Updates for the Neonatal Resuscitation Program and Resuscitation Guidelines.
Although most newborns require no assistance to successfully transition to extrauterine life, the large number of births each year and limited ability to predict which newborns will need assistance means that skilled clinicians must be prepared to respond quickly and efficiently for every birth. A successful outcome is dependent on a rapid response from skilled staff who have mastered the cognitive, technical, and behavioral skills of neonatal resuscitation. Since its release in 1987, over 4.5 million clinicians have been trained by the American Heart Association and American Academy of Pediatrics Neonatal Resuscitation Program®. The guidelines used to develop this program were updated in 2020 and the Textbook of Neonatal Resuscitation, 8th edition, was released in June 2021. The updated guidelines have not changed the basic approach to neonatal resuscitation, which emphasizes the importance of anticipation, preparation, teamwork, and effective ventilation. Several practices have changed, including the prebirth questions, initial steps, use of electronic cardiac monitors, the initial dose of epinephrine, the flush volume after intravascular epinephrine, and the duration of resuscitation with an absent heart rate. In addition, the program has enhanced components of the textbook to improve learning, added new course delivery options, and offers 2 course levels to allow learners to study the material that is most relevant to their role during neonatal resuscitation. This review summarizes the recent changes to the resuscitation guidelines, the textbook, and the Neonatal Resuscitation Program course.


Morphological transformation of a liquid micropattern on dynamically tunable microwrinkles.
When a very thin, hard layer supported by a soft substrate is laterally compressed beyond a critical strain, then buckling of the hard layer occurs, leading to the formation of small sinusoidal surface undulations (microwrinkles). The orientation of the wrinkle grooves can be reversibly altered by simply adding a strain externally. Using this nonlinear microtopological change, we demonstrate that the morphology of an array of liquid filaments formed on microwrinkle grooves is dramatically and reversibly transformed into liquid filaments with a different orientation or a regular array of microdroplets, "dots", depending on the predefined contact angle. The novel liquid transformation at nanomicrometer scales will find unique applications, such as switchable light diffraction grating, laboratories-on-a-chip systems as well as a simple liquid micropatterning technique.


A Single Center Experience with Coil Embolization for Cerebral Aneurysms Greater than 10 mm in the Internal Carotid Artery.
We investigated endovascular treatment for 10 mm or larger aneurysms in the internal carotid artery (IC), including the cavernous portion, the paraclinoid portion, and the posterior communication artery (PC). Between 2011 and 2014 at our hospital, there were 35 cases of aneurysms that were 10 mm or larger in the carotid artery. We analyzed these 35 cases retrospectively based on the size and location of the aneurysms, method of treatment, number of coils implanted, use of a stent, complications, rupture after treatment, ophthalmologic symptoms, and need for re-treatment. There was no bleeding after treatment. Of the 35 cases, four cases (11%) had permanent complications. Re-treatment was indicated in 11 cases (31%), including eight cases localized in the paraclinoid portion, two cases in the IC-PC, and one case in the cavernous portion. Among these re-treatment cases, two cases required a third treatment. Of the 16 cases with paraclinoid aneurysms, half required re-treatment. Of the 12 cases with ophthalmologic symptoms prior to treatment, 9 (75%) improved or had no change and 3 (25%) became worse. There were no complications in the 13 re-treatment procedures. Re-treatment is not uncommon, and a scheduled follow-up is needed. Coil embolization has been one of the main options for aneurysms that are 10 mm or larger in the IC. In the future, these large aneurysms will be treated with a flow diverter stent (FD).


Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack.
The lymphocyte differentiation antigen CD4 serves as a receptor for human retroviruses associated with acquired immunodeficiency syndrome (AIDS) through its interaction with the major envelope virion glycoprotein, gp120, which is also expressed on the surface of infected cells. In these experiments, purified gp120 was shown to bind to normal human T-lymphocyte populations. The gp120-CD4 complex served as a target antigen for antibody-dependent complement-mediated cytolysis by a goat serum raised against native gp120. However, patient sera that bound to gp120-adsorbed cells failed to direct their destruction in the presence of complement. In contrast, these sera were potent mediators of antibody-dependent cellular cytotoxicity. These studies demonstrate that gp120 situated on the cell surface can serve as an effective target for immune destruction by patient antibodies and effector lymphocytes. The possible contribution of this type of immunity to control of disease progression, on the one hand, and to lymphocyte destruction and immunopathology observed in AIDS, on the other, is discussed.


ramR mutations in clinical isolates of Klebsiella pneumoniae with reduced susceptibility to tigecycline.
Five Klebsiella pneumoniae isolates with reduced susceptibility to tigecycline (MIC, 2 microg/ml) were analyzed. A gene homologous to ramR of Salmonella enterica was identified in Klebsiella pneumoniae. Sequencing of ramR in the nonsusceptible Klebsiella strains revealed deletions, insertions, and point mutations. Transformation of mutants with wild-type ramR genes, but not with mutant ramR genes, restored susceptibility to tigecycline and repressed overexpression of ramA and acrB. Thus, this study reveals a molecular mechanism for tigecycline resistance in Klebsiella pneumoniae.


Bioactive Compounds in Functional Meat Products.
Meat and meat products are a good source of bioactive compounds with positive effect on human health such as vitamins, minerals, peptides or fatty acids. Growing food consumer awareness and intensified global meat producers competition puts pressure on creating new healthier meat products. In order to meet these expectations, producers use supplements with functional properties for animal diet and as direct additives for meat products. In the presented work seven groups of key functional constituents were chosen: (i) fatty acids; (ii) minerals; (iii) vitamins; (iv) plant antioxidants; (v) dietary fibers; (vi) probiotics and (vii) bioactive peptides. Each of them is discussed in term of their impact on human health as well as some quality attributes of the final products.


The neural and genetic substrates of sexual behavior in Drosophila.
fruitless (fru), originally identified with its mutant conferring male homosexuality, is a neural sex determination gene in Drosophila that produces sexually dimorphic sets of transcripts. In the nervous system, Fru is translated only in males. Fru proteins likely regulate the transcription of a set of downstream genes. The expression of Fru proteins is sufficient to induce male sexual behavior in females. A group of fru-expressing neurons called "mAL" neurons in the brain shows conspicuous sexual dimorphism. mAL is composed of 5 neurons in females and 30 neurons in males. It includes neurons with bilateral projections in males and contralateral projections in females. Terminal arborization patterns are also sexually dimorphic. These three characteristics are feminized in fru mutant males. The inactivation of cell death genes results in the production of additional mAL neurons that are of the male type in the female brain. This suggests that male-specific Fru inhibits mAL neuron death, leading to the formation of a male-specific neural circuit that underlies male sexual behavior. Fru orchestrates a spectrum of downstream genes as a master control gene to establish the maleness of the brain.


Entomopathogenic fungi of the order Entomophthorales (Zygomycotina) in adult black fly populations (Diptera: Simuliidae) in Quebec.
Infections by insect-pathogenic fungi of the order Entomophthorales in two adult black fly populations were studied in the Réserve Faunique du Saint-Maurice (Quebec). Entomophaga near limoniae infected Simulium verecundum/rostratum in June whereas Erynia curvispora predominantly parasitized Simulium decorum from the 2nd week of July to September and Erynia conica attacked the Simulium venustum complex, Simulium verecundum/rostratum, and the Simulium vittatum complex from May to September. The fungi did not infect the adult stage of Prosimulium species. Possible evidence of host specificity for Erynia conica is discussed.


Costus spicatus tea failed to improve diabetic progression in C57BLKS/J db/db mice, a model of type 2 diabetes mellitus.
Costus spicatus Sw. (Costaceae) is a prominent medicinal herb used by Dominicans in the Dominican Republic and the United States for the treatment of diabetes, a growing epidemic in the Hispanic community. An ethnobotanical survey of the Dominican community in New York City revealed the popular use of a tea from the insulina plant to treat hyperglycemia. Insulina was identified as Costus spicatus. We tested the ability of a tea made from the leaves of Costus spicatus to alter glucose homeostasis in C57BLKS/J (KS) db/db mice, a model of obesity-induced hyperglycemia with progressive beta cell depletion. From 6 to 16 weeks of age, Experimental and Control animals (n=6/5) were given ad lib access to Costus spicatus tea or water, respectively. Weight gain and progression of hyperglycemia and insulinopenia between the Experimental and Control groups were statistically indistinguishable. There was no difference between groups in average fed or fasting glucose and insulin concentrations. Intraperitoneal (IP) insulin tolerance testing after the 10-week study period showed that Costus spicatus tea consumption did not alter insulin sensitivity. These data suggest that at the dose given, tea made from Costus spicatus leaves had no efficacy in the treatment of obesity-induced hyperglycemia. More investigation is needed to more fully explore dosages and the possible utility and biological activity of this common Dominican herbal remedy for the treatment of type 2 diabetes mellitus.


Control of the simian fetal hemoglobin switch at the progenitor cell level.
This investigation was designed to define the cellular level at which the gamma to beta globin switch is established in the developing simian fetus in order to determine whether the switch is controlled by environmental influences within differentiating erythroid precursors or predetermined by the genetic program of erythroid progenitors. Samples of marrow and liver were obtained from rhesus fetuses throughout the switch period, and marrow was obtained from adult rhesus monkeys. Globin chain synthesis was then measured in differentiated erythroblasts and in erythroid progenitor-derived colonies grown in semisolid media. The relative rates of synthesis of gamma and beta chains were determined by the uptake of [(3)H]leucine into the respective chains separated by Triton gel electrophoresis and in some cases by urea carboxymethyl cellulose chromatography. Four periods of the switch were defined during fetal development. In the preswitch period both erythroblasts and progenitor-derived colonies produced <5% beta globin. In the early switch erythroblasts produced 5-15% beta globin, while progenitor-derived colonies produced 10-35% beta globin. In mid-switch erythroblasts synthesized 50% beta globin, whereas progenitor-derived colonies produced only 15-35% beta. At the completion of the switch erythroblasts produced 100% beta globin, while progenitor-derived colonies produced as little as 40% beta chains. We conclude that the program of globin synthesis that characterizes the fetal switch is established at the level of erythroid progenitors. Fetal erythroid burst-forming units (BFU-E) dominate the marrow prior to the switch. The early switch period is heralded by the appearances of adult erythroid burst-forming units programmed to express increasing beta chain synthesis in colonies. By mid-switch a second class of adult erythroid progenitors capable of giving rise to fetal and adult hemoglobin synthesis in in vitro colonies becomes apparent. These shifting populations of erythroid progenitors with unique globin synthesis programs give rise to the erythroblasts that create the sigmoid pattern of the fetal to adult hemoglobin switch in the developing simian fetus.


Differences in time to peak carbachol-induced contractions between circular and longitudinal smooth muscles of mouse ileum.
The muscular layer in the GI tract consists of an inner circular muscular layer and an outer longitudinal muscular layer. Acetylcholine (ACh) is the representative neurotransmitter that causes contractions in the gastrointestinal tracts of most animal species. There are many reports of muscarinic receptor-mediated contraction of longitudinal muscles, but few studies discuss circular muscles. The present study detailed the contractile response in the circular smooth muscles of the mouse ileum. We used small muscle strips (0.2 mm × 1 mm) and large muscle strips (4 × 4 mm) isolated from the circular and longitudinal muscle layers of the mouse ileum to compare contraction responses in circular and longitudinal smooth muscles. The time to peak contractile responses to carbamylcholine (CCh) were later in the small muscle strips (0.2 × 1 mm) of circular muscle (5.7 min) than longitudinal muscles (0.4 min). The time to peak contractile responses to CCh in the large muscle strips (4 × 4 mm) were also later in the circular muscle (3.1 min) than the longitudinal muscle (1.4 min). Furthermore, a muscarinic M2 receptor antagonist and gap junction inhibitor significantly delayed the time to peak contraction of the large muscle strips (4 × 4 mm) from the circular muscular layer. Our findings indicate that muscarinic M2 receptors in the circular muscular layer of mouse ileum exert a previously undocumented function in gut motility via the regulation of gap junctions.


Post-discharge impact and cost-consequence analysis of prehabilitation in high-risk patients undergoing major abdominal surgery: secondary results from a randomised controlled trial.
Prehabilitation may reduce postoperative complications, but sustainability of its health benefits and impact on costs needs further evaluation. Our aim was to assess the midterm clinical impact and costs from a hospital perspective of an endurance-exercise-training-based prehabilitation programme in high-risk patients undergoing major digestive surgery. A cost-consequence analysis was performed using secondary data from a randomised, blinded clinical trial. The main outcomes assessed were (i) 30-day hospital readmissions, (ii) endurance time (ET) during an exercise testing, and (iii) physical activity by the Yale Physical Activity Survey (YPAS). Healthcare use for the cost analysis included costs of the prehabilitation programme, hospitalisation, and 30-day emergency room visits and hospital readmissions. We included 125 patients in an intention-to-treat analysis. Prehabilitation showed a protective effect for 30-day hospital readmissions (relative risk: 6.4; 95% confidence interval [CI]: 1.4-30.0). Prehabilitation-induced enhancement of ET and YPAS remained statistically significant between groups at the end of the 3 and 6 month follow-up periods, respectively (ΔET 205 [151] s; P=0.048) (ΔYPAS 7 [2]; P=0.016). The mean cost of the programme was €389 per patient and did not increment the total costs of the surgical process (€812; CI: 95% -878 - 2642; P=0.365). Prehabilitation may result in health value generation. Moreover, it appears to be a protective intervention for 30-day hospital readmissions, and its effects on aerobic capacity and physical activity may show sustainability at midterm. NCT02024776.


Development of the competency-based medical curriculum for the new Augsburg University Medical School.
Aim: With the resolution from April 28, 2014, the Bavarian state government in Germany decided to found a new medical school at Augsburg University, thereby requiring the development of a competency-based medical curriculum. Methods: Two interdisciplinary groups developed a spiral curriculum (following Harden) employing the model of Thumser-Dauth & Öchsner. The curriculum focuses on specifically defined competencies: medical expertise, independent scientific reasoning, argumentation and scholarship, as well as communication skills. Results: The spiral curriculum was developed as a hybrid curriculum. Its modular structure incorporates the mandatory subjects required by the German regulations for medical licensure (Approbationsordnung) into organ- and system-centered blocks which are integrated both horizontally and vertically. Basic preclinical sciences are covered in the blocks "Movement," "Balance" and "Contact." The clinical sciences are organized according to six pillars (conservative medicine, surgical medicine, men's-women's-children's medicine, the senses, the nervous system and the mind, and general medicine) which students revisit three times each over the course of the program. A longitudinal clinical course incorporates interdisciplinary education. A particular focus is on scientific education encompassing a longitudinal course in the sciences (including interdisciplinary classes with other university departments), block practicums, and two scientific projects. Conclusion: It is not only the degree of integration und intensity of the Augsburg University undergraduate medical degree program, but also its targeted advancement of academic, social and communication skills that have not yet been realized to such an extent elsewhere in Germany. On July 8, 2016, the German Council of Science and Humanities unanimously gave this concept a positive evaluation. Future research will examine and evaluate the Augsburg medical curriculum and the impact of the new medical school on the hospital and university in Augsburg.


The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity.
The anticholinergic toxidrome is well described and relatively common. Despite controversy, studies have shown that physostigmine is relatively safe and effective in reversing this toxidrome. We would expect toxicologists would be liberal in its use. We retrospectively analyzed data in the Toxicology Investigators Consortium (ToxIC) registry, representing data from medical toxicologists in multiple institutions nationwide, searching for patients who exhibited an anticholinergic toxidrome, determining what treatment(s) they received, and classifying the treatments as physostigmine, benzodiazepines, physostigmine and benzodiazepines, antipsychotics, or no definitive treatment. The causal agents of the toxidrome were as reported by the treating toxicologist. Eight hundred fifteen consecutive patients with anticholinergic toxidromes were analyzed. Benzodiazepines alone were given in 28.7 %, 12.4 % were given physostigmine alone, 8.8 % received both physostigmine and benzodiazepines, 2.7 % were given antipsychotics, and 47.4 % were given no definitive treatment. In patients who received only physostigmine, there was a significant difference in the rate of intubation (1.9 vs. 8.4 %, OR 0.21, 95 % CI 0.05-0.87) versus other treatment groups. Physostigmine was given at varying rates based on causative agent with use in agents with mixed or unknown effects (15.1 %) being significantly lower than those with primarily anticholinergic effects (26.6 %) (p < 0.001). Patients with anticholinergic toxicity were more likely to receive benzodiazepines than physostigmine. Those patients who received only physostigmine had a significantly lower rate of intubation. Physostigmine was more likely to be used with agents exerting primarily anticholinergic toxicity than in those agents with multiple actions.


Peanut witches' broom (PnWB) phytoplasma-mediated leafy flower symptoms and abnormal vascular bundles development.
The peanut witches' broom (PnWB) phytoplasma causes virescence symptoms such as phyllody (leafy flower) in infected peanuts. However, the obligate nature of phytoplasma limits the study of host-pathogen interactions, and the detailed anatomy of PnWB-infected plants has yet to be reported. Here, we demonstrate that 4',6'-diamidino-2-phenylindole (DAPI) staining can be used to track PnWB infection. The DAPI-stained phytoplasma cells were observed in phloem/internal phloem tissues, and changes in vascular bundle morphology, including increasing pith rays and thinner cell walls in the xylem, were found. We also discerned the cell types comprising PnWB in infected sieve tube members. These results suggest that the presence of PnWB in phloem tissue facilitates the transmission of phytoplasma via sap-feeding insect vectors. In addition, PnWB in sieve tube members and changes in vascular bundle morphology might strongly promote the ability of phytoplasmas to assimilate nutrients. These data will help further an understanding of the obligate life cycle and host-pathogen interactions of phytoplasma.


Identification of genetic loci for early maturity in spring bread wheat using the association analysis and gene dissection.
Early maturity in spring bread wheat is highly desirable in the regions where it enables the plants to evade high temperatures and plant pathogens at the end of the growing season. To reveal the genetic loci responsible for the maturity time association analysis was carried out based on phenotyping for an 11-year period and high-throughput SNP genotyping of a panel of the varieties contrasting for this trait. The expression of candidate genes was verified using qPCR. The association between the SNP markers and the trait was validated using the biparental F2:3 population. Our data showed that under long-day conditions, the period from seedling to maturity is mostly influenced by the time from heading to maturity, rather than the heading time. The QTLs associated with the trait were located on 2A, 3B, 4A, 5B, 7A and 7B chromosomes with the 7BL locus being the most significant and promising for its SNPs accelerated the maturity time by about 9 days. Gene dissection in this locus detected a number of candidates, the best being TraesCS7B02G391800 (bZIP9) and TraesCS7B02G412200 (photosystem II reaction center). The two genes are predominantly expressed in the flag leaf while flowering. The effect of the SNPs was verified in F2:3 population and confirmed the association of the 4A, 5B and 7BL loci with the maturity time.


The Occurrence of Potential Harmful Cyanobacteria and Cyanotoxins in the Obrzyca River (Poland), a Source of Drinking Water.
Harmful cyanobacteria and their cyanotoxins may contaminate drinking water resources and their effective control remains challenging. The present study reports on cyanobacterial blooms and associated cyanotoxins in the Obrzyca River, a source of drinking water in Poland. The river was examined from July to October 2019 and concentrations of microcystins, anatoxin-a, and cylindrospermopsin were monitored. The toxicity of water samples was also tested using an ecotoxicological assay. All studied cyanotoxins were detected with microcystins revealing the highest levels. Maximal microcystin concentrations (3.97 μg/L) were determined in September at Uście point, exceeding the provisional guideline. Extracts from Uście point, where the dominant species were Dolichospermum flos-aquae (August), Microcystis aeruginosa (September), and Planktothrix agardhii (October), were toxic for Dugesia tigrina Girard. Microcystin concentrations (MC-LR and MC-RR) were positively correlated with cyanobacteria biovolume. Analysis of the chemical indicators of water quality has shown relationships between them and microcystins as well as cyanobacteria abundance.


Incremental solvation of nonionized and zwitterionic glycine.
Microsolvation and combined microsolvation-continuum approaches are employed in order to examine the structures and relative energies of nonionized (N) and zwitterionic (Z) glycine clusters. Bridging structures are predicted to be the global minima after 3-5 discrete water molecules are included in the calculations. Calculations incorporating electron correlation stabilize the zwitterionic structures by about 7-9 kcal/mol relative to the N structures regardless of the number of discrete water molecules considered. Continuum calculations stabilize the Z structures relative to N structures; this effect decreases as the number of discrete water molecules is increased. Eight water molecules do not appear to fully solvate glycine.


In vitro antioxidative effects and tyrosinase inhibitory activities of seven hydroxycinnamoyl derivatives in green coffee beans.
Seven kinds of hydroxycinnamic acid derivatives identified as 3-caffeoylquinic acid (3-CQA), 4-caffeolyquinic acid (4-CQA), 5-caffeoylquinic acid (5-CQA), 5-feruloylquinic acid (5-FQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and 4,5-dicaffoylquinic acid (4,5-diCQA) by MS, 1H NMR, and HPLC analyses were isolated from low-quality (immature) and commercial quality green coffee beans. The quantity of chlorogenic acid isomers (10.4 g/100 g), especially 5-CQA, in commercial green coffee beans [West Indische Bereiding (West India processing beans from Sumatra Island, Indonesia, WIB)] was higher than that in low-quality beans [9.1 g/100 g, Eerste Kwaliteit (Export low-quality beans from Java Island, Indonesia, EK-1, grade 4)], whereas little difference in diCQAs was detected between the two kinds of beans. The free radical scavenging activity of these isolates was evaluated in assay systems using DPPH free radicals and superoxide anion radicals generated by xanthine-XOD. The diCQAs showed strong (1.0-1.8-fold) free radical scavenging activity compared to commonly used antioxidants such as alpha-tocopherol and ascorbic acid. The potency order of superoxide anion radical scavenging activity was diCQAs > caffeic acid, CQAs > 5-FQA. The activities of the diCQAs were twice as effective as those of CQAs and 4 times as effective as that of 5-FQA. The diCQAs also exhibited more potent (2.0-2.2-fold) tyrosinase inhibitory activities compared to CQAs, arbutin, and ascorbic acid. The isolates exhibited antiproliferation activities in four cancer cell lines, U937, KB, MCF7, and WI38-VA. Among these, KB cells were most sensitive (IC50 = 0.10-0.56 mM).


The orthotopic T pouch ileal neobladder: experience with 209 patients.
A serous lined extramural ileal flap valve technique called the T limb was developed to prevent reflux of urine in an orthotopic bladder substitute called the T pouch. We evaluate our intermediate clinical and functional experience with the orthotopic T pouch ileal neobladder. From November 1996 through May 2000, 209 patients (169 men [80%], 40 women), with a mean age of 69 years (range 33 to 93) underwent construction of an orthotopic T pouch ileal neobladder after cystectomy. The indication for cystectomy included bladder cancer in 198 patients (95%). Median followup for the entire cohort was 33 months (range 0 to 69). Data were analyzed according to perioperative mortality, early (within 3 months) and late diversion related and diversion unrelated complications, radiographic evaluation of the upper urinary tract and urinary reservoir, and determination of renal function. Three patients (1.4%) died perioperatively. A total of 63 (30%) early complications occurred, 53 (25%) diversion unrelated and 10 (5%) diversion related. The most common early diversion unrelated complication was dehydration (10 patients). The most common early diversion related complication was urine leak in 6 patients. There were no early complications directly related to the antirefluxing T limb. Late complications occurred in 68 (32%) patients including 30 (14%) diversion unrelated and 38 (18%) diversion related. The most common late diversion unrelated complication was incisional hernia in 16 patients. Of the 38 late diversion related complications the most common were pouch calculi in 17 and ureteroileal obstruction in 9 patients. The only late complication directly related to the T limb was stenosis in 4 patients, 3 of whom received adjuvant pelvic radiation. A total of 181 patients had radiographic evaluation of the upper urinary tract including 162 (90%) with a normal radiographic study or evidence of postoperative decompression. An abnormal upper tract study was seen in 18 patients (10%) including 9 with ureteroileal obstruction and 4 with afferent T limb stenosis. Gravity cystography of the neobladder was normal in 143 of 158 (90%) evaluable patients. Reflux was seen in 15 patients (10%). Renal function as determined by serum creatinine was stable or improved in 96% of patients. Good daytime and nighttime continence was reported in 87% and 72% of evaluable patients, respectively. Overall 75% of patients complete void while 25% required some form of intermittent catheterization to empty the neobladder completely including 20% of men and 43% of women. With intermediate followup the functional results of the T pouch ileal neobladder are acceptable. The antirefluxing T limb provides unobstructed urinary flow in 95% and reflux prevention in 90% of patients. Although these results are encouraging, further followup is required to assess the long-term results of the T pouch ileal neobladder.


Inhibition of p38MAPK potentiates mesenchymal stem cell therapy against myocardial infarction injury in rats.
The present study aimed to investigate the protective effect of mesenchymal stem cell (MSC) therapy in combination with p38 mitogen‑activated protein (MAPK) inhibition against myocardial infarction (MI) injury in rats, and to elucidate the underlying mechanisms. An MI model was established by ligation of the anterior descending branch of the left coronary artery. The rats were divided into four groups: MSC transplantation, p38MAPK inhibitor (SB203580), MSC + SB203580 and model control group. HE staining and a TUNEL assay were performed to evaluate pathological changes and apoptosis. The expression levels of p38MAPK and transforming growth factor β‑activated kinase 1 (TAK1) were determined using reverse transcription‑polymerase chain reaction and western blot analyses. As shown by HE staining, classical morphological changes, including irregular cell arrangement and inflammatory infiltration were observed in the model rats, whereas MSC therapy or injection of the p38MAPK inhibitor ameliorated these pathological changes. Of note, the combined application of MSCs with the p38MAPK inhibitor exerted additive effects. The TUNEL assay showed that the combined application of MSCs with p38MAPK inhibitor also led to potentiation of effects, compared with either MSCs therapy or p38MAPK inhibitor injection alone. Mechanistically, the combined application of MSCs with p38MAPK inhibitor decreased the expression levels of TAK1 and p38MAPK at the mRNA and protein levels. In conclusion, p38MAPK inhibition potentiated the protective effects of MSCs therapy against MI in rats.


Visualizing choriocapillaris using swept-source optical coherence tomography angiography with various probe beam sizes.
Imaging choriocapillaris (CC) is a long-term challenge for commercial OCT angiography (OCTA) systems due to limited transverse resolution. Effects of transverse resolution on the visualization of a CC microvascular network are explored and demonstrated in this paper. We use three probe beams with sizes of ~1.12 mm, ~2.51 mm and ~3.50 mm at the pupil plane, which deliver an estimated transverse resolution at the retina of 17.5 µm, 8.8 µm and 7.0 µm, respectively, to investigate the ability of OCTA to resolve the CC capillary vessels. The complex optical microangiography algorithm is applied to extract blood flow in the CC slab. Mean retinal pigment epithelium (RPE) to CC (RPE-CC) distance, mean CC inter-vascular spacing and the magnitude in the radially-averaged power spectrum are quantified. We demonstrate that a clearer CC lobular capillary network is resolved in the angiograms provided by a larger beam size. The image contrast of the CC angiogram with a large beam size of 3.50 mm is 114% higher than that with a small beam size of 1.12 mm. While the measurements of the mean RPE-CC distance and CC inter-vascular spacing are almost consistent regardless of the beam sizes, they are more reliable and stable with the larger beam size of 3.50 mm. We conclude that the beam size is a key parameter for CC angiography if the purpose of the investigation is to visualize the individual CC capillaries.


A New Method for Heart Disease Detection: Long Short-Term Feature Extraction from Heart Sound Data.
Heart sounds have been extensively studied for heart disease diagnosis for several decades. Traditional machine learning algorithms applied in the literature have typically partitioned heart sounds into small windows and employed feature extraction methods to classify samples. However, as there is no optimal window length that can effectively represent the entire signal, windows may not provide a sufficient representation of the underlying data. To address this issue, this study proposes a novel approach that integrates window-based features with features extracted from the entire signal, thereby improving the overall accuracy of traditional machine learning algorithms. Specifically, feature extraction is carried out using two different time scales. Short-term features are computed from five-second fragments of heart sound instances, whereas long-term features are extracted from the entire signal. The long-term features are combined with the short-term features to create a feature pool known as long short-term features, which is then employed for classification. To evaluate the performance of the proposed method, various traditional machine learning algorithms with various models are applied to the PhysioNet/CinC Challenge 2016 dataset, which is a collection of diverse heart sound data. The experimental results demonstrate that the proposed feature extraction approach increases the accuracy of heart disease diagnosis by nearly 10%.


Novel approach for detection of hepatitis E virus infection in German blood donors.
The risk of transfusion-transmitted hepatitis E virus (HEV) infections by contaminated blood products remains unknown. In the present study, we evaluated and compared different nucleic acid amplification technique (NAT) methods for the detection of HEV in blood components. Minipools of a total of 16,125 individual blood donors were screened for the presence of HEV RNA using the highly sensitive RealStar HEV RT-PCR kit, revealing a minimum detection limit of 4.66 IU/ml. Thirteen donors were HEV RNA positive (0.08%), and of these donors, only three already showed reactive IgM antibody titers. The detected HEV strains all belonged to genotype 3 and were most closely related to German HEV strains from wild boars and pigs as well as from human hepatitis E cases. Furthermore, HEV RNA and HEV-specific IgM and IgG titers were determined in 136 blood donors with elevated alanine aminotransferase (ALT) levels and in 200 donors without pathological findings. HEV RNA was not detectable, but 8.08% (elevated ALT) and 0.5% (nonelevated ALT) of donors showed reactive HEV IgM titers. The overall seroprevalence rate of HEV IgG amounted to 5.94% (elevated ALT, 5.88%; nonelevated ALT, 6.0%). The clinical relevance of transfusion-associated hepatitis E infection still requires further investigation. However, in connection with raising concerns regarding blood safety, our NAT method provides a sensitive possibility for HEV testing.


Thrombomodulin (TM) in tumor cell differentiation and periphery blood immune microenvironment in oral squamous cell carcinoma.
Thrombomodulin (TM, also known as CD141), which functions as an anticoagulant, is widely expressed on cell surface of a variety of cell types, including human blood cells as well as certain immune cells. To determine whether TM could be a potential marker for OSCC diagnosis as well as a molecular target for OSCC therapy, we examined the expression of TM in an oral cancer tissue microarray with 153 oral cancer tissues. Further, we also analyzed the expression of TM on DCs of 36 OSCC patients and 36 healthy donors. The expression of TM was determined using standard immunohistochemistry on a tissue microarray of 153 OSCC patients. Flow cytometric analyses were performed to determine the proportions of CD141+ DCs in the PBMC of 36 OSCC patients and 36 healthy donors. Clinicopathological correlations were performed based on the available clinical data. Our results showed that in the univariate analysis, high TM expression was significantly associated with well differentiation of tumor cells (P=.001), but not correlated with overall survival and disease-free survival (P>.05). In addition, CD141+ DCs were both present in OSCC patients and healthy donors with about 0.04%. There was no significant difference with the percentages of CD141+ DCs in the PBMC of OSCC patients and that of the normal control group (P>.05). This study indicates that TM expression might play the most critical role in the differentiation of OSCC tumors. Functional distinctions of CD141+ DCs in OSCC patients deserve further investigation to provide important therapeutic understandings for future immunotherapy.


Balanced scorecards for performance management.
Nurse administrators who manage nursing case management programs are challenged to demonstrate the improved quality of patient care and financial outcomes to their organization that result from such programs. This article introduces the balanced scorecard and discusses its benefits and practical concerns for adopting the scorecard. The balanced scorecard is a useful performance management tool used to both evaluate and direct case management performance in meeting organizational missions and strategies.


The Risk of Acute Kidney Injury with Oral Anticoagulants in Elderly Adults with Atrial Fibrillation.
Anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant may be associated with AKI. Our objective was to assess the risk of AKI among elderly individuals with atrial fibrillation newly prescribed a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban) versus warfarin. Our population-based cohort study included 20,683 outpatients in Ontario, Canada, ≥66 years with atrial fibrillation who were prescribed warfarin, dabigatran, rivaroxaban, or apixaban between 2009 and 2017. Inverse probability of treatment weighting on the basis of derived propensity scores for the treatment with each direct oral anticoagulant was used to balance baseline characteristics among patients receiving each of the three direct oral anticoagulants compared with warfarin. Cox proportional hazards regression was performed in the weighted population to compare the association between the prescribed anticoagulant and the outcomes of interest. The exposure was an outpatient prescription of warfarin or one of the direct oral anticoagulants. The primary outcome was a hospital encounter with AKI, defined using Kidney Disease Improving Global Outcomes thresholds. Prespecified subgroup analyses were conducted by eGFR category and by the percentage of international normalized ratio measurements in range, a validated marker of anticoagulation control. Each direct oral anticoagulant was associated with a significantly lower risk of AKI compared with warfarin (weighted hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80 for dabigatran; weighted hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98 for rivaroxaban; and weighted hazard ratio, 0.81; 95% confidence interval, 0.72 to 0.93 for apixaban). In the subgroup analysis, the lower risk of AKI associated with each direct oral anticoagulant was consistent across each eGFR strata. The risk of AKI was significantly lower among users of each of the direct oral anticoagulants compared with warfarin users who had a percentage of international normalized ratio measurements ≤56%. Direct oral anticoagulants were associated with a lower risk of AKI compared with warfarin.


Type I interferon regulates pDC maturation and Ly49Q expression.
Ly49Q is expressed on peripheral mouse plasmacytoid dendritic cells (pDC). Immature Ly49Q-negative pDC precursors acquire Ly49Q in the bone marrow and then migrate into the periphery. While searching for molecules that regulate pDC maturation, we found that type I interferon (IFN) inhibited Ly49Q acquisition in vitro. Infections that induce type I IFN production by cells other than pDC (a condition mimicked by poly(I:C) injection in vivo) increase the prevalence of Ly49Q(-) pDC in the bone marrow and peripheral lymphoid organs in wild-type but not IFN-alpha/beta receptor knockout BALB/c mice. Moreover, in vivo exposure to type I IFN causes some Ly49Q(-), but not Ly49Q(+), pDC to convert to conventional DC, defined as B220(-) CD11c(+) CD11b(+) cells. These data suggest that type I IFN regulates pDC development and affects their distribution in the body.


Chlorophyll Fluorescence and Reflectance-Based Non-Invasive Quantification of Blast, Bacterial Blight and Drought Stresses in Rice.
Response of rice (Oryza sativa) exposed to both biotic and abiotic stresses can be quantified by employing fast and accurate optical methods. In this study, the overall stress responses of (i) 12 near-isogenic lines (NILs) in the genetic background of the rice blast-susceptible cultivar Lijiangxintuanheigu (LTH) and (ii) four NILs in the genetic background of the bacterial blight-susceptible cultivar IR24, were inspected by means of Chl fluorescence (Chl-F) imaging. The distribution of the maximum and effective quantum yield of PSII (Fv/FM and QY) and steady-state Chl-F (Ft) were found to be effective in differentiating symptomatic leaf tissue for both rice blast and bacterial blight, which correlated well with 30 cycles of rice blast and six cycles of bacterial blight previously screened using classical (manual) approaches. Subsequently, identified Chl-F parameters allowing detection under ambient light (QY and Ft) were tested across both biotic and abiotic (drought) stress experiments, for rice cultivars contrasting for drought stress response (N22, IR64 and NSIC Rc 222). Their applicability has been proven for both rice blast and bacterial blight; however, QY failed to detect the effect of drought. In addition to Chl-F, the usefulness of 11 selected vegetation indices (Vis) was tested on these three cultivars exposed to particular stresses: (i) rice blast was detectable by Vis calculated from the visible spectrum; (ii) bacterial blight by near-infrared-related Vis; and (iii) drought by Vis calculated from the visible spectrum. The key Chl-F parameters and/or Vis have been summarized and discussed.


Efficient DNA photocleavage by [Ru(bpy)2(dppn)]2+ with visible light.
The population and reactivity of two low-lying excited states in [Ru(bpy)(2)(dppn)](2+) (bpy = 2,2'-bipyridine, dppn = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine), a weakly emissive (3)MLCT state and a long-lived ligand-centered (3)pipi* state, lead to efficient photoinduced DNA damage. Irradiation with visible light results in nearly complete DNA cleavage within 30 s (lambda(irr) > or = 455 nm), likely from the combined action of guanine oxidation and the production of reactive oxygen species derived from (1)O(2).


Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.
Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.


Activation of human dendritic cells by bacillus Calmette-Guerin.
Dendritic cells are the most potent antigen presenting cells capable of initiating antitumor immune responses. We previously showed that bacillus Calmette-Guerin (BCG) stimulates cultured human dendritic cells. We extended these studies and tested the ability of cultured human dendritic cells to express interleukin IL-8 in response to BCG. We also investigated the T cell stimulatory potential of BCG treated dendritic cells in mixed leukocyte reactions. Dendritic cells were obtained by culturing plastic adherent mononuclear cells from peripheral blood for 6 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4. Spontaneous and BCG stimulated IL-8 protein release into culture supernatants was measured by a quantitative immunoassay. IL-8 gene transcription was assessed by reverse transcription-polymerase chain reaction. Untreated and BCG exposed dendritic cells were compared as stimulators of allogeneic T cell proliferation, measured as [3H]thymidine incorporation. BCG stimulated IL-8 messenger ribonucleic acid expression and IL-8 protein release. IL-8 secretion occurred in a dose and time dependent fashion. BCG induced IL-8 release was further enhanced in the presence of indomethacin. BCG treated dendritic cells were much more potent T cell stimulators than untreated dendritic cells. These data demonstrate that BCG enhances the production of IL-8, a potent chemokine of T cells and granulocytes, as well as the T cell stimulatory potential of human dendritic cells.


Parkinsonism Differentiates Idiopathic Normal Pressure Hydrocephalus from Its Mimics.
Parkinsonism is frequent in neurological conditions affecting gait and cognition, such as idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics, but its discriminating value between these two groups is still unidentified. This study aims to compare the prevalence of parkinsonism between iNPH and iNPH mimics and its discriminating value. Among 141 patients with suspicion of iNPH (75.7±7.1 years; 31.2% women), seventy-nine presented a possible or probable iNPH according to standardized diagnostic criteria and the remaining sixty-two were classified as iNPH mimics. Presence of parkinsonism and other seminal clinical symptoms of iNPH were systematically evaluated by a board-certified neurologist. Covariates include age, gender, comorbidities, and white matter disease burden using the age-related white matter changes scale. Logistic regressions were used to assess the association between parkinsonism and diagnostic groups. Parkinsonism was present in 40.3% of iNPH mimics and 20.3% of iNPH (p-value: 0.015). The presence of parkinsonism, but not iNPH symptoms, was associated with the diagnosis of mimics in the adjusted model (adjusted odds ratio: 2.28; 95% CI: 1.06-4.93), even when age-related white matter changes were accounted for. Compared to iNPH, the increased prevalence of parkinsonism in patients with iNPH mimics in the absence of significant white matter disease suggest an underlying neurodegenerative mechanism.


Risk of thyroid cancer in a lung cancer screening population of the National Lung Screening Trial according to the presence of incidental thyroid nodules detected on low-dose chest CT.
This study evaluated thyroid cancer risk in a lung cancer screening population according to the presence of an incidental thyroid nodule (ITN) detected on low-dose chest computed tomography (LDCT). Of 47,837 subjects who underwent LDCT, a lung cancer screening population according to the National Lung Screening Trial results was retrospectively enrolled. The prevalence of ITN on LDCT was calculated, and the ultrasonography (US)/fine-needle aspiration (FNA)-based risk of thyroid cancer according to the presence of ITN on LDCT was compared using the Fisher exact or Student t-test as appropriate. Of the 2,329 subjects (female:male=44:2,285; mean age, 60.9±4.9 years), the prevalence of ITN on LDCT was 4.8% (111/2,329). The incidence of thyroid cancer was 0.8% (18/2,329, papillary thyroid microcarcinomas [PTMCs]) and was higher in the ITN-positive group than in the ITN-negative group (3.6% [4/111] vs. 0.6% [14/2,218], P=0.009). Among the 2,011 subjects who underwent both LDCT and thyroid US, all risks were higher (P<0.001) in the ITNpositive group than in the ITN-negative group: presence of thyroid nodule on US, 94.1% (95/101) vs. 48.6% (928/1,910); recommendation of FNA according to the American Thyroid Association guideline and Korean Thyroid Imaging Reporting and Data System guideline, 41.2% (42/101) vs. 2.4% (46/1,910) and 39.6% (40/101) vs. 1.9% (37/1,910), respectively. Despite a higher risk of thyroid cancer in the LDCT ITN-positive group than in the ITN-negative group in a lung cancer screening population, all cancers were PTMCs. A heavy smoking history may not necessitate thorough screening US for thyroid incidentalomas.


Disruption of Biofilm by Bacteriophages in Clinically Relevant Settings.
Antibiotic-resistant bacteria are a growing threat to civilian and military health today. Although infections were once easily treatable by antibiotics and wound cleaning, the frequent mutation of bacteria has created strains impermeable to antibiotics and physical attack. Bacteria further their pathogenicity because of their ability to form biofilms on wounds, medical devices, and implant surfaces. Methods for treating biofilms in clinical settings are limited, and when formed by antibiotic-resistant bacteria, can generate chronic infections that are recalcitrant to available therapies. Bacteriophages are natural viral predators of bacteria, and their ability to rapidly destroy their host has led to increased attention in potential phage therapy applications. The present article sought to address a knowledge gap in the available literature pertaining to the usage of bacteriophage in clinically relevant settings and the resolution of infections particular to military concerns. PRISMA guidelines were followed for a systematic review of available literature that met the criteria for analysis and inclusion. The research completed for this review article originated from the U.S. Military Academy's library "Scout" search engine, which complies results from 254 available databases (including PubMed, Google Scholar, and SciFinder). The search criteria included original studies that employed bacteriophage use against biofilms, as well as successful phage therapy strategies for combating chronic bacterial infections. We specifically explored the use of bacteriophage against antibiotic- and treatment-resistant bacteria. A total of 80 studies were identified that met the inclusion criteria following PRISMA guidelines. The application of bacteriophage has been demonstrated to robustly disrupt biofilm growth in wounds and on implant surfaces. When traditional therapies have failed to disrupt biofilms and chronic infections, a combination of these treatments with phage has proven to be effective, often leading to complete wound healing without reinfection. This review article examines the available literature where bacteriophages have been utilized to treat biofilms in clinically relevant settings. Specific attention is paid to biofilms on implant medical devices, biofilms formed on wounds, and clinical outcomes, where phage treatment has been efficacious. In addition to the clinical benefit of phage therapies, the military relevance and treatment of combat-related infections is also examined. Phages offer the ability to expand available treatment options in austere environments with relatively low cost and effort, allowing the impacted warfighter to return to duty quicker and healthier.


Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction.
The α2-isoform of the Na,K-ATPase (α2) is the minor isoform of the Na,K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing α2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of α2 to further define the tissue-specific role of α2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of α2 in the heart using β-myosin heavy chain Cre. We have achieved a 90% knockout of α2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of α2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of α2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of α2 determines its unique roles in the regulation of cardiovascular function.


[Torsion of a seminoma in an intrascrotal testis. A case report].
We report a case of torsion of an intrascrotal testicular tumor. The patient was a 54-year-old man with a chief complaint of swelling and pain in the left scrotum. A testicular scan using 99mtechnetium RBC demonstrated a large cold area of isotope uptake showing loss of blood flow in his left scrotal content. Pre operative diagnosis was acute testicular torsion. A torsed testicle was delivered through an inguinal incision. The testicle appeared to be twisted 720 degrees clock wise. It was swollen and bluish in color. The blood flow did not recover after the relief of twisting. Radical orchiectomy was performed. The histology demonstrated a seminoma. He was free of disease 4 years after surgery. A torsion of testicular tumor in an undescended testis has been reported sporadically. However, the torsion of the intrascrotal testicular tumor is very rare. There have been 5 reported cases in the world literature and this case seems to be the first one in Japan.


Discrete-symmetry vortices as angular Bloch modes.
The most general form for symmetric modes of nonlinear discrete-symmetry systems with nonlinearity depending on the modulus of the field is presented. Vortex solutions are demonstrated to behave as Bloch modes characterized by an angular Bloch momentum associated to a periodic variable, periodicity being fixed by the order of discrete point-symmetry of the system. The concept of angular Bloch momentum is thus introduced to generalize the usual definition of angular momentum to cases where O2 symmetry no longer holds. The conservation of angular Bloch momentum during propagation is demonstrated.


[Virulence factors of Staphylococcus aureus associated with intramammary infections in cows: relevance and role as immunogens].
Staphylococcus aureus is the most prevalent mastitis pathogen in Argentina and worldwide. Lack of effectiveness of traditional control measures based on milking hygiene and antibiotic therapy against this organism has led to the development of alternatives directed to prevent the disease. Among them, the manipulation of host immune mechanisms through vaccination has been explored. The identification of virulence factors able to stimulate host immune defenses is key to developing a rational vaccine. S. aureus has multiple virulence factors that interact with the host at different stages of an intramammary infection. The use of some of these factors as immunogens has been shown to elicit protective responses in the host. The structure, function, and use as immunogens of S. aureus virulence factors considered to be relevant at different stages of intrammamary infections caused by this organism are reviewed in this article.


An enzyme-encapsulated microreactor for efficient theanine synthesis.
A flow-type microreactor containing glutaminase-mesoporous silica composites with 10.6 nm pore diameter (TMPS10.6) was developed for the continuous synthesis of theanine, a unique amino acid. High enzymatic activity was exhibited by the local control of the reaction temperature.


iRGD as a tumor‑penetrating peptide for cancer therapy (Review).
As a tumor-targeting and ‑penetrating peptide, iRGD binds to αv integrins and neuropilin‑1 receptors, which are expressed at high levels on tumor cells and the surfaces of vasculature. Subsequently, iRGD penetrates deep into the tumor parenchyma with antitumor drugs, imaging agents, immune modulators and biological products. These substances are either chemically linked to the peptide or co‑injected with the peptide. The iRGD peptide can be readily synthesized, exhibits significantly improved penetration, compared with traditional peptides, and can effectively inhibit tumor metastasis. Therefore, the peptide is now used widely for the diagnosis and treatment of cancer. However, whether the peptide is able to promote the entry of drugs into non‑targeted cells remains to be fully elucidated. In this review, an overview of iRGD is presented, focusing on its identification, mechanism of action and previous studies on its roles in various types of cancer. Studies in previous years have demonstrated the potential of the iRGD protein for tumors diagnosis and targeted treatment, which warrants further investigation.


Giant Antrochoanal Polyp-A Rare Presentation.
Antrochoanal polyp (ACP), also called as Killian polyp, is an infrequent, benign lesion of maxillary origin in non-atopic patients. The antrochoanal polyp is shaped according to the anatomical constraints of the lateral nasal wall, particularly the middle meatus and antrum, resembling typically a dumbbell. Here presenting a common problem with unusual presentation.


Mouse fibroblast (type I) and immune (type II) interferons: pronounced differences in affinity for gangliosides and in antiviral and antigrowth effects on mouse leukemia L-1210R cells.
Different interferons can be obtained from the same animal species depending on the cells and (or) the inducers used. Interferons of type I and type II differ not only antigenically but also in molecular weight and stability at low pH. We have investigated whether mouse type I and type II interferons also differ in properties relating to their biological action. We present evidence which suggests that the molecular mechanism leading to antiviral and antigrowth effects induced by both types of interferon in susceptible cells must differ in at least one important step. Antiviral and antigrowth activities of type I but not of type II interferon are both inhibited when gangliosides are added to cell cultures together with the interferon. Whereas type I interferon strongly binds to ganglioside affinity columns and can be eluted with solutions of N-acetylneuraminyllactose, type II interferon passes through such columns unretarded. L-1210 mouse leukemia cells (L-1210S) respond equally well to antiviral and antigrowth activities of type I and type II interferons. Type I interferon-resistant L-1210 cells (L-1210R), derived from L-1210S cells after continuous culture in the presence of mouse fibroblast interferon, lack antiviral and antigrowth response to mouse type I interferon [Gresser, I., Bandu, H.T. & Brouty-Boyé, D. (1974) J. Natl. Cancer Inst. 52, 553-559]. However, these cells display the same sensitivity toward type II interferon as do the parent L-1210S cells from which they were derived and respond equally well to its antiviral and antigrowth activities.


Undertreatment of Motor Problems in Children with ADHD.
BACKGROUND: Motor problems occur in 30% to 50% of children with ADHD, and have a severe impact on daily life. In clinical practice there seems to be little attention for this comorbidity with the possible consequence that these motor problems go undertreated. METHOD: Clinical interview and questionnaire survey of treatment by physiotherapy and factors predicting treatment of motor problems in 235 children with ADHD and 108 controls. RESULTS: Half of motor-affected children had received physiotherapy. Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder. Treated and untreated children were similar in age, and rated similarly on ADHD inattentive and hyperactive-impulsive scales and parental socio-economic status. CONCLUSION: Currently, undertreatment of motor problems in ADHD occurs. Behavioural factors play a role in referral and intervention.


Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.
Without an effective strategy for targeted therapy, glioblastoma is still incurable with a median survival of only 15 months. Both chronic inflammation and epigenetic reprogramming are hallmarks of cancer. However, the mechanisms and consequences of their cooperation in glioblastoma remain unknown. Here, we discover that chronic inflammation governs H3K27me3 reprogramming in glioblastoma through the canonical NF-κB pathway to target EZH2. Being a crucial mediator of chronic inflammation, the canonical NF-κB signalling specifically directs the expression and redistribution of H3K27me3 but not H3K4me3, H3K9me3 and H3K36me3. Using RNA-seq screening to focus on genes encoding methyltransferases and demethylases of histone, we identify EZH2 as a key methyltransferase to control inflammation-triggered epigenetic reprogramming in gliomagenesis. Mechanistically, NF-κB selectively drives the expression of EZH2 by activating its transcription, consequently resulting in a global change in H3K27me3 expression and distribution. Furthermore, we find that co-activation of NF-κB and EZH2 confers the poorest clinical outcome, and that the risk for glioblastoma can be accurately molecularly stratified by NF-κB and EZH2. It is notable that NF-κB can potentially cooperate with EZH2 in more than one way, and most importantly, we demonstrate a Synergistic effect of cancer cells induced by combinatory inhibition of NF-κB and EZH2, which both are frequently over-activated in glioblastoma. In summary, we uncover a functional cooperation between chronic inflammation and epigenetic reprogramming in glioblastoma, combined targeting of which by inhibitors guaranteed in safety and availability furnishes a potent strategy for effective treatment of this fatal disease.


Treatment response and long term follow-up results of nonspecific interstitial pneumonia.
The purpose of this study was to investigate the long-term clinical course of non-specific interstitial pneumonia (NSIP) and to determine which factors are associated with a response to steroid therapy and relapse. Thirty-five patients with pathologically proven NSIP were included. Clinical, radiological, and laboratory data were reviewed retrospectively. The male-to-female ratio was 7:28 (median age, 52 yr). Thirty (86%) patients responded to steroid therapy, and the median follow-up was 55.2 months (range, 15.9-102.0 months). Five patients (14%) showed sustained disease progression and three died despite treatment. In the five with sustained disease progression, NSIP was associated with various systemic conditions, and the seropositivity of fluorescent antinuclear antibody was significantly associated with a poor response to steroids (P = 0.028). The rate of relapse was 25%, but all relapsed patients improved after re-treatment. The initial dose of steroids was significantly low in the relapse group (P = 0.020). In conclusion, progression is associated with various systemic conditions in patients who show progression. A low dose of initial steroids is significantly associated with relapse.


Mechanisms underlying the contraction induced by bradykinin in the guinea pig epithelium-denuded trachea.
This study investigates some of the mechanisms by which bradykinin (BK) triggers contraction of epithelium-denuded strips of guinea pig trachea (GPT). Cumulative or single additions of BK, T-BK, L-BK, or ML-BK in the presence of captopril (30 microM) produced graded GPT contractions with the following rank order of potency (EC50 level): T-BK (31.3 nM) > BK (40.0 nM) > L-BK (56.0 nM) > ML-BK (77.0 nM). BK-induced contraction (100 nM) in GPT was completely inhibited by either HOE 140 or NPC 17731 with mean IC50 values of 17 and 217 nM, respectively. Addition of BK (100 nM) at 30 min intervals, induced progressive tachyphylaxis, which was complete after 4 h. The tachyphylaxis induced by BK was unaffected by L-NOARG (nitric oxide synthase inhibitor, 100 microM) or valeryl salicylate (a cyclooxygenase-1 (COX-1) inhibitor, 30 microM), but was prevented by a low concentration of indomethacin, diclofenac (non-selective COX inhibitors, 3 nM each) or by NS 398 (a COX-2 inhibitor, 10 nM). Furthermore, higher concentrations of indomethacin, diclofenac, phenidone (a lypooxygenase (LOX) and COX inhibitor), or NS 398, caused graded inhibition of BK-induced contraction, with mean IC50 values of 0.28, 0.08, 46.37, and 0.15 microM, respectively. Together, these results suggest that BK-induced contraction in GPT involves activation of B2 receptors and release of prostanoids from COX-2 pathway. Furthermore, the tachyphylaxis induced by BK was insensitive to the nitric oxide and COX-1 inhibitors, but was prevented by non-selective and selective COX-2 inhibitors, indicating a mediation via COX-2-derived arachidonic acid metabolites.


A team approach to supporting the nutritional needs of patients living with multiple sclerosis.
Multiple sclerosis is the most common cause of non-traumatic disability in young adults, with most diagnoses occurring between the ages of 25-49 years. Nutrition must be managed effectively and holistically to improve health and quality of life. Dysphagia management is collaborative and can enhance nutrition and hydration goals as well as reduce the risk of aspiration pneumonia. A case study demonstrates the specialist clinical skills and frameworks used to achieve nutrition, hydration, safety and patient focused outcomes.


Urrets-Zavalia syndrome following iris-claw phakic intraocular lens implantation.
To report a patient who had a fixed and dilated pupil after uneventful iris-claw phakic intraocular lens (IOL) implantation. A 27-year-old woman with bilateral high myopia underwent bilateral implantation of iris-claw phakic IOLs. No specific ocular findings were noted until postoperative week 1. Intraocular pressure (IOP) was within normal range in both eyes after surgery. At postoperative week 2, the right pupil was normal, but the left pupil was fully dilated and non-reactive to light, accommodative effort, and 0.125% and 2% pilocarpine. Best spectacle-corrected visual acuity was 1.0, and IOP was 13 mmHg in the left eye. There was no history of perioperative mydriatic use. Urrets-Zavalia syndrome, unrelated to IOP elevation, occurred after uneventful phakic IOL implantation. Clinicians performing phakic IOL implantation should be aware of this complication.


A technique of nasotracheal intubation in patients with recent facio-maxillary injury.
A technique of nasotracheal intubation in patients with recent facial injury is described. Oral intubation is performed initially to ensure the safety of the patient during the procedure of nasal intubation.


Diagnosis of leptospirosis and comparison of ELISA and MAT techniques.
Leptospirosis is perhaps the most common, most wide spread yet under diagnosed zoonosis in the world, Inada et al identified the causal agent in Japan in 1916. Microscopic agglutination test (MAT) developed initially by Martin and Pettit (1918) is the reference method that was successively done after ELISA test to evaluate and compare and make a reliable diagnosis. Blood samples were collected from August 2004 to September 2004 from hospitalized patients of South Gujarat region who were clinically suspected cases of leptospirosis according to WHO case definition. In our setup we separated the sera and carried out ELISA for detection of IgM antibodies and rest of the sera were stored at -20 degrees C. As we do not have the facility for performing MAT test in our centre, we personally carried these sera to Chennai for performing the MAT and identified the serovars prevalent in South Gujarat region. Out of 30 samples tested 16 samples (53.3%) were positive by ELISA and 12 samples (40%) were negative by ELISA. By MAT, 17 samples (56.67%) were found positive and 13 samples (43.33%) were negative. 2 samples were borderline by ELISA and these turned out to be negative by MAT. Cosidering MATas the gold standard the sensitivity of IgM ELISA in this study was 88% and specificity 90.90%. We concluded that IgM ELISA is rapid test and its results are quite similar to MAT. The most common serovars isolated and identified are L. hebdomadis, L. pyrogenes, L. autumnalis and L. grippotyphosa in this part of the country.


Catheter-implanted prosthetic heart valves. Transluminal catheter implantation of a new expandable artificial heart valve in the descending thoracic aorta in isolated vessels and closed chest pigs.
A new expandable artificial heart valve was developed for implantation by a transluminal catheter technique without using thoracotomy or extracorporeal circulation. The aim of this study was to implant the valve in isolated vessels of the descending thoracic aorta as well as in closed chest pigs, and furthermore to study the prosthesis' mechanical stability and the valve function. The artificial valve was made by mounting a porcine aortic valve on an expandable stent. Before implantation, the stent-valve was compressed on a deflated balloon catheter and mounted inside an introducer sheath. After intravascular introduction to the descending thoracic aorta the stent-valve was discharged from the sheath. Implantation was performed by balloon inflation which expanded the stent-valve to a diameter exceeding the internal vessel's diameter. After balloon deflation the stent-valve maintained an expanded configuration ensuring a stable fixation against the vessel wall. In vitro implantations were performed in 36 isolated descending thoracic aorta specimens obtained from 80 kg pigs. Mechanical stability was evaluated by applying a downing load to the prosthesis. No displacement occurred at loads < or = 1 kg when a large balloon (31 mm) was used for implantation. Transvalvular pressure differences between 11-47 mmHg (median) were obtained at antegrade flowrates between 5-8 l/min. Furthermore, only moderate leakage flows were measured during retrograde perfusion. In vivo implantations were performed in six 80 kg pigs. Implantation was safe and easy, and angiograph and haemodynamic evaluations revealed essentially no stenosis or regurgitation. No complications in migration, perforation, hemorrhage or thrombosis were observed. This study indicates a good mechanical stability and valve function of the new expandable artificial valves.


Vestibular unit transplantation in the coverage of gingival recession: a microsurgical approach.
The palate, maxillary tuberosity and edentulous ridges are generally used as the donor sites for connective tissue grafts. This article shows the use of vestibular soft tissue of a tooth in the coverage of localized gingival recession. The vestibular unit was harvested during crown lengthening procedures, sutured over the denuded root surface, and covered with a coronally advanced flap without vertical incisions. The healing was uneventful with complete coverage of the recession up to 18 months. The vestibular unit of a tooth can serve as the donor area for a connective tissue graft in the coverage of gingival recessions, resulting in stable outcomes.


Effect of beam size parameters on internal fields in an infinite cylinder irradiated by an elliptical Gaussian beam.
The scattered and internal fields of an infinite, homogeneous cylinder illuminated by a linearly polarized beam depend on the following parameters: the object size parameter of the cylinder (ka, where k=2pi/lambda, lambda is the wavelength of the incident beam in the surrounding medium, and a is the radius of cylinder), the complex relative refractive index of the object, the beam size parameters (komega(1) and komega(2), where omega(1), omega(2) are the representative beam dimensions), the angle between the cylinder axis and the Poynting vector of the incident wave, and the angle between the plane of polarization and the plane of incidence. Only when the dimensions of the beam are much greater than the cylinder diameter, and hence the portion of the beam interacting with the cylinder is essentially uniform, can the plane-wave solution be used in computing the scattered and internal fields. Hence a rigorous electromagnetic approach like the generalized Lorenz-Mie theory for spheres is used to study the effect of beam size parameters on the internal fields in an infinite cylinder irradiated by elliptical Gaussian beams. The significant effects of beam size parameters on the internal fields in an infinite cylinder are presented using specific cases of (1) resonance effects in a glass cylinder (ka=45.726, transverse-electric mode 53,3) and (2) a cylindrical microchannel (ka approximately 760) irradiated by a 632.8 nm laser beam.


Association of Hormone Receptor Expression with Survival in Ovarian Endometrioid Carcinoma: Biological Validation and Clinical Implications.
This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of estrogen receptor (ER) and progesterone receptor (PR) was assessed on 182 EC samples represented on tissue microarrays using the Alberta Ovarian Tumor Type (AOVT) cohort. Statistical analyses were performed to test for associations with ovarian cancer specific survival. ER or PR expression was present in 87.3% and 86.7% of cases, respectively, with co-expression present in 83.0%. Expression of each of the hormonal receptors was significantly higher in low-grade tumors and tumors with squamous differentiation. Expression of ER (Hazard Ratio (HR) = 0.18, 95% confidence interval 0.08-0.42, p = 0.0002) and of PR (HR = 0.22, 95% confidence interval 0.10-0.53, p = 0.0011) were significantly associated with longer ovarian cancer specific survival adjusted for age, grade, treatment center, stage, and residual disease. However, the five-year ovarian cancer specific survival among women with ER positive stage IC/II EC was 89.0% (standard error 3.3%) and for PR positive tumors 89.9% (standard error 3.2%), robustly below the 95% threshold where adjuvant therapy could be avoided. We validated the association of hormone receptor expression with ovarian cancer specific survival independent of standard predictors in an independent sample set of EC. The high ER/PR co-expression frequency and the survival difference support further testing of the efficacy of hormonal therapy in hormone receptor-positive ovarian EC. The clinical utility to identify a group of women diagnosed with EC at stage IC/II that could be spared from adjuvant therapy is limited.


Electrospray Modifications for Advancing Mass Spectrometric Analysis.
Generation of analyte ions in gas phase is a primary requirement for mass spectrometric analysis. One of the ionization techniques that can be used to generate gas phase ions is electrospray ionization (ESI). ESI is a soft ionization method that can be used to analyze analytes ranging from small organics to large biomolecules. Numerous ionization techniques derived from ESI have been reported in the past two decades. These ion sources are aimed to achieve simplicity and ease of operation. Many of these ionization methods allow the flexibility for elimination or minimization of sample preparation steps prior to mass spectrometric analysis. Such ion sources have opened up new possibilities for taking scientific challenges, which might be limited by the conventional ESI technique. Thus, the number of ESI variants continues to increase. This review provides an overview of ionization techniques based on the use of electrospray reported in recent years. Also, a brief discussion on the instrumentation, underlying processes, and selected applications is also presented.


Neuropeptides, nerve growth factor and the skin.
Cutaneous nerve fibers can modulate inflammatory reactions through local release of neuro-peptides (NP). In fact, NP are able to regulate both acute and chronic aspects of cutaneous inflammatory processes, such as vascular motility, cellular traffic-king, activation and trophism. Several experimental evidences suggest a participation of NP to the pathogenesis of inflammatory dermatoses: in particular, modulation of inflammatory reactions in the skin can be obtained through pharmacologic manipulation of the neuropeptidergic system. Furthermore, evidence of local alterations of NP levels in inflamed skin has been obtained. It has been hypothesized that the inflammatory process induces reactive changes in the neuronal NP content. The primary candidate as mediator of this neuronal recruitment in the course of inflammatory reactions is the neurotrophin nerve growth factor, that is produced in the skin in increased amounts during inflammatory processes and may regulate peptidergic synthesis at a neuronal level.


Update on thirdhand smoke: A comprehensive systematic review.
The objective of this study is to perform a comprehensive review of the literature about thirdhand smoke (THS). Systematic review of all aspects of THS. Standard methodological procedures were used to search the following databases through April 2018: MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science (WOS) in Indo-European languages. To identify published grey literature, the first 200 hits from Google Scholar™ were evaluated. Clinical trial databases, conference proceedings, and reference lists from the identified articles were also searched. Two unblinded review authors independently assessed trials for inclusion in the review. These same reviewers also extracted study data in accordance with PRISMA guidelines. The study protocol was registered with PROSPERO (CRD42018083619). Sixty-eight articles were included in this systematic review. Of these, 28 analyzed the concentration of nicotine as a component of THS (the most commonly-used method to measure THS in those studies was chromatography, followed by the mass spectrometry), 21 evaluated the exposure and impact of THS on health (11 studies analyzed the effect of THS in cells [human and animal], 4 in animals, 1 in adults, and 5 in children), 16 investigated the beliefs, behaviours, and policies related to THS, and 3 evaluated other aspects such as THS in e-cigarettes or hookahs. In these 68 studies, THS was determined by measuring the following components: nicotine (30 studies), nitrosamines (17 studies) and cotinine (15 studies). The findings from most of these studies suggest a potential health impact of THS exposure (i.e.: cytotoxicity, metabolic alterations in metabolism, in glycemia; or cell structure; alterations in liver, lung, skin and behaviour in mice), and low awareness about the risks of THS among the general population. Numerous specific biomarkers of THS were evaluated, with the most common being nicotine, nitrosamines, and cotinine. The most common method of preparing THS dust samples were cotton wipes, while chromatography, used alone or coupled with mass spectrometry, was the most common analytical technique. We have tried to establish common bases after reviewing all the current literature of the THS although, there is great heterogeneity between the studies and we have not always succeeded. The studies in this review demonstrate the harmful effects of THS on health in cells, in animal models, and in people including children. However, in people, the long-term effects remain unknown and more research is needed. These studies show that knowledge about THS and its potential harmful effects are poorly understood among the general population. For this reason, THS should receive greater emphasis in education and awareness policies.


Two metal-tolerance proteins, MTP1 and MTP4, are involved in Zn homeostasis and Cd sequestration in cucumber cells.
Metal-tolerance proteins (MTPs) are divalent cation transporters that have been shown to be essential for metal homeostasis and tolerance in model plants and hyperaccumulators. Due to the lack of genomic resources, studies on MTPs in cultivated crops are lacking. Here, we present the first functional characterization of genes encoding cucumber proteins homologous to MTP1 and MTP4 transporters. CsMTP1 expression was ubiquitous in cucumber plants, whereas CsMTP4 mRNA was less abundant and was not detected in the generative parts of the flowers. When expressed in yeast, CsMTP1 and CsMTP4 were able to complement the hypersensitivity of mutant strains to Zn and Cd through the increased sequestration of metals within vacuoles using the transmembrane electrochemical gradient. Both proteins formed oligomers at the vacuolar membranes of yeast and cucumber cells and localized in Arabidopsis protoplasts, consistent with their function in vacuolar Zn and Cd sequestration. Changes in the abundance of CsMTP1 and CsMTP4 transcripts and proteins in response to elevated Zn and Cd, or to Zn deprivation, suggested metal-induced transcriptional, translational, and post-translational modifications of protein activities. The differences in the organ expression and affinity of both proteins to Zn and Cd suggested that CsMTP1 and CsMTP4 may not be functionally redundant in cucumber cells.


Trends in hysterectomy rates among women veterans in the US Department of Veterans Affairs.
Prior studies demonstrate a higher prevalence of hysterectomy among veterans compared with nonveterans. While studies identify overall decreasing hysterectomy rates in the United States, none report rates of hysterectomy among women veterans. Given the increasing numbers of women veterans using Veterans Affairs health care, there is an ongoing need to ensure high-quality gynecology care. Therefore, it is important to examine current hysterectomy trends, including proportion of minimally invasive surgeries, among veterans using Veterans Affairs health care. Our objective was to describe hysterectomy trends and utilization of minimally invasive hysterectomy in the Veterans Affairs healthcare system. This longitudinal study used Veterans Affairs clinical and administrative data from fiscal year 2008 to 2014 to identify hysterectomies provided or paid for by Veterans Affairs. Crude and age-adjusted hysterectomy rates were calculated by indication (benign or malignant), mode (abdominal, laparoscopic, vaginal, robotic assisted, unspecified), and source of care (provided vs paid for by Veterans Affairs). Mode and indication for hysterectomy were classified using International Classification of Diseases, ninth revision, codes. The distribution of hysterectomy mode in each year was calculated by indication and source of care. Between fiscal year 2008 and fiscal year 2014, the total hysterectomy rate decreased from 4.0 per 1000 to 2.6 per 1000 unique women veteran Veterans Affairs users. Age-adjusted rates of abdominal hysterectomy for benign indications decreased over the study period from 1.54 per 1000 (95% confidence interval, 1.40-1.69) to 0.77 per 1000 (95% confidence interval, 0.69-0.85) for procedures provided by Veterans Affairs and 0.77 per 1,000 (95% confidence interval, 0.69-0.85) to 0.29 per 1,000 (95% confidence interval, 0.23-0.34) for those paid for by Veterans Affairs. Among hysterectomies for benign indications provided by (n = 5296) or paid for (n = 2610) by Veterans Affairs, the percentage of hysterectomies performed abdominally decreased from 67.2% to 46.8% and from 68.9% to 57.6%, respectively. These findings suggest that gynecology care provided within Veterans Affairs has kept pace with national trends in reducing hysterectomy rates and increasing utilization of minimally invasive surgical techniques.


Elderly Onset Celiac Disease: A Narrative Review.
Celiac sprue is a chronic disease, which usually occurs in children and young adults. However, it can develop in any age group, and the prevalence is increasing even in the elderly population. The atypical patterns of clinical presentation in this age group sometimes can cause a delay in diagnosis. Given the lower sensitivity and specificity of serological tests in the aged population, clinical suspect often arises in the presence of complications (autoimmune disorders, fractures, and finally, malignancy) and must be supported by endoscopic and imaging tools. In this review, we highlight the incidence and prevalence of celiac disease in the elderly, the patterns of clinical presentation, diagnosis, and the most frequent complications, with the aim of increasing awareness and reducing the diagnostic delay of celiac disease even in the elderly population.


Innovative and collaborative industrial mathematics in Europe.
This paper presents a brief review of how industrial mathematics, inspired by the Oxford Study Group activity, organized itself in Europe, gave rise to the European Consortium for Mathematics in Industry, the series of European Study Groups with Industry, and to new modes of productive contacts between industry and applied mathematicians in academia.


Iodine supplementation for women during the preconception, pregnancy and postpartum period.
Iodine is an essential nutrient required for the biosynthesis of thyroid hormones, which are responsible for regulating growth, development and metabolism. Iodine requirements increase substantially during pregnancy and breastfeeding. If requirements are not met during these periods, the production of thyroid hormones may decrease and be inadequate for maternal, fetal and infant needs. The provision of iodine supplements may help meet the increased iodine needs during pregnancy and the postpartum period and prevent or correct iodine deficiency and its consequences. To assess the benefits and harms of supplementation with iodine, alone or in combination with other vitamins and minerals, for women in the preconceptional, pregnancy or postpartum period on their and their children's outcomes. We searched Cochrane Pregnancy and Childbirth's Trials Register (14 November 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (17 November 2016), contacted experts in the field and searched the reference lists of retrieved studies and other relevant papers. Randomized and quasi-randomized controlled trials with randomisation at either the individual or cluster level comparing injected or oral iodine supplementation (such as tablets, capsules, drops) during preconception, pregnancy or the postpartum period irrespective of iodine compound, dose, frequency or duration. Two review authors independently assessed trial eligibility, risk of bias, extracted data and conducted checks for accuracy. We used the GRADE approach to assess the quality of the evidence for primary outcomes.We anticipated high heterogeneity among trials, and we pooled trial results using random-effects models and were cautious in our interpretation of the pooled results. We included 14 studies and excluded 48 studies. We identified five ongoing or unpublished studies and two studies are awaiting classification. Eleven trials involving over 2700 women contributed data for the comparisons in this review (in three trials, the primary or secondary outcomes were not reported). Maternal primary outcomesIodine supplementation decreased the likelihood of the adverse effect of postpartum hyperthyroidism by 68% (average risk ratio (RR) 0.32; 95% confidence interval (CI) 0.11 to 0.91, three trials in mild to moderate iodine deficiency settings, 543 women, no statistical heterogeneity, low-quality evidence) and increased the likelihood of the adverse effect of digestive intolerance in pregnancy by 15 times (average RR 15.33; 95% CI 2.07 to 113.70, one trial in a mild-deficiency setting, 76 women, very low-quality evidence).There were no clear differences between groups for hypothyroidism in pregnancy or postpartum (pregnancy: average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low-quality evidence, and postpartum: average RR 0.44; 95% CI 0.06 to 3.42, three trials, 540 women, no statistical heterogeneity, low-quality evidence), preterm birth (average RR 0.71; 95% CI 0.30 to 1.66, two trials, 376 women, statistical heterogeneity, low-quality evidence) or the maternal adverse effects of elevated thyroid peroxidase antibodies (TPO-ab) in pregnancy or postpartum (average RR 0.95; 95% CI 0.44 to 2.07, one trial, 359 women, low-quality evidence, average RR 1.01; 95% CI 0.78 to 1.30, three trials, 397 women, no statistical heterogeneity, low-quality evidence), or hyperthyroidism in pregnancy (average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low-quality evidence). All of the trials contributing data to these outcomes took place in settings with mild to moderate iodine deficiency. Infant/child primary outcomesCompared with those who did not receive iodine, those who received iodine supplements had a 34% lower likelihood of perinatal mortality, however this difference was not statistically significant (average RR 0.66; 95% CI 0.42 to 1.03, two trials, 457 assessments, low-quality evidence). All of the perinatal deaths occurred in one trial conducted in a severely iodine-deficient setting. There were no clear differences between groups for low birthweight (average RR 0.56; 95% CI 0.26 to 1.23, two trials, 377 infants, no statistical heterogeneity, low-quality evidence), neonatal hypothyroidism/elevated thyroid-stimulating hormone (TSH) (average RR 0.58; 95% CI 0.11 to 3.12, two trials, 260 infants, very low-quality evidence) or the adverse effect of elevated neonatal thyroid peroxidase antibodies (TPO-ab) (average RR 0.61; 95% CI 0.07 to 5.70, one trial, 108 infants, very low-quality evidence). All of the trials contributing data to these outcomes took place in areas with mild to moderate iodine deficiency. No trials reported on hypothyroidism/elevated TSH or any adverse effect beyond the neonatal period. There were insufficient data to reach any meaningful conclusions on the benefits and harms of routine iodine supplementation in women before, during or after pregnancy. The available evidence suggested that iodine supplementation decreases the likelihood of postpartum hyperthyroidism and increases the likelihood of the adverse effect of digestive intolerance in pregnancy - both considered potential adverse effects. We considered evidence for these outcomes low or very low quality, however, because of study design limitations and wide confidence intervals. In addition, due to the small number of trials and included women in our meta-analyses, these findings must be interpreted with caution. There were no clear effects on other important maternal or child outcomes though these findings must also be interpreted cautiously due to limited data and low-quality trials. Additionally, almost all of the evidence came from settings with mild or moderate iodine deficiency and therefore may not be applicable to settings with severe deficiency.More high-quality randomised controlled trials are needed on iodine supplementation before, during and after pregnancy on maternal and infant/child outcomes. However, it may be unethical to compare iodine to placebo or no treatment in severe deficiency settings. Trials may also be unfeasible in settings where pregnant and lactating women commonly take prenatal supplements with iodine. Information is needed on optimal timing of initiation as well as supplementation regimen and dose. Future trials should consider the outcomes in this review and follow children beyond the neonatal period. Future trials should employ adequate sample sizes, assess potential adverse effects (including the nature and extent of digestive intolerance), and be reported in a way that allows assessment of risk of bias, full data extraction and analysis by the subgroups specified in this review.


Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics.
The pharmacokinetic (PK) behavior of monoclonal antibodies in cynomolgus monkeys (cynos) is generally translatable to that in humans. Unfortunately, about 39% of the antibodies evaluated for PKs in cynos have fast nonspecific (or non-target-mediated) clearance (in-house data). An empirical model relating variable region (Fv) charge and hydrophobicity to cyno nonspecific clearance was developed to gauge the risk an antibody would have for fast nonspecific clearance in the monkey. The purpose of this study was to evaluate the predictability of this empirical model on cyno nonspecific clearance with antibodies specifically engineered to have either high or low Fv charge. These amino acid changes were made in the Fv region of two test antibodies, humAb4D5-8 and anti-lymphotoxin α. The humAb4D5-8 has a typical nonspecific clearance in cynos, and by making it more positively charged, the antibody acquires fast nonspecific clearance, and making it less positively charged did not impact its clearance. Anti-lymphotoxin α has fast nonspecific clearance in cynos, and making it more positively charged caused it to clear even faster, whereas making it less positively charged caused it to clear slower and within the typical range. These trends in clearance were also observed in two other preclinical species, mice and rats. The effect of modifying Fv charge on subcutaneous bioavailability was also examined, and in general bioavailability was inversely related to the direction of the Fv charge change. Thus, modifying Fv charge appears to impact antibody PKs, and the changes tended to correlate with those predicted by the empirical model.


Fluid and cellular pathways of rat lymph nodes in relation to lymphatic labyrinths and Aquaporin-1 expression.
The aim of the present study was to examine the organization of lymph fluid and cellular pathways and distribution of the membrane water channel Aquaporin-1 (AQP-1) in rat lymph nodes. Lymph fluid and cellular pathways within lymph nodes were examined by fluorescent protein tracer/confocal microscopy and by scanning electron microscopy (SEM), While the distribution of AQP-1 was studied immunohistochemically. Tracer studies showed the subcapsular sinuses continued directly at the hilum or via the intermediate sinuses to the medullary sinuses, and lymphatic labyrinths originating with blind-ends in the deep cortex drained into medullary sinuses. Afferent lymph tracers were also observed in node cortex interstitium. By SEM, lymphatic labyrinths appeared densely filled with lymphocytes and had few intraluminal sinus reticular cells, while medullary sinuses possessed well-developed networks of sinus reticular cells. The presence of many lymphocytes wedged in the walls of the lymphatic labyrinth suggested that lymphocytes migrate between the node parenchyma and lymphatic labyrinths. AQP-1 was distributed on the membrane of lymphatic endothelium and reticular cells as well as on both luminal and abluminal cell membranes of high endothelial venules (HEVs). Our SEM findings support the concept that lymphocytes migrate from the node parenchyma into lymphatic labyrinths in the deep cortex. The nodal distribution of AQP-1 plus the presence of a polarized distribution of ion pumps and/or ion channels in the HEV endothelium hypothesized in our discussion could explain the mechanism of the reported lymph-to-plasma fluid flux in lymph nodes and also facilitate the entry of afferent lymph antigens into the node cortex interstitium.