplasm and no obvious cytoplasmic localization was observed. Kinetics of accumulation of total RNA, which is mainly ribosomal, and poly (A)-containing RNA were consistent with levels of RNA polymerases I and II measured by others during oocyte growth (Moore and Lintern-Moore, '78). The number of ribosomes that could be made from the amount of rRNA present at various stages of growth was compared to the actual number of ribosomes calculated from a published morphometric study (Garcia et al., '79). Kinetic differences in accumulation between the theoretical and actual number of ribosomes suggested oocyte ribosomes are recruited into cytoplasmic lattice structures. These structures accumulate during oocyte growth and have been postulated to be a ribosomal storage form. In addition, the results from this study are compared to results derived from lower species.


Combination of ultra-micro angiography and sound touch elastography for diagnosis of primary Sjögren's syndrome: a diagnostic test.
Primary Sjogren's syndrome (PSS) is a prevalent systemic autoimmune disease. However, the current gold standard diagnostic method is invasive, increasing the difficulty of patient acceptance and then delaying treatment. Therefore, a non-invasive, convenient, and effective diagnostic method is required. Although salivary gland ultrasonography (SGUS) is a good choice, previous studies have not found suitable parameters to diagnose PSS. Salivary gland involvement in patients with PSS leads to changes in gland stiffness and vascularization, so we combined sound touch elastography (STE) and ultra-microangiography (UMA) to demonstrate the diagnostic effectiveness of ultrasonography in PSS. This prospective study included 27 patients with PSS and 20 healthy controls, with all participants forming a random series. Major salivary glands were examined with UMA and STE. Color pixel percentage (CPP), shear wave velocity (SWV), and Young's modulus values were investigated, and the combination of these parameters was evaluated by logistic regression analysis. For Young's modulus and SWV in the elasticity index, combined evaluation of both parotid glands and submandibular glands yielded an area under the receiver operating characteristic (ROC) curve (AUC) and confidence interval (CI) of 0.819, 0.699-0.938 and 0.801, 0.677-0.925, respectively. The levels of CPP in the parotid glands were significantly elevated (P<0.003) among patients compared to those in the control group, whereas the CPP values in the submandibular glands were not statistically different (P>0.086). We evaluated the elasticity values of the total 4 glands and the CPP of parotid glands together by logistic regression modeling. The ROC curve yielded an AUC of 0.954 (95% CI: specificity 0.849-0.994) which showed the best accuracy, with 92.6% sensitivity and 85.0% specificity. The use of STE and UMA to examine the salivary glands may aid in the diagnosis of PSS, and their combination may be a promising method. This is good news for patients with PSS who are not suitable or unwilling to undergo labial gland biopsy.


Retinal age gap as a predictive biomarker of future risk of Parkinson's disease.
retinal age derived from fundus images using deep learning has been verified as a novel biomarker of ageing. We aim to investigate the association between retinal age gap (retinal age-chronological age) and incident Parkinson's disease (PD). a deep learning (DL) model trained on 19,200 fundus images of 11,052 chronic disease-free participants was used to predict retinal age. Retinal age gap was generated by the trained DL model for the remaining 35,834 participants free of PD at the baseline assessment. Cox proportional hazards regression models were utilised to investigate the association between retinal age gap and incident PD. Multivariable logistic model was applied for prediction of 5-year PD risk and area under the receiver operator characteristic curves (AUC) was used to estimate the predictive value. a total of 35,834 participants (56.7 ± 8.04 years, 55.7% female) free of PD at baseline were included in the present analysis. After adjustment of confounding factors, 1-year increase in retinal age gap was associated with a 10% increase in risk of PD (hazard ratio [HR] = 1.10, 95% confidence interval [CI]: 1.01-1.20, P = 0.023). Compared with the lowest quartile of the retinal age gap, the risk of PD was significantly increased in the third and fourth quartiles (HR = 2.66, 95% CI: 1.13-6.22, P = 0.024; HR = 4.86, 95% CI: 1.59-14.8, P = 0.005, respectively). The predictive value of retinal age and established risk factors for 5-year PD risk were comparable (AUC = 0.708 and 0.717, P = 0.821). retinal age gap demonstrated a potential for identifying individuals at a high risk of developing future PD.


Comparison of 3 Minimally Invasive Methods for Distal Tibia Fractures.
This study compared the results of external fixation combined with limited open reduction and internal fixation (EF + LORIF), minimally invasive percutaneous plate osteosynthesis (MIPPO), and intramedullary nailing (IMN) for distal tibia fractures. A total of 84 patients with distal tibia shaft fractures were randomized to operative stabilization using EF + LORIF (28 cases), MIPPO (28 cases), or IMN (28 cases). The 3 groups were comparable with respect to patient demographics. Data were collected on operative time and radiation time, union time, complications, time of recovery to work, secondary operations, and measured joint function using the American Orthopaedic Foot and Ankle Society (AOFAS) score. There was no significant difference in time to union, incidence of union status, time of recovery to work, and AOFAS scores among the 3 groups (P>.05). Mean operative time and radiation time in the MIPPO group were longer than those in the IMN or EF + LORIF groups (P<.05). Wound complications after MIPPO were more common compared with IMN or EF + LORIF (P<.05). Anterior knee pain occurred frequently after IMN (32.1%), and irritation symptoms were encountered more frequently after MIPPO (46.4%). Although EF + LORIF was associated with fewer secondary procedures vs MIPPO or IMN, it was related with more pin-tract infections (14.3%). Findings indicated that EF + LORIF, MIPPO, and IMN all achieved similar good functional results. However, EF + LORIF had some advantages over MIPPO and IMN in reducing operative and radiation times, postoperative complications, and reoperation rate. [Orthopedics. 2016; 39(4):e627-e633.].


Eight Differential miRNAs in DN Identified by Microarray Analysis as Novel Biomarkers.
Diabetic nephropathy (DN) is the common cause of renal diseases such as end-stage renal disease (ESRD) and chronic kidney disease (CKD). Various diagnostic applications and treatment methods are used for clinical but remain some prognosis issues. To avoid morbidity and mortality related to DN, early detection of disease complications as well as targeted therapeutic strategies is essential. Considerable evidence indicates that non-coding RNA plays a vital role in the biological processes of various diseases, used as biomarkers and therapeutic targets. And the most known ncRNAs are the microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Our study aimed to identify potential prognostic ncRNAs involved in DN by bioinformatics analysis and validated expression levels through quantitative polymerase chain reaction (qPCR) and GEO database. Our research focuses on differential expression miRNAs (DEmiRNAs) in DN and their interactions with critical genes. We identified 8 up-regulated DEmiRNAs, including miR-103a-2-5p, miR-297, miR-548x-3p, miR-604, miR-644a, miR-1256, miR-3911 and miR-5047 finally. We further validated these miRNAs in a murine model. Identifying these up-regulated genes and elucidating these miRNAs regulatory network will contribute to a better understanding of the molecular mechanism of DN and how they can be used as new biomarkers and potential therapeutic targets for DN.


Global Surgery System Strengthening: It Is All About the Right Metrics.
Progress in achieving "universal access to safe, affordable surgery, and anesthesia care when needed" is dependent on consensus not only about the key messages but also on what metrics should be used to set goals and measure progress. The Lancet Commission on Global Surgery not only achieved consensus on key messages but also recommended 6 key metrics to inform national surgical plans and monitor scale-up toward 2030. These metrics measure access to surgery, as well as its timeliness, safety, and affordability: (1) Two-hour access to the 3 Bellwether procedures (cesarean delivery, emergency laparotomy, and management of an open fracture); (2) Surgeon, Anesthetist, and Obstetrician workforce >20/100,000; (3) Surgical volume of 5000 procedures/100,000; (4) Reporting of perioperative mortality rate; and (5 and 6) Risk rates of catastrophic expenditure and impoverishment when requiring surgery. This article discusses the definition, validity, feasibility, relevance, and progress with each of these metrics. The authors share their experience of introducing the metrics in the Pacific and sub-Saharan Africa. We identify appropriate messages for each potential stakeholder-the patients, practitioners, providers (health services and hospitals), public (community), politicians, policymakers, and payers. We discuss progress toward the metrics being included in core indicator lists by the World Health Organization and the World Bank and how they have been, or may be, used to inform National Surgical Plans in low- and middle-income countries to scale-up the delivery of safe, affordable, and timely surgical and anesthesia care to all who need it.


Doxycycline-loaded coaxial nanofiber coating of titanium implants enhances osseointegration and inhibits Staphylococcus aureus infection.
Few studies have been reported that focus on developing implant surface nanofiber (NF) coating to prevent infection and enhance osseointegration by local drug release. In this study, coaxial doxycycline (Doxy)-doped polycaprolactone/polyvinyl alcohol (PCL/PVA) NFs were directly deposited on a titanium (Ti) implant surface during electrospinning. The interaction of loaded Doxy with both PVA and PCL NFs was characterized by Raman spectroscopy. The bonding strength of Doxy-doped NF coating on Ti implants was confirmed by a stand single-pass scratch test. The improved implant osseointegration by PCL/PVA NF coatings in vivo was confirmed by scanning electron microscopy, histomorphometry and micro computed tomography (μCT) at 2, 4 and 8 weeks after implantation. The bone contact surface (%) changes of the NF coating group (80%) is significantly higher than that of the no NF group (<5%, p < 0.05). Finally, we demonstrated that a Doxy-doped NF coating effectively inhibited bacterial infection and enhanced osseointegration in an infected (Staphylococcus aureus) tibia implantation rat model. Doxy released from NF coating inhibited bacterial growth up to 8 weeks in vivo. The maximal push-in force of the Doxy-NF coating (38 N) is much higher than that of the NF coating group (6.5 N) 8 weeks after implantation (p < 0.05), which was further confirmed by quantitative histological analysis and μCT. These findings indicate that coaxial PCL/PVA NF coating doped with Doxy and/or other drugs have great potential in enhancing implant osseointegration and preventing infection.


Patient positioning for shoulder arthroscopy based on variability in lateral acromion morphology.
The purpose of this article is to highlight the variability among shoulders in the relationship between the lateral acromion and the humeral head and to describe how this variability may influence a surgeon's choice of patient positioning for shoulder arthroscopy. In cases of increased lateral coverage of the humeral head by the acromion, arthroscopic access to the superior aspect of the glenoid through lateral portals becomes increasingly difficult because of a narrowed corridor of approach. Placing the ipsilateral arm in traction will lower the station of the humeral head and widen the arthroscopic corridor of approach to the superior labrum. Based on preoperative assessment of lateral acromion morphology, if the surgeon determines that inferior displacement of the humeral head of 25% or more of the humeral head diameter will be necessary to achieve adequate arthroscopic accessibility of the superior glenoid through lateral portals, we recommend the lateral decubitus position with continuous traction on the ipsilateral arm over the beach-chair position.


Suppression and prevention of adjuvant arthritis in rats by a monoclonal antibody to the alpha/beta T cell receptor.
Adjuvant arthritis (AA) in rats is an experimentally induced autoimmune disease mediated by T lymphocytes specific for Mycobacterium tuberculosis. We raised the question whether T cells carrying the gamma/delta T cell receptor (TcR), reactive or not to mycobacterial antigens, are involved in the pathogenesis of AA. For this purpose, T cells bearing the TcR alpha/beta were depleted from circulation by treatment with a monoclonal antibody against the rat TcR alpha/beta (R73). This treatment efficiently suppressed existing disease. Even more efficient was pretreatment with R73 from birth, which prevented AA induction completely. In these alpha/beta+ T cell-depleted animals an elevated level of alpha/beta- T cells (about 15% vs. 1% in normal rats) was evident, which was not significantly increased by Mycobacterium tuberculosis injection. We found no positive evidence that gamma/delta + T cells do contribute to AA induction. Moreover, treatment with an anti-TcR alpha/beta monoclonal antibody may be very efficient treatment of T cell-mediated autoimmune diseases.


Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor-Associated Cardiotoxicity: A Recent Five-Year Pharmacovigilance Study.
Background: Clinical trials frequently reported anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) associated with cardiac adverse drug events (AEs) but minimal postmarketing data. We aimed to research real-world cardiac disorders associated with ALK-TKIs based on the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Extract reports from the FAERS from the first quarter of 2016 to the second quarter of 2021 were obtained. Data mining of cardiac disorders associated with ALK-TKIs was carried out using disproportionality analysis to determine the clinical characteristics of AEs. Results: In total, 605 cases were screened out. These events were found to be more prevalent in patients ≥45 years (50.74%) and women (50.74%). The onset time of cardiac disorders was variable and concentrated within 2 months, with a median time of 33 days. The outcomes tended to be poor, with 20.93% fatality proportion. Cardiac arrhythmia was a common adverse event of ALK-TKIs, especially bradycardia. Crizotinib and lorlatinib showed positive signals in cardiac disorders, especially in heart failure, and brigatinib presented no signals. The study also found that myocarditis caused by ceritinib and cardiomyopathy caused by lorlatinib may be potential new adverse drug reactions. Conclusion: ALK-TKIs were reported more frequently in cardiotoxicity than other drugs and could often manifest earlier. We also found potential new AE signals in specific drugs and need more clinical studies to confirm. Our study helps fill the safety information of ALK-TKIs in the heart and provides directions for further research.


Variation in the expression of ergot alkaloids between individual tillers of perennial ryegrass.
Epichloë fungal endophytes of cool season grasses are well-known to produce a range of alkaloids of benefit to the host. Some of these compounds are advantageous to agriculture due to qualities that promote pasture persistence (e.g., the loline class of alkaloids confer insect protection) while others are detrimental to the well-being of grazing livestock. The ergot alkaloids (e.g., ergovaline), produced in ryegrass and tall fescue associations, causes poor animal health in farming regions in many countries around the world and further study is required to improve our knowledge on this class of compounds. Here we present the application of a quantitative LC-MS/MS (liquid chromatography coupled to mass spectrometry) method measuring eight ergot alkaloids (chanoclavine, agroclavine, elymoclavine, lysergol, lysergic acid, ergine, lysergyl-alanine, ergovaline) produced by endophyte infected grasses, to monitor levels in individual tillers from multiple plants of a single cultivar of perennial ryegrass (Lolium perenne cv. "Grasslands Samson") infected with a common toxic endophyte strain (Epichloë festucae var. lolii). Monitoring the expression in individual tillers allows an estimation of the variability within a plant (between tillers) as well as between plants. The study showed that there is significant variation in the concentration of the ergot alkaloids between tillers of a single plant, at or exceeding the level of variation observed between individual plants of a population. This result emphasizes the fundamental importance of robust experimental design and sampling procedures when alkaloid expression assessment is required and these need to be rigorously tailored to the hypothesis being tested.


The influence of age on mortality and survival in patients undergoing oesophagogastrectomies. A seven-year experience in a tertiary centre.
The aim of this study was to evaluate the effects of advanced age on the outcome and survival of patients undergoing oesophagectomy for oesophageal cancer at a single high-volume centre. We retrospectively reviewed the hospital survival of 326 patients in oesophagogastrectomies (OGs) in a period from May 2001 to April 2008. We divided the patients into two groups. Group A (n=218) consisted of patients younger than 70 years of age, while Group B (n=108) consisted of patients 70 years of age or older. The two groups were comparable. In-hospital mortality for Group A was 11 out of 218 (5%), while in-hospital mortality for Group B was 13 out of 108 (12%). This difference was statistically significant (P=0.024). Multivariate analysis showed that risk factors for in-hospital mortality after OG included age over 70 years [odds ratio (OR)=2.79], reduced % of predicted FEV(1) (OR=0.13) and cardiac co-morbidity (OR=2.53). Despite age over 70 years proving not to be predictive of survival (P=0.21), significant independent predictors were advancing age [hazard ratio (HR)=1.03] and stage of disease (HR=1.84). P-values were 0.0278 and 0.018, respectively. Increasing age is a significant risk factor for mortality and survival after oesophageal resection operations. This mortality is particularly high if associated with a preoperative cardiac or respiratory morbidity.


Epithelial stem cells are formed by small-particles released from particle-producing cells.
Recent spatiotemporal report demonstrated that epidermal stem cells have equal potential to divide or differentiate, with no asymmetric cell division observed. Therefore, how epithelial stem cells maintain lifelong stem-cell support still needs to be elucidated. In mouse blood and bone marrow, we found a group of large cells stained strongly for eosin and containing coiled-tubing-like structures. Many were tightly attached to each other to form large cellular clumps. After sectioning, these large cell-clumps were composed of not cells but numerous small particles, however with few small "naked" nuclei. The small particles were about 2 to 3 μm in diameter and stained dense red for eosin, so they may be rich in proteins. Besides the clumps composed of small particles, we identified clumps formed by fusion of the small particles and clumps of newly formed nucleated cells. These observations suggest that these small particles further fused and underwent cellularization. E-cadherin was expressed in particle-fusion areas, some "naked" nuclei and the newly formed nucleated cells, which suggests that these particles can form epithelial cells via fusion and nuclear remodeling. In addition, we observed similar-particle fusion before epithelial cellularization in mouse kidney ducts after kidney ischemia, which suggests that these particles can be released in the blood and carried to the target tissues for epithelial-cell regeneration. Oct4 and E-cadherin expressed in the cytoplasmic areas in cells that were rich in protein and mainly located in the center of the cellular clumps, suggesting that these newly formed cells have become tissue-specific epithelial stem cells. Our data provide evidence that these large particle-producing cells are the origin of epithelial stem cells. The epithelial stem cells are newly formed by particle fusion.


Electrodeposition of germanium from the ionic liquid 1-butyl-1-methylpyrrolidinium dicyanamide.
The electrodeposition of germanium from the ionic liquid 1-butyl-1-methylpyrrolidinium dicyanamide ([BMP][DCA]) and a mixture of [BMP][DCA] and 1-butyl-1-methylpyrrolidinium chloride ([BMP]Cl) was studied using cyclic voltammetry and using an electrochemical quartz crystal microbalance (EQCM). [GeCl4(BuIm)2] (BuIm = N-butylimidazole) was used as germanium source as it has a solubility of 0.47 M, up to 13 times the solubility of GeCl4 in [BMP][DCA]. Cyclic voltammograms show an irreversible electrochemical behavior and two reduction waves were observed. The wave at the more positive potential was assigned to the reduction of Ge(4+) to Ge(2+). The wave at the more negative potential was attributed to the formation of Ge(0). The diffusion coefficient of Ge(4+) in [BMP][DCA] containing 0.1 M [GeCl4(BuIm)2] is 1.1 × 10(-12) m(2) s(-1), and the exchange current density is 2 × 10(-4) A m(-2) at 50 °C. Polymerization of dicyanamide anions took place at the anode in the solution of [BMP][DCA]. The polymerization reaction could be avoided by using an equimolar [BMP]Cl-[BMP][DCA] mixture as electrolyte. Smooth, porous germanium films were electrodeposited on both copper and silicon substrates.


Assessment of genetic variation in Apis mellifera jemenitica (Hymenoptera: Apidae) based on mitochondrial Cytochrome Oxidase Subunit II and III.
Morphometric and genetic characterization of many Apis mellifera subspecies are well-documented. A. m. jemenetica occurs naturally in Africa and Asia. In this study, genetic variation of mitochondrial Cytochrome Oxidase II (COII) and III (COIII) were analysed in 133 specimens of the endemic honeybee colonies within Saudi Arabia. The COII gene sequence length was 684 bp comprising nine synonymous (1.3%) and two non-synonymous single nucleotide polymorphisms (SNPs) (0.87%). Five variants of COII were not previously documented, one variant (MT755968) showed an extra restriction site when subjected to type II restriction endonuclease from Arthrobacter protophormiae (Apol) or to Haemophilus influenzae Rf (Hinf1). Changes in COII sequence separated samples into three haplogroups. Whereas, COIII gene sequence length was 780 bp, including 18 synonymous and five non-synonymous SNPs. Furthermore, variation in COII sequence was more informative based on restriction profiles and on amino acid changes compared with COIII gene sequence. Variants of COIII showed identical restriction sites when subjected to type II restriction endonuclease from Deinococcus radiophilus (DraI), and revealed high similarity to African subspecies. Results of this study are very useful in understanding genetic diversity and characterization of A. mellifera subspecies.


Breastfeeding Experiences of Mothers of Children with Down Syndrome.
Children with Down syndrome are less likely to be breastfed than typically developing children, and breastfeeding has a lower duration compared to recommendations of the World Health Organization. The aim of this study was to understand the breastfeeding experiences of mothers of children with Down syndrome, including their perceptions of the breastfeeding process and their specific practices. This is a qualitative study with 10 participants, mothers of children aged between 2 months and 9 years. Snowball sampling was used for participants' selection, and semi-structured interviews conducted in participants' households. Three categories emerged: "the breastfeeding experience," involving the process of breastfeeding, the breast milk, feelings, and difficulties of this practice; "experiences of health care," encompassing the support received by health professionals, dissatisfaction with health services, lack of support in breastfeeding, and discontent with health professional behavior; and "learning about Down syndrome," with search for information by parents and advice to health professionals. In this study, we found evidence that breastfeeding success relies very much on mothers' willingness and support of health professionals, namely, nurses. Findings from this study suggest that support of a multidisciplinary team is essential to the success of breastfeeding. Greater awareness is needed regarding the unique rewards and challenges of breastfeeding these infants, as well as how families cope with the ongoing challenges. Therefore, this research is relevant to understand the experiences of mothers of children with DS about breastfeeding, identifying the inhibiting factors, in order to create more appropriate strategies to intervene and implement practices that contribute to the support and promotion of breastfeeding. Results will also influence the education of health professionals, emphasizing the importance of multidisciplinary teams for a comprehensive care and contributing to increasing evidence available about this topic.


Therapeutic Drug Monitoring of Mycophenolic Acid Identifies Kidney Transplant Recipients Responsive to Two SARS-CoV-2 mRNA Vaccine Doses.
Immune-responsiveness to SARS-CoV-2 mRNA vaccination is reduced in kidney transplant recipients (KTRs). Previous reports point to a role of mycophenolic acid (MPA). Our observational cohort study included all KTRs at University Hospital Zurich receiving two SARS-CoV-2 mRNA vaccine doses more than 6 months post-transplantation, who were assessed by measuring anti-spike immunoglobulin G (IgG). We applied principles of therapeutic drug monitoring (TDM) to correlate MPA exposure and lymphocyte counts with SARS-CoV-2 IgG. MPA trough levels differ largely among KTRs with a median of 3.1 mg/L (range 0.7-9.5 mg/L). 34 of 84 KTRs (40%) developed positive SARS-CoV-2 IgG after two vaccine doses. KTRs who developed positive SARS-CoV-2 IgG showed significantly higher eGFR (p < 0.001), lower MPA trough levels (p < 0.001) and higher CD19+ lymphocytes (p < 0.001). MPA trough levels <2.5 mg/l and CD19+ lymphocytes >40/μl identify KTRs with seroconversion. Upon logistic regression, MPA trough levels <2.5 mg/L were associated with a 7-fold (CI 95%: 1.589-29.934) and ciclosporin use with a 6-fold (CI 95%: 1.148-30.853) increase in the odds of seroconversion. Our study indicates that immune-responsiveness to SARS-CoV-2 mRNA vaccines correlates with MPA exposure measured by MPA trough level but argues against a class effect of MPA. TDM-guided MPA dosing may be a strategy to increase seroconversion rate.


Perception, action, and experience: unraveling the golden braid.
Much of our human mental life looks to involve a seamless unfolding of perception, action and experience: a golden braid in which each element twines intimately with the rest. We see the very world we act in and we act in the world we see. But more than this, visual experience presents us with the world in a way apt for the control and fine guidance of action. Or so it seems. Milner and Goodale's [Milner, D., Goodale, M. (1995). The visual brain in action. Oxford: Oxford University Press; Milner, A., Goodale, M. (2006). Epilogue: Twelve years on. In Milner, A., Goodale, M. (Ed.), The visual brain in action (2nd ed., pp. 207-252). Oxford: Oxford University Press] influential work on the dual visual systems hypothesis casts doubt on certain versions of this intuitive vision. It does so by prising apart the twining strands of conscious visual perception and the fine control of visuomotor action. Such a bold proposal is of major interest both to cognitive science and philosophy. In what follows I first clarify the major claims that the bold proposal involves, then examine three sets of worries and objections. The first set concern some important matters of detail. The second set concern a certain kind of conceptual or philosophical worry to the effect that the perception/action model unfairly equates visual experience itself with what are in fact certain elements within visual experience. The third set concern the very idea of conscious experience as a well-defined conceptual or experimental target. I conclude that the boldest versions of the Dual Visual Systems (2VS) story underestimate the variety and richness of visual experience, but that the general picture of visual uptake as a fragmented, multi-stream, multipurpose adaptation is correct, and still revealing after all these years.


Temporal triangular alopecia: report of five cases in Asian children.
Temporal triangular alopecia (TTA) is a nonscarring alopecia first described in 1905. We report five cases of TTA in Asian children and review the literature.


Interrater reliability of the standardized Timed Up and Go Test when used in hospitalized and community-dwelling older individuals.
The purpose of this study was to determine the interrater reliability and measurement error of the standardized Timed Up and Go (TUG) Test manual using the fastest of the three timed TUG trials in hospitalized and community-dwelling older individuals. Thirty participants (19 from a hospital and 11 from an outpatient geriatric centre: 20 women, 10 men), 65 years or older, all of whom had been referred to physiotherapy due to a functional decline, were included. All participants performed the TUG Test across two sessions (three trials in each) on the same day, separated by a minimum of 30 min. The two raters were blinded to each other's ratings until the end of the study, and the rater order was randomized. Participants from the outpatient centre had a higher prereferral functional level when evaluated with the New Mobility Score and performed the TUG Test significantly faster than the hospital group. Accordingly, reliability estimates are reported for each specific group. Interrater reliability was excellent for both groups (intraclass correlation coefficient2.1 ≥ 0.93), and no systematic between-rater difference for obtained TUG times was found. The measurement error was acceptable both at the group (standard error of measurement [SEM] = 1.7 s and SEM% = 8 [hospital] vs. 0.7 s and 6 [outpatient]) and the individual (minimal detectable change [MDC95 ] = 4.6 s and MDC95 % = 23 [hospital] vs. 1.8 s and 17 [outpatient]) level. Findings suggest that using the fastest of the three TUG trials is highly reliable between raters and with acceptable measurement error. We, therefore, suggest that the standardized TUG manual with the fastest of the three timed trials be used for the assessment of functional mobility in hospitalized and community-dwelling older individuals.


Subpocket analysis method for fragment-based drug discovery.
Although two binding sites might be dissimilar overall, they might still bind the same fragments if they share suitable subpockets. Information about shared subpockets can be therefore used in fragment-based drug design to suggest new fragments or to replace existing fragments within an already known compound. A novel computational method called SubCav is described which allows the similarity searching and alignment of subpockets from a PDB-wide database against a user-defined query. The method is based on pharmacophoric fingerprints combined with a subpocket alignment algorithm. SubCav was shown to be effective in producing reasonable alignments for subpockets with low sequence similarity and be able to retrieve relevant subpockets from a large database of structures including those with different folds. It can also be used to analyze subpockets inside a protein family to facilitate drug design and to rationalize compound selectivity.


Bone level change at implant-supported fixed partial dentures with and without cantilever extension after 5 years in function.
The aim of this study was to retrospectively analyze whether the inclusion of cantilever extensions increased the amount of marginal bone loss at free-standing, implant-supported, fixed partial dentures (FPDs) over a 5-year period of functional loading. The patient material comprised 45 periodontally treated, partially dentate patients with a total of 50 free-standing FPDs supported by implants of the Astra Tech System. Following FPD placement (baseline) the patients were enrolled in an individually designed supportive care program. A set of criteria was collected at baseline to characterize the FPDs. The primary outcome variable was change in peri-implant bone level from the time of FPD placement to the 5-year follow-up examination. The comparison between FPDs with and without cantilevers was performed at three levels: FPD level, implant level, and surface level. Bivariate analysis was performed by the use of the Mann-Whitney U-test and stepwise regression analysis was utilized to evaluate the potential influence of confounding factors on the change in peri-implant bone level. The overall mean marginal bone loss for the implant-supported FPDs after 5 years in function was 0.4 mm (SD, 0.76). The bone level change at FPDs placed in the maxilla was significantly greater than that for FPDs in the mandible (0.6 versus 0.2 mm; p<0.05). No statistically significant differences were found with regard to peri-implant bone level change over the 5 years between FPDs with and without cantilevers at any of the levels of comparisons. The multivariate analysis revealed that the variables jaw of treatment and smoking had a significant influence on peri-implant bone level change on the FPD level, but not on the implant or surface levels. The model explained only 10% of the observed variance in the bone level change. The study failed to demonstrate that the presence of cantilever extensions in an FPD had an effect on peri-implant bone loss.


Correlation between halothane-induced myocardial depression and decreases in La3+-displaceable Ca2+ in cardiac muscle cells.
The relationship between myocardial contractility and the amount of La3+-displaceable Ca2+ was studied in the presence and absence of halothane using dog trabecular muscle. The La3+-displaceable Ca2+ is believed to represent surface-located Ca2+ which enters the cytoplasm and interacts with the contractile proteins during membrane depolarization. It was found that there was a linear relationship between the halothane-induced decrease in contractility and the reduction in the amount of La3+-displaceable Ca2+. Additional data suggest that halothane increases the Ca2+ binding of the plasma membrane, thereby decreasing the availability of the surface-located Ca2+.


Shape and radius of posterior corneal surface.
The posterior corneal surface is often ignored in predictive models concerned with refractive surgery. In previous studies, the radius of this surface has been measured in a variety of ways, primarily over a large chord diameter of the surface, with the common assumption that the surface is spherical. The asphericity of this surface has not been adequately addressed in the past. An algorithm is derived for the calculation of posterior corneal surface apical radius and using characteristics of the anterior corneal surface and topographic corneal thickness variation. Anterior corneal asphericity was measured using a commercially available photoelectric keratoscope. Using a marked soft contact lens, a simple method of locating noncentral corneal sites is described as an aid to ultrasonic pachometry. In a group of 20 normal subjects ranging in age from 19 to 23 years, the average posterior corneal surface apical radius and asphericity (p) was 5.80 mm (SD = +/- 0.42) and 0.64 (SD = 0.37) for the vertical meridian, and 5.82 mm (SD = +/- 0.40) and 0.52 (SD = 0.30) for the horizontal meridian. Average central corneal thickness was 533 mu (SD = +/- 19). The average asphericity values are below 1, hence the posterior corneal surface is described as a flattening ellipse. The rate of flattening of this surface is greater than the rate of flattening along the averaged anterior corneal surface.