New perspectives for a new century: implications of pathogen responses for the future of antimicrobial therapy.
Although the discovery of new classes of antibiotics has lagged behind in the last three decades, the incidence of life-threatening nosocomial infections that are resistant to multiple antibacterial agents has increased steadily. Recent advances in bacterial pathogenicity through the identification of a number of virulence factors and the bacterial genetics behind it have opened the way to a clearer understanding of the pathogen-host relationship. Bacteria communicate with each other through specific signaling chemicals to act as a community rather than individual cells to achieve a critical density or a "quorum." Establishment of quorum is the initiating signal for turning on a variety of virulence factors essential for the pathogenicity and dissemination of pathogens through the host. Pathogenic bacteria use a variety of biochemical mediators, collectively called "virulence factors," to invade and attack host tissues and to avoid detection and elimination by the host immune system. Delineating the specific responses the host immune system elicits in response to specific virulence factors and quorum-sensing molecules is essential to the development of new diagnostic methods for early detection of an infection and the prognosis to a given antibacterial therapy. Identification of inhibitors of virulence factors will represent new antimicrobial therapeutic modalities, and this can be used synergistically with current antibiotic therapy because they act through independent prokaryotic pathways to inhibit bacterial growth and survival.


Post-Perruche: what responsibilities for professionals?
Damage compensation relating to handicapped new-borns, the wrongful life law, was put in place after a great controversy in France by the Perruche ruling of November 13th 2000. The French parliaments have voted a special law against wrongful life action. But questions about medical liability are not answered by the new law. For wrongful life, what are now the medical errors likely to directly provoke a handicap or aggravate it or obstruct measures to alleviate it? For a wrongful birth claim it limits parental damages to psychological damages only, due to a lack of mental preparation, whilst denying economic losses, thus preventing complete compensation arising from medical malpractice for all the other types of difficulty suffered by the parents. Why does it give a new definition of medical malpractice as a "characterized fault" and insist upon the qualification 'blatant" in the field of medical liability? For health professionals, it is a question of knowing and being acquainted with the errors that fall under their liability with regard to handicapped persons and a "characterized fault" with regard to parents. It is through a review of past and present case law that we will try to answer these medical questions. All court rulings that awarded monetary damages to the child were reviewed. We include only three decisions after the new law, which do not allow damage compensation in respect of a handicapped new-born. The rulings incorporate decisions taken by the French Supreme Court, of the council of state as well as by courts of appeal. Failure of voluntary termination of pregnancy, missing rubella immune antibody, omission of mandatory tests during pregnancy, typical medical fetal malpractice, were and are professional faults.


Age independent expression of myocilin in the human trabecular meshwork.
Glaucoma is a leading cause of blindness. Primary open-angle glaucoma, the most common form of glaucoma, is known to increase in prevalence with age. One of its major risk factors is an elevated intraocular pressure believed to be related to the trabecular meshwork (TM), a specialized tissue located at the chamber angle of the eye. Myocilin, a gene linked to open-angle glaucomas (OAG), has been found to be expressed in the TM and a broad range of other ocular and non-ocular tissues. The purpose of this study was to examine the distribution of myocilin protein and mRNA in the TM of normal human eyes to determine whether age-related changes exist. Studies with glaucomatous eyes were carried out concurrently. Immunoperoxidase staining experiments demonstrated positive immunoreactivity for myocilin protein in both the cells and beams in all regions of the TM. The staining intensity and the myocilin level as determined by dot blot assays were not correlated with the ages of donors ranging from 8 weeks to 93 years. Neither did myocilin mRNA, detected by in situ hybridization in cells throughout the TM and quantified by relative quantitative RT-PCR, vary with age. Myocilin mRNA and protein expression in diseased tissues was either comparable to that of normal tissues or reduced. This study represents the first in-depth investigation of myocilin expression in relation to age in the TM of human eyes. The results indicate an age independence, argue thus against a direct role of myocilin and reiterate the involvement of additional factors in the pathogenesis of glaucoma.


Molecular self-assembly on graphene.
The formation of ordered arrays of molecules via self-assembly is a rapid, scalable route towards the realization of nanoscale architectures with tailored properties. In recent years, graphene has emerged as an appealing substrate for molecular self-assembly in two dimensions. Here, the first five years of progress in supramolecular organization on graphene are reviewed. The self-assembly process can vary depending on the type of graphene employed: epitaxial graphene, grown in situ on a metal surface, and non-epitaxial graphene, transferred onto an arbitrary substrate, can have different effects on the final structure. On epitaxial graphene, the process is sensitive to the interaction between the graphene and the substrate on which it is grown. In the case of graphene that strongly interacts with its substrate, such as graphene/Ru(0001), the inhomogeneous adsorption landscape of the graphene moiré superlattice provides a unique opportunity for guiding molecular organization, since molecules experience spatially constrained diffusion and adsorption. On weaker-interacting epitaxial graphene films, and on non-epitaxial graphene transferred onto a host substrate, self-assembly leads to films similar to those obtained on graphite surfaces. The efficacy of a graphene layer for facilitating planar adsorption of aromatic molecules has been repeatedly demonstrated, indicating that it can be used to direct molecular adsorption, and therefore carrier transport, in a certain orientation, and suggesting that the use of transferred graphene may allow for predictible molecular self-assembly on a wide range of surfaces.


Demographic Effects of Habitat Restoration for the Grey-Crowned Babbler Pomatostomus temporalis, in Victoria, Australia.
Considerable resources are spent on habitat restoration across the globe to counter the impacts of habitat loss and degradation on wildlife populations. But, because of time and resourcing constraints on many conservation programs, the effectiveness of these habitat restoration programs in achieving their long-term goals of improving the population viability of particular wildlife species is rarely assessed and many restoration programs cannot demonstrate their effectiveness. Without such demonstration, and in particular demonstrating the causal relationships between habitat restoration actions and demographic responses of the target species, investments in restoration to achieve population outcomes are of uncertain value. Here, we describe an approach that builds on population data collected for a threatened Australian bird - the Grey-crowned Babbler Pomatostomus temporalis - to evaluate how effectively targeted habitat restoration work improves its viability. We built upon an extensive historical survey by conducting surveys 13 years later at 117 sites stratified by presence/absence of restoration works and by detection or not of birds in the first survey. Our performance metric was the number of individuals in a social group, which is both a measure of local abundance and directly related to breeding success. We employed an occupancy model to estimate the response of Grey-crowned Babbler social group size to the effects of time, restoration works, local habitat as measured by the density of large trees, and distance to the nearest other known group of babblers. Babbler group size decreased over the survey period at sites without restoration works, but restoration works were effective in stemming declines where they were done. Restoration was responsible for a difference of about one bird per group of 3-5 individuals; this is an important effect on the reproductive success of the social group. Effectiveness of restoration works targeted at the Grey-crowned Babbler was only demonstrable by sampling through time and including control sites without restoration works. This work demonstrates that while calls for better monitoring of restoration are valid, scope exists to recover a signal of effectiveness from opportunistic retrospective analyses.


Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.
The ability of cancer vaccines to induce tumor-specific CD8+ T cells in the circulation of cancer patients has been shown to poorly correlate with their clinical effectiveness. In this study, we report that although Ags presented by different types of mature dendritic cells (DCs) are similarly effective in inducing CD8+ T cell expansion, the acquisition of CTL function and peripheral-type chemokine receptors, CCR5 and CXCR3, requires Ag presentation by a select type of DCs. Both "standard" DCs (matured in the presence of PGE2) and type 1-polarized DCs (DC1s) (matured in the presence of IFNs and TLR ligands, which prevent DCs "exhaustion") are similarly effective in inducing CD8+ T cell expansion and acquisition of CD45RO+IL-7R+IL-15R+ phenotype. However, granzyme B expression, acquisition of CTL activity, and peripheral tissue-type chemokine responsiveness are features exclusively exhibited by CD8+ T cells activated by DC1s. This advantage of DC1s was observed in polyclonally activated naive and memory CD8(+) T cells and in blood-isolated melanoma-specific CTL precursors. Our data help to explain the dissociation between the ability of cancer vaccines to induce high numbers of tumor-specific CD8+ T cells in the blood of cancer patients and their ability to promote clinical responses, providing for new strategies of cancer immunotherapy.


Organocatalytic Synthesis of Methylene-Bridged N-Heterobiaryls.
A one-step synthesis of 1,1'- and 2,2'-methylene-bridged N-heterobiaryls directly from the corresponding N-heterocycles in a reaction with methylmagnesium chloride in the presence of catalytic amounts of N,N,N',N'-tetramethylethylenediamine under thermal and microwave conditions is reported. The split-and-merge methylenation of 2,2'-N-heterobiaryls and the direct ortho-alkylation of quinoline and isoquinoline with Grignard reagents have also been developed. Mechanistic studies identified several intermediates and provided insight into the formation and roles of magnesium hydride species in the process.


Perioperative/periprocedural effects of statin treatment for patients undergoing vascular surgery or endovascular procedures: an update.
We reviewed the literature for studies evaluating the effects of statins on vascular patients undergoing open surgical or endovascular procedures. MEDLINE was searched using the search terms "statins and vascular surgery", "statins and endovascular procedures", "statins and perioperative effects" and "statins and postoperative complications". Preoperative statin use is associated with lower perioperative/periprocedural death, myocardial infarction and stroke rates. Statins may also reduce postoperative complications as well as hospitalization rates and costs. Statins reduce the incidence of postoperative/postprocedural renal insufficiency and help the earlier recovery of complete kidney function in vascular patients. A loading dose of statins prior to a procedure may be associated with improved cardiovascular outcomes. Statins are associated with several beneficial actions in patients undergoing open surgical or endovascular procedures. Nevertheless, statin use in vascular patients still remains underutilized and suboptimal. Ideally, statins should be initiated a minimum of 2 weeks before the procedure. Extended-release formulas may be preferable perioperatively to cover the first 1-2 days after the procedure when oral intake may not be feasible. Statins should be administered to all vascular disease patients, whether they are managed conservatively or are undergoing open surgical or endovascular procedures.


Unsaturated fatty acid effects on human breast cancer cell adhesion.
Polyunsaturated fatty acids influence several steps involved in metastasis formation in animal tumor models. During the process of metastasis from the primary site, tumor cells adhere to the endothelium and underlying basement membrane before extravasation and secondary growth. The purpose of this study was to determine the effect of unsaturated fatty acids on adhesion of human breast cancer cell lines to components of the basement membrane. Cells were cultured in low-serum medium for five days with or without added unsaturated fatty acids. Adhesion assays were conducted by incubating cells with basement membrane substrates coated on 96-well plates, washing to remove nonadherent cells, and staining adherent cells with crystal violet. Linoleic acid (LA) and eicosapentaenoic acid increased adhesion of the metastatic cell line MDA-MB-231 to Matrigel and type IV collagen, while eicosapentaenoic acid decreased adhesion of the less metastatic cell line SK-BR-3 to these two basement membrane substrates. Oleic acid increased adhesion of MDA-MB-231 cells to Matrigel and fibronectin. Nordihydroguaiaretic acid and high concentrations of indomethacin, each of which inhibits the lipoxygenase pathway of arachidonate metabolism, were effective in reversing the stimulatory effect of LA on MDA-MB-231 cell adhesion. A protein kinase C inhibitor likewise suppressed the increase in adhesion observed when MDA-MB-231 cells were incubated in media with added LA. Unsaturated fatty acids modified the adhesive properties of human breast cancer cell lines in vitro, and LA appeared to increase human breast cancer cell adhesion to extracellular matrix components by activating lipoxygenase and/or protein kinase C pathways.


Child Health Advice and Parental Obligation: The Case of Safe Sleep Recommendations and Sudden Unexpected Death in Infancy.
This article considers whether there is a parental obligation to comply with child health advice which is aimed at the general population and grounded in population-based research. Drawing upon the concept of role obligations, I argue that there is a temptation to use child health advice as a set of rules to which parents are morally obligated to comply, but that this temptation should be resisted. Using the case of Safe Sleep recommendations, designed to reduce the risk of sleep-related infant deaths, I present three reasons for doubting that parents are obligated, as a matter of course, to comply with child health advice. I suggest that, rather than compliance, deliberation about child health advice is obligatory, and that parents should have reasons for not following credible child health advice.


The University of Iowa Nursing Collaboratory: a partnership for creative education and practice.
This article describes a comprehensive partnership between a college of nursing and its corresponding department of nursing services. The Nursing Collaboratory was created to provide an infrastructure for the generation, dissemination, and application of knowledge to improve nursing practice and patient outcomes. In addition to creative problem solving, the Collaboratory serves as an "incubator" of ideas and innovation, engaging nursing staff, faculty, and students in the development of new products and services to enhance nursing education and practice. J Prof Nurs 17:114-120, 2001.


A multidisciplinary approach for the management of hypodontia: case report.
Hypodontia is the congenital absence of one or more teeth and may affect permanent teeth. Several options are indicated to treat hypodontia, including the maintenance of primary teeth or space redistribution for restorative treatment with partial adhesive bridges, tooth transplantation, and implants. However, a multidisciplinary approach is the most important requirement for the ideal treatment of hypodontia. This paper describes a multidisciplinary treatment plan for congenitally missing permanent mandibular second premolars involving orthodontics, implantology and prosthodontic specialties.


[Use of diagnostic tests in the context of evidence-based medicine].
The advances of medicine over the last twenty years include the use of new tests and diagnostic methods in clinical practice. At the same time, we have witnessed the introduction of a strong movement, named Evidence Based Medicine, which basically includes a serious attempt for rationalizing the findings of more than 50 years of biomedical research, and to apply them properly to our patients as well as to the whole population. Review of the published literature. All the recommendations are used in a practical example. Summary of the current existing recommendations for the assessment of a new diagnostic tool before its clinical application, and discussion of possible solutions for achieving a more efficient use of these tests. There are enough evidences for defining criteria for a uniform evaluation process of new diagnostic tests. The criteria could be useful for the clinical application of these tests.


Observation of vacuum ultraviolet laser oscillation in nitric oxide.
We report recent experiments that demonstrate the line tunability of a fluorine laser-pumped nitric oxide laser. Laser oscillation has been observed at 589, 234, 226, 218, 211, and 163 nm. The possibility of achieving laser oscillation on further UV and vacuum UV laser transitions in nitric oxide is discussed.


Effects of metabolic rate on thermal responses at different air velocities in -10 degrees C.
The effects of exercise intensity on thermoregulatory responses in cold (-10 degrees C) in a 0.2 (still air, NoWi), 1.0 (Wi1), and 5.0 (Wi5) m x s(-1) wind were studied. Eight young and healthy men, preconditioned in thermoneutral (+20 degrees C) environment for 60 min, walked for 60 min on the treadmill at 2.8 km/h with different combinations of wind and exercise intensity. Exercise level was adjusted by changing the inclination of the treadmill between 0 degrees (lower exercise intensity, metabolic rate 124 W x m(-2), LE) and 6 degrees (higher exercise intensity, metabolic rate 195 W x m(-2), HE). Due to exercise increased heat production and circulatory adjustments, the rectal temperature (T(re)), mean skin temperature (Tsk) and mean body temperature (Tb) were significantly higher at the end of HE in comparison to LE in NoWi and Wi1, and T(re) and Tb also in Wi5. Tsk and Tb were significantly decreased by 5.0 m x s(-1) wind in comparison to NoWi and Wi1. The higher exercise intensity was intense enough to diminish peripheral vasoconstriction and consequently the finger skin temperature was significantly higher at the end of HE in comparison to LE in NoWi and Wi1. Mean heat flux from the skin was unaffected by the exercise intensity. At LE oxygen consumption (VO2) was significantly higher in Wi5 than NoWi and Wi1. Heart rate was unaffected by the wind speed. The results suggest that, with studied exercise intensities, produced without changes in walking speed, the metabolic rate is not so important that it should be taken into consideration in the calculation of wind chill index.


Interaction of glyceryl trinitrate and sodium nitroprusside with bovine pulmonary vein homogenate and 10,000 x g supernatant: biotransformation and nitric oxide formation.
The current proposed mechanism of action of nitrovasodilator drugs involves biotransformation to nitric oxide, which is postulated to be the active vasodilator substance. Our objective was to determine whether nitric oxide was formed from two prototype nitrovasodilator drugs, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), after incubation with bovine pulmonary vein (BPV) preparations. GTN or SNP was incubated in an argon atmosphere with phosphate buffer, BPV homogenate, or the 10,000 x g supernatant fraction of the homogenate. Nitric oxide formation, as determined by a chemiluminescence-headspace gas method, was measurable following the incubation of SNP with BPV homogenate and 10,000 x g supernatant. There was no detectable formation of nitric oxide from the incubation of GTN with the two BPV preparations, although GTN was biotransformed to glyceryl dinitrate, as determined by gas-liquid chromatography. There was decreased recovery of nitric oxide during the incubation of authentic nitric oxide with the two BPV preparations as compared with buffer. In conclusion, formation of nitric oxide was measured for the interaction of SNP, but not GTN, with BPV preparations. However, the data do not exclude the possible formation of nitric oxide from GTN, as nitric oxide was shown to be sequestered or transformed by the BPV preparations.


The prevalence of human papillomavirus vaccination among racial and ethnic minority adolescents during the COVID-19 pandemic.
Human papillomavirus (HPV) vaccination among adolescents has steadily improved over the past several years. However, research conducted to determine whether the COVID-19 pandemic disrupted this positive trend in HPV vaccine initiation among racial and ethnic minority adolescents is limited. Therefore, this study was conducted to determine if the COVID-19 pandemic and the resulting changes in the US health-care sector affected the increasing HPV vaccine initiation among non-Hispanic Black and Hispanic adolescents aged 13-17 years. Using a cross-sectional design to examine data from the National Immunization Survey-Teen (2019-2021), logistic regression and moderation analysis were used to model race-specific variations in HPV vaccine initiation (n = 49 031). Two-sided P values of up to .05 were considered statistically significant. Hispanic (adjusted odds ratio [AOR] = 1.35, 95% confidence interval [CI] = 1.16 to 1.57) and non-Hispanic Black (AOR = 1.29, 95% CI = 1.10 to 1.51) adolescents had higher odds of HPV vaccine initiation than did non-Hispanic White adolescents. Additionally, the odds of HPV vaccine initiation were higher in 2021 (AOR = 1.22, 95% CI = 1.08 to 1.38) than in 2019. Other variables-age, region, sex, insurance status, and poverty status-were also associated with HPV vaccine initiation. These findings demonstrate that during the COVID-19 pandemic, racial and ethnic minorities had higher odds of receiving the HPV vaccine. Therefore, more research of the impact of the pandemic on HPV vaccine initiation among non-Hispanic White and racial and ethnic minority adolescents is needed.


Localization, topology, and function of the LCB1 subunit of serine palmitoyltransferase in mammalian cells.
Serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step in the biosynthesis of sphingolipids, comprises two different subunits, LCB1 and LCB2. LCB1 has a single highly hydrophobic domain near the N terminus. Chinese hamster ovary cell mutant LY-B cells are defective in SPT activity because of the lack of expression of an endogenous LCB1 subunit. Stable expression of LCB1 having an epitope tag at either the N or C terminus restored SPT activity of LY-B cells, suggesting that the epitope tag did not affect the localization or topology of LCB1. Indirect immunostaining showed that the N- and C-terminal epitopes are oriented toward the lumenal and cytosol side, respectively, at the endoplasmic reticulum. Interestingly, there was far less LCB2 in LY-B cells than in wild-type cells, and the amount of LCB2 in LY-B cells was restored to the wild-type level by transfection with LCB1 cDNA. In addition, overproduction of the LCB2 subunit required co-overproduction of the LCB1 subunit. These results indicated that the LCB1 subunit is most likely an integral protein having a single transmembrane domain with a lumenal orientation of its N terminus in the endoplasmic reticulum and that the LCB1 subunit is indispensable for the maintenance of the LCB2 subunit in mammalian cells.


Forty Years of State Alcohol and Pregnancy Policies in the USA: Best Practices for Public Health or Efforts to Restrict Women's Reproductive Rights?
Alcohol consumption during pregnancy remains a public health problem despite >40 years of attention. Little is known about how state policies have evolved and whether policies represent public health goals or efforts to restrict women's reproductive rights. Our data set includes US state policies from 1970 through 2013 obtained through original legal research and from the National Institute for Alcohol Abuse and Alcoholism's (NIAAA)'s Alcohol Policy Information System. Policies were classified as punitive to women or supportive of them. The association between numbers of punitive policies and supportive policies in 2013 with a measure of state restrictions on reproductive rights and Alcohol Policy Effectiveness Scores (APS) was estimated using a Pearson's correlation. The number of states with alcohol and pregnancy policies has increased from 1 in 1974 to 43 in 2013. Through the 1980s, state policy environments were either punitive or supportive. In the 1990s, mixed punitive and supportive policy environments began to be the norm, with punitive policies added to supportive ones. No association was found between the number of supportive policies in 2013 and a measure of reproductive rights policies or the APS, nor was there an association between the number of punitive policies and the APS. The number of punitive policies was positively associated, however, with restrictions on reproductive rights. Punitive alcohol and pregnancy policies are associated with efforts to restrict women's reproductive rights rather than effective efforts to curb public health harms due to alcohol use in the general population. Future research should explore the effects of alcohol and pregnancy policies. The number of states with alcohol and pregnancy policies has increased since 1970 (1 in 1974 and 43 in 2013). Alcohol and pregnancy policies are becoming increasingly punitive. These punitive policies are associated with efforts to restrict women's reproductive rights rather than policies that effectively curb alcohol-related public health harms.


Malnutrition, malaria and intestinal worms in young children.
A study is reported from two indonesian villages on the prevalence of malnutrition, malaria and intestinal worms among children aged 6-17 months. Malnutrition, insofar as it is reflected by blood haemoglobin levels, was the most widespread problem and was evidently caused by food shortages and unsatisfactory traditional feeding practices rather than by disease or other environmental risk factors.


Telephone intervention promoting weight-related health behaviors.
Recent national surveys have documented that the majority of adults in the United States do not meet the recommended levels of healthy lifestyle-related behaviors. The Nutrition and Physical Activity (NuPA) study was designed to promote fruit and vegetable consumption, physical activity, and weight management for a working population. Data were collected nationwide, USA, from 2005 to 2007 and analyzed in 2008. A total of 2470 employed participants were randomized into the self-help (SH: n=1191) or self-help plus telephone counseling (SH+C: n=1279) group. The SH+C group received nine structured telephone counseling sessions in addition to the print materials. A series of hierarchical regression analyses for each of the health behavior outcomes in the present-at-follow-up subsample (n=1098-1148) revealed that the SH+C was effective in increasing fruit and vegetable consumption. Among the overweight and obese participants, weight loss was significant in both the SH and SH+C groups. Using a theory-based behavioral change counseling technique and targeting multiple health behaviors among employed individuals, our findings demonstrate that the addition of telephone counseling to mailed self-help materials is effective in promoting healthy diet and weight management.


Connectosomes for Direct Molecular Delivery to the Cellular Cytoplasm.
Transport of biomolecules, drugs, and other reagents across the cell's plasma membrane barrier is an inefficient and poorly controlled process, despite its fundamental importance to biotechnology, cell biology, and pharmaceutics. In particular, insufficient membrane permeability frequently limits the accumulation of drugs and reagents in the cytoplasm, undermining their efficacy. While encapsulating drugs in particles increases uptake by cells, inefficient release of drugs from these particles into the cytoplasm ultimately limits drug efficacy. In contrast, gap junctions provide a direct route to the cytoplasm that bypasses the plasma membrane. As transmembrane channels that physically connect the cytoplasm of adjacent cells, gap junctions permit transport of a diverse range of molecules, from ions and metabolites to siRNA, peptides, and chemotherapeutics. To utilize gap junctions for molecular delivery we have developed Connectosomes, cell-derived lipid vesicles that contain functional gap junction channels and encapsulate molecular cargos. Here we show that these vesicles form gap junction channels with cells, opening a direct and efficient route for the delivery of molecular cargo to the cellular cytoplasm. Specifically, we demonstrate that using gap junctions to deliver the chemotherapeutic doxorubicin reduces the therapeutically effective dose of the drug by more than an order of magnitude. Delivering drugs through gap junctions has the potential to boost the effectiveness of existing drugs such as chemotherapeutics, while simultaneously enabling the delivery of membrane-impermeable drugs and reagents.


An Analysis of Adherence to Vaccination Recommendations in a Thoracic Organ Transplant Cohort.
(1) Background: Vaccination of solid organ transplant (SOT) candidates and recipients is vital to decrease infection-related morbidity and mortality. Here we describe our heart and lung transplant programs' rates of completion of hepatitis B and pneumococcal vaccinations and identify potential opportunities for improvement. (2) Methods: This is a single-center retrospective study that included all heart and lung transplant recipients between 1 July 2013 and 31 July 2018. We assessed demographics, causes of organ failure, pretransplant hepatitis B immune status, and completion rates for hepatitis B vaccine series, pneumococcal conjugate vaccine (PCV13), and pneumococcal polysaccharide vaccine (PPSV23). (3) Results: A total of 41 patients were included in the heart transplant cohort. Twelve (29.3%) had baseline hepatitis B immunity. Only 8/29 (27.6%) completed the entire 3-dose hepatitis B vaccination series pretransplant. Pretransplant PCV13 and PPSV23 vaccination rates were 58.5% (24/41) and 48.8% (20/41), respectively; no additional patients received PCV13 or PPSV23 post-transplant. In the heart transplant cohort, a majority (82.9%) of patients were evaluated by the Transplant Infectious Diseases consultative service (TxID) pretransplant, and this had a statistically significant association with increased pneumococcal vaccination rates (p = 0.0017, PCV13 and p = 0.0103, PPSV23). In total, 55 patients were included in the lung transplant cohort. Five (9.1%) had baseline hepatitis B immunity; 33/50 (66.0%) completed the hepatitis B vaccine series in the pretransplant setting. Pretransplant PCV13 and PPSV23 vaccination rate was 40.0% (22/55) and 69.1% (38/55), respectively. There was only a 47.3% and 72.3% completion rate overall in the post-transplant setting. (4) Conclusions: There continues to be a need for a comprehensive and coordinated effort to increase vaccine adherence for all SOT candidates in the pretransplant setting.


Decreased Expression of Sirt1 Contributes to Ocular Behçet's Disease Progression via Th17 and Th22 Response.
Previous studies have indicated that Sirtuin 1 (Sirt1) plays an important role in suppressing inflammatory responses in many diseases. However, the Sirt1 levels and role of Sirt1 in ocular Behçet's disease (OBD) have not been fully elucidated. The objective of this study was to investigate the role of Sirt1 in the pathogenesis of OBD. Sirt1 and cytokine levels were measured using ELISA. Cell viability was determined using the Cell Counting Kit-8. The frequencies of Th17 and Th22 cells were detected using flow cytometry. We found decreased expression of Sirt1 in CD4+ T cells obtained from patients with active OBD. SRT1720, an agonist of Sirt1, significantly upregulated Sirt1 expression in CD4+ T cells from patients with active OBD. Sirt1 activation by SRT1720 significantly suppressed the production of interleukin (IL)-17 and IL-22 by CD4+ T cells and inhibited the expansion of Th17 and Th22 cells. Our results suggest that decreased Sirt1 expression might be involved in the pathogenesis of OBD and that activation of Sirt1 might be considered a potential target for OBD.


The Use of Aminoguanidine, a Selective iNOS Inhibitor, to Evaluate the Role of Nitric Oxide in the Development of Autoimmune Diabetes
Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting beta cells found in islets of Langerhans. The biochemical mechanisms associated with beta-cell destruction have remained elusive. Cytokines, released from T lymphocytes, macrophages, and monocytes during islet insulitis, have been implicated as effector molecules that participate in beta-cell death. Recently, cytokine-induced expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide by beta cells has been suggested as one potential mechanism associated with beta-cell destruction. Treatment of rat islets with interleukin 1 (IL-1) results in a potent inhibition of insulin secretion followed by islet destruction. The inhibitory and destructive effects of this cytokine on islet function are completely prevented by the inhibition of iNOS enzymatic activity. Islets contain a heterogeneous population of both endocrine and nonendocrine cells including a low level of resident tissue macrophages ( approximately0.5% of all islet cells). The intraislet macrophage appears to one cellular source of IL-1. Activation of resident islet macrophages results in both the expression of iNOS and the release of IL-1. Intraislet macrophage production of nitric oxide (in the absence of IL-1) does not modulate beta-cell function; however, macrophage release of IL-1 and IL-1-induced iNOS expression by beta cells results in a potent inhibition of beta-cell function. These findings support a role for nitric oxide as a potential mediator of cytokine-induced inhibition of beta-cell function and implicate the intraislet macrophage as one cellular source of IL-1. Direct support for a role of nitric oxide in the development of diabetes includes the ability of inhibitors of iNOS to prevent or delay the development of this disease condition in animal models. Important to these studies has been the identification of selective inhibitors of iNOS. Many inhibitors of nitric oxide synthase have been developed; however, few selective inhibitors for the individual isoforms of NOS (inducible, endothelial, neuronal) have been described. Aminoguanidine has been identified as one of the first iNOS selective inhibitors. Aminoguanidine is over 50-fold more effective at inhibiting the enzymatic activity of iNOS than endothelial or neuronal NOS. The effects of aminoguanidine on the development of diabetes in the nonobese diabetic mouse using an adoptive transfer protocol has been evaluated. Aminoguanidine delays the onset of diabetes in this animal model by 7-10 days. These studies, which provide in vivo evidence implicating a role for nitric oxide in the development of autoimmune diabetes, also support the use of selective inhibitors of iNOS for the attenuation of disease conditions associated with the expression of iNOS and an increased production of nitric oxide.


[Satisfaction and overall quality of life in BRCA positive women after prophylactic surgeries].
Genetic mutations are responsible for 5-10% of all breast and ovarian carcinomas, while most of them are caused by a mutation of the BRCA gene. Women with this type of mutation have a lifetime risk of breast and ovarian cancer and therefore, they require very intensive medical care, including surgical prevention. Specifically, prophylactic bilateral mastectomy and prophylactic salpingo-oophorectomy are done, which undoubtedly decrease the riskof cancer. The aim of this review article is to inform healthcare professionals and the general public about the satisfaction of BRCA positive women with their decision to undergo these prophylactic surgeries, and also about the impact of these procedures on sexuality, menopausal symptoms, mental health and the overall quality of life. Search of original studies and review articles onthe influence of prophylactic surgeries on the life of women with BRCA genemutation. In general, although some changes are observed after the prophylactic surgeries, the overall quality of life does not change. A significant reduction in anxiety and fear of cancer is observed after both prophylactic bilateral mastectomy andprophylactic bilateral salpingo-oophorectomy, providing great psychological relief to the affected women. However, prophylactic bilateral salpingo-oophorectomy causes premature menopause in premenopausal women at the time of surgery and the associated occurrence of menopausal symptoms. Some of the symptoms can be significantly reduced by hormone replacement therapy but will not be eliminated altogether. In postmenopausal women, no or minimal worsening of menopausal symptoms was reported. After prophylactic bilateral mastectomy, particularly appearance-related problems were observed. In both types of surgery, sexual problems were also observed. The relief of reducingthe risk of cancerappears to be so great and so important for women that it outweighs the other negative effects of these prophylactic procedures.Key words: BRCA1/2 mutation - breast cancer - ovarian cancer - prophylactic bilateral salpingo-oophorectomy - prophylactic bilateral mastectomy.


Silent myocardial ischemia: diagnosis, clinical significance and management.
With the inception of continuous ECG monitoring with high-fidelity reproduction of the ST-segment, silent myocardial ischemia has been regarded with increasing importance in the detection and management of coronary artery disease. With the aid of a variety of invasive and noninvasive methods, the validity of ST-segment depression as indicative of myocardial ischemia, even in the absence of symptoms, has been adequately documented. In completely asymptomatic subjects with positive evidence of silent ischemia in the exercise ECG or Holter monitoring, the risk of developing a future manifestation of coronary artery disease may be up to ten-fold higher than in individuals with negative tests In patients with established coronary artery disease, concomitant use of continuous ECG monitoring and exercise testing, methods which complement each other rather than being mutually exclusive, a substantial number of patients with otherwise typical angina pectoris may be found to have silent ischemic episodes. An adequate differentiation between those with symptomatic and those who are asymptomatic based on characterization with respect to age, sex, hypertension, coronary anatomy, etc., has not been successful. Patients with silent ischemia during exercise may also exhibit more episodes of silent ischemia during daily activities and up to 75% of ischemic episodes may be asymptomatic. In general, however, silent ischemia during exercise appears more common than silent ischemia only during daily activities. In the latter case, since there is usually no increase in heart rate, the pathophysiology is regarded as dissimilar from that associated with exercise-induced ischemia. While the presence of silent ischemia appears quite common in patients after acute myocardial infarction, its occurrence, to date, has not been confirmed to carry additional risk, whereas in unstable angina, the association of silent ischemia is indicative of a higher probability of subsequent cardiac events.


Negative symptoms of psychosis: A life course approach and implications for prevention and treatment.
Negative symptoms are a cause of enduring disability in serious mental illness. In spite of this, the development of effective treatments for negative symptoms has remained slow. The challenge of improving negative symptom outcomes is compounded by our limited understanding of their aetiology and longitudinal development. A literature search was conducted for life course approach of negative symptoms using PubMed. Further articles were included following manual checking of reference lists and other search strategies. The paper contains a theoretical synthesis of the literature, summarized using conceptual models. Negative symptom definitions are compared and considered within a context of the life course. Previous studies suggest that several illness phases may contribute to negative symptoms, highlighting our uncertainty in relation to the origin of negative symptoms. Similar to other aspects of schizophrenia, negative symptoms likely involve a complex interplay of several risk and protective factors at different life phases. Concepts suggested in this article, such as "negative symptom reserve" theory, require further research, which may inform future prevention and treatment strategies.


Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases.
Elastin is a unique protein providing deformability and resilience to dynamic tissues, such as arteries and lungs. It is an absolute basic requirement for circulation and respiration. Elastin can be degraded by elastases and has a high calcium affinity. Elastin calcification and elastin degradation are two pathological processes that impair elastin's functioning. Furthermore, elastin degradation can be associated to elastin calcification. Matrix Gla Protein (MGP) is probably the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. Measuring circulating levels of inactive MGP (dp-ucMGP) is a frequently used method to assess vitamin K status. Dp-ucMGP reflects the burden of vitamin K-dependent proteins that have not been activated by vitamin K and could therefore best be regarded as a biomarker of a vitamin K deficit. Dp-ucMGP levels decrease after vitamin K supplementation. Since the amino acids desmosine and isodesmosine (DES) are unique to crosslinked elastin fibers, systemic elastin degradation can be assessed with the plasma DES assay. Recently, we discovered a strong correlation between plasma dp-ucMGP and plasma DES levels in both patients with chronic obstructive pulmonary disease (COPD) and controls. The 'Vitamin K deficit and elastolysis theory' posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. If this hypothesis holds true and is universally found in every state and condition, it will have an unprecedented impact on the management of every single pulmonary disease characterized by accelerated elastin degradation, such as alpha-1 antitrypsin deficiency, bronchiectasis, COPD and cystic fibrosis. Theoretically, a plasma dp-ucMGP concentration of zero would be associated with a near-complete standstill of elastin degradation and disease progression in patients with any of these debilitating conditions.


[Laparoscopic ilio-femoral by-pass. A case-review].
The authors introduce a laparoscopically conducted ilio-femoral by-pass operation for the external iliac artery occlusion. The common pelvic artery preparation, the clips application, the arteriotomy and the central anastomosis, all were conducted laparoscopically, the peripheral anastomosis was then carried out through a standard inguinal incision. The laparoscopic approach represents, together with angioplasties and stentgraft implantations, yet another technical variation in vascular surgery.


Induction of the immune response to Legionella pneumophila cytolysin by monoclonal anti-idiotypic antibodies.
A panel of mAb (IgG1, IgG3, IgM) against Legionella pneumophila cytolysin (CL)-protease of 37 kDa was obtained. Subtyping of L. pneumophila strains of serogroup 1 by using mAb against CL (mAb-CL) was carried out. The results of comparative analysis of the specificity of mAb-CL and the panel of mAb kindly provided by Dr. J. M. Barbaree (Centers for Disease Control, Atlanta, GA) allowed us to recommend mAb-CL to be used as a diagnostic tool to reveal the pathogenicity of L. pneumophila strains of serogroup 1. Hybridomas were also raised in a syngenic system which produced anti-idiotypic mAb (mAb2) against anti-CL mAb B6/1. The Ab2 belonged to Ab2 gamma type: 1) Ab2 reacted with B6/1 Id only, 2) Ab2 inhibited the interaction of B6/1 Ab1 with CL, and 3) CL inhibited the reaction of Ab2 with Ab1. The use of Ab2 allowed us to show that B6/1 Id is expressed in 4 to 32% of serum antibodies during the primary and secondary immune responses of BALB/c mice to CL. Ab2 induced the production of anti-anti-idiotypic antibodies (Ab3) in BALB/c mice, and some of them reacted with CL. Thus, we have demonstrated the possibility of inducing an antibody response to CL (one of the main L. pneumophila pathogenic factors) in intact syngenic mice with anti-idiotypic antibodies.


Maintaining primary closure after guided bone regeneration procedures: introduction of a new flap design and preliminary results.
Various flap designs have been proposed by numerous authors for the maintenance of passive primary soft tissue closures following guided bone regeneration (GBR) procedures. A previous publication by the present author documented the maintenance of passive soft tissue primary closures 96.1% of the time at least 6 months after GBR therapy in all areas of the mouth. Although seemingly impressive, a 96.1% success rate means that there is premature membrane exposure 3.9% of the time. A new flap design is introduced for use in conjunction with previously described flap designs to lessen the incidence of premature membrane exposure. A total of 173 sites treated with GBR therapy were examined up to 6 months postoperatively to assess the ability to maintain passive soft tissue primary closure. Any membrane exposure during this 6-month postoperative period was deemed a failure, even if the site was successfully treated with an implant placement and restoration. A total of 171 of 173 GBR-treated sites demonstrated the maintenance of a soft tissue passive primary closure 6 months postoperatively, yielding a success rate of 98.8%. The introduction of the proposed flap design for use in conjunction with previously described flap designs significantly reduced the incidence of premature membrane exposure after a variety of GBR procedures.


Effect of glyceryl trinitrate on distensibility of peripheral muscular arteries in humans is not mediated by prostaglandins.
Vasodilator prostaglandins have been claimed to be responsible for the coronary haemodynamic and venodilator effects of glyceryl trinitrate, although conflicting results have been reported. The aim of this study was to evaluate whether vasodilator prostaglandins play a role in the effect of glyceryl trinitrate on the distensibility of peripheral muscular arteries in healthy humans. A non-invasive technique, impedance plethysmography, was applied to the assessment of the effects of sublingual glyceryl trinitrate on the compliance of the forearm and digital arteries. The subjects studied received placebo (on two separate occasions), indomethacin (100 mg orally), or ibuprofen (800 mg orally) 1 h before glyceryl trinitrate (0.3 mg sublingual) on four occasions separated from each other by at least 48 h. Blood pressure and heart rate were measured by standard techniques; changes in peripheral arterial compliance were evaluated by impedance plethysmography of the forearm and finger. The study was double blind, cross over, placebo controlled, and randomised. 12 healthy male volunteers were enrolled in the study. All subjects were fasting for at least 10 h and had abstained from smoking and from methylxanthine or alcohol containing beverages. Glyceryl trinitrate increased heart rate by 11.6(SEM 1.6) beats.min-1 (p less than 0.0005) and diastolic blood pressure by 8.7(1) mm Hg (p less than 0.01), and decreased systolic blood pressure by 8.7(1.5) mm Hg (p less than 0.01) in placebo treated volunteers; the amplitude of the plethysmograph c wave in the forearm and in the finger was also augmented, by 120(11)% and 78(13)% respectively, indicating an increase in arterial compliance. The results obtained in the two placebo sessions did not differ, indicating good reproducibility of the system. Pretreatment with either indomethacin or ibuprofen did not modify the effects of glyceryl trinitrate on heart rate, blood pressure, and arterial compliance in the forearm and the finger. Both indomethacin and ibuprofen suppressed prostaglandin synthesis, as shown by the striking inhibition of serum TxA2 concentration, by 97.2(1.5)% and 93.7(3.0)%, respectively. Sublingual glyceryl trinitrate, in doses used clinically, induces a reproducible increase in peripheral arterial compliance in healthy volunteers; prostaglandins do not play any significant role in this effect.


Micro-computed tomographic evaluation of a new system for root canal filling using calcium silicate-based root canal sealers.
This study evaluated by using micro-computed tomography (micro-CT) the filling ability and sealer apical extrusion promoted by a new Sealer Injection System (SIS; Angelus) with side openings needle, in comparison with the conventional injection system, associated with a new ready-to-use calcium silicate-based sealer (Bio-C Sealer). Acrylic resin models containing a main curved artificial canal and 3 simulated lateral canals in apical, middle and cervical thirds were used. The main root canals were prepared using a rotary system up to size 35.05. The canals were filled with Bio-C sealer by using a single cone technique and the conventional delivery system or SIS. Samples were scanned in micro-CT. The percentage of voids throughout the entire extension of the main root canal and in each third of the lateral canals, besides the apical extrusion of the sealer was calculated. Data were submitted to t-test (p < 0.05). There was no difference between both systems in the main root canals filling. Although the volume percentage of voids was similar in the apical and middle thirds of lateral canals, SIS had the greatest filling ability of the cervical third lateral canal. Moreover, the conventional system showed the highest apical extrusion of the sealer. The conventional and SIS obturation systems had an appropriate filling ability of the main root canal. SIS had the best filling of the cervical third of the lateral canals, besides lower sealer apical extrusion, suggesting its clinical indication.


[The metabolism of blood glucose and lipid in breast cancer patients after the first chemotherapy].
Objective: To analyze the metabolism of blood glucose and lipid in breast cancer patients after the first chemotherapy. Methods: Breast cancer patients who received chemotherapy for the first time from December 2016 to January 2020 were collected in our hospital, and their blood glucose and lipid levels were monitored. Patients were grouped according to different treatment plans. Non-parametric rank sum test was used for statistical analysis on SPSS software. Results: There were 1 356 female breast cancer patients were enrolled, blood glucose and lipid levels were compared before and after chemotherapy. Our results showed that baseline medium blood glucose was 5.2 mmol/L, lower than 5.3 mmol/L after chemotherapy (P<0.05). The baseline triglyceride (TG) was 1.2 mmol/L, lower than 1.6 mmol/L after chemotherapy (P<0.05). The baseline small dense low-density lipoprotein (sdLDL) was 0.7 mmol/L, lower than 0.8 mmol/L after chemotherapy (P<0.05). The baseline high density lipoprotein (HDL) was 1.3 mmol/L, higher than 1.2 mmol/L after chemotherapy (P<0.05). Patients' menstrual status and body mass index were related with blood glucose, TG, LDL and sdLDL (all P< 0.05). Conclusions: Abnormal metabolism of blood glucose and lipid are observed in breast cancer patients after the first chemotherapy. More awareness of cardiovascular disease in breast cancer patients might ensure their overall clinical benefits.


Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy.
Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.


Pediatric Medicaid Visits for Soil-Transmitted Helminth Infections in the Black Belt Region-Alabama, 2010-2018.
Areas of rural Alabama may be at risk for re-emergence of soil-transmitted helminthiasis (STH) where environmental conditions are favorable for STH transmission, including in the agricultural Black Belt region. We describe pediatric Medicaid STH visits in Alabama and compare STH visit rates in Black Belt counties with those of non-Black Belt counties. Alabama Medicaid visit claims among children aged 0-18 years who received an STH diagnosis during January 2010-December 2018 were examined. STH-related pediatric visits were uncommon, but several counties with higher STH rates were identified. Visit rates did not differ meaningfully when comparing Black Belt with non-Black Belt region counties (rate ratio: 1.10; 95% CI: 0.73-1.64). Additional studies examining STH prevalence among children living in communities at risk for STH in Alabama can further clarify STH burden and identify communities experiencing environmental and sanitation conditions favorable to STH endemicity.


[Regulatory mechanism of gastric acid secretion and mucosal integrity--an analysis with various gene deficient mice].
Mechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K(+)-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-alpha were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.


Predictive factors for ambulatory state in critical limb ischemia patients at discharge.
[Purpose] In patients with critical limb ischemia, the ambulatory state often has a lasting impact on recovery and wound healing. The aim of this study was to examine the predictive factors connected with the ambulatory state in wounds with critical limb ischemia. [Participants and Methods] This study included 125 inpatients with critical limb ischemia, who underwent physical therapy between January 2015 and December 2018. We retrospectively studied factors from the participant's medical records and comparisons were made between the ambulatory and non-ambulatory groups. Next, we analyzed the differences between factors using multiple logistic regression analysis. [Results] The factors associated with the ambulatory state in patients with critical limb ischemia, as determined by multiple logistic regression analysis, were knee extension muscle strength, off-loading the foot duration, and the presence or absence of heart disease. [Conclusion] Shortening off-loading the foot period and intensive rehabilitation at an early stage after amputation need to be prioritized to maintain the quality of life and ambulatory status of patients with wounds in critical limb ischemia.


Engineered microparticles and nanoparticles for fibrinolysis.
Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the decades since their introduction into clinical practice, several limitations of have been identified in terms of both efficacy and bleeding risk associated with these agents. Engineered nanoparticles and microparticles address some of these limitations by improving circulation time, reducing inhibition and degradation in circulation, accelerating recanalization, improving targeting to thrombotic occlusions, and reducing off-target effects; however, many particle-based approaches have only been used in preclinical studies to date. This review covers four advances in coupling fibrinolytic agents with engineered particles: (a) modifications of plasminogen activators with macromolecules, (b) encapsulation of plasminogen activators and plasmin in polymer and liposomal particles, (c) triggered release of encapsulated fibrinolytic agents and mechanical disruption of clots with ultrasound, and (d) enhancing targeting with magnetic particles and magnetic fields. Technical challenges for the translation of these approaches to the clinic are discussed.


Cell Walls of Germinating Uredospores: II. Carbohydrate Polymers.
Polymeric carbohydrates in (14)C-labeled germ tube and uredospore walls of Uromyces phaseoli var. typica were studied by permethylation and by enzymatic hydrolysis. The native structure of the uredospore wall limited the effectiveness of both techniques with this wall, but evidence for two distinct polysaccharides was obtained. A linear (1-->3) glucan, containing minor quantities of (1-->6) linkages, may account for most of the glucose in the uredospore wall. A second uredospore polymer was a glucomannan similar to one reported for other rust fungi in that it consisted of approximately equal numbers of beta(1-->3) and beta(1-->4) mannosidic linkages with glucose as a minor component at the nonreducing end. Branching, most likely by (1-->6) mannose links, was low. In contrast to uredospore wall, considerably more germ tube polysaccharide was accessible to enzymes and to methylation. Methylation studies indicate that (1-->3) glucose and mannose bonds occur predominantly. Evidence from hydrolysis with exo- (beta)-(1-->3) glucanase suggests distinct wall regions of beta(1-->3) glycan, highly branched by (1-->6) bonds, as well as wall regions of a glucomannan with alternating (1-->3) glucose and (1-->3) mannose residues. Polymer heterogeneity was indicated by differences in the proportions of mannose, glucose, and galactose as reducing end groups in different solubility fractions. In germ tube walls, but not in uredospore walls, glucosamine apparently existed as part of chitin polymer as evidenced by the isolation of N,N-diacetylchitobiose from chitinase digestion.


Possible involvement of uncoupling protein 1 in appetite control by leptin.
Leptin reduces body fat by decreasing food intake and increasing energy expenditure. Uncoupling protein (UCP) 1, a key molecule for brown adipose tissue (BAT) thermogenesis, was reported to contribute to the stimulatory effect of leptin on energy expenditure. To clarify whether UCP1 is also involved in the anorexigenic effect of leptin, in this study we examined the effect of leptin on food intake using wild-type (WT) and UCP1-deficient (UCP1-KO) mice. Repeated injection of leptin decreased food intake more markedly in WT mice than in UCP1-KO mice, while a single injection of leptin showed similar effects in the two groups of mice. As chronic leptin stimulation induces UCP1 expression in BAT and ectopically in white adipose tissue (WAT), we mimicked the UCP1 induction by repeated injection of CL316,243 (CL), a highly specific β3-adrenoceptor agonist, and measured food intake in response to a single injection of leptin. Two-week treatment with CL enhanced the anorexigenic effect of leptin in WT mice, but not in UCP1-KO mice. Three-day treatment with CL in WT mice also enhanced the anorexigenic effect of leptin and leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the arcuate nucleus of the hypothalamus, without any notable change in adiposity. These results indicate that UCP1 enhances leptin action at the hypothalamus level, suggesting UCP1 contributes to the control of energy balance not only through the regulation of energy expenditure but also through appetite control by modulating leptin action.


Successful substitution of fetal calf serum by human plasma for bulk cultivation of Leishmania donovani promastigotes.
The potential of human plasma (HP) or serum (HS) as a replacement for fetal calf serum (FCS) was evaluated in a liver infusion tryptose (LIT) medium for bulk cultivation of Leishmania donovani promastigotes. The promastigote yield with the LIT-FCS standard medium was 0.4-1.8×10(7) ml(-1), and yields of 0.5-3.4×10(7) (P = 0.527) and 0.4-2.4×10(7) (P = 0.062) were recorded for two LIT medium variants containing HP or HS as supplement instead of FCS. Significantly, higher promastigote yields of 1.3-4.9×10(7) ml(-1) were demonstrated when LIT medium was supplemented with HP of blood group O but not A, B, AB or equally pooled ABO (P = 0.007-0.020). Matching (P = 0.56) strong positive (1 : 10 2400 to ≥1 : 262 144 00) and weak negative (1 : 5-1 : 160) direct agglutination test (DAT) titres, respectively, were demonstrated in 24 visceral leishmaniasis (VL) and 45 non-VL sera for both standard LIT-FCS and alternative LIT-HP derived antigens. Our findings indicate strong potential for sustainable production of promastigotes for important diagnostic procedures such as DAT in the VL affected areas.


Update From the Advisory Committee on Immunization Practices.
A 9-valent human papillomavirus vaccine is now recommended as a 2-dose series (0, 6-12 months) for healthy adolescents 9-14 years. Meningococcal type B (MenB)-FHbp (Trumenba), previously a 3-dose series, may be given in a 2-dose series (0, 6 months) to healthy adolescents; MenB vaccination remains a Category B recommendation (individual clinical decision making) for healthy adolescents. The wording for the recommendations for the hepatitis B vaccine birth dose was strengthened to encourage administration of the birth dose by 24 hours of age.


Sodium Alginate as a Potential Therapeutic Filler: An In Vivo Study in Rats.
Filler injection demand is increasing worldwide, but no ideal filler with safety and longevity currently exists. Sodium alginate (SA) is the sodium salt of alginic acid, which is a polymeric polysaccharide obtained by linear polymerization of two types of uronic acid, d-mannuronic acid (M) and l-guluronic acid (G). This study aimed to evaluate the therapeutic value of SA. Nine SA types with different M/G ratios and viscosities were tested and compared with a commercially available sodium hyaluronate (SH) filler. Three injection modes (onto the periosteum, intradermally, or subcutaneously) were used in six rats for each substance, and the animals were sacrificed at 4 or 24 weeks. Changes in the diameter and volume were measured macroscopically and by computed tomography, and histopathological evaluations were performed. SA with a low M/G ratio generally maintained skin uplift. The bulge gradually decreased over time but slightly increased at 4 weeks in some samples. No capsule formation was observed around SA. However, granulomatous reactions, including macrophage recruitment, were observed 4 weeks after SA implantation, although fewer macrophages and granulomatous reactions were observed at 24 weeks. The long-term volumizing effects and degree of granulomatous reactions differed depending on the M/G ratio and viscosity. By contrast, SH showed capsule formation but with minimal granulomatous reactions. The beneficial and adverse effects of SA as a filler differed according to the viscosity or M/G ratio, suggesting a better long-term volumizing effect than SH with relatively low immunogenicity.


Synthesis and characterization of histidine-phosphorylated peptides.
Posttranslational phosphorylation of proteins is an important event in many cellular processes. Whereas phosphoesters of serine, threonine, and tyrosine have been studied extensively, only limited information is available for other amino acids modified by a phosphate group. The formation of phosphohistidine residues in proteins was discovered originally in prokaryotic organisms, but also has been found recently in eukaryotic cells. We describe methods for the synthesis and analysis of phosphohistidine-containing peptides, a prerequisite for the investigation of the role of this posttranslational modification in cellular processes.


[Clinical features and hospital costs of neonatal sepsis caused by bacteria and fungi: a comparative analysis].
To study the clinical features and hospital costs of neonatal sepsis caused by Gram-positive (G(+)) bacteria, Gram-negative (G(-)) bacteria, and fungi. The clinical data of 236 neonates with sepsis were analyzed retrospectively. Among these neonates, 110 had sepsis caused by G(+) bacteria, 68 had sepsis caused by G(-) bacteria, and 58 had sepsis caused by fungi. Full-term infants accounted for 62% and 38%, respectively, in the G(+) bacteria and G(-) bacteria groups, and preterm infants accounted for 86% in the fungi group. The neonates in the fungi group had significantly lower gestational ages and birth weights than those in the G(+) and G(-) bacteria groups (P<0.05). Compared with the G(+) bacteria group, the G(-) bacteria and fungi groups had significantly higher rates of multiple births (P<0.0125). Compared with the G(+) bacteria and fungi groups, the rates of premature rupture of membranes >18 hours, grade III amniotic fluid contamination, and early-onset sepsis in the G(-) bacteria group were significantly higher (P<0.0125). Compared with the G(-) bacteria and fungi groups, the G(+) bacteria group showed significantly higher rates of abnormal body temperature, omphalitis or herpes as the symptom suggesting the onset of such disease (P<0.0125). The fungi group had significantly higher incidence rates of apnea and low platelet count than the G(+) and G(-) bacteria groups (P<0.0125). The comparison of length of hospital stay and total hospital costs between any two groups showed that the fungi group had a significantly longer hospital stay and significantly higher total hospital costs than the G(+) and G(-) bacteria groups (P<0.05). Sepsis caused by G(+) bacteria mainly occurs in full-term infants, and most cases of sepsis caused by G(-) bacteria belong to the early-onset type. Sepsis caused by fungi is more common in preterm infants and low birth weight infants, and has high incidence rates of apnea and low platelet count, as well as a longer hospital stay and higher hospital costs than sepsis caused by bacteria.


[Isolated lesions of the gallbladder, in closed abdominal injuries. Apropos of 7 cases].
The authors report 7 cases of isolated injuries of the gallbladder, in closed abdominal trauma. The literature indicates the frequency to lie between one and five percent. The postprandial period and fasting alcohol levels, responsible for the distention of the gallbladder, are mostly the cause of such lesions. Four groups of injuries are described: 1) laceration 2) avulsion 3) simple contusion 4) traumatic cholecystitis Early diagnosis of such injuries is difficult as abdominal signs are poor and little specific; the authors note the value of peritoneal puncture and lavage. The treatment of gallbladder trauma is always surgical, cholecystectomy giving the best results; raphy and cholecystostomy are second choice treatments. The prognosis is usually favorable, even if surgery is delayed, and depends essentially on the nature of associated extra-abdominal injuries.


Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical β-catenin levels. In addition, Myc, a downstream target of β-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of β-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.


Plant and algal structure: from cell walls to biomechanical function.
Plant and algal cell walls are complex biomaterials composed of stiff cellulose microfibrils embedded in a soft matrix of polysaccharides, proteins and phenolic compounds. Cell wall composition differs between taxonomic groups and different tissue types (or even at the sub-cellular level) within a plant enabling specific biomechanical properties important for cell/tissue function. Moreover, cell wall composition changes may be induced in response to environmental conditions. Plant structure, habit, morphology and internal anatomy are also dependent on the taxonomic group as well as abiotic and biotic factors. This review aims to examine the complex and incompletely understood interactions of cell wall composition, plant form and biomechanical function.


Ophthalmoplegia associated with the anti-Ri antibody.
Anti-Ri antibodies most often occur in patients with breast cancer and typically are associated with the paraneoplastic syndrome of opsoclonus-myoclonus-ataxia. This study reports a patient with diplopia and ophthalmoplegia. She had anti-Ri antibodies, and despite an exhaustive search for malignancy at presentation, breast cancer was not detected for six months.


Exploring the effect of laryngeal neuromuscular electrical stimulation on voice.
This study was conducted to explore the potential use of neuromuscular electrical stimulation as an adjunctive treatment for muscle tension dysphonia. Voice data and ratings of fatigue and soreness were obtained for two experiments. Experiment one examined the vocal effects of neuromuscular electrical stimulation applied to the neck for 15 minutes. Experiment two examined the recovery effect of laryngeal neuromuscular electrical stimulation following a vocal loading task among normophonic women. No significant differences in vocal function following 15 minutes of laryngeal neuromuscular electrical stimulation were found. Six of 11 participants receiving laryngeal neuromuscular electrical stimulation exhibited improved recovery following the vocal loading task. A short session of laryngeal neuromuscular electrical stimulation may be beneficial in reducing muscle fatigue for some individuals. Further investigation is warranted to determine the applicability of laryngeal neuromuscular electrical stimulation in voice therapy.


Heat shock activates c-Src tyrosine kinases and phosphatidylinositol 3-kinase in NIH3T3 fibroblasts.
There is increasing evidence that cellular responses to stress are in part regulated by protein kinases, although specific mechanisms are not well defined. The purpose of these experiments was to investigate potential upstream signaling events activated during heat shock in NIH3T3 fibroblasts. Experiments were designed to ask whether heat shock activates p60 c-Src tyrosine kinase or phosphatidylinositol 3-kinase (PI 3-kinase). Using in vitro protein kinase activity assays, it was demonstrated that heat shock stimulates c-Src and PI 3-kinase activity in a time-dependent manner. Also, there was increased PI 3-kinase activity in anti-phosphotyrosine and anti-c-Src immunoprecipitated immunocomplexes from heated cells. Heat shock activated mitogen-activated protein kinase (MAPK) and p70 S6 kinase (S6K) in these cells. The role of PI 3-kinase in regulating heat shock activation of MAPK and p70 S6K was investigated using wortmannin, a specific pharmacological inhibitor of PI 3-kinase. The results demonstrated that wortmannin inhibited heat shock activation of p70 S6K but only partially inhibited heat activation of MAPK. A dominant negative Raf mutant inhibited activation of MAPK by heat shock but did not inhibit heat shock stimulation of p70 S6K. Genistein, a tyrosine kinase inhibitor, and suramin, a growth factor receptor inhibitor, both inhibited heat shock stimulation of MAPK activity and tyrosine phosphorylation of MAPK. Furthermore, a selective epidermal growth factor receptor (EGFR) inhibitor, tryphostin AG1478, and a dominant negative EGFR mutant also inhibited heat shock activation of MAPK. Heat shock induced EGFR phosphorylation. These results suggest that early upstream signaling events in response to heat stress may involve activation of PI 3-kinase and tyrosine kinases, such as c-Src, and a growth factor receptor, such as EGFR; activation of important downstream pathways, such as MAPK and p70 S6K, occur by divergent signaling mechanisms similar to growth factor stimulation.


Cerebellar atrophy is infrequently [corrected] associated with non-paraneoplastic sensory neuronopathy.
Sensory neuronopathies (SN) are peripheral nervous system disorders associated with degeneration of dorsal root ganglion neurons. Despite the evidence of a defective proprioceptive sensory input in SN,the prominent gait and truncal ataxia raises the question of a concomitant involvement of the cerebellum. To evaluate cerebellar atrophy in SN. We analyzed MRI-based volumetry of anterior lobe (paleocerebellum) and total cerebellum in patients with non-paraneoplastic chronic SN and compared to age- and gender-matched controls. Cerebellum and anterior lobe MRI volumetry were performed in 20 patients and nine controls. Mean anterior lobe and cerebellar volume were not statistically different. Three patients (15%), however, had an abnormal anterior lobe and cerebellar volume index (values outside 2.5 standard deviations). One of them also had a specific atrophy of the anterior lobe. All these patients had infectious or dysimmune associated SN. Cerebellar atrophy is infrequently associated with SN, but can be found in some patients with SN related to infectious or immune mediated conditions. It can be more prominent in the anterior lobe and may contribute to the ataxia seen in these patients.


Arthroscopic Transtibial Pull-Out Repair for Meniscal Posterior Root Tear: The Slip Knot Technique.
A meniscal root tear can increase the tibiofemoral contact pressure to approximate that of total meniscectomy and eventually lead to degenerative change. An anatomic and stable meniscal root repair is essential in restoring the tibiofemoral contact pressure back to that of a normal knee. Suture anchor technique and pull-out suture technique are the 2 main arthroscopic root repair procedures with equivalent success; nonetheless, there remains a lack of an optimal technique with a biomechanical property matching that of the intact root. This article presents a technically simple, fast, and robust pull-out suture construct that incorporates 2 slip-knot locking loops at the meniscus-suture interface. This technique can be used for both medial and lateral posterior root repair, as well as concomitantly with cruciate ligament reconstruction.


Individual cognitive changes in subjective cognitive decline, mild cognitive impairment and Alzheimer's disease using the reliable change index methodology.
The development of Alzheimer's disease (AD) can be assessed using the neuropsychological test battery Vienna (NTBV). The objective of this study was to investigate whether the NTBV test scores of a diagnostic group have changed significantly over time and whether this change is due to disease progression. In this study 358 patients referred to a memory outpatient clinic because of cognitive deterioration were analyzed. The same patients were surveyed in a follow-up assessment after a mean interval of 25.96 months to examine cognitive performance and disease progression. Patients were divided into the subgroups healthy controls (HC), subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD on the basis of the test results. Reliable change index methodology was used to assess improvement or deterioration in test scores in diagnostic groups compared to HC. Deterioration in the SCD group ranged from 0% to 18.8%. The MCI group showed declines between 1.6% and 29.1%. Patients who developed AD deteriorated between 0% and 54.2%. Improvements ranged from 0% to 73.4% in the SCD group and from 0% to 25.1% for the MCI group. The improvement in the AD group ranged between 0% and 44.0%. The results reflect the cognitive deterioration of patients during the disease progression. Nevertheless, improvements in diagnostic groups could be detected. The significantly positive changes might be due to practice effects, also a lack of motivation or attention in the first test could have yielded "improvement" in the retest.


Adrenergic regulation of cAMP/protein kinase A pathway in corneal epithelium and endothelium.
The G-protein-coupled receptor/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells. The aim of this study was to characterize subtypes of adrenergic G-protein-coupled receptors and their influence on cAMP concentration and PKA activity in bovine corneal epithelial and endothelial cells. Adrenergic receptors and PKA were studied using polyclonal antibodies. cAMP concentration was determined with an enzyme immunoassay, and PKA activity was estimated by the kinases consumption of adenosine triphosphate. In bovine corneal epithelial and endothelial cells, immunocytochemistry and Western blot were positive for alpha(1)-, alpha(2A)-, beta(1)- and beta(2)-adrenergic receptors. Stimulation of corneal epithelial and endothelial beta-adrenoceptors with isoprenaline led to a dose-dependent increase in cAMP concentration and activation of PKA. Stimulation of corneal alpha(2A)-adrenoceptors with brimonidine resulted in a dose-dependent decrease in cAMP concentration and the inhibition of PKA activity. In corneal epithelial and endothelial cells, beta-adrenergic stimulation leads to activation of PKA via stimulation of adenylyl cyclase, and alpha(2A)-adrenoceptor stimulation inhibits PKA activity via inhibition of adenylyl cyclase. Stimulation and inhibition of the corneal cAMP-PKA pathway may play a role in important corneal functions such as wound healing or homeostasis. Long-term therapy with alpha(2A)-agonists or beta-antagonists may influence these functions in a currently unknown way.


Hostility During Training: Historical Roots of Primary Care Disparagement.
The environment during medical school has been shown to dissuade students from choosing primary care careers. The purpose of this study was (1) to explore how long-standing this hostility toward primary care is historically and (2) to understand the mechanisms through which the environment conveys disparagement of primary care to students. The study is based on a qualitative analysis of 52 primary care physician oral histories. The data are from the Primary Care Oral History Collection, created by Fitzhugh Mullan and deposited in the National Library of Medicine. Transcripts were analyzed using qualitative data analysis and the constant comparative method. Respondents (63.5%) reported experiencing discouragement or disparagement about primary care, and this proportion remained fairly high through 5 decades. Findings indicate that hostility toward primary care operates through the culture and the structure of medical training, creating barriers to the portrayal of primary care as appealing and important. Support for primary care choice was uncommon but was reported by some respondents. The primary care shortage and primary care's unfavorable representation during medical training is a multifaceted problem. The evidence reported here shows that cultural and structural factors are critical components of the problem, and have existed for decades. For policy responses to be most effective in meeting the primary care workforce problem, they must address the presence and power of persistent hostility against primary care during training.


Aspects of fast-ion dosimetry.
A first step in the dosimetry of fast-ion beams is the determination of accurate Bragg (ionization) functions. Bragg functions for several substances have been measured and calculated for 3480 MeV carbon ions. In the measurements, the ions first traverse an absorber in which the energy is reduced to either 1900 or 1200 MeV, then a "range gauge" followed by a thin ionization chamber. Functions are calculated with an analytical method using convolutions of straggling functions. This approach gives results without the stochastic variations implicit in Monte Carlo methods. The comparison of measured and calculated functions shows how reliable the calculations are. An important part of the calculations is the determination of the total range of the ions. The range can be determined from the Bragg function. The measured range is given by the sum of the thickness of the absorber and the residual range measured with the range gauge. For water, the range is about 150 mm, and the precision of the measurements is +/-0.05 mm. Because the ion energy at the surface of the absorber fluctuates with time, measurements with water are used to define this energy. Thus the ranges (or average stopping powers) in absorbers are obtained relative to those in water. Measured ranges R(m) are compared with ranges R(0) calculated with a current version of the Bethe theory. For light absorbers (atomic number Z < 20), differences between R(m) and R(0) are less than +/-0.3 mm; for Z > 20 differences are between 0 and +/-0.6 mm. This agreement between calculated and measured ranges confirms the value I = 80 eV for water measured earlier for protons. The ionization by nuclear fragments is obtained from the difference between measured and calculated ionization functions, and has little influence on the ranges of the primary ions.


Novel one-dimensional nanogap created with standard optical lithography and evaporation procedures.
This article details a simple four-step procedure to create a one-dimensional nanogap on a buried oxide substrate that relies on conventional photolithography performed on a stack of silicon/silicon oxide/silicon, metal evaporation, and hydrofluoric acid oxide removal. Once the nanogap was fabricated it was bridged with an assembly of 1,8-octanedithiol and 5 nm Au nanoparticles capped with a sacrificial dodecylamine coating. Before assembly, characterization of the nanogaps was performed through electrical measurements and SEM imaging. Post assembly, the resistance of the nanogaps was evaluated. The current increased from 70 fA to 200 microA at +1 V bias, clearly indicating a modification due to nanoparticle molecule assembly. Control experiments without nanoparticles or octanedithiol did not show an increase in current.


Fetal alcohol exposure, iron-deficiency anemia, and infant growth.
Our goals were to determine whether prenatal alcohol exposure is associated with an increased incidence of iron-deficiency anemia in infancy and to compare effects of fetal alcohol exposure and iron-deficiency anemia on infant growth. We also tested whether effects of fetal alcohol exposure on growth are mediated or moderated by iron-deficiency anemia. A total of 96 infants born to mothers from the Coloured (mixed ancestry) community in Cape Town, South Africa, were recruited prenatally; 42 mothers drank heavily during pregnancy, and 54 abstained or drank small amounts of alcohol. Growth was assessed at birth and 6.5 and 12 months, and iron-deficiency anemia was assessed at 6.5 or 12 months. Infants whose mothers binge drank during pregnancy (> or = 4 drinks per occasion) were 3.6 times more likely to be diagnosed with iron-deficiency anemia at 12 months than were infants whose mothers did not binge drink. Prenatal alcohol exposure was associated with reduced weight at birth, 6.5 months, and 12 months and with shorter length at 6.5 and 12 months. Iron-deficiency anemia was related to reduced 12-month weight and head circumference and to slower growth velocity between 6 and 12 months. The effects of prenatal alcohol on weight were not mediated by iron-deficiency anemia; however, they were seen primarily in infants with iron-deficiency anemia. The association of maternal binge drinking with an increased incidence of iron-deficiency anemia may reflect disruption of accumulation of fetal iron stores or postnatal deficiencies in iron uptake, absorption, or intake. Moreover, iron deficiency seems to exacerbate the prenatal alcohol effects on growth.


A novel spatially designed and functionally graded electrospun membrane for periodontal regeneration.
A periodontal membrane with a graded structure allows tailoring of the layer properties to design a material system that will retain its physical, chemical and mechanical characteristics for a period long enough to optimize periodontal regeneration. In this work a novel functionally graded membrane (FGM) was designed and fabricated via sequential multilayer electrospinning. The FGM consists of a core layer (CL) and two functional surface layers (SLs) interfacing with bone (nano-hydroxyapatite, n-HAp) and epithelial (metronidazole, MET) tissues. The CL comprises a neat poly(DL-lactide-co-ε-caprolactone) (PLCL) layer surrounded by two composite layers composed of a protein/polymer ternary blend (PLCL:PLA:GEL). Electrospinning parameters involved in fabrication of the individual layers (i.e. neat PLCL, ternary blend, PLA:GEL+10%n-HAp and PLA:GEL+25%MET) were optimized to obtain fibrous layers free of beads. Morphology, structure and mechanical property studies were carried out on each electrospun layer. The individual fiber morphology and roughness of the functional SLs, which are the n-HAp containing and drug-incorporating layers were evaluated by atomic force microscopy. The CL structure demonstrated higher strength (8.7 MPa) and a more elastic behavior (strain at break 357%) compared with the FGM (3.5 MPa, 297%). Incorporation of n-HAp to enhance osteoconductive behavior and MET to combat periodontal pathogens led to a novel FGM that holds promise at solving the drawbacks of currently available membranes.


Comparison of imaging-based gross tumor volume and pathological volume determined by whole-mount serial sections in primary cervical cancer.
To investigate the accuracy of imaging-based gross tumor volume (GTV) compared with pathological volume in cervical cancer. Ten patients with International Federation of Gynecology and Obstetrics stage I-II cervical cancer were eligible for investigation and underwent surgery in this study. Magnetic resonance imaging (MRI) and fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET)/computed tomography (CT) scans were taken the day before surgery. The GTVs under MRI and (18)F-FDG PET/CT (GTV-MRI, GTV-PET, GTV-CT) were calculated automatically by Eclipse treatment-planning systems. Specimens of excised uterine cervix and cervical cancer were consecutively sliced and divided into whole-mount serial sections. The tumor border of hematoxylin and eosin-stained sections was outlined under a microscope by an experienced pathologist. GTV through pathological image (GTV-path) was calculated with Adobe Photoshop. The GTVs (average ± standard deviation) delineated and calculated under CT, MRI, PET, and histopathological sections were 19.41 ± 11.96 cm(3), 12.66 ± 10.53 cm(3), 11.07 ± 9.44 cm(3), and 10.79 ± 8.71 cm(3), respectively. The volume of GTV-CT or GTV-MR was bigger than GTV-path, and the difference was statistically significant (P < 0.05). No significant difference was observed between GTV-PET and GTV-path (P > 0.05). Spearman correlation analysis showed that GTV-CT, GTV-MRI, and GTV-PET were significantly correlated with GTV-path (P < 0.01). There was no significant difference in the lesion coverage factor among the three modalities. The present study showed that GTV defined under 40% of maximum standardized uptake value in PET images was very similar to the pathological volume of cervical cancer. This result should be replicated in a larger number of patients with cervical cancer in a future study of ours.


Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.


Distribution of Secondary Plant Metabolites and Their Biosynthetic Enzymes in Pea (Pisum sativum L.) Leaves : Anthocyanins and Flavonol Glycosides.
Leaves of a novel strain of peas (Pisum sativum L.) were used to determine the distribution of secondary metabolites and their biosynthetic enzymes. Leaf epidermal layers in this strain are easily separated from the parenchyma. Anthocyanins and flavonol glycosides were localized in epidermal vacuoles only. Among the biosynthetic enzymes studied, phenylalanine ammonia-lyase (PAL, EC 184.108.40.206), S-adenosyl-1-methionine (SAM):caffeic acid and SAM:quercetin methyltransferases (o-dihydric phenol methyltransferase, EC 184.108.40.206) and a flavonoid 7-O-glucosyltransferase (EC 18.104.22.168) were chiefly localized in the parenchyma, whereas trans-cinnamate 4-monooxygenase (EC 184.108.40.206), hydroxycinnamate:CoA ligases (EC 220.127.116.11) and a flavonoid 3-O-glucosyltransferase (EC 22.214.171.124) were found mainly in the epidermis. Flavanone (chalcone) synthase activity was found only in the epidermis, whereas chalcone isomerase (EC 18.104.22.168) was evenly distributed in epidermal and parenchyma tissues.


Socioeconomic disparities and neuroplasticity: Moving toward adaptation, intersectionality, and inclusion.
Childhood socioeconomic status (SES) has far-reaching linkages with children's cognitive and socioemotional development, academic achievement, health, and brain structure and function. Rather than focusing on understandings about the neuroscience of socioeconomic inequality that have recently been reviewed elsewhere, the present article reviews several new directions in the field, beginning first with a consideration of the deficit versus adaptation framework. Although scientists largely agree that socioeconomic disparities in brain development are experience-dependent phenomena rooted in neuroplasticity, historically, such differences have been framed as deficits, which may benefit from intervention. However, emerging research suggests that some developmental differences among children experiencing adversity may alternatively be considered context-appropriate adaptations to the individual's environment. We next discuss how socioeconomic circumstances are inextricably intertwined with race, and consider how measurement of racism and discrimination must be part of a full understanding of the neuroscience of socioeconomic inequality. We argue that scientists must consciously recruit racially and socioeconomically diverse samples-and include measures of SES, race, and discrimination in analyses-to promote a more complete understanding of the neuroplasticity specifically, and psychological science more broadly. We discuss the extent to which researcher and editor positionality have contributed to these problems historically, and conclude by considering paths forward. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16, and 22: their incidence, likely origins, and mechanisms for cell lineage compartmentalization.
Analysis of confined placental mosaicism (CPM) for trisomies 2, 3, 7, 8, 9, 16, and 22, in diagnostic chorionic villus sampling procedures, demonstrates apparent incidences of CPM for individual trisomies of between 9 and 91 cases per 100,000 pregnancies, with trisomy 7 being the most common. More detailed analysis of the percentage of aneuploid cells present, and the distribution of abnormality between the cytotrophoblast and extra-embryonic mesoderm cell lineages, shows a highly specific pattern for each chromosome. Theoretical considerations, in conjunction with direct observations, indicate that the overriding influence on the patterns of cell distribution seen in CPM is the distribution of aneuploid cells laid down during blastogenesis. This in turn reflects closely the origin of mosaicism from either correction of a trisomic conception or post-fertilization somatic error. The pattern of aneuploid cells for each trisomy, as seen at the end of the first trimester and later in pregnancy, can therefore be used to predict the relative contribution of meiotic and mitotic errors to CPM, and hence the likely incidences of uniparental disomy from this source, upd(16)mat being the most common (1 in 10,000 continuing pregnancies). In addition, CPM for trisomies 2, 3, and 8 shows strong evidence of a non-random distribution of aneuploid cells between the different extra-embryonic cell lineages. Analysis of comparable data from spontaneous abortion material repeats this non-random pattern for trisomies 2 and 3, and suggests that a similar phenomenon may also be occurring for trisomy 22. A non-random distribution could be attributable to selection for or against, or intolerance of, particular trisomic cells in certain lineages, but is more probably a result of either cell lineage-specific non-disjunction or consistent uneven compartmentalization of aneuploid cells during blastocyst development.