Nanoparticles of Short Cationic Peptidopolysaccharide Self-Assembled by Hydrogen Bonding with Antibacterial Effect against Multidrug-Resistant Bacteria.
Cationic antimicrobial peptides (AMPs) and polymers are active against many multidrug-resistant (MDR) bacteria, but only a limited number of these compounds are in clinical use due to their unselective toxicity. The typical strategy for achieving selective antibacterial efficacy with low mammalian cell toxicity is through balancing the ratio of cationicity to hydrophobicity. Herein, we report a cationic nanoparticle self-assembled from chitosan-graft-oligolysine (CSM5-K5) chains with ultralow molecular weight (1450 Da) that selectively kills bacteria. Further, hydrogen bonding rather than the typical hydrophobic interaction causes the polymer chains to be aggregated together in water into small nanoparticles (with about 37 nm hydrodynamic radius) to concentrate the cationic charge of the lysine. When complexed with bacterial membrane, these cationic nanoparticles synergistically cluster anionic membrane lipids and produce a greater membrane perturbation and antibacterial effect than would be achievable by the same quantity of charge if dispersed in individual copolymer molecules in solution. The small zeta potential (+15 mV) and lack of hydrophobicity of the nanoparticles impedes the insertion of the copolymer into the cell bilayer to improve biocompatibility. In vivo study (using a murine excisional wound model) shows that CSM5-K5 suppresses the growth of methicillin-resistant Staphylococcus aureus (MRSA) bacteria by 4.0 orders of magnitude, an efficacy comparable to that of the last resort MRSA antibiotic vancomycin; it is also noninflammatory with little/no activation of neutrophils (CD11b and Ly6G immune cells). This study demonstrates a promising new class of cationic polymers-short cationic peptidopolysaccharides-that effectively attack MDR bacteria due to the synergistic clustering of, rather than insertion into, bacterial anionic lipids by the concentrated polymers in the resulting hydrogen-bonding-stabilized cationic nanoparticles.


Human immunodeficiency virus type 1 Vpr alters bone marrow cell function.
Vpr, a 96 amino acid protein, encoded by the human immunodeficiency virus type I (HIV-1), is important for efficient infection of mononuclear phagocytic cells. These cells are abundant in whole bone marrow, which can easily be cultured in vitro to support hematopoiesis. Our experiments indicate that Vpr plays a role in the potent activation of murine and human mononuclear phagocytic cells within a hematopoietic microenvironment. In murine cultures, avid erythrophagocytosis is triggered by transduction of marrow cells with supernatant derived from PA317 cells transfected with a murine retroviral delivery vector bearing a Vpr expression cassette. Supernatants derived from cells transfected with the same vector carrying sequences for the expression of other relevant viral and nonviral proteins do not induce erythrophagocytosis to any marked degree. The effect on human marrow cells is similar, where treatment promotes adhesion of mononuclear phagocytic cells to culture plates in association with other nucleated and nonnucleated cells that undergo subsequent engulfment. The differential effects of Vpr point and deletion mutants in both marrow culture systems fortify the view that the effect is specific to HIV-1 Vpr. Addition of low molar quantities of purified Vpr to marrow cultures is also capable of promoting cell adhesion and phagocytosis, suggesting that extracellular Vpr is the effector of the phenomenon. Accelerated phagocytosis is a hallmark of promonocyte, monocyte, and macrophage activation and its occurrence within a hematopoietic microenvironment may account for critical in vivo pathogenic features of HIV-1 infection. First, activation of mononuclear phagocytes may promote productive viral infection; and second, premature phagocytosis could provide, at least in part, a molecular explanation for the induction of the idiopathic cytopenias that are typical of individuals infected with HIV-1.


Pharmacological therapies for management of opium withdrawal.
Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium. To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials. Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days. We used the standard methodological procedures expected by Cochrane. We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.


[Circulating microRNAs in the diagnostics of endocrine neoplasms].
MicroRNAs (miRNA, miR) are short - 19-25 nucleotide long - single stranded (in their mature form), non-coding RNA molecules that regulate gene expression mostly at the posttranscriptional level. microRNAs are involved in the regulation of various physiological processes such as cell differentiation and proliferation, development, haematopoesis, cell death, while their aberrant expression is observed in numerous diseases, like autoimmune disorders, inflammations, vascular diseases or tumorigenesis. microRNAs are expressed in a tissue specific fashion. Beyond their appearance in tissues, they can be found in body fluids as well. microRNAs are present in blood, mother milk, semen, saliva, urine, etc. MicroRNAs in body fluids, especially the blood-borne circulating microRNAs can be exploited as minimally invasive biomarkers of tumor diagnosis. The number of endocrine tumor-associated circulating microRNA alterations is relatively low, mostly described for papillary thyroid cancer, adrenocortical cancer, ovarian and neuroendocrine tumors. As the histological diagnosis including the establishment of malignancy of some of these neoplasms is difficult, studies on circulating microRNAs might have great perspectives. Orv. Hetil., 2017, 158(13), 483-490.


Paraneoplastic Phenomena of Disseminated Intravascular Coagulopathy in Hepatic Angiosarcoma - Rare, Challenging and Fatal. Case Report and Literature Review.
Hepatic angiosarcoma is an uncommon, malignant, primary liver tumor, comprising 2% of liver cancers and accounting for < 1% of all sarcomas. Patients usually present with nonspecific symptoms, such as fatigue, weight loss, right upper quadrant pain, anemia, which leads to late diagnosis of an advanced stage tumor. The median life expectancy after the diagnosis of hepatic angiosarcoma is about 6 months, with only 3% of patients surviving more than 2 years. Liver failure and hemoperitoneum are the leading causes of death in patients with liver angiosarcoma. In rarer cases, it might cause paraneoplastic syndromes such as disseminated intravascular coagulopathy. The treatment of angiosarcomas is complicated as there are no established and effective treatment guidelines due to the tumor's low frequency and aggressive nature. We present the case of a 68-year old woman who was admitted to the hospital due to fatigue and severe anemia (hemoglobin 65 g/l). Laboratory results also revealed high-grade thrombocytopenia (8 × 109/l). The abdominal ultrasound and computed tomography scan showed multiple lesions throughout the liver, spleen and kidneys. After the histological examination of the liver biopsy, the patient was diagnosed with hepatic angiosarcoma. The treatment with first-line chemotherapy (doxorubicin) was initiated despite ongoing paraneoplastic syndrome - disseminative intravascular coagulopathy. However, the disease was terminal, and the patient died 2 months since diagnosed. Hepatic angiosarcoma is a rare and terminal tumor. Therefore, knowledge about its manifestations and effective treatment methods is lacking. Disseminative intravascular coagulopathy is a unique clinical characteristic of angiosarcoma seen in a subset of patients.


Sources of parenting information in low SES mothers.
This study examined 3 questions: (1) What are sources from which low socioeconomic status (SES) mothers of newborns receive parenting information? (2) To what extent are sociodemographic characteristics associated with sources? (3) To what extent are sources associated with intentions regarding activities with infants? In this cross-sectional analysis, mothers were interviewed during the postpartum period about potential sources of information about parenting and asked if and when they planned to initiate shared reading and television exposure during infancy. Maternal high school graduation, US birth, non-Latina ethnicity, language English, higher SES, and firstborn child were each associated with one or more categories representing important sources of parenting information. In adjusted analyses, print, physicians and other health care professionals, and family/friends as important sources of information were each significantly associated with increased frequency of intention to begin shared reading in infancy; television as an important source was associated with intention to begin television in infancy.


Insuring the uninsured through private action: ideas and initiatives.
The growing issue of health coverage for the uninsured has no single solution, but private initiatives hold promise for some alleviation. The keys to increasing coverage are: more insurance pooling (to share risk and management); different insurance products, especially ones featuring better spending controls (to be attractive yet affordable at the low end of the market); and subsidy plus information (to encourage voluntary enrollment). Lack of insurance is not a problem for employees in large workplaces because relatively low prices and high incomes, as well as employer and tax code paternalism, assure coverage to almost 100% of workers in large groups. People on their own or in small groups, as well as increasing numbers of dependents of workers in large groups, are significantly disadvantaged in comparison. Considerable progress should be possible privately, but no one should expect large improvements without more cultural change or social intervention.


Galanin mediates features of neural and behavioral stress resilience afforded by exercise.
Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels.


Acute hypertension in a nonhuman primate: humoral and hemodynamic mechanisms.
The present study assessed the contribution of the renin-angiotensin system (RAS), dietary sodium, and cardiac output (CO) to the genesis of primate hypertensin in a one-kidney model which was developed to test species-specific renin inhibitors. Reduction of renal perfusion pressure increased mean arterial pressure (MAP) from 105 +/- 4 to 127 +/- 3 mm Hg (p less than 0.0005), associated with increased plasma renin activity (PRA) from 4.9 +/- 0.7 to 13.8 +/- 1.1 ng. ml-1.hr-1 (p less than 0.0005). Correlation of MAP with PRA yielded an r value of 0.662 (p less than 0.0005). Significant blood pressure elevation was obtained with both regular (R) and low sodium (LS) diet (p less than 0.0005), although the MAP change was greater with LS. With both R and LS diet, hypertension was associated with increased PRA (p less than 0.0005), and normotensive pressures were achieved with converting enzyme inhibitor (teprotide). The hemodynamic change with hypertension was an increase of systemic vascular resistance (SVR) from 0.89 +/- 0.12 to 1.17 +/- 0.09 units (p less than 0.05); cardiac output (CO) and central blood volume did not change significantly. Thus, acute hypertension, mediated by the RAS, was developed in a one-kidney primate model. The hemodynamic correlate of hypertension was increased SVR; CO and volume redistribution were not initiating factors.


Human immunodeficiency virus (HIV) transcripts identified in HIV-related psoriasis and Kaposi's sarcoma lesions.
Persons with HIV infection sometimes develop aggressive psoriasis or Kaposi's sarcoma (KS) not usually seen in other immunosuppressed patients. However, a specific and direct pathophysiological role for HIV-1 in these AIDS-associated disorders remains unclear since HIV has not been easily detected in these skin lesions. By combining in situ hybridization with the sensitive detection technique of confocal laser scanning microscopy, we have demonstrated HIV RNA transcripts in 5 of 15 lesional skin biopsies from HIV-infected psoriasis patients, and in 3 of 8 Kaposi's sarcoma biopsies from HIV-infected patients. HIV transcripts were not detected in normal appearing skin from HIV-infected patients or in psoriatic and normal skin biopsies from uninfected individuals (P = 0.006). Although previous attempts to demonstrate viral sequences in psoriasis and KS lesions have been unsuccessful, in situ hybridization with confocal microscopy has shown the presence of HIV RNA transcripts predominantly within CD4+, Factor XIIIa positive dermal dendrocytes. HIV or cytokines produced by infected cells in skin lesions may therefore play a direct role in the pathogenesis of HIV-associated psoriasis and KS.


[Prececal crude protein digestibility and absorption of amino acids from lupines in swine].
The apparent precaecal (pc) digestibility of crude protein (CP) and the apparent pc absorption of the key amino acids (AA) lysine, methionine, cystine, isoleucine, threonine and tryptophan from two yellow sweet lupine (L. luteus) varieties (Bornova, Borluta) and one narrow-leafed sweet lupine (L. angustifolius) were determined with ileorectostomized pigs. When the influence of the basal diet (barley or protein free rations) was checked with regard to absorption there were significant differences in a few cases only. In comparison to soybean meal (SBM) the methionine of the lupines was significantly worse, the cystine significantly better absorbed. The CP and the other key AA of the lupines showed approximately the same or even slightly higher pc absorption than those of SBM. With the example of the pc-absorbable AA amounts it was shown that sweet lupines with an approximately equally high CP content as in SBM cannot completely substitute the latter even after lysine and methionine supplementation because the absorbable tryptophan is by far insufficient, and isoleucine and threonine make up only 75% in comparison to SBM. On the basis of the content of pc-digestible CP and pc-absorbable AA it becomes possible to substitute high-grade imported protein concentrates according to their ability of AA supply in the feeding of pigs completely or partly by home-made protein feeds.


The Nurse Advocate in End-of-Life Care.
End-of-life nursing encompasses many aspects of care: pain and symptom management, culturally sensitive practices, assisting patients and their families through the death and dying process, and ethical decisionmaking. Advocacy has been identified as a key core competency for the professional nurse, yet the literature reveals relevant barriers to acquiring this skill. Challenges exist, such as limitations in nursing school curricula on the death and dying process, particularly in multicultural settings; differing policies and practices in healthcare systems; and various interpretations of end-of-life legal language. Patricia Benner's conceptual model of advocacy behaviors in end-of-life nursing provides the framework in which nurses can become effective patient advocates. Developing active listening and effective communication skills can enhance the nurse-patient trust relationship and create a healing environment.


A case of oropharyngeal bullous pemphigoid presenting with haemoptysis.
Objective. Bullous pemphigoid is well known for its cutaneous features; however in rare cases it may present with mucosal involvement. We report a case of bullous pemphigoid presenting with haemoptysis, initially presenting to the Ear, Nose and Throat Department for investigation. Methods. An 87-year-old lady was admitted with haemoptysis. She also complained of a spreading, pruritic, bullous rash, which first began three weeks previously. Initial investigations, which included nasendoscopy, revealed a normal nasal mucosa and a normal postnasal space. A large deroofed blister was observed on the soft palate. The presenting symptoms and signs raised the suspicion of an immunobullous disease including bullous pemphigoid. Conclusion. Bullous pemphigoid (BP) is a subepidermal immunobullous disease that typically manifests in elderly patient populations. Although rare, BP can present in a mucocutaneous fashion akin to its more aggressive variant, mucous membrane pemphigoid (MMP). Differentiation of the two is based on clinical grounds, with the prevailing feature for the latter being the predominance of mucosal involvement, which may be extensive. The mainstay of treatment for bullous pemphigoid is steroid therapy, which may be administered both topically and systemically. A deeper understanding into the pathophysiology of the various immunobullous diseases may assist in our understanding of how the various disease entities manifest themselves.


Influence of sumanene modifications with boron and nitrogen atoms to its hydrogen adsorption properties.
We investigate the influence of sumanene modifications on its adsorption properties towards the hydrogen molecule. The benzylic positions of sumanene were substituted with boron and nitrogen atoms, which changed its hydrogen storage properties. H2 binding energies were calculated using the LMP2, DFT and DFT-D3 approaches with several exchange-correlation functionals and the results indicate a physisorption mechanism. Physisorption was confirmed by fragment analysis and special attention was paid to non-covalent interactions. All non-covalent interactions, based on reduced density gradient surfaces, were identified and calculated for better understanding of the adsorption mechanism. Moreover, the significance of charge separation by inducing boron and nitrogen atoms is emphasized and special attention is paid to the z-component of the dipole moment of sumanene derivatives.


Deep learning of the splicing (epi)genetic code reveals a novel candidate mechanism linking histone modifications to ESC fate decision.
Alternative splicing (AS) is a genetically and epigenetically regulated pre-mRNA processing to increase transcriptome and proteome diversity. Comprehensively decoding these regulatory mechanisms holds promise in getting deeper insights into a variety of biological contexts involving in AS, such as development and diseases. We assembled splicing (epi)genetic code, DeepCode, for human embryonic stem cell (hESC) differentiation by integrating heterogeneous features of genomic sequences, 16 histone modifications with a multi-label deep neural network. With the advantages of epigenetic features, DeepCode significantly improves the performance in predicting the splicing patterns and their changes during hESC differentiation. Meanwhile, DeepCode reveals the superiority of epigenomic features and their dominant roles in decoding AS patterns, highlighting the necessity of including the epigenetic properties when assembling a more comprehensive splicing code. Moreover, DeepCode allows the robust predictions across cell lineages and datasets. Especially, we identified a putative H3K36me3-regulated AS event leading to a nonsense-mediated mRNA decay of BARD1. Reduced BARD1 expression results in the attenuation of ATM/ATR signalling activities and further the hESC differentiation. These results suggest a novel candidate mechanism linking histone modifications to hESC fate decision. In addition, when trained in different contexts, DeepCode can be expanded to a variety of biological and biomedical fields.


Norovirus gastroenteritis.
Recent epidemiologic studies have shown that norovirus is one of the most frequent causes of acute nonbacterial gastroenteritis. Reverse-transcription polymerase chain reaction and nucleotide sequencing are the means by which the hundreds of norovirus strains have been identified, named, and classified into genogroups and genetic clusters. They are also the means by which a particular strain is traced from the source of an outbreak throughout its spread. These molecular techniques have been combined with classic epidemiology to investigate norovirus outbreaks in diverse settings, including hospitals, nursing homes, dining locations, schools, daycare centers, and vacation venues. Outbreaks are difficult to control because of the apparent ease of transmission through food, water, person-to-person contact, and environmental surfaces. Almost all patients with norovirus gastroenteritis recover completely, but hospital and nursing home outbreaks have been associated with morbidity and mortality. The diagnostic and management approach to an individual patient is to use clinical and epidemiologic findings to rule out "not norovirus." At the first sign that there is an outbreak, strict compliance with cleaning, disinfection, and work release guidelines is important to prevent further spread.


Making mental health services affordable.
The prevalence of mental health problems is far more than what is perceived by the general public. The billions of dollars of lost productivity due to mental health problems and the affect of mental health on total health costs cannot be ignored.


Polyphenols Targeting MAPK Mediated Oxidative Stress and Inflammation in Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder, predominantly symmetric, which causes joint inflammation, cartilage degeneration and bone erosion, resulting in deformity and the loss of physical function. Although the management of RA has steadily improved, the pathophysiological mechanism is incompletely elucidated, and therapeutic options are still limited. Due to shortcomings in the efficacy or safety profiles of conventional RA therapies, therapeutic alternatives have been considered. Therefore, natural extracts containing polyphenolic compounds can become promising adjuvant agents for RA global management, due to their antioxidant, anti-inflammatory and apoptotic properties. Polyphenols can regulate intracellular signaling pathways in RA and can generate different immune responses through some key factors (i.e., MAPK, interleukins (ILs 1 and 6), tumor necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF-κB), and c-Jun N-terminal kinases (JNK)). The critical function of the Toll like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) signaling pathway in mediating the pathogenic characteristics of RA has been briefly discussed. Oxidative stress can trigger a change in transcription factors, which leads to the different expression of some genes involved in the inflammatory process. This review aims to provide a comprehensive perspective on the efficacy of polyphenols in mitigating RA by inhibiting signaling pathways, suggesting future research perspectives in order to validate their use.


The therapeutic effect of ALT-711 on erectile function in rats treated with high-level AGEs (advanced glycation end products) containing diet.
To investigate, if advanced glycation end products (AGEs) are involved in erectile dysfunction (ED) and also ALT-711, a cross-link breaker of AGEs, has the therapeutic potential against the development of ED in rats treated with high concentrated AGEs including food. For this purpose, 30 male Harlan Spraque-Dawley rats randomly were divided into three groups; (1) control rats treated with regular diet, (2) rats treated with high-level of AGE specific diet for 6 months, and (3) rats having AGE-diet treated with ALT-711 for the final 3 months of 6 months of AGE-diet period. Erectile response to cavernosal nerve stimulation (CNS), protein expression of neuronal nitric oxide synthase (nNOS) and levels of AGEs, Malondialdehyde (MDA), cyclic guanosine monophosphate (cGMP) were determined in penile tissues. Erectile responses to CNS and penile nNOS and cGMP content were significantly reduced, while AGEs and MDA were elevated in penises of Group-2. Treatment with ALT-711 reversed ED and depletion of both nNOS and cGMP. Additionally, ALT-711 treatment reduced penile tissue AGEs and MDA expression. In present study: rats without any co-morbidity such as diabetes mellitus (DM) and chronic renal failure (CRF) were treated with high-level AGEs containing food. Our results suggest that ALT-711 may be an interesting and promising approach in the treatment of AGEs-related ED.


SEQUOIA: significance enhanced network querying through context-sensitive random walk and minimization of network conductance.
Network querying algorithms provide computational means to identify conserved network modules in large-scale biological networks that are similar to known functional modules, such as pathways or molecular complexes. Two main challenges for network querying algorithms are the high computational complexity of detecting potential isomorphism between the query and the target graphs and ensuring the biological significance of the query results. In this paper, we propose SEQUOIA, a novel network querying algorithm that effectively addresses these issues by utilizing a context-sensitive random walk (CSRW) model for network comparison and minimizing the network conductance of potential matches in the target network. The CSRW model, inspired by the pair hidden Markov model (pair-HMM) that has been widely used for sequence comparison and alignment, can accurately assess the node-to-node correspondence between different graphs by accounting for node insertions and deletions. The proposed algorithm identifies high-scoring network regions based on the CSRW scores, which are subsequently extended by maximally reducing the network conductance of the identified subnetworks. Performance assessment based on real PPI networks and known molecular complexes show that SEQUOIA outperforms existing methods and clearly enhances the biological significance of the query results. The source code and datasets can be downloaded from http://www.ece.tamu.edu/~bjyoon/SEQUOIA .


Utilization of central disk of blastoderm and germinal crescent region for production of interspecific germline chimera between chicken and quail.
The production of interspecific germline chimeras between chicken and quail were attempted employing the dissociated cells derived from the blastodermal central disk (stage X) and the germinal crescent region of embryo (stage 7-8). The central disk (CD) of the area pellucida in chicken blastoderm (stage X) and the germinal crescent region (GCR) of embryo (stage 7-8) were dispersed and injected into the subgerminal cavity of quail blastoderm (stage X). Injected eggs were incubated for 7 days or to hatching. The donor chicken DNA was detected by the polymerase chain reaction. In day-7 embryos, chicken DNA was detected in 5 gonads and 9 brains from 53 survived embryos received chicken CD cells, and 1 gonads and 6 brains from 27 survived embryos received chicken GCR. Chicken DNA was also detected from the semen of one adult male hatched from eggs received chicken GCR cells. CD and GCR cells as the donors showed the possibility to produce the interspecific germline chimera, but further studies are needed to make necessary improvement.


Concomitant fibromyalgia in primary Sjögren's syndrome in the French ASSESS cohort: comparison of the ACR 1990 and ACR 2016 criteria, FiRST questionnaire and physician's opinion.
Dryness, fatigue, and pain are classic symptoms in primary Sjögren's syndrome (pSS) but are also common in fibromyalgia (FM). We compared the characteristics of FM assessed by different criteria (American College of Rheumatology (ACR) 2016 and 1990 criteria), physician's opinion and Fibromyalgia Rapid Screening Tool (FiRST) questionnaire) in a cohort of patients with pSS. Eight hospital departments tested 134 patients with pSS according to AECG criteria from the Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. FM was present in 19%, 18%, 20%, and 29% of cases according to ACR 2016, ACR 1990 criteria, physician's opinion and the FiRST questionnaire, respectively. FM criteria-positive patients had higher EULAR SS Patient-Reported Index (ESSPRI) score, but not higher EULAR SS Disease Activity Index (ESSDAI) score. The objective measurements of dryness and the use of corticosteroids and immunosuppressive drugs did not differ between FM positive and negative patients. Regarding the ESSPRI dryness and fatigue subscale scores, depression and anxiety scores and the use of anxiolytics and antidepressants, the FiRST questionnaire exhibited a higher difference between positive and negative patients than ACR 2016 criteria. ACR 1990 and physician's opinion were somewhere in the middle. ACR 2016 exhibited moderate agreement with ACR 1990 (κ=0.52) and the physician's opinion (κ=0.60) and poor agreement with FiRST (κ=0.39). The FM criteria identified pSS patients with higher ESSPRI scores but not higher ESSDAI systemic disease scores. Agreement between the different FM criteria was moderate, and the characteristics they described did not fully coincide.


Estimating Burdens of Neglected Tropical Zoonotic Diseases on Islands with Introduced Mammals.
Many neglected tropical zoonotic pathogens are maintained by introduced mammals, and on islands the most common introduced species are rodents, cats, and dogs. Management of introduced mammals, including control or eradication of feral populations, which is frequently done for ecological restoration, could also reduce or eliminate the pathogens these animals carry. Understanding the burden of these zoonotic diseases is crucial for quantifying the potential public health benefits of introduced mammal management. However, epidemiological data are only available from a small subset of islands where these introduced mammals co-occur with people. We examined socioeconomic and climatic variables as predictors for disease burdens of angiostrongyliasis, leptospirosis, toxoplasmosis, toxocariasis, and rabies from 57 islands or island countries. We found strong correlates of disease burden for leptospirosis, Toxoplasma gondii infection, angiostrongyliasis, and toxocariasis with more than 50% of the variance explained, and an average of 57% (range = 32-95%) predictive accuracy on out-of-sample data. We used these relationships to provide estimates of leptospirosis incidence and T. gondii seroprevalence infection on islands where nonnative rodents and cats are present. These predicted estimates of disease burden could be used in an initial assessment of whether the costs of managing introduced mammal reservoirs might be less than the costs of perpetual treatment of these diseases on islands.


Induction of cell death in rat brain by a gliotoxic factor from cerebrospinal fluid in multiple sclerosis.
The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients contains a 17 kDa glycoproteic factor with gliotoxic properties in vitro. In order to study the physiopathological role of this gliotoxic factor in vivo, we have injected a partially purified preparation and appropriate controls in rat CSF and investigated whether it induces cell death in the rat central nervous system (CNS), 10 days and 3 months after injection. We used the TUNEL assay in association with specific immunohistochemistry to characterize dying cells in the gliotoxic factor- treated rat CNS. At 10 days post-injection, TUNEL-positive cells were observed in the whole rat CNS. They were particularly numerous in the choroid plexus, ependymal epithelium, cerebral white matter, cerebral vascular endothelium, arachnoid spaces and less frequent in the gray matter of brain and spinal cord. The predominant type of TUNEL-positive cells observed at 10 days post-injection was astrocytes, in white matter, gray matter, occasionnally around damaged endothelial cells in periventricular and subpial spaces. Other TUNEL-positive cells were identified as oligodendrocytes by an oligodendrocyte specific RIP immunostaining, at 10 days post-treatment with the gliotoxic factor. Interestingly, demyelination and death of oligodendrocytes were more important 3 months post-injection: TUNEL-RIP positive oligodendrocytes were generally associated with multifocal demyelinating areas. Clearly, the 17 kDa gliotoxic factor injection in rat CSF triggers demyelination and may be used as a new animal model for MS. Also, our results suggest a new possible scenario for MS pathogenesis: death of oligodendrocytes and astrocytes, stimulated by the MS gliotoxic factor causes the breakdown of the blood-brain barrier (BBB) and the demyelinating cascade.


Perspectives on state vaccine education mandate policy and implementation among public health department officials: a qualitative study.
In response to the increase in non-medical vaccine exemptions (NME), many states have adopted education mandates (EM), required vaccine education for parents requesting NMEs for their school-age children, but these EMs vary greatly in implementation. In order to learn about the administrative aspects of each state's EM, we interviewed fourteen health department officials from nine states with EMs. Interviews were conducted over the phone, transcribed by a professional transcription service, and double-coded using NVivo 12 by two members of the study staff. The coding resulted in 3698 comments overall, 98.5% inter-coder reliability, and a κ statistic of 0.691. We found no consistent format for content delivery, and methods used included in-person dialogs, web-based education, and video modules. Content of the education is not standardized, and education length ranges from 15 to 60 minutes. Four major themes about the EM policies emerged: (1) the use of EMs to eliminate "convenience exemptions;" (2) the importance of health department communication with health-care providers; (3) facilitators and barriers to implementation; and (4) the positive recommendation for other states to adopt EM policies. We concluded that current EM implementation varies greatly, but officials in states which have adopted EMs for parents requesting NMEs for school-entry vaccinations overwhelmingly recommend other states to adopt them as well. Key features of successful programs may include conversations with parents requesting NMEs and strong communication channels with health-care providers. Systematic tracking of vaccine status after exemption requests and education is necessary to quantitatively determine the effectiveness of EM programs.


Carbon monoxide-releasing molecule-2 enhances coagulation and diminishes fibrinolytic vulnerability in diluted plasma in vitro.
A carbon monoxide-releasing molecule (tricarbonyldichlororuthenium (II) dimer; CORM-2) enhances coagulation and attenuates vulnerability to fibrinolysis in normal and hemophiliac human plasma. We tested the hypothesis that plasma diluted with resuscitative fluids would demonstrate improved coagulation and decreased fibrinolytic vulnerability after exposure to CORM-2. Normal, platelet-poor plasma was diluted 0%, 20%, 30%, 40%, or 50% with 0.9% NaCl (NS) or low-molecular-weight hydroxyethyl starch (VOL) and, subsequently, exposed to 0 μmol/L or 100 μmol/L CORM-2 before activation with tissue factor (n = 4 per condition). Additional plasma samples diluted with NS or VOL (0% or 30%) were exposed to 0 μmol/L or 100 μmol/L CORM-2 and 0 U/mL or 100 U/mL tissue-type plasminogen activator to assess fibrinolytic vulnerability (n = 8 per condition). Thrombelastographic data were collected until either clot strength stabilized or clot lysis occurred, as appropriate. CORM-2 exposure maintained normal to supranormal velocity of clot formation and strength in plasma diluted up to 40% with NS. In contrast, although CORM-2 exposure improved coagulation kinetics, dilution with VOL markedly degraded thrombus formation kinetics. Similarly, fibrinolytic vulnerability to tissue-type plasminogen activator was markedly improved by CORM-2 exposure in samples diluted with NS, whereas VOL-diluted thrombi were still abnormally weak and easily lysed compared with undiluted samples despite CORM-2 exposure. CORM-2 exposure attenuated the decrease in coagulation kinetics and enhancement of fibrinolytic vulnerability associated with hemodilution. Extensive preclinical investigation remains to be performed to determine the route of administration, safety, and efficacy of CORM-2 and other CORMs to treat trauma-associated bleeding.


Filter-feeders have differential bottom-up impacts on green and brown food webs.
Nutrient recycling by consumers can strongly impact nutrient availability for autotrophic and heterotrophic microbes, thus impacting functions such as primary production and decomposition. Filter-feeding freshwater mussels form dense, multispecies assemblages in aquatic ecosystems and have been shown to play a critical role in nutrient cycling. Mussel excretion can enhance benthic primary production and influence algal species composition. However, the role of mussels in brown or detritus-based food webs and species-specific differences has received considerably less attention. Here, using mesocosm experiments, we assessed how three species of freshwater mussels that occupy three different phylogenetic tribes influenced benthic algal accrual, ecosystem metabolism, cotton strip decomposition, leaf litter (Acer saccharum) decomposition, and litter-associated fungal biomass measured as ergosterol. Additionally, we measured mussel excretion and biodeposition rates and assessed the stoichiometry (C:N, C:P, and N:P) of the benthic algae, cotton strips, and leaf litter. In comparison to controls without mussels, generally, mussel treatments had higher benthic algal biomass composed of more diatoms, higher gross primary productivity and net ecosystem production rates, and higher cotton strip tensile strength loss, but there was not a difference in ecosystem respiration rates, leaf litter decomposition rates, or fungal biomass. Benthic algae had lower C:N and higher N:P in mussel treatment tanks and cotton strip C:N was lower in mesocosms with mussels. Our results suggest that nutrient regeneration by mussels most strongly regulates green food webs, with some impacts to brown food webs, suggesting that consumers have interactive effects on microbial functioning in freshwaters.


We must teach more effectively: here are four ways to get started.
Research on how people learn shows that teaching using active learning is more effective than just lecturing. We outline four concrete ways instructors can begin to apply active learning in their teaching: backward instruction design; expecting students to learn more than facts; posing "messy" problems for students to solve; and expecting students to talk, write, and collaborate. Each tactic is supported with references demonstrating its efficacy and advice and links to resources for getting started with active learning.


Cytokine profiles and virological markers highlight distinctive immune statuses, and effectivenesses and limitations of NAs across different courses of chronic HBV infection.
The characteristics of cytokine/chemokine(CK) profiles across different courses of chronic hepatitis B virus infection and the effects of NAs antiviral therapy on cytokine profiles remain unclear. This report provides evidence from 383 patients with chronic HBV infection. The Luminex multiple cytokine detection technology was used to detect CK profiles. The predictive power of CKs across course of disease was assessedusing univariate analyses and with receiver operating characteristic (ROC) curves. Compared to healthy control (HC), expression levels of interleukin 6 (IL)-6, IL-8, IL-21, matrix metalloproteinases (MMP)-2 and tumor necrosis factor receptor (TNFR)-1 showed a significant increasing trend during chronic HBV infection. IL-23 and IL-33 increased respectively in chronic hepatitis B patients (CHB). interferon (IFN)-gamma and TNF-α changed significantly only in liver cirrhosis (LC) patients. Whereas, myeloid-related markers decreased dramatically in those with hepatocellular carcinoma (HCC). The ROC result suggests that combining IL-6, IL-8, CXCL9 and CXCL13 into a nomogram has closely correlation with HCC during chronic HBV infection. In addition, nucleotide analogues (NAs) antiviral treatments are capable of recoveringnormal liver functions and significantly reducing the viral loads, however, they seem to have a limited effect in changing CKs, especially specific antiviral factors. The differential CK and virological markers may serve as potential indicators of distinct immune statuses in chronic HBV infection. They also underscore the varying efficacy and limitations of NAs antiviral therapies. This next step would to break new ground in the optimization of current anti-HBV treatment programs although this requires further research.


Prevalence of pulmonary tuberculosis on the roof of the world.
The Shimshal Valley, a remote village in Northern Pakistan, is one of the seven Pamirs of Central Asia, widely known as the roof of the world. To investigate the prevalence of pulmonary tuberculosis (TB) in the Shimshal Valley. The Rapid Village Survey Method (RVS) was used to investigate the prevalence of pulmonary tuberculosis. The selection criteria were chronic cough, hemoptysis, past history of TB and close contact with a tuberculous patient. After clinical examination, a chest radiograph was done and a single spot sputum sample was obtained for smear examination. The total population of the village was 1077, of whom 231 cases were studied. Overcrowding affected 75% of the study population. The prevalence of smear positive pulmonary TB in the village studied was 554 per 100000 population, and the prevalence of active smear-negative TB was estimated at 1949/100 000. The prevalence of active pulmonary TB increased with age and the only risk factor for active TB was age over 45 years. Of the 21 cases with a past history of pulmonary TB, only 38% had completed a full course of chemotherapy. Pulmonary TB is a very serious health issue in the rural community (Shimshal Valley) of Pakistan. This study highlights the lack of efficacy of national tuberculosis control programs in the country.


The severity of herpes simplex viral keratitis in mice does not reflect the severity of disease in humans.
Four herpes simplex type 1 virus (HSV) isolates were selected from patients with mild ocular disease and four from patients with severe ocular disease on the basis of the number of epithelial recurrences, presence or absence of stromal disease, visual acuity, and the need for corneal transplantation. The scarified right corneas of 20 BALB/c mice were inoculated with each low-passage HSV isolate (1.0 x 10(7) plaque-forming units/ml) and examined three times per week for 2 weeks for the presence and severity of epithelial and stromal disease. The eight individual virus isolates differed with respect to the incidence of dendritic disease (P less than 0.001), the severity of dendritic disease (P less than 0.001), the incidence of stromal disease (P = 0.002), and the severity of stromal disease (P = 0.001) they produced in the mouse. The severity of disease was compared for the two groups of viruses: (1) those that had caused mild disease in their human hosts and (2) those that had caused severe disease. There were no statistically significant differences in the severity or incidence (44 versus 43 animals, respectively) of dendritic disease or stromal disease (27 of 80 animals in each group) between the two groups. These data suggest that the naive BALB/c mouse model of acute HSV keratitis after topical ocular inoculation does not reflect clinically significant differences in the severity of human HSV keratitis that might be caused by variations in the virus genome.


Palliative thoracic radiotherapy for lung cancer: a systematic review.
The optimal dose of radiotherapy (RT) to palliate symptomatic advanced lung cancer is unclear. We systematically reviewed randomized controlled trials (RCTs) of palliative thoracic RT. RCTs comparing two or more dose fractionation schedules were reviewed using the random-effects model of a freely available information management system. The relative risk and 95% CI for each outcome were presented in Forrest plots. Exploratory analysis comparing dose schedules after conversion to the time-adjusted biologically equivalent dose (BED) was performed to investigate for a dose-response relationship. A total of 13 RCTs involving 3,473 randomly assigned patients were identified. Outcomes included symptom palliation, overall survival, toxicity, and reirradiation rate. For symptom control in assessable patients, lower-dose (LD) RT was comparable with higher-dose (HD), except for the total symptom score (TSS): 65.4% of LD and 77.1% of HD patients had improved TSS (P = .003). Greater likelihood of symptom improvement was seen with schedules of 35 Gy(10) versus lower BED. At 1 year after HD and LD RT, 26.5% versus 21.7% of patients were alive, respectively (P = .002). Sensitivity analysis suggests this survival improvement was seen with 35 Gy(10) BED schedules compared with LDs. Physician-assessed dysphagia was significantly greater in the HD arm (20.5% v 14.9%; P = .01), and the likelihood of reirradiation was 1.2-fold higher after LD RT. No significant differences were observed for specific symptom-control end points, although improvement in survival favored HD RT. Consideration of palliative thoracic RT of at least 35 Gy(10) BED may therefore be warranted, but must be weighed against increased toxicity and greater time investment.


[Complications of tracheal intubation in pediatrics].
To describe the frequency and types of tracheal intubation complications and their main causes. Cross sectional study of patients who were submitted to tracheal intubation for more than 24 hours at the Pediatric ICU of Santa Casa de Misericórdia de São Paulo, between May 1998 and December 1999. Exclusion criteria were previous intubations, surgeries or traumas in the cervical region or oropharynx. A study of 147 patients with ages varying from 1 month to 15 years and 3 months was carried out. An inadequate tracheal tube had been used in 31.3% of patients submitted to tracheal intubation and 14.3% needed 5 or more attempts to achieve intubation. Resident physicians had more difficulty with intubation. Most tracheal intubation attempts were related to increased traumas, hypoxia, bradycardia and worsening of the Downes score after extubation. Accidental extubation was observed in 21.8%, related to worsening in the score of Downes and need for reintubation. The resident physicians also caused a higher number of traumas and bradycardia. Most complications may be attributed to lack of experience and training of the physician performing the tracheal intubation. We should implement training programs and increase supervision during tracheal intubation to minimize these outcomes.


Endonuclease activity on damaged DNA in rat regenerating liver.
The activity of an endonuclease(s) acting on double-stranded, ultraviolet-irradiated, and 2-acetylaminofluorene-bound DNA but not on double-stranded undamaged DNA triples within two hr after partial hepatectomy. Although the activity drops between four and six hr after operation, it remains above levels measured in livers of nonhepatectomized rats until 36 hr after operation. Between 36 and 48 hr after operation, the enzyme activity drops below the levels in liver of nonhepatectomized rats and then rises slowly to reach levels observed in nonhepatectomized animals between 48 hr and seven days after the operation. Studies on the effect of actinomycin on the activity of crude enzyme and on the incorporation of [14C]leucine and [14C]valine on the purified enzyme indicate that the increase in enzyme activity results from de novo synthesis. Eight % of endonucleolytic activity detectable in the crude homogenate is inhibited by an hyperimmune serum prepared against the purified enzyme. By adjusting the time of injection of 2-[14C]acetylaminofluorene with respect to the levels of enzyme activity after partial hepatectomy, an inverse correlation between binding and enzyme activity was demonstrated.


Validation of the Human Arm Stiffness Estimation Method Developed for Overground Physical Interaction Experiments.
To build a physically interactive robot for overground applications, it is crucial to first understand the biomechanics of humans underlying overground physical human-robot interaction (pHRI) tasks. Estimating human arm stiffness during overground interactive tasks is a promising first step toward this goal. For this, an arm stiffness estimation technique was developed in our previous works that consider the unique challenges involving overground pHRI, such as the need to estimate the arm stiffness from a short duration of data with fewer repetitions. In this work, our stiffness estimation method is further validated with a passive spring setup with known stiffness values, as well as with a human experiment setup that resembles the widely used seated reaching tasks. Results show that our method can estimate the passive spring stiffness within 0.5% of error. We also show that the human arm stiffness measured through our method is comparable to those reported in well-known literature. In addition, our method was able to discern experimental conditions such as early vs. late trials or differences in arm movement conditions. Implications of these results are discussed further.Clinical Relevance- This method can aid the design and development of overground interactive robots for human movement assistance and rehabilitation.


Teratology in Mexico. 19th Century.
It was not until the last third of the 19th century, the period in which, according to historiography, the country definitely inserted itself into modernity, that anomalies and monstrosities had a presence in Mexico. Therefore, what I present here are four moments of teratology in Mexico, four dates in which I try to recount how teratology, which still occupied a marginal place within the main themes of national science, not only reached to cover the realm of medical discussions at the time, but also laid the foundations for new disciplines like biology and anthropology.


Association of Temperament With Preoperative Anxiety in Pediatric Patients Undergoing Surgery: A Systematic Review and Meta-analysis.
Preoperative anxiety is associated with poor behavioral adherence during anesthetic induction and adverse postoperative outcomes. Research suggests that temperament can affect preoperative anxiety and influence its short- and long-term effects, but these associations have not been systematically examined. To examine the associations of temperament with preoperative anxiety in young patients undergoing surgery. Studies from MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched from database inception to June 2018. All prospective studies reporting associations of temperament with preoperative anxiety were included. Overall, 43 of 5451 identified studies met selection criteria. Using the PRISMA guidelines, reviewers independently read 43 full-text articles, extracted data on eligible studies, and assessed the quality of each study. Data were pooled using the Lipsey and Wilson random-effects model. Primary outcome was the association of temperament with preoperative anxiety in patients undergoing surgery. A total of 23 studies, with 4527 participants aged 1 to 18 years, were included in this review. Meta-analysis of 12 studies including 1064 participants revealed that emotionality (r = 0.11; 95% CI, 0.04 to 0.19), intensity of reaction (r = 0.29; 95% CI, 0.11 to 0.46), and withdrawal (r = 0.40; 95% CI, 0.23 to 0.55) were positively associated with preoperative anxiety, whereas activity level (r = -0.23; 95% CI, -0.31 to -0.16) was negatively correlated with preoperative anxiety. Impulsivity was not significantly associated with preoperative anxiety. This systematic review and meta-analysis provided evidence suggesting that temperament may help identify pediatric patients at risk of preoperative anxiety and guide the design of prevention and intervention strategies. Future studies should continue to explore temperament and other factors influencing preoperative anxiety and their transactional effects to guide the development of precision treatment approaches and to optimize perioperative care.


Comparing the trabecular outflow by the response to topical pilocarpine in patients with and without glaucoma filtering surgery.
To compare the trabecular outflow by the response to topical pilocarpine administration in patients with and without prior glaucoma filtering surgery. Prospective, cross-sectional, randomized, double-blinded study. Open-angle glaucoma (OAG) patients without any prior glaucoma surgery, and those with prior trabeculectomy or tube shunt surgery aged 18-90 years were included. Both groups were randomized into pilocarpine or artificial tears (ATs). Intraocular pressure (IOP) was measured before and 90 min after the instillation of eye drops. A total of 189 eyes of 189 patients were included: 92 eyes in the pilocarpine and 97 eyes in the ATs group. There was a mean ± standard deviation of - 0.81 ± 3.08 mmHg decrease in IOP with pilocarpine in those without prior surgery, significantly higher than the ATs group (0.55 ± 2.31 mmHg; p = 0.02). No significant change in IOP with pilocarpine was noted in the surgical group compared to the ATs group (p = 0.90). In the surgery group, greater IOP reduction was observed with pilocarpine in those who had undergone surgery within the last three years than those who had surgery three or more years prior (- 1.56 ± 2.64 versus 1.41 ± 2.77 mmHg; p = 0.001). Less IOP reduction was observed with pilocarpine in patients who had filtering surgery more than three years previously compared to those with more recent surgery.


Vitamin E and mast cells.
Mast cells play an important role in the immune system by interacting with B and T cells and by releasing several mediators involved in activating other cells. Hyperreactivity of mast cells and their uncontrolled accumulation in tissues lead to increased release of inflammatory mediators contributing to the pathogenesis of several diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and allergic disorders such as asthma and allergic rhinitis. Interference with mast cell proliferation, survival, degranulation, and migration by synthetic or natural compounds may represent a preventive strategy for the management of these diseases. Natural vitamin E covers a group of eight analogues-the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols, but only alpha-tocopherol is efficiently retained by the liver and distributed to peripheral tissues. Mast cells preferentially locate in the proximity of tissues that interface with the external environment (the epithelial surface of the skin, the gastrointestinal mucosa, and the respiratory system), what may render them accessible to treatments with inefficiently retained natural vitamin E analogues and synthetic derivatives. In addition to scavenging free radicals, the natural vitamin E analogues differently modulate signal transduction and gene expression in several cell lines; in mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration. In this chapter, the possibility that vitamin E can prevent diseases with mast cells involvement by modulating signal transduction and gene expression is evaluated.


Changes in platelet calcium concentration by thromboxane A2 stimulation in patients with nephrotic syndrome of childhood.
In order to examine the intracellular thromboxane A2 (TXA2) signal transduction system in platelets of patients with nephrotic syndrome, we measured the levels of TXA2 metabolites in urine and blood and platelet calcium ion level as a result of STA2, an analog of STA2 (9,11-dimethylmethano-11,12-methano-TXA2) stimulation, and obtained the following results: (1) In pediatric patients with nephrotic syndrome, urinary thromboxane B2 (TXB2) and 11-dehydro-TXB2 excretion were signficantly higher in the onset and relapse groups compared to the remission and control groups. (2) The blood 11-dehydro-TXB2 level in the onset group was significantly higher than those in the remission and control groups. (3) Platelet calcium concentrations due to STA2 stimulation were significantly increased in the onset, relapse and remission groups compared to the control group. These findings suggest activation of the TXA2 signal transduction system in platelets of pediatric patients with nephrotic syndrome.


Inhibitory Effect of Piceatannol on TNF-α-Mediated Inflammation and Insulin Resistance in 3T3-L1 Adipocytes.
Piceatannol, a bioactive component in grape and blueberry, was examined for its potential in decreasing the inflammatory activities in adipocytes using a cocultured adipocyte and macrophage system, and suppressing tumor necrosis factor-α (TNF-α)-mediated inflammation and the related insulin resistance using a 3T3-L1 adipocyte model. Piceatannol at 10 μM significantly reduced the release of inflammatory cytokines of TNF-α and monocyte chemoattractant protein-1 (MCP-1) by 19 and 31% in the cocultured system, respectively. Pretreatment with piceatannol also inhibited TNF-α-induced expression of interleukin-6 (IL-6) and MCP-1 at both mRNA and protein levels in the 3T3-L1 adipocytes. Piceatannol also partially improved the malfunction of insulin-stimulated glucose uptake, which was reduced by TNF-α in 3T3-L1 adipocytes. Furthermore, the inhibitions were mediated by significant blocking of IκBα phosphorylation and nuclear factor-κB (NF-κB) activation through suppressing nuclear translocation of NF-κB p65 along with c-Jun N-terminal kinase (JNK)-mitogen activated protein kinase (MAPK) activation. In addition, the Akt-dependent forkhead box O1 (FoxO1) signaling pathway was involved in the restoration of insulin-stimulated glucose uptake through suppressing the down-regulation of phosphorylation of Akt and FoxO1 expressions. These results suggested the potential of piceatannol in improving chronic inflammatory condition and insulin sensitivity in obese adipose tissues.


Haemophilus influenzae and the complement system.
The respiratory tract pathogen Haemophilus influenzae is responsible for a variety of infections in humans including septicemia, bronchitis, pneumonia, and acute otitis media. The pathogenesis of H. influenzae relies on its capacity to resist human host defenses including the complement system, and thus H. influenzae has developed several efficient strategies to circumvent complement attack. In addition to attracting specific host complement regulators directly to the bacterial surface, the capsule, lipooligosaccharides, and several outer membrane proteins contribute to resistance against complement-mediated attacks and hence increased bacterial survival. Insights into the mechanisms of complement evasion by H. influenzae are important for understanding pathogenesis and for developing vaccines and new therapies aimed at patients with, for example, chronic obstructive pulmonary disease. Here we overview current knowledge on the different mechanisms by which H. influenzae evades attack by the host complement system.


[Ampiphilic creams. 1. study of formation and consistency].
Ambiphilic type creams were prepared and their consistency was investigated by rheological method. It was established, that a surfactant named Emulgator BTO formed ambifilic character in the case of given portion of oil- and water phases. The type of ambiphilic creams and the values of structural viscosity were changed after the dilution with water or oil.


Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy.
To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (> or = 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping. Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.


Tryptophan biosynthesis in the marine luminous bacterium Vibrio harveyi.
Tryptophan biosynthetic enzyme levels in wild-type Vibrio harveyi and a number of tryptophan auxotrophs of this species were coordinately regulated over a 100-fold range of specific activities. The tryptophan analog indoleacrylic acid evoked substantial derepression of the enzymes in wild-type cells. Even higher enzyme levels were attained in auxotrophs starved for tryptophan, regardless of the location of the block in the pathway. A derepressed mutant selected by resistance to 5-fluorotryptophan was found to have elevated basal levels of trp gene expression; these basal levels were increased only two- to threefold by tryptophan limitation. The taxonomic implications of these and other biochemical results support previous suggestions that the marine luminous bacteria are more closely related to enteric bacteria than to other gram-negative taxa.


Smartphone applications for pain management.
Smartphone applications (or apps) are becoming increasingly popular. The lack of regulation or guidance for health-related apps means that the validity and reliability of their content is unknown. We have conducted a review of available apps relating to the generic condition of pain. The official application stores for five major smartphone platforms were searched: iPhone, Android, Blackberry, Nokia/Symbian and Windows Mobile. Apps were included if they reported a focus on pain education, management or relief, and were not solely aimed at health-care professionals (HCPs). A total of 111 apps met the inclusion criteria. The majority of apps reviewed claimed some information provision or electronic manual component. Diary tracking of pain variables was also a common feature. There was a low level of stated HCP involvement in app development and content. Despite an increasing number of apps being released, the frequency of HCP involvement is not increasing. Pain apps appear to be able to promise pain relief without any concern for the effectiveness of the product, or for possible adverse effects of product use. In a population often desperate for a solution to distressing and debilitating pain conditions, there is considerable risk of individuals being misled.


[Mutagenic action of static electric fields on Drosophila melanogaster females].
The effect of the 24-hours' action of 1500 v/cm and 3300 v/cm static electric fields (SEF) on the non-disjunction and sex-linked recessive lethal mutations in Drosophila melanogaster females was studied. Both SEFs increased the frequency of sex-linked recessive lethals, that was shown to be independent of the boltage of the field. The action of SEF exerted on effect on the frequency of non-disjunction of X-chromosomes.


Black Women with Multiple Sex Partners: The Role of Sexual Agency.
Motivations of low-income substance using heterosexual Black women in New York City for having multiple sexual partners are explored in this paper. Analysis of in-depth interviews with 50 study participants demonstrates that their relationships consisted of those who had: (1) a main sex partner and a secondary sex partner; or (2) two or more "casual" partners. Individual-level motivations for extra relational sex fell into four dominant themes: sexual pleasure, partner infidelity, sex exchange and past main partners. Using a Black feminist framework, we describe how participants displayed considerable autonomy by actively forming and withdrawing from sexual relationships with men. However, women described low rates of condom use with main partners and inconsistent use of condoms with more casual sexual partners. This contradiction becomes an important area for sexual health interventions. Women who had sexual relations with only one current mate in the past two years were recruited as a monogamous comparison group.


The formation of amyloid-like fibrils of α-chymotrypsin in different aqueous organic solvents.
The formation of amyloid-like fibrils of α-chymotrypsin was studied in aqueous ethanol, methanol, tertbutanol, dimethylformamide and acetonitrile. Thioflavin T (ThT), Congo red (CR) and 1-anilino-8-naphthalenesulfonic acid (ANS) binding, turbidity, intrinsic fluorescence and far-UV circular dichroism measurements were employed to characterize the amyloid fibril formation. The greatest extent of fibril formation after incubation for 24 h at pH 7.0 and at 24 °C was in ethanol at 55%, in methanol and dimethylformamide (DMF) at 60-70% and in tert-butanol at 60-80%. The ANS binding and intrinsic fluorescence results showed that the hydrophobic residues are more solvent-exposed in the aggregated form of α-chymotrypsin. The ThT, CR binding and far-UV CD measurements indicated that the formation of the cross-β structure of α-chymotrypsin depends on the polarity of the organic solvent. To determine the role of surface charges in the aggregation, chemically modified forms of α-chymotrypsin were prepared. The citraconylated and succinylated enzymes exhibited a higher and the enzyme forms modified with aliphatic aldehydes a lower propensity for aggregation. These results suggest the important role of surface charges in the aggregation of α-chymotrypsin.


Melanocortin crosstalk with adipose functions: ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes.
The melanocortin (MC) system is a pivotal component of the hypothalamo-pituitary-adrenal (HPA) stress axis and plays an important role in the pathogenesis of obesity and the metabolic syndrome. Adipose dysfunction is implicated in the pathogenesis of these disorders. We investigated direct ACTH effects on adipose functions in immortalised murine white and brown adipocytes. MC receptor types 2 and 5 were expressed at the mRNA and protein levels and were strongly up-regulated during differentiation. Chronic ACTH stimulation did not affect adipogenesis. Insulin-induced glucose uptake in white adipocytes was acutely and transiently reduced by 45% upon ACTH treatment. Visfatin and adiponectin gene expression was reduced by about 50% in response to ACTH, while interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were acutely up-regulated by 2100 and 60% respectively. Moreover, IL-6 secretion was increased by 1450% within 4 h of ACTH treatment. In brown adipocytes, stimulation with ACTH caused a 690% increase in uncoupling protein (UCP)-1 mRNA levels within 8 h, followed by a 470% increase in UCP-1 protein concentrations after 24 h. Consistently, p38 mitogen-activated protein kinase (MAPK) phosphorylation was acutely increased by 1800% in response to ACTH stimulation, and selective inhibition of p38 MAPK abolished the ACTH-mediated UCP-1 protein increase. Taken together, ACTH acutely promotes an insulin-resistant, pro-inflammatory state and transiently enhances energy combustion. In conditions characterised by a dysregulation of the HPA stress axis such as the metabolic syndrome, direct MC interaction with adipocytes may contribute to dysregulated energy balance, insulin resistance and cardiometabolic complications.


Control and prevention of tuberculosis: a code of practice.
The Joint Tuberculosis Committee has compiled a report that is designed to answer the questions most commonly asked about the control and prevention of tuberculosis. Advice is given on assessing the degree of infectivity and on the segregation of patients. The measures necessary to protect National Health Service workers depend on the risk of exposure, and health authorities should follow the advice given by the Department of Health and Social Security. Chest x ray examinations may be recommended for those entering the teaching profession and may be necessary for staff and children when tuberculosis is discovered in a school child. The diagnostic, protective, and therapeutic measures required for contacts depend on the degree of infectivity in the index case, the closeness of contact, and the ethnic group of the index case. The incidence of tuberculosis is much higher among some immigrant populations than among the native population and screening programmes are needed (a) to detect cases of active tuberculosis, (b) to identify infected individuals without active disease, and (c) to identify those in need of vaccination. Finally, the current recommendation that BCG vaccinations should be offered routinely in schools to children aged 10-14 has been highly effective in preventing tuberculosis and should be maintained.


Morphine 6beta glucuronide: fortuitous morphine metabolite or preferred peripheral regulatory opiate?
Morphine-6beta-glucuronide (M6G), a metabolite of morphine that the brain can produce, is an opiate agonist that appears to have a greater analgesic potency than morphine. M6G has a 1-octanol/water partition coefficient 187 times lower than that of morphine and M6G has a blood brain barrier permeability 57 times lower than morphine. The brain uptake rate however is only 32 times lower, suggesting that an active transport mechanism might be present. Furthermore, evidence for a distinct receptor for M6G also appears to be emerging. Real time polymerase chain reactions allowed for the discovery of single nucleotide polymorphisms (SNP's) in the human mu opioid receptor gene. The most common SNP is a substitution at base118 where A is replaced with G (A118G). This SNP has a decreased potency for M6G in individuals possessing it whereas the potency of morphine is unaffected by this SNP. The possibility that a peripheral opiate signaling system, using M6G and its distinct receptor, exists seems plausible. Taken together, if a distinct M6G signaling mechanism does exist, the fact that morphine can be converted into a more water soluble compound that might be more potent would not be an accident.


Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: a 6-month, masked, multicenter trial.
To compare the safety and intraocular pressure (IOP)-lowering efficacy of once-daily travoprost (0.0015% and 0.004%) to twice-daily timolol 0.5%. Prospective, 6-month, randomized, controlled, multicenter, double-masked, phase III study. Six hundred five patients with open-angle glaucoma or ocular hypertension. Patients with an 8 AM IOP between 24 to 36 mmHg in at least one eye (the same eye) at two eligibility visits received either travoprost 0.0015%, travoprost 0.004% (dosed every day), or timolol 0.5% (dosed twice daily). Mean IOP at 8 AM, 10 AM, and 4 PM in the patient's eye with the higher baseline IOP. The mean IOP was significantly lower for both concentrations of travoprost compared with timolol. Travoprost was statistically superior to timolol at 9 of 13 visits, with differences in IOP reductions ranging from 0.9 to 1.8 mmHg (0.0015%) and 10 of 13 visits with differences in IOP reductions from 0.9 to 2.4 mmHg (0.004%). Mean IOP changes from baseline ranged from -6.0 to -7.5 mmHg (0.0015%), -6.5 to -8.0 mmHg (0.004%), and -5.2 to -7.0 mmHg for timolol. Hyperemia was experienced at rates of 29.2% (59 of 202) for travoprost 0.0015%, 42.8% (86 of 201) for travoprost 0.004%, and 8.9% (18 of 202) for timolol. Iris pigmentation changes were observed in 1.0% (2 of 200) of patients receiving travoprost 0.004% with no changes noted in the travoprost 0.0015% group or the timolol group. A decrease in pulse and systolic blood pressure was observed in the timolol group. There were no other clinically relevant or statistically significant changes from baseline in ocular signs or laboratory values, and no serious, related, unexpected adverse events were reported for any group. Travoprost (0.0015% and 0.004%), dosed once daily in the evening, is statistically superior or equal to timolol 0.5% dosed twice daily at all treatment visits during this 6-month study. IOP reductions of up to 2.0 mmHg greater than timolol were found in the travoprost 0.004% pooled data group. Travoprost is safe and well tolerated in patients with open-angle glaucoma or ocular hypertension.


The long terminal repeat of the intracisternal A particle as a target for transactivation by oncogene products.
It has been shown recently that the c-mos oncogene becomes activated in myeloma XRPC-24 via insertion of an intracisternal A particle (IAP) long terminal repeat (LTR). The inserted LTR serves as a promoter from which transcription of the 3' rearranged c-mos initiates. The insertion is in a head-to-head orientation such that the transcriptional orientations of the IAP and the 3' rearranged c-mos are opposite. It has already been shown that this IAP LTR has two promoters, one transcribing the IAP genome and the other transcribing the rearranged c-mos. Since the IAP genomes are actively transcribed in mouse myelomas but not in normal cells, it was interesting to test whether transcriptional activation of the IAP occurs in the presence of active oncogene products, especially nuclear ones. The 5' LTR of the IAP inserted in myeloma XRPC-24 was chosen as a convenient model to test the effect of viral and cellular oncogene products. These included simian virus 40 (SV40) large-T antigen, the adenovirus early 1A (E1A) gene product, the myc gene product, and p53. The LTR was coupled to the bacterial gene coding for chloramphenicol acetyltransferase (CAT) in two orientations, and the levels of CAT directed by the LTR promoters were assayed in either the presence or the absence of the oncogene products. The levels of CAT directed by the 5' LTR promoter transcribing the IAP were significantly elevated in the presence of SV40 large-T antigen, the adenovirus E1A and myc gene products, and p53. The promoter transcribing the rearranged c-mos was transactivated by SV40 large-T antigen and the adenovirus E1A gene product. The results indicate that oncogene products may have an important role in turning on promoters of other genes. The IAP LTR may serve as a useful model for studying the effect of various gene products on promoters which are known to be activated in the malignant state.


Nano-Assemblies from J-Aggregated Dyes: A Stimuli-Responsive Tool Applicable To Living Systems.
Controlling the packing arrangements of dyes is a facile way of tuning their photophysical and/or photochemical properties, thus enabling new sensing mechanisms for photofunctional tools. Here, we present a general and robust strategy toward water-stable J-aggregated dye-templated nanoassemblies by incorporating an amphiphilic diblock copolymer and a stimuli-responsive dye as the only two building components. An iodo-substituted boron dipyrromethene (BODIPY) was adopted as a template to direct the self-assembly of poly(ethylene glycol)- block-polycaprolactone (PEG-PCL), forming a core-shell nanoplate with slip-stacked BODIPYs as core surrounded by hydrophilic PEG shell. The self-assembled nanoplate is stable in cell culture medium and possesses a built-in stimuli-responsiveness that arises from BODIPY bearing meso-carboxylate protecting group, which is efficiently removed upon treatment with peroxynitrite. The resulting negative charges lead to rearrangement of dyes from J-stacking to nonstacking, which activates photoinduced singlet oxygen production from the nanoassemblies. The stimuli-activatable photosensitivity has been exploited for specific photodynamic ablation of activated RAW 264.7 cells with excessive endogenous peroxynitrite. In light of the generality of the sensing mechanism, the concept described herein will significantly expand the palette of design principles to develop diverse photofunctional tools for biological research and clinical needs.


A comparison of the clinical performance of students in two grading systems: letter and pass-fail.
The effects of letter and pass-fail grading systems on student performance have been little tested in the clinical setting. Thus, the present experiment was conducted to compare (1) the clinical performance of dental hygiene students in the two grading systems, and (2) student impressions regarding the effects of each grading system on performance. Performance was defined as the number of errors detected at the completion of three scaling/polishing procedures. Student impressions were assessed using a two-question, posttest questionnaire. Dental hygiene students (N = 19) in their first semester of patient care experiences were randomly assigned to letter and pass-fail groups. At the end of six months, the mean performances of the two groups were compared using the Student's t-test. Student impressions were compared using the Mann-Whitney test. No difference in clinical performance was detected between the two groups (p = .702), with a high level of performance demonstrated by both groups (about four total errors). Significant differences in student impressions were found, with the pass-fail subjects perceiving both types of grades as less important and less motivating to clinical performance than the letter subjects (p less than .05). These findings imply that a similar level of performance can occur with either grading system in the clinical setting. However, a pass-fail system may be more appropriate, since (1) it may motivate more task interest in clinical activities, and (2) the use of letter grades is more problematic. If further studies demonstrate similar results, dental hygiene educators should seriously consider implementation of pass-fail systems in the clinical setting.


Comparison of the chemical, physical, and survival properties of normal and Z-variant alpha-1-antitrypsins.
A procedure has been developed for the purification of Z-type alpha-1-antitrypsin (alpha-1-AT) which is rapid, gentle, and results in good yields. From 4 units (750 ml) of fresh human plasma, obtained from two individuals possessing the Pizz phenotype, 53 mg of pure Z-type alpha-1-AT was obtained. The preparation was homogeneous by the criteria of polyacrylamide gel electrophoresis, both in the presence and absence of sodium dodecyl sulfate, and by analytical ultracentrifugation. When compared to pure alpha-1-AT from plasma of individuals possessing the normal PiMM phenotype, the two proteins were indistinguishable with respect to amino acid composition, sedimentation coefficient (s20w of 3.33 for both M and Z), molecular weight (51,000 by sodium dodecyl sulfate gel electrophoresis and 47,000 by sedimentation equilibrium for both M and Z), and trypsin-combining ratio (0.91 for Z and 0.99 for M). The only difference which was observed between the variant forms of alpha-1-AT was in the carbohydrate composition. The Z-type alpha1-AT contains between 20 and 25% less carbohydrate than the M-type alpha-1-AT. Specifically, the Z-type alpha-1-AT is deficient in 1 glucosamine residue, 3 neutral sugar residues (1 mannose and 2 galactose), and 2 sialic acid residues. Although the Z-variant is deficient in sialic acid, its survival time in the serum of a rabbit was not significantly different from that of M-type alpha-1-AT.


Hereditary red cell membrane disorders and laboratory diagnostic testing.
This overview describes two groups of nonimmune hereditary hemolytic anemias caused by defects in membrane proteins located in distinct layers of the red cell membrane. Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP) represent disorders of the red cell cytoskeleton. Hereditary stomatocytoses represents disorders of cation permeability in the red cell membrane. The current laboratory screening tests for HS are the osmotic fragility test, acid glycerol lysis time test (AGLT), cryohemolysis test, and eosin-5'-maleimide (EMA)-binding test. For atypical HS, SDS-polyacrylamide gel electrophoresis of erythrocyte membrane proteins is carried out to confirm the diagnosis. The diagnosis of HE/HPP is based on abnormal red cell morphology and the detection of protein 4.1R deficiency or spectrin variants using gel electrophoresis. None of screening tests can detect all HS cases. Some testing centers (a survey of 25 laboratories) use a combination of tests (e.g., AGLT and EMA). No specific screening test for hereditary stomatocytoses is available. The preliminary diagnosis is based on presenting a compensated hemolytic anemia, macrocytosis, and a temperature or time dependent pseudohyperkalemia in some patients. Both the EMA-binding test and the osmotic fragility test may help in differential diagnosis of HS and hereditary stomatocytosis.


Proton beam radiotherapy for esophagus cancer: state of the art.
The majority of esophageal cancer patients are diagnosed with locoregionally confined disease, which is often amenable to curative intent therapy. Chemoradiotherapy (CRT) improves overall survival (OS) in stage II and III esophagus cancer in the neoadjuvant and definitive settings. Due to the close proximity of organs at risk (OARs), including lungs, heart, stomach, bowel, kidneys, and spinal cord, esophageal CRT can result in profound acute and late toxicities. Acute toxicities can include esophagitis, nausea, vomiting, fatigue, and cytopenias. Late complications may also occur months or years after completion of thoracic radiotherapy, including significant cardiac, pulmonary, liver, kidney, or bowel toxicities, which can be life-threatening or fatal. Photon-based radiotherapy exposes OARs to significant doses of radiation, whereas proton beam therapy (PBT) has unique physical properties, as it lacks an exit dose. This allows PBT to deliver, a more conformal dose to the target and minimize the volume of OARs exposed to radiation. This dosimetric advantage may portend an increased therapeutic ratio of CRT for esophagus cancer. The objective of this review is to discuss the evolution of photon and proton-based radiotherapy techniques, rationale, dosimetric and clinical studies comparing outcomes of photon- and proton-based techniques, ongoing prospective trials, and future directions of PBT as a means of reducing toxicity and improving oncologic outcomes for patients with esophagus cancer.


Activity of water in aqueous systems; a frequently neglected property.
In this critical review, the significance of the term 'activity' is examined in the context of the properties of aqueous solutions. The dependence of the activity of water(l) at ambient pressure and 298.15 K on solute molality is examined for aqueous solutions containing neutral solutes, mixtures of neutral solutes and salts. Addition of a solute to water(l) always lowers its thermodynamic activity. For some solutes the stabilisation of water(l) is less than and for others more than in the case where the thermodynamic properties of the aqueous solution are ideal. In one approach this pattern is accounted for in terms of hydrate formation. Alternatively the pattern is analysed in terms of the dependence of practical osmotic coefficients on the composition of the aqueous solution and then in terms of solute-solute interactions. For salt solutions the dependence of the activity of water on salt molalities is compared with that predicted by the Debye-Hückel limiting law. The analysis is extended to consideration of the activities of water in binary aqueous mixtures. The dependence on mole fraction composition of the activity of water in binary aqueous mixtures is examined. Different experimental methods for determining the activity of water in aqueous solutions are critically reviewed. The role of water activity is noted in a biochemical context, with reference to the quality, stability and safety of food and finally with regard to health science.


Distract yourself: prediction of salient distractors by own actions and external cues.
Distracting sensory events can capture attention, interfering with the performance of the task at hand. We asked: is our attention captured by such events if we cause them ourselves? To examine this, we employed a visual search task with an additional salient singleton distractor, where the distractor was predictable either by the participant's own (motor) action or by an endogenous cue; accordingly, the task was designed to isolate the influence of motor and non-motor predictive processes. We found both types of prediction, cue- and action-based, to attenuate the interference of the distractor-which is at odds with the "attentional white bear" hypothesis, which states that prediction of distracting stimuli mandatorily directs attention towards them. Further, there was no difference between the two types of prediction. We suggest this pattern of results may be better explained by theories postulating general predictive mechanisms, such as the framework of predictive processing, as compared to accounts proposing a special role of action-effect prediction, such as theories based on optimal motor control. However, rather than permitting a definitive decision between competing theories, our study highlights a number of open questions, to be answered by these theories, with regard to how exogenous attention is influenced by predictions deriving from the environment versus our own actions.


Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway.
All bactericidal antibiotics were recently proposed to kill by inducing reactive oxygen species (ROS) production, causing destabilization of iron-sulfur (Fe-S) clusters and generating Fenton chemistry. We find that the ROS response is dispensable upon treatment with bactericidal antibiotics. Furthermore, we demonstrate that Fe-S clusters are required for killing only by aminoglycosides. In contrast to cells, using the major Fe-S cluster biosynthesis machinery, ISC, cells using the alternative machinery, SUF, cannot efficiently mature respiratory complexes I and II, resulting in impendence of the proton motive force (PMF), which is required for bactericidal aminoglycoside uptake. Similarly, during iron limitation, cells become intrinsically resistant to aminoglycosides by switching from ISC to SUF and down-regulating both respiratory complexes. We conclude that Fe-S proteins promote aminoglycoside killing by enabling their uptake.


Pharmacological mechanism of topical lodoxamide treatment in vernal keratoconjunctivitis: a flow-cytometric study.
The aim of this study was to investigate the possible effect of lodoxamide 0.1% ophthalmic solution (LOS) on tear T lymphocytes, especially Th2 (T helper 2 subgroup of helper T lymphocytes), in the tear specimens of patients with vernal keratoconjunctivitis (VKC) and to explore the mechanism of the anti-allergic effect of this drug. Twenty-eight active VKC patients were randomly divided into two groups each containing 14 patients. We obtained tear samples from all patients at the beginning of the study. LOS was prescribed to the study group (group A), but the controls (group B) received placebo over the course of 6 weeks. Tear samples were also collected from all patients following a 6-week course of treatment with either LOS or placebo. The percentages of Th1, Th2 and Th cells in the tear samples were measured by using a flow-cytometric technique and the results were compared to each other by using Wilcoxon matched-pairs signed-rank and Mann-Whitney U tests. We found that LOS treatment decreased the percentages of Th2 and Th cells in the tears of group A patients, while placebo had no effect on these values. Th1 cell count in the tears of both groups of patients did not show any significant change between the pre- and posttreatment stages. Our data suggest that LOS exerts, at least, some part of its anti-allergic effect via decreasing the Th2 cell number in the tears of VKC patients.


Possible Relation between Marine Fungi and Limnoria Attack on Submerged Wood.
Wood submerged in the sea at Friday Harbor and at Naples contained only occasional hyphae, which showed no relationship to Limnoria burrows. Cultures of Limnoria established in "unconditioned" wood and in autoclaved wood were maintained in the absence of fungi. These results indicate that marine fungi have no significance for the activities of Limnoria.


Computed tomographic findings of dogs with cubital joint lameness.
The purpose of this study was to identify the incidence of abnormal computed tomography (CT) findings in dogs with lameness of one or both elbows. CT examinations of 102 elbows in 51 dogs were reviewed individually and by group consensus by 3 examiners and graded for various abnormalities. Frequently encountered abnormalities included abnormal shape and sclerosis of the medial coronoid process of the ulna, irregularity of the radial incisure of the ulna, and ulnar trochlear notch sclerosis. Other abnormalities included distinct/separate or fissure/in situ fragmentation of the medial coronoid; lucency of the radial incisure; ununited anconeal process; sclerosis, lucency, or flattening of the medial aspect of the humeral condyle; osteophyte formation; and joint incongruity. In conclusion, CT of the canine cubital joint is useful in identification of various lesions beyond simple fragmentation of the medial coronoid process of the ulna.


Efficient frequency doubling at 399 nm.
We describe a reliable, high-power, and narrow-linewidth laser source at 399 nm, which is useful for cooling and trapping of ytterbium atoms. A continuous-wave titanium-sapphire laser at 798 nm is frequency doubled using a lithium triborate crystal in an enhancement cavity. Up to 1.0 W of light at 399 nm has been obtained from 1.3 W of infrared light, with an efficiency of 80%.