Novel immune check point inhibiting antibodies in cancer therapy-Opportunities and challenges.
Drug resistance of tumor cells to chemotherapy is limiting the therapeutic efficacy of most anticancer drugs and represents a major obstacle in medical oncology. However, treatment of various human malignancies with biologics, mostly monoclonal antibodies (mAbs), is not limited by such chemoresistance mechanisms. However, other resistance or evasion mechanisms limit the efficacy to anticancer therapeutic mAbs that engage tumor-associated antigens on the surface of the malignant cells. Immune checkpoint blocking monoclonal antibodies are heralded as a promising therapeutic approach in clinical oncology. These mAbs do not directly attack the malignant cells as most anticancer mAbs; rather, they enhance the anti-tumor response of the immune system by targeting immune regulatory pathways. Three mAbs targeting immune checkpoint molecules are currently used in the clinic and new mAbs that target other potential inhibitory targets are being actively investigated. This therapeutic approach, while proving as highly beneficial for many patients, is prone to toxicities and side effects of an autoimmune nature. Defining suitable management algorithms and biomarkers that predict therapeutic effects and adverse toxicity are required to provide survival benefit for larger numbers of cancer patients. Overcoming these challenges, along with opportunities for new agents and combinatorial strategies are the main focus of immune checkpoint blockade research today.


Heterozygote carrier testing in high schools abroad: what are the lessons for the U.S.?
The main value of carrier detection in the general population is to determine reproductive risks. In this manuscript I examine the practice of providing carrier screening programs in the school setting. While the data show that high school screening programs can achieve high uptake, I argue that this may reflect a lack of full understanding about risks, benefits, and alternatives, and the right not to know. It may also reflect the inherent coercion in group testing, particularly for adolescents who are prone to peer pressure. The problem of carrier screening in the schools is compounded when the condition has a predilection for certain groups based on race, ethnicity or religion. I examine programs around the world that seek to test high school students for Tay Sachs and Cystic Fibrosis carrier status. I argue that carrier programs should be designed so as to minimize stigma and to allow individuals to refuse. The mandatory school environment cannot achieve this. Rather, I conclude that screening programs should be designed to attract young adults and not adolescents to participate in a more voluntary venue.


Photodynamic inactivation of bacteria: Why it is not enough to excite a photosensitizer.
The development of multidrug resistance (MDR) in infectious agents is one of the most serious global problems facing humanity. Antimicrobial photodynamic therapy (APDT) shows encouraging results in the fight against MDR pathogens, including those in biofilms. Photosensitizers (PS), monocationic methylene blue, polycationic and polyanionic derivatives of phthalocyanines, electroneutral and polycationic derivatives of bacteriochlorin were used to study photodynamic inactivation of Gram-positive and Gram-negative planktonic bacteria and biofilms under LED irradiation. Zeta potential measurements, confocal fluorescence imaging, and coarse-grained modeling were used to evaluate the interactions of PS with bacteria. PS aggregation and photobleaching were studied using absorption and fluorescence spectroscopy. The main approaches to ensure high efficiency of bacteria photosensitization are analyzed. PS must maintain a delicate balance between binding to exocellular and external structures of bacterial cells and penetration through the cell wall so as not to get stuck on the way to photooxidation-sensitive structures of the bacterial cell.


Production of monozygotic mouse twins from microsurgically bisected morulae.
Mouse monozygotic twins were produced by bisection of the compacted morulae and transfer of the pairs of half-embryos after culture in vitro. The compacted morulae (about 16 cells) were microsurgically bisected, using a fine glass needle attached to a micromanipulator, without any supporting micro-instruments, after pretreatment for zona-softening and decompaction. About 80% of the morulae were bisected without visible cell damage. After 20 h in culture, the half-embryos were classified morphologically as eu-blastocysts, pseudo-blastocysts, or trophectodermal vesicles or non-integrated forms. After culture of 131 pairs of bisected morulae, 75 (57.3%) pairs of eu-blastocysts, 20 (15.3%) pairs comprising a eu-blastocyst and pseudo-blastocyst, and 9 (6.9%) pairs of pseudo-blastocysts, were obtained. The pseudo-blastocysts were considered to be derived from half-morulae in which some blastomeres were destroyed or dissociated as a result of micromanipulation. From 30 pairs of eu-blastocysts transferred to 21 recipients, 5 twin fetuses on Day 17 (18 pairs/9 recipients) and 3 twin male young (12 pairs/12 recipients) were obtained. Survival rate of the twin-embryo pairs was 27.8% at autopsy and 25.0% at term. None of the 20 pairs of pseudo-blastocysts transferred to 10 recipients gave rise to normal conceptuses.


Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma.
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.


Pyogenic granuloma: A tumor that mimics infection.
This article describes a patient whose cutaneous pyogenic granuloma was mistaken for infection after injury from a fractured smartphone screen. Clinicians should suspect pyogenic granuloma in patients with these types of injuries so that patients can avoid unnecessary procedures, antibiotics, and discomfort.


[The median functional slope of the tibia. Principle. Technique of measurement. Value. Interest].
The tibial slope is an important datum in knee surgery; the levelling by a uni- or bicompartmental prosthesis preserving both cruciate ligaments requires to maintain this slope. The postoperative rehabilitation of the A.C.L. plasties, especially those performed with a patellar tendon and the surgical cure of a genu recurvatum, must integrate this notion. Even if the anatomical slopes are usable in prosthetic surgery, they do not seem precise enough in the field of A.C.L. and tibia recurvatum surgery. In these indications, the authors propose to determine the functional tibial slope defined as being the complement of the angle formed by the tangent to the tibial medial plateau and the lateral mechanical axis of the leg. Measured to an average of 7 degrees on 238 knees, the average median functional slope cannot be deduced from anatomical slopes; it must be measured on a lateral teleradiographic view of the lower limb, the knee being in full extension and X-rayed in true posterior and inferior lateral view.


A novel DNA nucleotide in Trypanosoma brucei only present in the mammalian phase of the life-cycle.
The existence of an unusual form of DNA modification in the bloodstream form of the African trypanosome Trypanosoma brucei has been inferred from partial resistance to cleavage of nuclear DNA with PstI and PvuII (Bernards et al, 1984; Pays et al, 1984). This putative modification is correlated with the shut-off of telomeric Variant-specific Surface Glycoprotein (VSG) gene expression sites (ESs). The modification only affects inactive VSG genes with a telomeric location, and it is absent in procyclic (insect form) trypanosomes in which no VSG is made at all. Previous attempts to detect unusual nucleosides in T.brucei DNA were unsuccessful, but we now report the detection of two unusual nucleotides, called pdJ and pdV, in T.brucei DNA, using the 32P-postlabeling technique. Nucleotide pdV was present in both bloodstream form and procyclic T.brucei DNA and co-migrated in two different two-dimensional thin layer chromatography (2D-TLC) systems with hydroxymethyldeoxyuridine 5'-monophosphate (pHOMedU). In contrast, nucleotide pdJ was exclusively present in bloodstream form trypanosomal DNA. Levels of pdJ were higher in DNA enriched for telomeric sequences than in total genomic DNA and pdJ was also detected in other Kinetoplastida species exhibiting antigenic variation. Postlabeling and 2D-TLC analyses showed base J to be different from the known eukaryotic unusual DNA bases 5-methylcytosine, N6-methyladenine and hydroxymethyluracil, and also from (glucosylated) hydroxymethylcytosine, uracil, alpha-putrescinylthymine, 5-dihydroxypentyluracil and N6-carbamoylmethyladenine. We conclude that pdJ is a novel eukaryotic DNA nucleotide and that it is probably responsible for the partial resistance to cleavage by PvuII and PstI of inactive telomeric VSG genes. It may therefore be involved in the regulation of ES activity in bloodstream form trypanosomes.


An optogenetic toolbox of LOV-based photosensitizers for light-driven killing of bacteria.
Flavin-binding fluorescent proteins (FPs) are genetically encoded in vivo reporters, which are derived from microbial and plant LOV photoreceptors. In this study, we comparatively analyzed ROS formation and light-driven antimicrobial efficacy of eleven LOV-based FPs. In particular, we determined singlet oxygen (1O2) quantum yields and superoxide photosensitization activities via spectroscopic assays and performed cell toxicity experiments in E. coli. Besides miniSOG and SOPP, which have been engineered to generate 1O2, all of the other tested flavoproteins were able to produce singlet oxygen and/or hydrogen peroxide but exhibited remarkable differences in ROS selectivity and yield. Accordingly, most LOV-FPs are potent photosensitizers, which can be used for light-controlled killing of bacteria. Furthermore, the two variants Pp2FbFP and DsFbFP M49I, exhibiting preferential photosensitization of singlet oxygen or singlet oxygen and superoxide, respectively, were shown to be new tools for studying specific ROS-induced cell signaling processes. The tested LOV-FPs thus further expand the toolbox of optogenetic sensitizers usable for a broad spectrum of microbiological and biomedical applications.


Blunt renal trauma-blessing in disguise?
The purpose of this study was to quantify pathologic lesions of the kidney found incidentally during the workup of a blunt renal trauma. A retrospective review of the medical records of 103 patients ages 0 to 18 years with blunt renal injuries admitted to a level 1 pediatric trauma center between January 1, 1991 and December 31, 1999 was performed. All patients underwent ultrasonography and Doppler of their renal vessels. Additional investigations with computed tomography (CT) scan, cystography, or nuclear medicine functional studies were performed as indicated. Coexisting urogenital lesions were identified in 13 of 103 (12.6%) patients reviewed, and 7 (54%) required surgical treatment. The majority of the patients (9 of 13, 69%) suffered minimal trauma. All patients presented with gross hematuria as their main symptom. Stenosis of the uretero-pelvic junction was the most frequent diagnosis (n = 7): 3 patients required uretero-pyeloplasty, and 3 required nephrectomy. Two heterogeneous renal masses were discovered in which the diagnosis of a malignant process could not be eliminated; elective resection and open biopsy were performed. The diagnoses of multicystic kidney and solitary cyst with complex hematoma, respectively, were confirmed on pathology. Grade III ureterovesical reflux with pyelonephritis (n = 1), polycystic kidney (n = 1), extrarenal pelvis without obstruction (n = 1), and horseshoe kidney (n = 1) were the other lesions discovered. Pathologic lesions of the urinary tract are uncommon; however, they may complicate an otherwise negligible renal trauma. The diagnostic and therapeutic approach to blunt renal trauma must be modified in these cases. A high index of suspicion must be maintained when a patient presents with gross hematuria with a minimal force blunt abdominal trauma.


Transformation of rat fibroblasts by cloned defective polyoma DNA.
Defective polyoma DNA molecules isolated from mouse cells infected with high-multiplicity-passaged virus were cloned in pBR322, and the recombinant plasmids were tested for their capacity to transform Fischer rat 3T3 cells in culture. Recombinants carrying an intact proximal portion of the early region, i.e., the region coding for both small and middle T antigens, were able to induce the transformed phenotype. A recombinant plasmid containing a defective polyoma genome with a deletion of about 300 base pairs in the region coding for the C-terminal segment of middle T antigen failed to transform.


Reproductive outcomes of women and men born very preterm and/or with a very low birth weight in 1983: a longitudinal cohort study in the Netherlands.
The aims of this study were to analyze reproductive outcomes of women and men born very preterm (gestational age <32 weeks) or with a very low birth weight (<1500 g) in 1983 in the Netherlands and to compare their reproductive outcomes with the total population at a similar age of 28 years. Young adults who were born after a pregnancy complicated by very preterm (VP) delivery or with a very low birth weight (VLBW) in the Netherlands in 1983 (Project on Preterm and Small for Gestational Age Infants (POPS) cohort) were invited to complete an online questionnaire at the age of 28. In total, 293 POPS-28 participants (31.6%) completed the questionnaire including 185 female and 108 male participants. Female and male participants who were born VP or with a VLBW had significant reduced reproductive rates compared to the total Dutch population at 28 years of age (female 23.2 vs 31.9% and male 7.4 vs 22.2%). Pregnancies of the female participants were in 14% complicated by preterm delivery in at least one pregnancy. This study indicates that women and men born VP or with a VLBW have reduced reproductive rates at the age of 28 compared to the total Dutch population at a similar age.


Future directions in sex- and Gender-specific Emergency Medicine.
The 2014 Academic Emergency Medicine (AEM) consensus conference "Gender-Specific Research in Emergency Medicine: Investigate, Understand, and Translate How Gender Affects Patient Outcomes" convened a diverse group of stakeholders to target gaps in emergency medicine (EM) sex- and gender-specific research and identify research priorities. At the close of the conference, the executive committee sought feedback from group leaders and conference attendees about the next critical steps in EM sex- and gender-specific research, goals for their own future research, and anticipated barriers in pursuing this research. This article summarizes this feedback on the future directions in sex- and gender-specific research in emergency care and strategies to overcome barriers.


Clinicopathological features of cystic lesions in the eyelid.
The aim of the present study was to investigate the clinicopathological features of cystic lesions in the eyelid. Clinicopathological profiles were retrospectively searched based on medical records of 35 patients with cystic lesions of the eyelids, which were surgically resected from January 2003 to June 2016. The cohort consisted of 16 men and 19 women. The mean age of the patients was 57±24 years. The main locations of the cysts were the upper eyelid in 22 patients, followed by the lower eyelid in 5 patients. Eyelid skin and its appendages were the most common as the origin of cysts, followed by the tarsus, palpebral conjunctiva and lacrimal gland. The histopathological diagnoses were 16 epidermal cysts, 5 intratarsal keratinous cysts, 3 conjunctival cysts, 2 trichilemmal cysts, 1 dermoid cyst, 1 apocrine hidrocystoma, 1 lacrimal gland cyst and 6 unclassifiable cysts. All cysts did not recur following resection. In summary, cystic lesions of the eyelid were frequently observed in the upper eyelid. The most frequent diagnoses were epidermal cysts, followed by intratarsal keratinous cysts, while a definitive diagnosis in some cysts could not be pathologically determined, as they lacked epithelia and/or the contents or they resembled apocrine hidrocystoma and intratarsal keratinous cysts with atypical findings. The results of the current study indicate that the incidence and differential diagnosis of eyelid cystic lesions may contribute to the application of appropriate treatment for patients with eyelid tumors.


The importance of age and menopausal status in endometrial complex hyperplasia with atypia.
The effects of menopausal status and age on the intra-operative and post-operative pathology results of patients operated on with a pre-operative diagnosis of complex hyperplasia with atypia (CHA) were assessed. A hundred and eleven patients diagnosed in our centre between January 1993 and March 2013 were included. Cancer was detected in the paraffin blocks (PBs) of 52 (46.8%) patients. Among these, 50 patients had stage-IA disease. In 31.1% of the pre-menopausal patients and 66% of the post-menopausal patients, PB revealed cancer (p < 0.0001). The results of frozen section (FS) and PB were concordant in 51% and 70% in the pre-menopausal and post-menopausal patients, respectively (p = 0.041). In the patients operated on with a pre-operative diagnosis of CHA, the probability of detecting cancer in PB increases with increasing age and menopause. The reliability of FS is limited in younger and pre-menopausal patients.


Cardiac transplantation: a comprehensive nursing perspective. Part 1.
Orthotopic cardiac transplantation has become the treatment of choice for selected patients with end-stage heart disease. Proliferation of cardiac transplantation centers and relaxed selection criteria have resulted in increasing populations of transplant candidates and recipients. As these numbers continue to grow, so too do the numbers of nursing personnel who must respond to the intricacies and demands of cardiac transplantation. Nursing care begins with physiologic and psychologic support of a patient with terminal cardiac disease and continues throughout the transplantation evaluation, waiting, surgical, postoperative, and outpatient periods. In addition to routine postsurgical care, the nurse involved in cardiac transplantation needs to be familiar with the function of a denervated heart, as well as with the effects of unbalanced immunosuppression and immunocompetence. The surge of organ transplantation in the last several years has brought about administrative concerns regarding the financial impact of increasing numbers of transplantations, as well as an inadequate supply of necessary donor organs. This critical shortage of suitable donors demands that nurses and other health care professionals become active in enlarging the donor organ pool by identifying potential organ donors, maintaining optimal hemodynamics and oxygenation so as to ensure organ viability, and providing emotional support of the grieving family.


Pharmacologic modulation of acute ocular inflammation with quercetin.
Anti-inflammatory potentials of a safe, common dietary component, quercetin, were investigated in suppression of intraocular inflammation induced by retinal S antigen. Lewis rats sensitized to S antigen were treated daily with intraperitoneal injections of quercetin. Control rats with S-antigen-induced uveitis were similarly treated with diluent. When compared with controls the treated group showed marked reduction in uveal and retinal inflammation and in vasculitis and perivasculitis. Morphometric analysis revealed a significant reduction (p less than 0.005) in choroidal thickness when compared with that of control animals. These results clearly show the antiphlogistic effects of quercetin in experimental uveitis.


Origin of symptoms in chronic heart failure.
Skeletal muscle abnormalities are highly prevalent in chronic heart failure and are associated with an increase in the ergoreflex, a muscle reflex stimulated by work done. Stimulation of the ergoreflex results in increased ventilation and contributes to the increased sympathetic activation of the heart failure syndrome. The origin of the skeletal myopathy is related to a chronic imbalance between catabolic and anabolic processes, presumably as a consequence of chronic haemodynamic stress. Symptoms arise from the skeletal myopathy, causing the sensation of fatigue and contributing to the sensation of breathlessness as the myopathy affects respiratory muscle. Ergoreflex activation causes a greater ventilatory response to exercise than normal, contributing to the sensation of breathlessness.


Medication therapy management services in community pharmacy: a pilot programme in HIV specialty pharmacies.
Pharmacist-provided medication therapy management services (MTMS) have been shown to increase patient's adherence to medications, improve health outcomes and reduce overall medical costs. The purpose of this study was to describe a pilot programme that provided pharmacy-based MTMS for patients with HIV/AIDS in the state of California, USA. Pharmacists from the 10 pilot pharmacies were surveyed using an online data collection tool. Information was collected to describe the types of MTMS offered, proportion of patients actively using specific MTMS, pharmacist beliefs regarding effect on patient outcomes and barriers to providing MTMS, ability to offer MTMS without pilot programme funding and specialized pharmacist or staff training. Each responding pharmacy (7 of 10) varied in the number of HIV/AIDS patients served and prescription volume. All pharmacists had completed HIV/AIDS-related continuing education programmes, and some had other advanced training. The type of MTMS being offered varied at each pharmacy with 'individualized counselling by a pharmacist when overuse or underuse was detected' and 'refill reminders by telephone' being actively used by the largest proportion of patients. Most, but not all, pharmacists cited reimbursement as a barrier to MTMS provision. Pharmacists believed the MTMS they provide resulted in improved satisfaction (patient and provider), medication usage, therapeutics response and patient quality of life. The type of MTMS offered, and proportion of patients actively using, varied among participating pilot pharmacies.


[Patient readmission for surgical site infection: integrative review].
Surgical site infections (SSI) represent an inherent risk after surgical procedures associated both to the surgical procedure and to the patient clinical conditions. To analyze in an integrative review the studies related to patient readmission due to SSI. The review was carried out by LILACS, CINHAL, MEDLINE and COCHRANE databases and articles published from 1966 to 2010 were selected. It was analyzed 13 studies classified as transversal (7), cohort (4) and longitudinal (2). Few studies analyzed only the readmissions related to the SSI. Time to define the readmission ranged from 28 to 90 days after surgery and studies related to orthopedic procedures were more frequent. The ISS readmission rates were lower than 5%. The main aetiological agents isolated from ISS were Staphylococcus aureus and coagulase-negative staphylococci. Monitoring readmissions due to SSI could contribute to dimension the occurrence of ISS post-discharge, once about half of the SSI post-discharge was diagnosed at the readmission moment.


The bovine neutrophil: Structure and function in blood and milk.
Migration of polymorphonuclear neutrophil leukocytes (PMN) into the mammary gland provide the first line of defense against invading mastitis pathogens. Bacteria release potent toxins that activate white blood cells and epithelial cells in the mammary gland to secrete cytokines that recruit PMN that function as phagocytes at the site of infection. While freshly migrated PMN are active phagocytes, continued exposure of PMN to inhibitory factors in milk such as fat globules and casein, leads to altered PMN morphology and reduced phagocytosis. In the course of phagocytosing and destroying invading pathogens, PMN release chemicals that not only kill the pathogens but that also cause injury to the delicate lining of the mammary gland. This will result in permanent scarring and reduced numbers of milk secretory cells. The life span of PMN is limited by the onset of apoptosis. To minimize damage to mammary tissue, PMN undergo a specialized process of programmed cell death known as apoptosis. Macrophages quickly engulf and phagocytose apoptotic PMN, thereby minimizing the release of PMN granular contents that are damaging to tissue. The PMN possess an array of cell surface receptors that allow them to adhere and migrate through endothelium and to recognize and phagocytose bacteria. One receptor found on phagocytes that is receiving considerable attention in the control of infections by Gram-negative bacteria is CD14. Binding of lipopolysaccharide (LPS) to membrane bound CD14 causes release of tumor necrosis factor-alpha and sepsis. Binding of LPS to soluble CD14 shed from CD14-bearing cells results in neutralization of LPS and rapid recruitment of PMN to the site of infection. Recent advances in the fields of genomics and proteomics should greatly enhance our understanding of the PMN role in controlling intramammary infections in ruminants. Further, manipulation of PMN, through either recombinant proteins such as soluble CD14 that enhance PMN response or agents that mediate PMN apoptosis, may serve as novel therapeutics for the treatment of mastitis.


The effect of two glucan carboxymethyl derivatives with various substitution degrees on cyclophosphamide immunosuppression in mice.
Carboxymethylglucan (CMG) in two different degrees of substitution of carboxymethyl groups (0.56 and 0.89) was administered to cyclophosphamide (CY) treated (200 mg/kg) C57B1/6 mice in three doses (10, 50, and 100 mg/kg) 24 h after CY. The influence of CMG administration on the cell suppression caused by CY was observed in the subsequent days. The cellularity of spleen, bone marrow and peripheral blood was quantified on days 2, 5, 8, 11, 15, and 21 after CY treatment. CY treated mice developed a significant decrease in peripheral blood cell counts, and spleen and bone marrow cellularity during the initial 5 days, followed by recovery in the next 15 days, with an overshoot reaction in spleen cellularity and erythrocyte levels. The initial cellularity depression and the following recovery was modified by both carboxymethyl derivatives of glucan. Cyclophosphamide treated mice exhibited less pronounced immunosuppression and more rapid hematopoietic recovery when administered with CMG, although this reaction was only of a modest degree. The effects were not dose dependent and the differences between the two glucans were not significant.


Interactions between surround suppression and interocular suppression in human vision.
Several types of suppression phenomena have been observed in the visual system. For example, the ability to detect a target stimulus is often impaired when the target is embedded in a high-contrast surround. This contextual modulation, known as surround suppression, was formerly thought to occur only in the periphery. Another type of suppression phenomena is interocular suppression, in which the sensitivity to a monocular target is reduced by a superimposed mask in the opposite eye. Here, we explored how the two types of suppression operating across different spatial regions interact with one another when they simultaneously exert suppressive influences on a common target presented at the fovea. In our experiments, a circular target grating presented to the fovea of one eye was suppressed interocularly by a noise pattern of the same size in the other eye. The foveal stimuli were either shown alone or surrounded by a monocular annular grating. The orientation and eye-of-origin of the surround grating were varied. We found that the detection of the foveal target subjected to interocular suppression was severely impaired by the addition of the surround grating, indicating strong surround suppression in the fovea. In contrast, when the interocular suppression was released by superimposing a binocular fusion ring onto both the target and the dichoptic mask, the surround suppression effect was found to be dramatically decreased. In addition, the surround suppression was found to depend on the contrast of the dichoptic noise with the greatest surround suppression effect being obtained only when the noise contrast was at an intermediate level. These findings indicate that surround suppression and interocular suppression are not independent of each other, but there are strong interactions between them. Moreover, our results suggest that strong surround suppression may also occur at the fovea and not just the periphery.


Ultrastructural immunocytochemistry of autoimmune bullous diseases.
Advanced immunopathological assays have been developed to elucidate the pathophysiology and provide more precise nosological definitions of the immunobullous diseases. Forty-seven patients suffering from autoimmune bullous diseases (intra- or subepidermal) were studied by immunoelectron microscopy (direct and indirect). Peroxidase staining was revealed by diaminobenzidine (determination of immune deposit location) in the majority of the cases of subepidermal bullous diseases, but in less than half of the cases of intraepidermal bullous diseases. Immunoelectron microscopy features contributed in verifying the diagnosis of rare entities such as cicatricial pemphigoid, paraneoplastic autoimmune bullous disease, linear IgA disease and epidermolysis bullosa acquisita.


Electrodeposition of spinel MnCo₂O₄ nanosheets for supercapacitor applications.
Herein, we report a facile, low-cost and one-step electrodeposition approach for the synthesis MnCo2O4 (MCO) nanosheet arrays on indium doped tin oxide (ITO) coated glass substrates. The crystalline phase and morphology of the materials are studied by x-ray diffraction, energy dispersive x-ray analysis and field-emission scanning electron microscopy. The supercapacitor performance of the MCO nanosheets are studied in a three-electrode configuration in 2 M KOH electrolyte. The as-prepared binder-free electrode shows a high specific capacitance of 290 F g(-1) at 1 mV s(-1) with excellent cyclic stability even after 1000 charge/discharge cycles. The obtained energy density and power density of the MCO nanosheets are 10.04 Wh kg(-1) and 5.2 kW kg(-1) respectively. The superior electrochemical performances are mainly attributed to its nanosheet like structure which provides a large reaction surface area, and fast ion and electron transfer rate.


Braking of fast and accurate elbow flexions in the monkey.
The processes responsible for braking fast and accurate elbow movements were studied in the monkey. The movements studied were made over different amplitudes and against different inertias . All were made to the same end position. Only fast movements that showed the typical biphasic or triphasic pattern of activity in agonists and antagonists were analysed in detail. For movements made over different amplitudes and at different velocities there was symmetry between the acceleration and deceleration phases of the movements. For movements of the same amplitude performed at different velocities there was a direct linear relation between peak velocity and both the peak acceleration (and integrated agonist burst) and peak deceleration (and integrated antagonist burst). The slopes of these relations and their intercept with the peak velocity axis were a function of movement amplitude. This was such that for large and small movements of the same peak velocity and the same end position (i) peak acceleration and phasic agonist activity were larger for the small movements and (ii) peak deceleration and phasic antagonist activity were larger for the small movements. The slope of these relations and the symmetry between acceleration and deceleration were not affected by the addition of an inertial load to the handle held by the monkey. The results indicate that fast and accurate elbow movements in the monkey are braked by antagonist activity that is centrally programmed. As all movements were made to the same end position, the larger antagonist burst in small movements, made at the same peak velocity as large movements, cannot be due to differences in the viscoelastic contribution to braking (cf. Marsden, Obeso & Rothwell , 1983).(ABSTRACT TRUNCATED AT 250 WORDS)


Ribonucleoprotein particles in the amphibian oocyte nucleus. Possible intermediates in ribosome synthesis.
Studies of the sedimentation properties of RNP(1) material from the nucleus of the amphibian oocyte have indicated (1) that there are few, if any, 78S ribosomes in the nucleus, (2) that there are smaller particles sedimenting at 50-55S and 30S, and (3) that the larger of these is the precursor of the 60S subunit of the cytoplasmic ribosomes. Although the nature of the 30S material is not completely clear, it probably includes precursor particles to the 40S ribosomal subunit. Heavy (50-55S) particles are predominant in immature oocytes of Triturus viridescens, whereas in immature oocytes of Triturus and Amblystoma mexicanum they are reduced greatly in amount, but are still detectable. Double-labeling studies of RNA and protein reveal that both types of particle incorporate uridine-(3)H, but that the 50-55S material of immature oocytes does not incorporate (14)C-labeled amino acids. However, other evidence exists that favors the RNP nature of this material. Sedimentation analyses after SDS extraction show that 50-55S particles contain 40 and 30S RNA, whereas 30S particles contain 20S RNA. These types of RNA represent at least 80% of all the extractable nuclear RNA. The 50-55S particles are probably heterogeneous, including both particles containing mostly 40S RNA and particles containing only 30S RNA.


[Decomposition of herbaceous species in reservoir riparian region of Three Gorges Reservoir under flooding condition].
A total of 10 annuals and perennials of herbaceous species were investigated in reservoir riparian region of Three Gorges Reservoir. The correlations between the plants' nutrient release rate and the substrate composition and structural matter were studied under flooding condition. The decomposition rates of different species differed substantially, with the maximum of Alternanthera philoxeroides (decomposition rate constant k = 0.0228 d(-1)) and the minimum of Microstegium vimineum (k = 0.0029 d(-1)). There was no significant difference in k between annuals and perennials. There was no significant difference in nitrogen and phosphorus contents between annuals and perennials. Paspalum paspaloides and Bidens pilosa released more nutrients into the water than the other species. A. philoxeroides had a higher potential to release nitrogen while it had little effect on water phosphorus compared with the other species. Total N, P contents in the water were negatively correlated with the plants' decomposition rate, initial C content, C:N ratio, lignin:N ratio, and positively correlated with initial contents of K, Ca and N in plants.


Aggravation of L-DOPA-induced neurotoxicity by tetrahydropapaveroline in PC12 cells.
Tetrahydropapaveroline (THP) is formed in Parkinsonian patients receiving L-DOPA therapy and is detected in the plasma and urine of these patients. In this study, we have investigated the effects of THP on L-DOPA-induced neurotoxicity in cultured rat adrenal pheochromocytoma, PC12 cells. Exposure of PC12 cells up to 10 microM THP or 20 microM L-DOPA after 24 or 48 hr, neither affected the cell viability determined by MTT assay, nor induced apoptosis by flow cytometry and TUNEL staining. However, at concentrations higher than 15 microM, THP showed cytotoxicity through an apoptotic process. In addition, THP at 5-15 microM for both incubation time points significantly enhanced L-DOPA-induced neurotoxicity (L-DOPA concentration, 50 microM). Exposure of PC12 cells to THP, L-DOPA and THP plus L-DOPA for 48 hr resulted in a marked increase in the cell loss and percentage of apoptotic cells compared with exposure for 24hr. The enhancing effects of THP on L-DOPA-induced neurotoxicity were concentration- and treated-time-dependent. THP, L-DOPA and THP plus L-DOPA produced a significant increase in intracellular reactive oxygen species generation and decrease in ATP levels, supporting the involvement of oxidative stress in THP- and L-DOPA-induced apoptosis. The antioxidant N-acetyl-L-cysteine strongly inhibited changes in apoptosis, decreases in cell viability and ROS generation induced by THP associated with L-DOPA. These results suggest that THP aggravates L-DOPA-induced oxidative neurotoxic and apoptotic effects in PC12 cells. Therefore, Parkinsonian patients treated with L-DOPA for long-term need to be monitored for the relationship between plasma concentration of THP and the symptoms of neurotoxicity.


Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.
Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.


From burden to relief: The economic and quality-of-life advantages of pseudo continent perineal colostomy in ultra-low rectal cancer patients.
Pseudo Continent Perineal Colostomy (PCPC) is an alternative technique to left iliac colostomy (LIC) after abdominoperineal resection for ultra low rectal cancer (ULRC). It allows placing the stoma in the perineum to preserve patients' body image. However, concerns about its impact on quality of life and management costs have limited its adoption. We aimed to compare the early outcomes and financial burden of PCPC and LIC in ULRC patients in Morocco, a low-middle-income country. From January 2018 to December 2019, all patients who underwent abdomino-perineal resection (APR) with LIC or PCPC were prospectively enrolled. For each patient, baseline characteristics, and in hospital and 90 days morbidity with a focus on perineal complications were reported. Quality of life (QOL) was assessed using the validated EORTC-C30 and CR29 questionnaires. Financial burden to patients was reported using declarative out-of-pocket costs (OOPC) analysis. Among 49 patients who underwent APR, 33 received PCPC and 16 received definitive LIC. Similar rates of early perineal complications were observed between the two groups (p = 0.49). Readmission rate at POD90 was higher in the LIC-group due to perineal sepsis (p = 0.09). QOL analysis at 6 months revealed that patients with PCPC had a higher global health status (p = 0.006), a better physical functioning and reported fewer symptoms of flatulence and fecal incontinence (p = 0.001). Patients with a LIC reported more financial difficulties with higher median OOPC of stoma management up to €23 versus €0 per month for PCPC (p = 0.0024). PCPC was the only predictive factor of improved patient reported outcomes. PCPC is a cost-effective alternative to the standard definitive colostomy without alteration of the QOL or additional perineal complications during the first 6 months following the surgery. These findings may help convince surgeons to offer this option to patients refusing definitive LIC.


Advances in protein subunit vaccines against tuberculosis.
Tuberculosis (TB), also known as the "White Plague", is caused by Mycobacterium tuberculosis (Mtb). Before the COVID-19 epidemic, TB had the highest mortality rate of any single infectious disease. Vaccination is considered one of the most effective strategies for controlling TB. Despite the limitations of the Bacille Calmette-Guérin (BCG) vaccine in terms of protection against TB among adults, it is currently the only licensed TB vaccine. Recently, with the evolution of bioinformatics and structural biology techniques to screen and optimize protective antigens of Mtb, the tremendous potential of protein subunit vaccines is being exploited. Multistage subunit vaccines obtained by fusing immunodominant antigens from different stages of TB infection are being used both to prevent and to treat TB. Additionally, the development of novel adjuvants is compensating for weaknesses of immunogenicity, which is conducive to the flourishing of subunit vaccines. With advances in the development of animal models, preclinical vaccine protection assessments are becoming increasingly accurate. This review summarizes progress in the research of protein subunit TB vaccines during the past decades to facilitate the further optimization of protein subunit vaccines that may eradicate TB.


Challenges in healthcare education: a correlational study of outcomes using two learning techniques.
Electronic learning has become an important tool in today's changing healthcare environment. Institutions confronted with limited resources, in the face of increased demands for education and a shortage of educators, have found electronically based education a significant resource. This study compares electronic-blended instruction technique with instructor-led delivery of the same content and examines the correlation of learning effectiveness to each delivery method.


Sulfurane [S(IV)]-Mediated Fusion of Benzynes Leads to Helical Dibenzofurans.
Here we disclose a sulfurane-mediated method for the formation of dimeric dibenzofuran helicenes via the reaction between diaryl sulfoxides and hexadehydro-Diels-Alder (HDDA) derived benzynes. A variety of S-shaped and U-shaped helicenes were formed under thermal conditions. Both experimental and DFT studies support a sulfur(IV)-based coupling (aka ligand coupling) mechanism involving tetracarbo-ligated S(IV) intermediates undergoing reductive elimination to afford the helicene products. This process involves the de novo generation of five new rings in a single operation and constitutes a new method for the construction of topologically interesting, polycyclic aromatic compounds.


Spin-transfer torque on a single magnetic adatom.
We theoretically show how the spin orientation of a single magnetic adatom can be controlled by spin polarized electrons in a scanning tunneling microscope configuration. The underlying physical mechanism is spin assisted inelastic tunneling. By changing the direction of the applied current, the orientation of the magnetic adatom can be completely reversed on a time scale that ranges from a few nanoseconds to microseconds, depending on bias and temperature. The changes in the adatom magnetization direction are, in turn, reflected in the tunneling conductance.


Solitary neuroendocrine cells and neuroepithelial bodies in the lower airways of embryonic, fetal, and postnatal sheep.
The sheep pulmonary intraepithelial APUD system was studied by histochemical, immunocytochemical, and electron microscopy techniques during different periods of lung development: embryonic, fetal (pseudoglandular, canalicular, and alveolar), and postnatal. The cells of the ovine pulmonary intraepithelial APUD system were found randomly distributed throughout the conducting and respiratory or undifferentiated airways. They appeared as isolated cells (solitary neuroendocrine cells) or in groups (neuroepithelial bodies). These cells were argyrophilic and immunoreactive for neuron-specific enolase but were not argentaffin. Ultrastructurally they were characterized by a basal position in the respiratory epithelium and by the presence of neurosecretory granules (dense-core vesicles) ranging between 65 and 230 nm of diametre. Quantitative studies showed that single neuroendocrine cells were more numerous in distal conducting airways and at fetal stages. The earliest identifiable argyrophilic and NSE-immunoreactive neuroendocrine cells in sheep airways appeared at gestational week 5, close to the term of the embryonic period.


Hyperglycaemia and intramitochondrial glycogen granules in the brain of mice. Ultrastructural study.
The mechanism of cytotoxic effects of hyperglycaemia on the brain has not yet been explained and the proposed hypotheses are not fully convincing. In the present study, we aimed to assess the effect of high doses of glucose on the ultrastructure of the mice brain. The results, which are in agreement with the literature data, show that the administration of a single high dose of glucose, as well as its chronic application, leads to accumulation of glycogen granules in the cytoplasm of astrocytes. A new observation is the detection of glycogen granules in the ultrastructurally changed mitochondria of astrocytes as well as in the mitochondria of some synapses. Our hypothesis assumes that excess of glucose may cause an increase in the vulnerability of the brain mitochondria. This in turn may enable glucose and cytoplasmic enzymes to penetrate into the mitochondria and they therein synthesise glycogen. Mitochondrial dysfunction may in turn lead to neurodegeneration by apoptotic process.


High Membrane Curvature Enhances Binding, Conformational Changes, and Fibrillation of Amyloid-β on Lipid Bilayer Surfaces.
Aggregation of the amyloid-β (Aβ) protein and the formation of toxic aggregates are the possible pathogenic pathways in Alzheimer's disease. Accumulating evidence suggests that lipid membranes play key roles in protein aggregation, although the intermolecular forces that drive the interactions between Aβ-(1-40) and the membranes vary in different membrane systems. Here, we observed that a high positive curvature of lipid vesicles with diameters of ∼30 nm enhanced the association of Aβ with anionic phosphatidylglycerol membranes in the liquid-crystalline phase and with zwitterionic phosphatidylcholine membranes in the gel phase. The binding modes of Aβ to these membranes differ in terms of the location of the protein on the membrane and of the protein secondary structure. The fibrillation of Aβ was accelerated in the presence of the vesicles and at high protein-to-lipid ratios. Under these conditions, the protein accumulated on the surfaces, as demonstrated by a high (10(7) M(-1)) binding constant. Our findings suggest that packing defects on membranes with high curvatures, such as the intraluminal vesicles in multivesicular bodies and the exosomes, might result in the accumulation of toxic protein aggregates.


Current-level discrimination and spectral profile analysis in multi-channel electrical stimulation.
In experiment 1, six cochlear-implant (CI) listeners discriminated a stimulation pattern eliciting equal loudness for each electrode from a stimulation pattern in which the stimulation at one or more electrodes was increased (peak) or decreased (notch). Three cochlear locations and three bandwidths were tested, without and with level roving. Listeners could always detect peaks but not always notches. Increasing the bandwidth beyond two electrodes produced no improvement in just-noticeable differences (JNDs). JNDs for the basal location were higher than for the apical and middle locations, although listeners had highly individual tendencies. In experiment 2, listeners discriminated changes in the peak heights and notch depths. JNDs for higher peaks were better while JNDs for deeper notches were worse than for experiment 1. In experiment 3, listeners discriminated the electrode position of peaks or notches. JNDs were approximately one electrode. In experiment 4, the first three experiments were repeated with large amounts of level roving. There was no evidence that CI listeners performed an across-channel comparison in these tasks.


An Amoebal Grazer of Cyanobacteria Requires Cobalamin Produced by Heterotrophic Bacteria.
Amoebae are unicellular eukaryotes that consume microbial prey through phagocytosis, playing a role in shaping microbial food webs. Many amoebal species can be cultivated axenically in rich media or monoxenically with a single bacterial prey species. Here, we characterize heterolobosean amoeba LPG3, a recent natural isolate, which is unable to grow on unicellular cyanobacteria, its primary food source, in the absence of a heterotrophic bacterium, a Pseudomonas species coisolate. To investigate the molecular basis of this requirement for heterotrophic bacteria, we performed a screen using the defined nonredundant transposon library of Vibrio cholerae, which implicated genes in corrinoid uptake and biosynthesis. Furthermore, cobalamin synthase deletion mutations in V. cholerae and the Pseudomonas species coisolate do not support the growth of amoeba LPG3 on cyanobacteria. While cyanobacteria are robust producers of a corrinoid variant called pseudocobalamin, this variant does not support the growth of amoeba LPG3. Instead, we show that it requires cobalamin that is produced by the Pseudomonas species coisolate. The diversity of eukaryotes utilizing corrinoids is poorly understood, and this amoebal corrinoid auxotroph serves as a model for examining predator-prey interactions and micronutrient transfer in bacterivores underpinning microbial food webs.IMPORTANCE Cyanobacteria are important primary producers in aquatic environments, where they are grazed upon by a variety of phagotrophic protists and, hence, have an impact on nutrient flux at the base of microbial food webs. Here, we characterize amoebal isolate LPG3, which consumes cyanobacteria as its primary food source but also requires heterotrophic bacteria as a source of corrinoid vitamins. Amoeba LPG3 specifically requires the corrinoid variant produced by heterotrophic bacteria and cannot grow on cyanobacteria alone, as they produce a different corrinoid variant. This same corrinoid specificity is also exhibited by other eukaryotes, including humans and algae. This amoebal model system allows us to dissect predator-prey interactions to uncover factors that may shape microbial food webs while also providing insight into corrinoid specificity in eukaryotes.


[A case report of crossed renal ectopia with renal stone].
Crossed renal ectopia is a relatively rare renal anomaly. A 49-year-old man with macrohematuria and right flank pain was admitted to our hospital. Various urological examinations were carried out, and a diagnosis of left crossed renal ectopia with renal stone was made. Pyelolithotomy was performed and stone analysis revealed a calcium oxalate. In Japan, 166 cases of crossed renal ectopia have been reported and 15 of them including our case were associated with urinary tract stones.


Risk Factors of Delayed Onset Posttraumatic Stress Disorder in Chronically Critically Ill Patients.
The main aim of this study was to investigate factors associated with a delayed-onset posttraumatic stress disorder (PTSD) after the intensive care unit (ICU) treatment of patients with a chronic critical illness (CCI). Patients (n = 97) with critical illness polyneuropathy or critical illness myopathy were interviewed via the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. The diagnosis of the acute stress disorder was assessed within 1 month (t1), the diagnosis of PTSD at 3 (t2) and 6 (t3) months after transfer from the acute care ICU to the post-acute ICU. Patients showing a delayed-onset or persistent course of PTSD were subsumed in one group; 24.7% (n = 24) showed a delayed-onset PTSD. Significant risk factors were as follows: the severity of the medical illness, the perceived fear of dying at the ICU, the number of traumatic memories from the ICU, and the presence of a coronary heart disease. Every fourth patient with CCI showed a delayed-onset PTSD up to 6 months after the ICU treatment. Markers for a delayed-onset PTSD should already be assessed at the time of discharge from the ICU.


Evolution of social organization: a reappraisal for primates by using phylogenetic methods.
For many animal taxa, the extent to which phylogeny can account for the form of species' social systems has seldom been investigated formally. A quantitative phylogenetic analysis of social systems in the order Primates reveals that social organization may be strongly conserved in some lineages, even in the face of considerable ecological variability. This result has important implications for efforts to understand the evolution of animal societies and for attempts to reconstruct the social organization of early humans.


The Frizzled family of unconventional G-protein-coupled receptors.
The Frizzled (FZD) family of receptors is critically involved in embryogenesis, and there is substantial evidence that members of this family also regulate tissue homeostasis in many different organs in the adult. FZD receptors have seven transmembrane-spanning domains and are activated by the WNT family of lipoglycoproteins. Many aspects of FZD signal transduction and pharmacology are still unclear. In this review, we summarize recent advances and some of the key questions about the molecular pharmacology of FZDs, FZD-associated proteins and signal transduction. We also discuss what little is known about the pharmacological binding profiles and the degree of selectivity of WNTs and other extracellular ligands for FZDs. Finally, we focus on signaling events that occur as a direct consequence of FZD activation, signaling via the central phosphoprotein Dishevelled (DVL) and FZD coupling to heterotrimeric G proteins. Here, we outline the current state of knowledge on FZDs and FZD signal transduction and pinpoint aspects of debate and future directions.


Annular excursion contributes to efficient cardiac output: a three-dimensional echocardiographic approach.
The heart produces an efficient cardiac output by repeating diastole and systole. With the evolution of three-dimensional (3D) echocardiography, it is possible to evaluate cardiac motion using detailed 3D morphologic echocardiography. The study aim was to evaluate mitral and aortic annulus excursions towards the apex of the left ventricle, using 3D echocardiography. Measurements of the angle variation between the mitral and aortic valve throughout the cardiac cycle were performed to determine the effects of annulus excursion on cardiac function. Seven healthy adolescents (five males, two females; mean age 15.9 +/- 1.1 years; Group H) and seven patients with dilated cardiomyopathy (seven males; mean age 63.6 +/- 12.9 years; Group D) were selected. All subjects underwent 3D echocardiography between November 2007 and June 2008. Annulus excursion (AE) was defined as the annular motion towards the apex. The Ex-Ratio A (%) and Ex-Ratio M (%) were defined as the ratios of aortic or mitral excursion, respectively, to the maximal distance from the annulus to the left ventricular apex. The annulus was defined simply as a flat round disc, and the annular area calculated as the annular distance between the anterior and posterior annulus as a circle diameter. The annulus excursion volume (AEV) was calculated by multiplying the annular area by AE, and determined for each valve of each patient. The total AEV was the summation of the mitral and aortic AEVs. The ratio of AEV to left ventricular diastolic volume was expressed as AEV/EDV. Angular variation between the valves was measured during the cardiac cycle with the following values: maximal angle (Dmax), minimal angle (Dmin), and the difference between Dmax and Dmin (Dmax-min). In all cases, the apex was in a fixed position. The AE was significantly greater for group H than for group D. While AEV did not differ between groups, AEV/EDV(A) and AEV/EDV(M) were greater for group H than for group D. The angle between the mitral and aortic annulus changed throughout the cardiac cycle. The Dmax-min value was significantly greater for group H than for group D. Annulus excursion contributes to an efficient cardiac output. The angle variation was measured during the cardiac cycle and found to be greater in healthy adolescents. 3D echocardiography represents a useful modality for clarifying 'motional cardiac morphology'.


It's every nurse's duty to help prevent terrorism.
Manchester is my home city and, like many people across the North West and in London, I have been devastated by the appalling terrorist attacks of recent months, which have felt very close to home. We can all be proud of the incredible way that the NHS family responded to the attacks, swiftly and with such heroic professionalism.


Protein unfolding, amyloid fibril formation and configurational energy landscapes under high pressure conditions.
High hydrostatic pressure induces conformational changes in proteins ranging from compression of the molecules to loss of native structure. In this tutorial review we describe how the interplay between the volume change and the compressibility leads to pressure-induced unfolding of proteins and dissociation of amyloid fibrils. We also discuss the effect of pressure on protein folding and free energy landscapes. From a molecular viewpoint, pressure effects can be rationalised in terms of packing and hydration of proteins.


Extubation strategy following difficult intubation.
Airway management relates to the period of tracheal intubation, maintenance of endotracheal tube in situ, and finally extubation. Problems related to difficult extubation still pose significant challenge for both anesthesiologists and intensivists. This article reviews current approach to extubation strategy following difficult intubation. Guidelines and algorithm may be helpful in order to ensure safe management of the patient during this delicate period of airway management.


[Diagnosis and treatment of arrhythmogenic right ventricular cardiomyopathy in children].
To summarize the experience in diagnosis and treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC) in children. A total of 14 children (7 females and 7 males) with ARVC were involved. The cases underwent electrocardiography, echocardiography, cardiac CT or MRI examinations. All cases were treated with sotalol or amiodarone in combination with propranolol. In 2 cases with drug-refractory ventricular extrasystoles, catheter ablation treatment was performed. In 6 cases with obvious impaired ventricular function, additional pharmacological therapy including vasodilators, diuretics, and digitalis were given. Ventricular extrasystoles occurred in all 14 cases and ventricular tachycardia in 8 cases. Ten cases showed Epsilon wave on electrocardiography. All 14 cases had enlarged right ventricle and reduced right ventricular ejection fraction. CT or MRI examination showed right ventricular dilatation and a thinned wall of right ventricle in 10 cases. Ventricular extrasystoles or tachycardia disappeared in 7 cases and was reduced in 4 cases after treatment. The two children receiving catheter ablation treatment did not present ventricular extrasystoles or tachycardia in a 3-month follow-up. The heart function was improved in the 6 children with obvious impaired ventricular function after pharmacological therapy. The clinical manifestations are diverse in children with ARVC. A definite diagnosis of ARVC should be based on a combination of electrocardiography and echocardiography examinations. Pharmacological therapy is effective partially. Catheter ablation treatment appears to be a promising option in patients with drug-refractory ventricular extrasystoles.


Masseteric cooptation and crossfacial nerve grafting: Is it still applicable 22 months after the onset of facial palsy?
Eighteen months is usually considered the cutoff time within which recovery of the mimic muscle remains possible using facial nerve cooptation. Few reports on the use of cooptation after this interval have appeared. Purpose of this study is to investigate the feasibility of this procedure also after 22 months. Six patients treated via crossfacial nerve grafting between healthy and paralyzed middle and middle-upper facial nerve branches and masseteric cooptation of the main trunk of the paralyzed facial nerve between 20 and 24 months after the onset of palsy were analyzed. Population consisted of two males and four females ages 8-42 years (mean 24 years). Facial palsy developed after acoustic neuroma resection in three patients, after the removal of a cerebellopontine angle astrocytoma in one, and as a consequence of Bell's palsy or cerebral hemorrhage in the other two (one each). House-Brackman and Sunnybrook clinical evaluation systems and FDI questionnaire were used to assess results. House-Brackman scores changed from VI before the operation for all patients to II for two patients and III for four patients. Sunnybrook scores were 0-10 before the operation, but 62-84 at the last visit. Mean FDI scores moved from 24 to 38.5 meaning a statistical high significant improvement (P < .01). Masseteric/crossfacial nerve grafting is feasible for patients with palsies 20-24 months in duration, affording satisfactory functional and esthetic results and a dramatic improvement in quality of life.


Malignant teratoma of the thyroid: case report.
Teratomas in the neck are rare neoplasms. Most of them occur in infants less than 1 year and are benign. In contrast, thyroid teratomas in adults are malignant and have fatal outcomes because of spread of tumor refractory to treatment. We report a case of a primary thyroid malignant teratoma in a 37-year-old woman. She was treated successfully with a combination of surgery, postoperative cis-platinum-based chemotherapy, and radiation therapy to the neck. Although the time of follow-up is short (24 months), we attribute her successful outcome to the use of this intensive therapeutic approach.


Improving hepatitis B birth dose coverage through village health volunteer training and pregnant women education.
Hepatitis B is highly endemic in the Republic of Kiribati, while the coverage of timely birth dose vaccination, the primary method shown to prevent mother-to-child transmission of hepatitis B virus, was only 66% in 2014. Children born at home are especially at high risk, as they have limited access to timely birth dose (i.e. within 24 h) vaccination. To improve birth dose coverage, a project to improve linkages between village health volunteers and health workers and educate pregnant women on hepatitis B vaccination was carried out in 16 communities with low birth dose coverage in Kiribati from November 2014 to May 2015. After project completion, the coverage of timely birth dose administration increased significantly both in the densely populated capital region of South Tarawa (from 89% to 95%, p=0.001) and the Outer Islands (from 57% to 83%, p<0.001). The coverage of timely birth dose administration among infants born at home increased significantly from 70% to 84% in South Tarawa (p=0.001) and from 49% to 75% in the Outer Islands (p<0.001). Timely birth dose was associated with being born in a hospital, being born during the study period and caregivers having developed an antenatal birth dose plan. The project demonstrates a successful model for improving hepatitis B vaccine birth dose coverage that could be adopted in other areas in Kiribati as well as other similar settings.


Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors.
Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.


Non-orthogonal optical multicarrier access based on filter bank and SCMA.
This paper proposes a novel non-orthogonal optical multicarrier access system based on filter bank and sparse code multiple access (SCMA). It offers released frequency offset and better spectral efficiency for multicarrier access. An experiment of 73.68 Gb/s filter bank-based multicarrier (FBMC) SCMA system with 60 km single mode fiber link is performed to demonstrate the feasibility. The comparison between fast Fourier transform (FFT) based multicarrier and the proposed scheme is also investigated in the experiment.


Embraces are lateralized in spider monkeys (Ateles fusciceps rufiventris).
Side biases observed in behavior are thought to reflect underlying asymmetric brain function or hemispheric specialization. Previous work in multiple species identified left side biases (associated with the right hemisphere) for processing social behavior. In highly social species such as primates, many behaviors may be categorized as social, yet differences between such behaviors have not been examined as a test of asymmetric brain function. Using Colombian spider monkeys (Ateles fusciceps rufiventris), we observed lateral positioning during two types of behaviors widely categorized as social affiliative: embracing and grooming, and identified a left bias for embracing, but not grooming. Our findings partially support prior research in hemispheric specialization, but suggest that there may be differences between social behaviors that drive specialization. We discuss these results in light of current theory on hemispheric specialization and highlight differences between embracing and grooming.


Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation.
In this randomised, multicentre clinical study, dogs with musculoskeletal pain and inflammation were treated with either vedaprofen or meloxicam administered orally at the recommended dose rates. Clinical examinations were carried out regularly and clinical severity scores assigned. In total, 214 cases (73 acute, 141 chronic) were evaluated. Treatment with vedaprofen and meloxicam was continued for 14 and 17 days, respectively, in the acute cases, and 38 and 39 days in the chronic cases. NSAID treatment resulted in a significant improvement in clinical scores. The overall response to treatment ('responders') at the final clinical examination was 89 per cent and 87 per cent in the acute cases and 72 per cent and 65 per cent in the chronic cases in the vedaprofen and meloxicam groups, respectively. Mild transient gastrointestinal signs were observed in both groups (11 per cent vedaprofen, 12 per cent meloxicam). Adverse effects related to NSAIDs resulted in treatment cessation in 5 per cent of the dogs in each group. Vedaprofen and meloxicam were efficacious in, and well tolerated by, most of the dogs in the study.


Prediction of conversion to dementia disorders based on timed up and go dual-task test verbal and motor outcomes: a five-year prospective memory-clinic-based study.
While assessment tools can increase the detection of cognitive impairment, there is currently insufficient evidence regarding clinical outcomes based on screening for cognitive impairment in older adults. The study purpose was to investigate whether Timed Up and Go dual-task test (TUGdt) results, based on TUG combined with two different verbal tasks (name different animals, TUGdt-NA, and recite months in reverse order, TUGdt-MB), predicted dementia incidence over a period of five years among patients (N = 186, mean = 70.7 years; 45.7% female) diagnosed with Subjective Cognitive Impairment (SCI) and Mild Cognitive Impairment (MCI) following assessment at two memory clinics. Associations between TUG parameters and dementia incidence were examined in Cox regression models. During follow-up time (median (range) 3.7 (0.1-6.1) years) 98 participants converted to dementia. Novel findings indicated that the TUGdt parameter words/time, after adjustment for age, gender, and education, can be used for the prediction of conversion to dementia in participants with SCI or MCI over a period of five years. Among the TUG-related parameters investigated, words/time showed the best predictive capacity, while time scores of TUG and TUGdt as well as TUGdt cost did not produce significant predictive results. Results further showed that the step parameter step length during TUGdt predicts conversion to dementia before adjustment for age, gender, and education. Optimal TUGdt cutoffs for predicting dementia at 2- and 4-year follow-up based on words/time were calculated. The sensitivity of the TUGdt cutoffs was high at 2-year follow-up: TUGdt-NA words/time, 0.79; TUGdt-MB words/time, 0.71; reducing respectively to 0.64 and 0.65 at 4-year follow-up. TUGdt words/time parameters have potential as cost-efficient tools for conversion-to-dementia risk assessment, useful for research and clinical purposes. These parameters may be able to bridge the gap of insufficient evidence for such clinical outcomes. ClinicalTrials.gov Identifier: NCT05893524: https://www. gov/study/NCT05893524?id=NCT05893524&rank=1 .


The Conundrum of Hydrogen Peroxide Signaling and the Emerging Role of Peroxiredoxins as Redox Relay Hubs.
Hydrogen peroxide (H2O2) is known to act as a messenger in signal transduction. How H2O2 leads to selective and efficient oxidation of specific thiols on specific signaling proteins remains one of the most important open questions in redox biology. Recent Advances: Increasing evidence implicates thiol peroxidases as mediators of protein thiol oxidation. Recently, this evidence has been extended to include the peroxiredoxins (Prxs). Prxs are exceptionally sensitive to H2O2, abundantly expressed and capture most of the H2O2 that is generated inside cells. The overall prevalence and importance of Prx-based redox signaling relays are still unknown. The same is true for alternative mechanisms of redox signaling. It will be important to clarify the relative contributions of Prx-mediated and direct thiol oxidation to H2O2 signaling. Many questions relating to Prx-based redox relays remain to be answered, including their mechanism, structural organization, and the potential role of adaptor proteins. Antioxid. Redox Signal. 28, 558-573.


PinX1-Promoted Autophagy Inhibits Cell Proliferation and Induces Cell Apoptosis by Inhibiting the NF-κB/p65 Signaling Pathway in Nasopharyngeal Carcinoma.
The role of Pin2 telomeric repeat factor 1-interacting telomerase inhibitor 1 (PinX1) in tumorigenesis and development has been extensively studied. As we previously demonstrated, PinX1 plays an important role in modulating epithelial-mesenchymal transition (EMT), stemness, cell proliferation, and apoptosis in nasopharyngeal carcinoma (NPC). However, the relationship between PinX1, autophagy, and cell function in NPC remains unclear. This study aimed to investigate the mechanisms by which PinX1 regulates autophagy in NPC, and to explore its biological role and clinical significance in disease progression. The proliferative capacity of NPC cells was assessed by MTT and xenograft tumorigenicity assays. Autophagic flux was monitored using a tandem monomeric DAPI-FITC-LC3 reporter assay. The rates of apoptosis and the cell cycle in NPC cells were analyzed using flow cytometry. The activation of autophagy and the signaling status of the AKT/mTOR and NF-κB/p65 pathways were evaluated by Western blot analysis. In addition to promoting autophagy and apoptosis, PinX1 overexpression suppressed proliferation, migration, invasion, and decelerated cell-cycle progression in NPC cells. These effects were reversed by inhibiting autophagy with 3-methyladenine. Mechanistic investigations clarified that PinX1 overexpression significantly reduced the expression of p-AKT, p-mTOR, p65, and p-p65. Chloroquine treatment in PinX1-overexpressing cells did not significantly alter p-AKT and p-mTOR levels, whereas 3-MA treatment in PinX1-overexpressing cells resulted in increased p65 and p-p65 expression, relative to untreated PinX1-overexpressing cells. It appears that PinX1 promotes autophagy by inhibiting the AKT/mTOR signaling pathway, which then inhibits NF-κB/p65 pathways, and consequently inhibiting cell proliferation and causing cell apoptosis in NPC cells.


Effect of polymorphisms within probe-target sequences on olignonucleotide microarray experiments.
Hybridization-based technologies, such as microarrays, rely on precise probe-target interactions to ensure specific and accurate measurement of RNA expression. Polymorphisms present in the probe-target sequences have been shown to alter probe- hybridization affinities, leading to reduced signal intensity measurements and resulting in false-positive results. Here, we characterize this effect on exon and gene expression estimates derived from the Affymetrix Exon Array. We conducted an association analysis between expression levels of probes, exons and transcripts and the genotypes of neighboring SNPs in 57 CEU HapMap individuals. We quantified the dependence of the effect of genotype on signal intensity with respect to the number of polymorphisms within target sequences, number of affected probes and position of the polymorphism within each probe. The effect of SNPs is quite severe and leads to considerable false-positive rates, particularly when the analysis is performed at the exon level and aimed at detecting alternative splicing events. Finally, we propose simple solutions, based on 'masking' probes, which are putatively affected by polymorphisms and show that such strategy results in a large decrease in false-positive rates, with a very modest reduction in coverage of the transcriptome.


Preparation of ultrasmall cyclodextrin nanogels by an inverse emulsion method using a cationic surfactant.
Stable water-in-oil emulsion membranes can be prepared using [dilauryl(dimethyl)ammonium] bromide (DDAB), a cationic surfactant. We prepared ultrasmall cyclodextrin (γ-CyD) nanogels (γ-CyDngs) by forming ionic pairs between the secondary hydroxyl groups of γ-CyDs and DDAB. Fluorescence and NMR characterisation of the obtained γ-CyDngs revealed superior inclusion affinities compared with native γ-CyDs, beneficial for the solubilisation of hydrophobic compounds in water.


Visible-Light-Induced Metal- and Photocatalyst-Free Radical Cascade Cyclization of Cinnamamides for Synthesis of Functionalized Dihydroquinolinones.
Visible-light-promoted metal- and photocatalyst-free radical cascade cyclization of cinnamamides with α-oxocarboxylic acids is described for sustainable synthesis of diverse pharmaceutically important dihydroquinolinone scaffolds in one pot under mild conditions. The decarboxylative cascade cyclization proceeded efficiently at room temperature without the need for expensive photocatalysts such as Ir or Ru complexes, which indicates the practicability and environmentally benign nature of this protocol. Preliminary mechanistic studies reveal that the blue LED irradiation efficiently cleaves the I-O bond of the hypervalent iodine reagent PhI(O2CCOAr)2 formed through ligand exchange between iodobenzene diacetate and arylglyoxylic acid to initiate the cascade reaction. The synthetic value of this operationally simple and energy-efficient method is further demonstrated by late-stage functionalization of drug molecules in excellent yields.


Comparison of sulphide and nitrate removal from synthetic wastewater by pure and mixed cultures of nitrate-reducing, sulphide-oxidizing bacteria.
In this study, the activities of hydrogen sulphide (H2S) oxidation and nitrate (N-NO3-) reduction by three pure and mixed strains of nitrate-reducing, sulphide oxidizing bacteria (NR-SOB) were determined. Batch experiments were performed at 35 °C and pH 7.0-8.0 with initial H2S concentrations of 650-900 ppmv and N-NO3- concentrations of ∼120 mg/L. The strains MAL 1HM19, TPN 1HM1 and TPN 3HM1 were capable of removing 100% gas-phase H2S. The co-cultures showed better performance for H2S and N-NO3- removal. The mixed NR-SOB strains showed a higher H2S oxidation rate (143 ± 18 ppmv/h), while the highest N-NO3- removal rate (5.5 ± 0 and 5.1 ± 0.6 N-NO3- mg/L·h) was obtained by a mixture of two NR-SOB strains. The 16S rDNA sequence analysis revealed that all strains belonged to the sub-class Alphaproteobacteria and are closely related to Paracoccus sp. (>99%).


Insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) modulate tenascin-C and fibrillin-1 in bullous keratopathy stromal cells in vitro.
Pseudophakic bullous keratopathy (PBK) is a major indication for corneal transplantation. Previous studies showed that PBK corneas had increased levels of insulin-like growth factor-I (IGF-I), bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGF-beta), interleukin-1alpha (IL-1alpha) and IL-8. The PBK corneas also had accumulations of tenascin-C (TN-C), fibrillin-1 (Fib-1), matrix metalloproteinase-2 (MMP-2), inflammatory cells but not myofibroblasts. Our goal is to determine if the growth factors/cytokines that are elevated in PBK corneas alter the expression of extracellular matrix (ECM) and/or degradative enzymes in vitro. Stromal cell cultures from normal and PBK human corneas were established and treated for 6 days with IGF-I, BMP-4, IL-1alpha, IL-8 or TGF-beta1/beta2. Immunostaining, Western blot and dot blot analyses for TN-C, Fib-1, alpha-smooth muscle actin (alpha-SMA, a marker for myofibroblasts) or tissue inhibitor of metalloproteinase-1 (TIMP-1) were performed. RNAs were collected and analyzed with Northern blots for TN-C, Fib-1 and beta(2)-microglobulin. Culture media were analyzed using gelatin zymography with or without ethylenediaminetetraacetic acid (EDTA). Some samples were activated with p-aminophenylmercuric acetate (APMA) and reduction/alkylation, and the degradative activities were measured by the MMP-gelatinase activity assay kit. The IGF-I and TGF-beta1/TGF-beta2 increased (a) TN-C protein deposition, and (b) Fib-1 protein and RNA levels, but (c) had no significant affect on TIMP-1, matrix metalloproteinase-2 (MMP-2) or gelatinase activities. TGF-beta1/TGF-beta2 induced alpha-SMA protein (myofibroblasts) while IGF-I did not. BMP-4, IL-1alpha and IL-8 had little affect on the cells. Based upon our data, the fibrotic markers, TN-C and Fib-1, found in PBK corneas may be accounted for by IGF-I and TGF-beta. These growth factors promote fibrosis and ECM deposition without promoting proteolysis. While the other growth factors/cytokines are elevated in PBK corneas, their role(s) in PBK pathogenesis are not clear. In addition, exogenous IGF-I most closely elicited a response that was most similar to the characteristics of the PBK/ABK corneas, i.e. accumulation of TN-C and Fib-1 proteins in the absence of myofibroblasts.


SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair.
When transcribed DNA is damaged, the transcription and DNA repair machineries must interact to ensure successful DNA repair. The mechanisms of this interaction in the context of chromatin are still being elucidated. Here we show that the SIRT6 protein enhances non-homologous end joining (NHEJ) DNA repair by transiently repressing transcription. Specifically, SIRT6 mono-ADP ribosylates the lysine demethylase JHDM1A/KDM2A leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels. Furthermore, we found that through HP1α binding, H3K36me2 promotes subsequent H3K9 tri-methylation. This results in transient suppression of transcription initiation by RNA polymerase II and recruitment of NHEJ factors to DNA double-stranded breaks (DSBs). These data reveal a mechanism where SIRT6 mediates a crosstalk between transcription and DNA repair machineries to promote DNA repair. SIRT6 functions in multiple pathways related to aging, and its novel function coordinating DNA repair and transcription is yet another way by which SIRT6 promotes genome stability and longevity.


Assessment of some cultural experimental methods to study the effects of antibiotics on microbial activities in a soil: An incubation study.
Oxytetracycline (OTC) and sulfamethoxazole (SMX) are two of most widely used antibiotics in livestock and poultry industry. After consumption of antibiotics, a major portion of these compounds is excreted through the feces and urine of animals. Land application of antibiotic-treated animal wastes has caused increasing concern about their adverse effects on ecosystem health. In this regard, inconsistent results have been reported regarding the effects of antibiotics on soil microbial activities. This study was conducted based on the completely randomized design to the measure microbial biomass carbon, cumulative respiration and iron (III) reduction bioassays. Concentrations of OTC and SMX including 0, 1, 10, 25, 50, and 100 mg/kg were spiked in triplicate to a sandy loam soil and incubated for 21 days at 25°C. Results showed that the effects of OTC and SMX antibiotics on cumulative respiration and microbial biomass carbon were different. SMX antibiotic significantly affected soil microbial biomass carbon and cumulative respiration at different treatments compared to control with increasing incubation time. OTC antibiotic, on the other hand, negatively affected cumulative respiration compared to control treatment throughout the incubation period. Although OTC antibiotic positively affected microbial biomass carbon at day one of incubation, there was no clear trend in microbial biomass carbon between different treatments of this antibiotic after that time period. Nevertheless, sulfamethoxazole and oxytetracycline antibiotics had similar effects on iron (III) reduction such that they considerably affected iron (III) reduction at 1 and 10 mg/kg, and iron (III) reduction was completely inhibited at concentrations above 10 mg/kg. Hence, according to our results, microbial biomass carbon and cumulative respiration experiments are not able alone to exhibit the effect of antibiotics on soil microbial activity, but combination of these two experiments with iron (III) reduction test could well display the effects of sulfamethoxazole (SMX) and oxytetracycline (OTC) antibiotics on soil biochemical activities.


Phototransduction for human melatonin suppression.
Human adult males were exposed to combinations of two illuminances and two broadband spectral power distributions over the course of four night-time sessions. Results showed that melatonin suppression is dominated by short visible wavelengths (420-520 nm), consistent with recently published studies. Although the authors of these recent studies suggest that a novel opsin underlies melatonin suppression, the present paper offers a more conservative interpretation of the data based on what is known about existing photoreceptors and associated neuroanatomy and neurophysiology.


The sctR of Salmonella enterica serova Typhimurium encoding a homologue of MerR protein is involved in the copper-responsive regulation of cuiD.
We have identified the cuiD gene in Salmonella enterica serova Typhimurium that codes for a putative multicopper oxidase. Expression of cuiD is induced by copper ion and its promoter/operator has sequence similarity to the promoters controlled by the transcriptional regulators of the MerR family. We also identified and isolated a gene from S. enterica serova Typhimurium that encodes a 138-amino acid residue protein, sctR, a new member of the MerR family of transcriptional regulators. Transposon-insertional disruption of sctR shows sensitivity to copper ion and no response of cuiD expression. Copper-responsive induction and copper tolerance were restored by providing sctR in trans, suggesting that SctR plays an important role in intracellular copper detoxification.


Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats.
Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide (LPS). Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin (5 and 20 mg/kg) for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases (MAPK) p38 in lung were detected by real-time polymerase chain reaction (PCR), immunohistochemistry or Western blotting. Tumor necrosis factor (TNF)-alpha and IL-8 in bronchoalveolar lavage fluid (BALF) were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay (ELISA). Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung (P <0.05). Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-alpha and IL-8 in BALF follows LPS stimulation (P < 0.05). The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung (P <0.05). Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation (P < 0.05). However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration. Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.


Effects of dual tasks and dual-task training on postural stability: a systematic review and meta-analysis.
The use of dual-task training paradigm to enhance postural stability in patients with balance impairments is an emerging area of interest. The differential effects of dual tasks and dual-task training on postural stability still remain unclear. A systematic review and meta-analysis were conducted to analyze the effects of dual task and training application on static and dynamic postural stability among various population groups. Systematic identification of published literature was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, from inception until June 2016, on the online databases Scopus, PEDro, MEDLINE, EMBASE, and SportDiscus. Experimental studies analyzing the effects of dual task and dual-task training on postural stability were extracted, critically appraised using PEDro scale, and then summarized according to modified PEDro level of evidence. Of 1,284 records, 42 studies involving 1,480 participants met the review's inclusion criteria. Of the studies evaluating the effects of dual-task training on postural stability, 87.5% of the studies reported significant enhancements, whereas 30% of the studies evaluating acute effects of dual tasks on posture reported significant enhancements, 50% reported significant decrements, and 20% reported no effects. Meta-analysis of the pooled studies revealed moderate but significant enhancements of dual-task training in elderly participants (95% CI: 1.16-2.10) and in patients suffering from chronic stroke (-0.22 to 0.86). The adverse effects of complexity of dual tasks on postural stability were also revealed among patients with multiple sclerosis (-0.74 to 0.05). The review also discusses the significance of verbalization in a dual-task setting for increasing cognitive-motor interference. Clinical implications are discussed with respect to practical applications in rehabilitation settings.


Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works.
Bipolar disorder, characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems, is a recurrent and often becomes chronic psychiatric illness. However, bipolar subtypes are not often recognized in psychiatric settings, especially bipolar II subtype, until Akiskal and Angst made clear definition to bipolar I (BP-I) and bipolar II (BP-II) disorder in 1999. More and more studies, not only on family inheritance, diagnosis, but also on disease process have been reported that BP-I and BP-II are two different disorders with distinct pathological mechanisms. In general, patients with BP-II express less symptoms and have shorter hypomania stages than BP-I. According to a longitudinal research, patients with BP-II have poor recovery than do BP-I patients. Memantine used to be recognized as a noncompetitive N-methyl-d-aspartate receptor antagonist. However, it was found to have neuroprotective and neurogenesis effect in several neurodegenerative diseases in the past years. We found that memantine could inhibit brain inflammatory response through its action on neuroglial cells and provide neurotrophic effect. The above evidences of benefit on auto-immune system with memantine would support that memantine as add-on therapy to valproate might be more effective than valproate alone on improvement of the neuron degeneration in bipolar disorders. Review articles indicate that not only the mood stabilizers provide with good neuroprotection, but the memantine also have conspicuous anti-autoimmune and neurogenesis effect. Therefore, we propose that drugs with neuroprotective effect and neurotrophic effect may treat neurodegenerative diseases including BP-II. The combination treatment of mood stabilizers memantine may not only augment and improve the remedy for bipolar disorders, but also repair the damaged neurons and neurogenesis through activation of astroglial cell and release of neurotrophic factors.


Assessment of glucose and lipid metabolism in patients with polycystic ovary syndrome with and without Hashimoto's thyroiditis.
To investigate glucose and lipid metabolism in patients with polycystic ovary syndrome (PCOS) with and without Hashimoto's thyroiditis (HT). In the present study, 103 women were included as controls and a total of 213 patients (49 patients with HT and 164 patients without HT) diagnosed with PCOS. The oral glucose tolerance, insulin release, thyroid function, and lipid levels were measured. PCOS patients had significantly higher levels of fasting insulin (FINS), hemostasis of model assessment-insulin resistance, low-lipoprotein cholesterol, triglyceride, apolipoprotein B, apolipoprotein B/apolipoprotein A1, and homocysteine than the controls. PCOS Patients with HT + had higher FINS, 60FINS, 120FINS, and insulin resistance levels than those without Hashimoto's thyroiditis group. HT + group had higher total cholesterol, and thyroid-stimulating hormone levels, while free triiodothyronine, and free thyroxine levels were significantly lower. PCOS can lead to disorders of glucolipid metabolism, PCOS with Hashimoto's thyroiditis may further exacerbate disorders of glucose and lipid metabolism, and therefore thyroid function assessment in patients with PCOS needs to be emphasized.


Renal involvement in chronic graft-versus-host disease: a report of two cases.
We report details of renal involvement during the course of chronic graft-versus-host disease (cGVHD) in two patients undergoing bone marrow transplantation as treatment for acute leukemia. In both cases, the clinical picture was primarily characterized by proteinuria without hypertension or renal failure. Electron microscopy of renal biopsy specimens revealed a similar pattern in the two cases with extensive coalescence of foot processes and intramembraneous deposition of electron-dense material. Our data suggest that the kidney may be a target organ in chronic GVHD.


Reactive oxygen species are involved in the morphology-determining mechanism of Fremyella diplosiphon cells during complementary chromatic adaptation.
Fremyella diplosiphon modifies the pigment composition of its major light-harvesting complexes, i.e. phycobilisomes, and cell and filament morphology according to ambient light quality in a process termed complementary chromatic adaptation (CCA). The cells are red in colour and rectangular shaped, and filaments are longer under green light (GL), in contrast with blue-green, spherical cells and shorter filaments under red light (RL). In this study, we report that wild-type (WT) UTEX 481 and WT-pigmented, shortened filament strain SF33 of F. diplosiphon accumulate reactive oxygen species (ROS) under both GL and RL, with the level of oxidative stress being higher under RL as compared with GL. During CCA, higher levels of ROS under RL are correlated with the RL-specific spherical cell shape and filament fragmentation - cells exhibiting elevated levels of ROS under RL have reduced cell length, yet the width of cells is not affected. Addition of ascorbic acid to RL-grown cultures resulted in lower ROS levels and a concomitant shift to GL-associated cellular morphology, i.e. an increased cell length. This observation identifies an RL-dependent oxidative-stress-mediated regulation of morphogenesis in a bacterial system. Spherical cell morphology may result from ROS-dependent changes in the cell membrane integrity or cell wall loosening and associated cell expansion.


DNA targeting specificity of RNA-guided Cas9 nucleases.
The Streptococcus pyogenes Cas9 (SpCas9) nuclease can be efficiently targeted to genomic loci by means of single-guide RNAs (sgRNAs) to enable genome editing. Here, we characterize SpCas9 targeting specificity in human cells to inform the selection of target sites and avoid off-target effects. Our study evaluates >700 guide RNA variants and SpCas9-induced indel mutation levels at >100 predicted genomic off-target loci in 293T and 293FT cells. We find that SpCas9 tolerates mismatches between guide RNA and target DNA at different positions in a sequence-dependent manner, sensitive to the number, position and distribution of mismatches. We also show that SpCas9-mediated cleavage is unaffected by DNA methylation and that the dosage of SpCas9 and sgRNA can be titrated to minimize off-target modification. To facilitate mammalian genome engineering applications, we provide a web-based software tool to guide the selection and validation of target sequences as well as off-target analyses.