An online discussion between students and teachers: a way forward for meaningful teacher feedback?
Student evaluation is an essential component in feedback processes in faculty and learner development. Ease of use and low cost have made paper evaluation forms a popular method within teaching programmes, but they are often seen as a formality, offering variable value towards the improvement of teaching. Students report poor motivation to engage with existing feedback tools whilst teachers describe receiving vague, contradicting, or irrelevant information. We believe that feedback for teachers needs to be a two-way process, similar to feedback for students, for it to be effective. An online feedback tool has been implemented for third-year medical students from Imperial College London to promote open discussion between teachers and students. The feedback tool is accessible throughout students' clinical attachment with the option of maintaining anonymity. We aim to explore the benefits and challenges of this online feedback tool and assess its value as a method for teacher feedback. Qualitative data was obtained from both volunteer third-year medical students of Imperial College London and Clinical Teaching Fellows using three focus groups and a questionnaire. Data was analysed through iterative coding and thematic analysis to provide over-arching analytical themes. Twenty-nine students trialled this feedback tool with 17 responding to the evaluative questionnaire. Four over-arching themes were identified: reasons for poor participation with traditional feedback tools; student motivators to engage with 'open feedback'; evaluative benefits from open feedback; concerns and barriers with open feedback. This feedback tool provides a platform for two-way feedback by encouraging open, transparent discussion between teachers and learners. It gives a unique insight into both teachers and peers' perspectives. Students engage better when their responses are acknowledged by the teachers. We elaborate on the benefits and challenges of public open feedback and approaches to consider in addressing the self-censorship of critical comments.


Mechanical strain in the mouse astrocytic lamina increases after exposure to recombinant trypsin.
The responses of astrocytes in the optic nerve head (ONH) to mechanical and biochemical stimuli are important to understanding the degeneration of retinal ganglion cell axons in glaucoma. The ONH in glaucoma is vulnerable to stress produced by the intraocular pressure (IOP). Notably, after three days of elevated IOP in a mouse model, the junctions between the astrocytic processes and the peripapillary sclera were altered and the structural compliance of the ONH increased. In order to simulate this aspect of glaucomatous remodeling, explanted mouse eyes were treated with TrypLE, a recombinant trypsin enzyme. Treatment with TrypLE caused the periphery of the astrocytic lamina to contract radially by 0.044 ± 0.038. Transmission electron microscopy showed that TrypLE caused a separation of the end-feet of the astrocyte processes from the basement membrane at the junction with the sclera. Inflation testing after treatment with TrypLE caused an increased strain response in the astrocytic lamina compared to the strain response before treatment. The greatest increase was in the radial Green-Lagrange strain, Err = 0.028 ± 0.009, which increased by 340%. The alterations in the microstructure and in the strain response of the astrocytic lamina reported in mouse experimental glaucoma were partially reproduced by experimental treatment of mouse eyes with TrypLE. The results herein suggest that separation of junctions between the astrocyte processes and the sclera may be instrumental in increasing the structural compliance of the ONH after a period of elevated IOP. STATEMENT OF SIGNIFICANCE: Astrocytes of the optic nerve of the eye spread out from edge to edge across the optic nerve in a region referred to as the astrocytic lamina. In an experimental model of glaucoma caused by elevated eye-pressure, there is disruption of the connections between astrocytes and the edge of the astrocytic lamina. We caused a similar event in the lamina by incubating explanted mouse eyes with an enzyme. Disruption of the astrocyte connections to the edge of their tissue caused the tissue to stretch more when we increased the eye-pressure, compared to the control tissue. This work is the first on the tissue of the optic nerve to demonstrate the importance of cell connections in preventing the over-stretching of the astrocytic lamina.


A polysaccharide-based bioflocculant BP50-2 from banana peel waste: Purification, structure and flocculation performance.
In this study, the purification and characterization of a polysaccharide-based bioflocculant BP50-2 of banana peel waste were investigated. BP50-2 was purified and identified through HPLC, XPS, TG, SEM, AFM, etc. The results showed that BP50-2 was a heteropolysaccharide composed of Mannose, Rhamnose, Glucuronic acid, Galacturonic acid, Glucose, Galactose, and Fucose at a molar ratio of 8.97:5.36:1.92:1.00:32.52:8.30:2.64, respectively. The MW of BP50-2 was 1.47 × 10 3 KDa. BP50-2 had high pH stability that maintained flocculation activity on kaolin suspension for a pH range from 3 to 11, and high-temperature stability ranged from room temperature to 90 °C. BP50-2 was non-sensitive to cation and affected by HCl, EDTA, little affected by urea, which showed that the BP50-2 was non-cation dependent and its main binding mode with kaolin was ionic bond and contained a small amount of hydrogen bond. And flocculation mechanisms were discussed, which indicated that adsorption bridging was the main mechanism of the flocculation process of BP50-2-Kaolin or BP50-2-Mg2+-Kaolin. Moreover, BP50-2 had decolorization activity on RhB and removal activity of heavy metal ion, of which removal rate of Pb2+ was the highest. In brief, BP50-2 showed good performance on the removal of pigment, adsorption of heavy metals, and flocculation of particles.


Syndrome resembling tropical pulmonary eosinophilia but of non-filarial aetiology: serological findings with filarial antigens.
Although the tropical pulmonary eosinophilia (TPE) syndrome of filarial aetiology has very distinctive clinical and immunological features, its clinical profile is not unique; other helminths sometimes induce similar presentations. We carefully evaluated 7 individuals with non-filarial TPE-like syndromes and found that serological tests based on detection of 'antifilarial' immunoglobulin (Ig) G, IgG4, and IgE antibodies that are usually considered diagnostic for filarial TPE were equally elevated in patients with non-filarial, TPE-like syndromes and were therefore unhelpful diagnostically. The apparent reasons were immunological hyper-responsiveness of such individuals and the shared (i.e., cross-reactive) antigenicity found in the filarial antigen preparations used routinely for diagnosis. Because appropriate treatment for those different pulmonary eosinophilia conditions requires different drugs and management, and because delay in effective treatment results in significant morbidity in such patients, diagnostic capabilities must be improved by identifying and obtaining unique antigens that can serologically discriminate between filarial TPE and other similar, but non-filarial, pulmonary eosinophilia syndromes.


Survival of Hydroxyapatite-Coated Versus Non-hydroxyapatite-Coated Total Hip Arthroplasty Implants in a Veteran Population.
Hydroxyapatite (HA) coatings were introduced to improve uncemented implant osteointegration and to prevent loosening and osteolysis. However, data regarding these implants have been inconsistent. We studied the effect of HA coating of femoral stems and acetabular cups on component revision after primary total hip arthroplasty (THA) in the veteran population. We identified patients who underwent uncemented primary THA at any Veterans Health Administration (VHA) hospital from 2000 to 2017 and who had implants that were available as either HA-coated or non-HA-coated models. The endpoint was removal of the component of interest for any reason. For each individual stem and shell, unadjusted and adjusted (for age and body mass index) Cox proportional hazards models were used to estimate hazard ratios for the risk of explantation between HA-coated and non-HA-coated implants of the same type. A total of 262 HA-coated cups, 4580 non-HA-coated cups, 4767 HA-coated stems, and 9397 non-HA-coated stems were available for analysis. The mean follow-up time was 9.01 years (43,627 total implant-years) for cups and 7.13 years (101,004 total implant-years) for stems. One of the two shells reviewed had significantly lower survivorship and an elevated hazard ratio for explantation with HA coating. Among the five implant pairs of stems, and the other shell, implant survival and hazard ratios for explantation were not affected by HA coating. HA coating did not improve THA implant survival in our veteran population. Although HA-coated versions of hip implants tend to be more costly than their noncoated counterparts, these results do not support their general use.


A revised method for generation of unitary postsynaptic potentials for quantal analysis in the hippocampus.
For quantal analysis of excitatory postsynaptic potentials (EPSPs) in hippocampal CA3 neurons, a method was devised to evoke trains of unitary EPSPs at intended intervals and to control the number of unitary EPSPs composing each train at will. The amplitudes of the first EPSPs in EPSP trains evoked with this method were measured. From the mean and variance of the EPSP amplitudes, the mean number of quanta (m) released by a single impulse and the mean amplitude of EPSPs induced by individual quanta (q) were estimated in a standard solution and in a high calcium solution.


Acute bone marrow aplasia associated with intravenous administration of deferoxamine (desferrioxamine).
The authors report the clinical course and fatal outcome of a case of acute bone marrow aplasia, after intravenous administration of deferoxamine (desferrioxamine) to a 16-year-old girl with homozygous beta-thalassaemia. The type of aplasia was mainly that of a megakaryocytic thrombocytopenia, but the 2 other haemopoetic series were also involved. The absence of any other toxic factors and the quite rapid onset of the bone marrow failure after this type of treatment strongly suggest that intravenous administration of high doses of deferoxamine was the potential toxic factor.


Detection of gene loops by 3C in yeast.
"Chromosome conformation capture" (3C) is a powerful method to detect physical interaction between any two genomic loci. 3C involves formaldehyde crosslinking to stabilize transient interactions, followed by restriction digestion, ligation and locus-specific PCR. Accordingly, 3C reveals complex three-dimensional interactions between distal genetic elements within intact cells at high resolution. Here, we describe a modified 3C protocol designed for detection of transient chromatin interactions in the yeast Saccharomyces cerevisiae. Using this protocol, we are able to detect juxtaposition of promoter and terminator regions of genes with ORFs as short as 1kb in length. We anticipate that this method will be generally applicable to detect dynamic, short-range chromatin interactions and will facilitate the characterization of gene loops and their functional consequences.


Regulation of stress-induced reduced myelopoiesis in rats.
In this work we demonstrate that the stress-induced reduction in bone marrow granulocyte-macrophage colonies, reported previously from our laboratory, is prevented by both the inhibition of the hypothalamic-pituitary-adrenal axis (HPAA) and the blockage of opioid receptors. The inhibition of the HPAA was obtained through the administration of dexamethasone (1 mg/kg). The blockage of opioid receptors was done in two ways, by the administration of naltrexone (8 mg/kg) and induction of tolerance to morphine. On the other hand, no protection was observed in metyrapone treated rats. We suggest that the two physiological systems, opioid and HPAA, mediate the stress-induced myelosuppression and that these systems may function independently in this particular situation.


Electron microscopy of treponemes subjected to the Treponema pallidum immobilization (TPI) test. I. Comparison of immunoimmobilized cells and control cells.
The ultrastructure of cells of T. pallidum Nichols subjected to the TPI test was studied in negatively stained specimens. Cells incubated in basal medium to which was added either human syphilis serum or heated guineapig serum (GPS) showed a normal morphology. This was also the cause for cells incubated with basal medium to which was added either human syphilis serum and heated GPS or normal human serum and unheated GPS. By dark-field microscopy cells obtained from these different incubation mixtures were found to be motile. In contrast, cells incubated in basal medium to which was added human syphilis serum and unheated GPS were all immobilized, and in the electron microscope they presented a morphology strikingly different from that of normal cells. The immunoimmobilized cells were swollen and their surface was completely covered with a layer of fuzzy material. The nature of this material and its possible role in rendering the treponemes immobile is discussed.


An update on the available and emerging pharmacotherapy for adults with testosterone deficiency available in the USA.
Introduction: Testosterone deficiency (TD) is defined as low serum testosterone associated with symptoms and signs. There has been an increasing prevalence of TD in recent decades, especially in males aged 15-39. Many of these men will require long-term testosterone therapy (TT). Although the end-goals for all treatments are essentially the same, strategies for increasing serum testosterone should be decided individually.Areas covered: This review focuses on the pharmacological management of TD in adults which includes TT with different routes of administration, such as transdermal, buccal, intramuscular and subcutaneous injections, pellets, nasal gel, and oral (pills). The authors review the options for TT available in the USA with emphasis on newer therapies. Furthermore, they examine the efficacy of these therapies with comparison between potential advantages or disadvantages related to dosing, administration method, and adverse events.Expert opinion: Treating TD can be difficult due to the wide range of available medications, diverse side effects related to testosterone replacement and route-of-administration, and necessity for long-term therapy. The combination of pharmacological and non-pharmacological therapies can improve symptoms of TD and patient satisfaction. Each patient should be managed individually, and clinicians should consider available treatment regimens based on the route-of-administration, efficacy, safety, and cost based on a shared decision-making approach.


A model of the burglar alarm hypothesis of prey alarm calls.
When approached by a predator many prey species will emit an "alarm call" as a form of anti-predator behavior. One hypothesis for the function of alarm calls is the "burglar alarm" hypothesis whereby upon attack, a prey renders itself dangerous to a predator by generating an alarm call that attracts a predator at higher trophic levels in the food chain; that is, attracts a predator to the prey's own predator. This paper concerns a model incorporating a mechanism to test the burglar alarm hypothesis. We prove in one space dimension global existence, of positive bounded classical solutions, and establish existence of non-constant equilibrium solutions and assess their stability. We provide some representative numerical simulations to emphasize the nature of pattern formation for this model and demonstrate the benefit achieved by a signal inducing prey species under the burglar alarm hypothesis.


Improved response rate in patients with prognostically poor locally advanced rectal cancer after treatment with induction chemotherapy and chemoradiotherapy when compared with chemoradiotherapy alone: A matched case-control study.
The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics. Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics.


The multi-functional role of insulin-like growth factor binding proteins in bone.
The insulin-like growth factor (IGF) system is an important regulator of bone formation. The IGFs (IGF-I and IGF-II) are the most abundant growth factors produced by bone, and are regulated by their six high affinity binding proteins (IGFBPs). The IGFBPs are produced by osteoblasts and are responsible for transporting the IGFs and extending their half-lives. In general, IGFBP-1, -2, -4, and -6 inhibit and IGFBP-3 and -5 stimulate osteoblast function. IGFBP-4 and -5 are the most abundant IGFBPs produced by osteoblasts, and therefore they are the primary focus of this review. IGFBP-5 is an important stimulator of bone formation and may also function independently of IGFs. IGFBP-4 inhibits osteoblast function by sequestering IGF and preventing it from binding to its receptor. This review focuses on the specific IGF-dependent and IGF-independent roles of the IGFBPs in bone formation, as well as their potential mechanisms of action. In addition, discussion of the regulation of the IGFBPs by post-translational modification (i.e., proteolysis) has been included. Studies on the regulation of production and actions of IGFBPs suggest that the IGFBP system in bone is pleiotropic and capable of serving multiple effector inputs from systemic and local sources.


France's blood scandal draws blood.
The trial in France of four government officials for complicity in the use of contaminated blood may have ended with the verdicts announced last Friday, but the recriminations will continue.


Overexpression of delta-opioid receptors in recombinant baculovirus-infected Trichoplusia ni "High 5" insect cells.
"High 5" cells derived from Trichoplusia ni ovaries were infected with baculovirus bearing the cDNA of the mouse delta-opioid receptor. The maximal binding capacity for the narcotic antagonist [3H] naltrindole was 1.4 pmol/mg of membrane protein, and that for the agonist [3H][D-penicillamine2,D-penicillamine5]enkephalin (DPDPE) was 0.3 pmol/mg. DPDPE proved highly potent in competing with its tritiated analogue at delta-receptors of NG108-15 hybrid cells and of High 5 and Sf9 insect cells. However, in insect cells the opioid was more than 100-fold less effective in competing with [3H]naltrindole as compared with the mammalian cells. This decline in potency was counteracted in a dose-dependent manner by exposure of High 5 membranes to the exogenous G protein G(o), which increased the binding capacity for DPDPE. Functional studies revealed a dose-dependent inhibition (up to 30%) by opioids on forskolin-stimulated cyclic AMP synthesis, and this effect was potentiated by G(o). Quantification of G alpha o and G alpha i disclosed striking differences between Sf9 and High 5 insect cells, both of which overexpressed the cloned delta-opioid receptor. Although no inhibitory G proteins were detected in membranes of Sf9 cells, High 5 cells contained 0.5 pmol of G alpha o/mg of membrane protein, and a 20-fold higher concentration for G alpha i. The distinct G-protein expression in insect cells may be considered an advantage for studying functions of G protein-coupled receptors.


Anxiety-like behavior in female mice is modulated by STAT3 signaling in midbrain dopamine neurons.
The central signaling actions of cytokines are mediated by signal transducer and activator of transcription (STAT3). STAT3 activation plays a pivotal role in the behavioral responses to the adiposity hormone leptin, including in midbrain dopamine (DA) neurons where it mediates the influence of leptin to diminish physical activity and running reward in male mice. Leptin also has anxiolytic effects which have been tied to the mesolimbic DA system. To assess the contribution of STAT3 signaling in mesolimbic DA neurons on feeding, mesolimbic DA tone and anxiodepressive behaviors in female mice, we generated DA-specific STAT3 knockout mice by crossing mice expressing Cre under the control of the dopamine transporter with STAT3-LoxP mice. Feeding, locomotion, wheel running, conditioned place preference for palatable food and amphetamine locomotor sensitization were unaffected by DA-specific STAT3 deletion. Conversely, knockout mice exhibited heightened anxiety-like behavior (open field test and elevated plus maze) along with increased basal and stress-induced plasma corticosterone, whereas indices of behavioral despair (forced swim and tail-suspension tasks) were unchanged. In accordance with biochemical evidence of increased D1 receptor signaling (phospho-DARPP32Thr34) in the central nucleus of the amygdala (CeA) of knockout mice, local microinjections of a D1 receptor antagonist reversed the anxiogenic phenotype of knockout mice. In addition to alluding to sex differences in the signaling mechanisms mediating anxiety-like behavior, our findings suggest that activation of STAT3 in midbrain dopamine neurons projecting to the CeA dampens anxiety in a D1R-dependent manner in female mice.


Smoking Obstructive Sleep Apnea: Arguments for a Distinctive Phenotype and a Personalized Intervention.
This is the first study that aims to define smoking, with obstructive sleep apnea (OSA), as a phenotype (SOSA). Moreover, we wanted to demonstrate the deleterious effects of the continuation of smoking on OSA. The cross-sectional study highlighted four dimensions of SOSA: the demographic and anthropometric features, the symptoms, the comorbidities, and the sleep study parameters. This study compared these characteristics between current smokers (CS), those who have never smoked (NS), and ex-smokers (ES) with OSA. More men (83.95% in CS, versus 66.67% in NS) and an earlier onset of OSA (average age = 50.05 in CS, versus 52.26 in NS, p = 0.04) were recorded among CS. The distinguishing symptom of CS was daytime sleepiness, with an Epworth score that was significantly higher than in NS. Chronic obstructive pulmonary disease (COPD) was significantly more prevalent in CS (38.27%) than in NS (1.51%) (p < 0.001). The severity of OSA, consisting of a higher apnea-hypopnea index, a higher oxygen desaturation index, and a longer time spent below 90% oxygen saturation during sleep was significantly influenced by smoking. The SOSA phenotype includes younger male patients with a higher waist circumference, suggesting central obesity. They have a higher prevalence of COPD and a greater severity of OSA, in correlation with the number of pack-years of smoking.


RETRA induces necroptosis in cervical cancer cells through RIPK1, RIPK3, MLKL and increased ROS production.
Cervical cancer is the fourth most prevalent cancer in women worldwide, predominantly infected with human papillomavirus (HPV). The current chemo and radiotherapies are mostly futile due to acquired resistance to apoptosis and warrant new therapeutic approaches targeting potent non-apoptotic cell death pathways to eliminate cervical cancer cells. Induction of necroptosis by pharmaceutical interventions is emerging as a promising tool in multiple apoptotic resistant cancer cells. RETRA (REactivation of Transcriptional Reporter Activity) is a small molecule known to induce expression of p53 regulated genes in mutant (mt) p53 cells but, detailed mechanisms of its anticancer effects are poorly known. The present study investigated the potentials of RETRA as an anticancer agent and found that it induces necroptosis selectively in cervical cancer cells irrespective of p53 status through the phosphorylation of receptor-interacting protein kinase 1,3 (RIPK1, RIPK3) and mixed lineage kinase domain-like protein (MLKL) with no cytotoxic effects in normal human peripheral blood mononuclear cells (PBMCs). RETRA-treated cells also displayed necroptotic morphology of disintegrated plasma membranes with intact nuclei and also showed cell cycle arrest at the S phase with the upregulation of p21 and downregulation of cyclin-D3. Intriguingly, the combinatorial approach of using RETRA with Necrostain-1, a known inhibitor of necroptosis, reversed the effect of RETRA and rescued cell death. Moreover, induction of necroptosis by RETRA is associated with mitochondrial hyperpolarization and elevated ROS production. Collectively, these findings suggest that RETRA induces cell death via necroptosis with increased production of ROS, accentuating the therapeutic implication of RETRA in cervical cancer cells.


A tutorial on protein ontology resources for proteomic studies.
The protein ontology (PRO) is designed as a formal and well-principled open biomedical ontologies (OBO) foundry ontology for proteins. The components of PRO extend from the classification of proteins, on the basis of evolutionary relationships at the full-length level, to the representation of the multiple protein forms of a gene, such as those resulting from alternative splicing, cleavage and/or posttranslational modifications, and protein complexes. As an ontology, PRO differs from a database in that it provides description about the protein types and their relationships. In addition, the representation of specific protein types, such as a phosphorylated protein form, allows precise definition of objects in pathways, complexes, or in disease modeling. This is useful for proteomics studies where isoforms and modified forms must be differentiated, and for biological pathway/network representation where the cascade of events often depends on a specific protein modification. PRO is manually curated starting with content derived from scientific literature. Only annotation with experimental evidence is included, and is in the form of relationship to other ontologies. In this tutorial, you will learn how to use the PRO resources to gain information about proteins of interest, such as finding conserved isoforms (ortho-isoforms), and different modified forms and their attributes. In addition, it will provide some details on how you can contribute to the ontology via the rapid annotation interface RACE-PRO.


Candida tropicalis cellulitis in a patient with cirrhosis, well-controlled HIV and diabetes.
We present the case of a patient with multiple comorbidities, including cirrhosis, poorly controlled diabetes mellitus and HIV infection, who was diagnosed with skin and soft-tissue infection of right lower limb. Outcome was poor after prescribing standard antibiotic therapy, and we finally obtained isolation of Candida tropicalis in cultures of infected tissue. The patient's condition improved after antifungal treatment was started, and he could be discharged with oral therapy. Here, we report the literature's first case of cellulitis provoked by C. tropicalis in a patient with cirrhosis.


Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis.
Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-γ) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8-24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5%, compared to 67% in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100%. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response.


Regeneration of gamma-fusimotor axons after nerve-freeze injury in the cat.
Nerve injury was produced by application of dry ice to the common peroneal nerve. After 20 weeks, muscle-spindle primary endings responded normally to stretch and the spindles were found to have a fully functional fusimotor innervation.


Non-Bee Insects as Visitors and Pollinators of Crops: Biology, Ecology, and Management.
Insects other than bees (i.e., non-bees) have been acknowledged as important crop pollinators, but our understanding of which crop plants they visit and how effective they are as crop pollinators is limited. To compare visitation and efficiency of crop-pollinating bees and non-bees at a global scale, we review the literature published from 1950 to 2018 concerning the visitors and pollinators of 105 global food crops that are known to benefit from animal pollinators. Of the 105 animal-pollinated crops, a significant proportion are visited by both bee and non-bee taxa (n = 82; 77%), with a total gross domestic product (GDP) value of US$780.8 billion. For crops with a narrower range of visitors, those that favor non-bees (n = 8) have a value of US$1.2 billion, compared to those that favor bees (n = 15), with a value of US$19.0 billion. Limited pollinator efficiency data were available for one or more taxa in only half of the crops (n = 61; 58%). Among the non-bees, some families were recorded visiting a wide range of crops (>12), including six families of flies (Syrphidae, Calliphoridae, Muscidae, Sarcophagidae, Tachinidae, and Bombyliidae), two beetle families (Coccinelidae and Nitidulidae), ants (Formicidae), wasps (Vespidae), and four families of moths and butterflies (Hesperiidae, Lycaenidae, Nymphalidae, and Pieridae). Among the non-bees, taxa within the dipteran families Syrphidae and Calliphoridae were the most common visitors to the most crops, but this may be an artifact of the limited data available. The diversity of species and life histories in these groups of lesser-known pollinators indicates that diet, larval requirements, and other reproductive needs will require alternative habitat management practices to bees.


Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.
T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.


Interaction of bovine renal mitochondrial cytochrome P-450 with antioxidants.
The antioxidants butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguiaretic acid (NDGA), benzyl sulfoxide (BS), ferulic acid (FA), caffeic acid (CA), dimethyl sulfoxide (Me2SO), protocatechuic acid (PCA), and P-450 inhibitor metyrapone all acted to slow the previously noted loss of vitamin D3 1 alpha-and 24-hydroxylase activities in cultured bovine proximal tubule cells. The slowing of the loss of hydroxylase activities by antioxidants was increased by culturing cells in 5% O2 vs 19% O2. These same antioxidants also directly inhibited 1 alpha- and 24-hydroxylase activities. For a single antioxidant, or metyrapone, Ki's for inhibition of both hydroxylases were equal, ED50's for stabilization of both hydroxylase activities were equal, and Ki's and ED50's were not significantly different. These antioxidants prevented tert-butylhydroperoxide (tert-BOOH)-mediated proximal tubule cell death at concentrations, i.e., 0.1 mM, which were effective in stabilizing hydroxylase activities. When added together, the antioxidants H2SeO3, uric acid, and trolox c gave slight stabilization of hydroxylase activities without inhibiting hydroxylase activities. Singly, these antioxidants did not stabilize or directly inhibit hydroxylase activities. This antioxidant combination augmented BHA- or BHT-mediated stabilization of both hydroxylase activities independent of any effects on inhibition. But the most potent antioxidants which acted to stabilize hydroxylase activities in culture also directly acted to inhibit hydroxylase activities. Antioxidant effects were additive for both inhibition and stabilization of hydroxylase activities. Stabilization of hydroxylase activities was dissociated from inhibition in the presence of maximal FA, CA, and BHA or FA, CA, and BHT combinations. Bovine renal mitochondrial cytochrome P-450 levels decreased in cultured bovine proximal tubule cells to nondetectable levels by 8 days in culture. When cultures were treated with BHA and BS, mitochondrial P-450 levels were almost twofold greater than in untreated controls. Percentage changes in mitochondrial P-450 levels closely paralleled percentage changes in hydroxylase activities elicited by antioxidant treatment regimes. Antioxidants which were effective inhibitors of hydroxylase activities in cultured bovine proximal tubule cells were also effective in inhibiting hydroxylase activities in isolated proximal tubule mitochondria, supplemented with a NADPH-generating source. Ki's for inhibition of hydroxylase activities were very similar in cultured cells and in isolated mitochondria.(ABSTRACT TRUNCATED AT 400 WORDS)


Assessment of Iranian orthodontists' practice with regard to the prevention and treatment of white spot lesions.
White spot lesions (WSLs) are common adverse effect of orthodontic treatment, which can be prevented and treated by orthodontists. This study was conducted to assess Iranian orthodontists' practice regarding the prevention and treatment of WSLs in their patients. In this cross-sectional study, 109 Iranian orthodontists were selected from the Iranian Association of Orthodontists' directory by cluster sampling. For data collection, a questionnaire was designed and its validity and reliability was confirmed (Cronbach's α =0.85). The questionnaire included eight general questions and eight questions about practice with regard to the prevention and treatment of WSL. Data were analyzed by descriptive tests, ANOVA test, and t-test in SPSS 20 software. P < 0.05 was considered statistically significant. The mean score of orthodontists' practice was 7.62 (range: 0-8), and 94.4% of the participants were rated as good, while 3.7% and 1.9% were rated as moderate and weak, respectively. Women's score was significantly higher than that of men (P = 0.001). With increasing participants' age, their practice has been improved (P = 0.001), but there was no significant relation between years of experience and their practice (P = 0.230). Nearly 94.4% of the orthodontists prescribed fluoride products. Toothpastes and fluoride mouth rinses were the most common prescribed products (34%). With regard to Iranian orthodontists' practice, it was fortunate to note that majority of the respondents were taking care of their patients with regarding to the prevention and treatment of WSLs. For enhancing their competencies, it is recommended to plan educational courses which are useful for promoting their knowledge and practice about new products and procedures used for the prevention and treatment of WSLs.


A high-resolution MS/MS based strategy to improve xenobiotic metabolites analysis by metabolic pathway extension searching combined with parallel reaction monitoring: Flavonoid metabolism in wound site as a case.
For the analysis of xenobiotic metabolism, metabolites are commonly qualified by high-resolution mass spectrometry such as orbitrap or time-of-flight mass spectrometers, and quantified by triple-quadrupole (QQQ) mass spectrometer based multiple reaction monitoring. While this workflow shows drawback in the difficulty for instrumental parameters transfer, and QQQ provides less specificity. In this work, we constructed a high-resolution MS/MS (HR-MS/MS) based strategy to improve the discovery and quantification of unknown xenobiotic metabolites by metabolic pathway extension (MPE) searching combined with parallel reaction monitoring (PRM). Taking the flavonoid metabolism in diabetes wound S9 incubates as a test case. Firstly, MPE approach was used to screen all potential metabolites. In this step, an m/z value library of all theoretic flavonoid metabolites were constructed based on predefined flavonoid structures through 21 common xenobiotic metabolic reactions, and this library was matched with all features extracted from raw data (MS1 scan) of flavonoid-S9 co-incubate, then the matched features were exported into target list for MS2 fragmentation for structure validation. Secondly, the metabolites were relatively quantified by PRM mode based on their characteristic product ions. As a result, 131 metabolites of 9 different kinds of flavonoids in the skin and muscle were identified. To our best knowledge, this is the first report on the metabolism of flavonoids in the skin or muscle tissue. The results also validated the proposed HR-MS/MS-based strategy provided high specificity throughout both discovery and quantitation process of unknown xenobiotic metabolites without need of instrumental parameter transfer.


[Epidemiology of dyslipidemias in a general adult population of the basic health area "La Orden de Huelva"].
To find the prevalence of dyslipaemias in the general adult population. A crossover epidemiological study of a population base. Primary Care. "La Orden" Health Centre, Huelva. 878 people over 19 chosen by random sampling stratified according to age and gender; obtained from the 1991 Municipal Census covering our Health area. 802 people completed the study, which included a survey of demographic data, personal histories, cigarette consumption and recordings of weight, height, blood pressure, glycaemia, total cholesterol (TC), cHDL, cLDL, and triglycerides (TG). Prevalence of Hypercholesterolaemia (TC > 250) was 25.5% (CI 95%: 22.4-28.6); breaking down as 28.7% in men and 22.5% in women. Hypertriglyceridaemia (TG > 200) was 8.9% (CI 95%: 6.2-11.6); 15% in men and 3.2% in women. cHDL < 35 was 3.5% (CI: 2.2-4.8); 5.7% in men and 1.5% in women. cLDL > 150 was 43.6% (CI: 40.1-47.1%); 48.9% in men and 41.4% in women. Multiple linear regression showed links of TC and cLDL to age (p < 0.001). TGs increase in line with age, the Quetelet index (QI) and cigarette consumption (CC) (p < 0.001). cHDL diminishes in line with increases in the QI and CC (p < 0.0001). Given the high levels of dyslipaemias found, intervention measures must be based on the search for lipid disturbances in patients attending clinics as well as on strategies directed towards modifying hygiene-dietary habits, something necessary for over 70% of the population.


Lumbar bone mineral density in normal subjects aged 3-6 years: a prospective study.
Longitudinal studies on bone mineral density (BMD) accrual in young children are scarce. The purpose of the present study was to evaluate prospectively the development of spinal BMD in healthy Finnish children aged 3-6 y by dual-energy x-ray absorptiometry (DXA). Lumbar spine (L2-L4) areal BMD (g/cm2) was measured by DXA (Lunar DPX) in 20 children (10M, 10F) aged 3.3-6.9 y (median 4.8 y) at baseline and after a median follow-up of 1.0y (range 0.8-1.1 y). Apparent volumetric BMD (BMDvol, g/cm3) was calculated to minimize the effect of bone size on BMD in growing spine. At baseline, lumbar areal and volumetric BMDs (mean +/- SD) for males were 0.623+/-0.087 g/cm2 and 0.270+/-0.034 g/cm3, respectively, and for females 0.620+/-0.082 g/cm2 and 0.254+/-0.035 g/cm3, respectively. During the median follow-up of 1 y, lumbar areal and volumetric BMDs (mean +/- SD) increased in males by 4.7+/-2.7% (p < 0.01) and 3.5+/-3.5% (p <0.05), respectively, and in females by 7.2+/-5.3% (p <0.01) and 3.1+/-3.1% (p <0.05), respectively. No statistically significant difference in the BMD values was observed between the sexes. A significant increase in both areal and apparent volumetric BMD was observed in children aged 3-6 y during a follow-up of I y. The increase in volumetric BMD indicated that there was a real accrual of BMD in growing spine measured by DXA. The present study provides prospective data on BMD accrual in young children for the evaluation of bone mass development in early childhood.


Adenoma of the ampulla of Vater: a case report.
Lesions of the ampulla of Vater are rare histological entities with an incidence of between 0.1 and 0.2% of gastrointestinal tumors. Until recently the main response to this kind of lesion was duodenopancreatectomy, regardless of the cellular atypia and local edema. In this study, we propose the application of transduodenal local excision of the ampulla of Vater especially in recognized cases of nonmalignant adenomas. In this case report we analyze the case of a 78-year-old Greek man who revealed symptoms such as icterus, abdominal pain without constipation and bloody stools. A physical examination showed painless swelling of the gallbladder (Courvoisier sign). No previous abdominal operations or hernias were identified. Blood tests, computed tomography scan analysis, gastroscopy and endoscopic retrograde cholangiopancreatography along with biopsies and cytological tests diagnosed nonmalignant adenoma of the ampulla of Vater with high-grade dysplasia. The treatment we followed was transduodenal local excision of his ampulla of Vater. Transduodenal local excision of the ampulla of Vater has limited side effects and postoperative complications, suggesting this particular technique to be the proper treatment for nonmalignant cases of adenomas.


Minimal incision surgical approach to sesamoid pathology.
Medical and lateral sesamoid problems, subhallucal sesamoid problems, and pinch callous problems are discussed in this article. Surgical procedures are described.


Benzalkonium Chloride, Even at Low Concentrations, Deteriorates Intracellular Metabolic Capacity in Human Conjunctival Fibroblasts.
The objective of this study was to clarify the effects of benzalkonium chloride (BAC) on two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblast (HconF) cells, which are in vitro models replicating the epithelial barrier and the stromal supportive functions of the human conjunctiva. The cultured HconF cells were subjected to the following analyses in the absence and presence of 10-5% or 10-4% concentrations of BAC; (1) the barrier function of the 2D HconF monolayers, as determined by trans-endothelial electrical resistance (TEER) and FITC dextran permeability, (2) real-time metabolic analysis using an extracellular Seahorse flux analyzer, (3) the size and stiffness of 3D HconF spheroids, and (4) the mRNA expression of genes that encode for extracellular matrix (ECM) molecules including collagen (COL)1, 4 and 6, and fibronectin (FN), α-smooth muscle actin (α-SMA), ER stress related genes including the X-box binding protein-1 (XBP1), the spliced XBP1 (sXBP1) glucose regulator protein (GRP)78, GRP94, and the CCAAT/enhancer-binding protein homologous protein (CHOP), hypoxia inducible factor 1α (HIF1α), and Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α). In the presence of BAC, even at low concentrations at 10-5% or 10-4%, the maximal respiratory capacity, mitochondrial respiratory reserve, and glycolytic reserve of HconF cells were significantly decreased, although the barrier functions of 2D HconF monolayers, the physical properties of the 3D HconF spheroids, and the mRNA expression of the corresponding genes were not affected. The findings reported herein highlight the fact that BAC, even such low concentrations, may induce unfavorable adverse effects on the cellular metabolic capacity of the human conjunctiva.


Co-biomembrane-coated Fe3O4/MnO2 multifunctional nanoparticles for targeted delivery and enhanced chemodynamic/photothermal/chemo therapy.
Here, the co-membrane system of MCF-7 breast cancer cell membrane (MM) and Escherichia coli membrane (EM)-coated Fe3O4/MnO2 multifunctional composite nanoparticles loaded with DOX (Fe3O4/MnO2/MM/EM/D) was used for targeted drug delivery and biological imaging.


Evolución clínica de trabajadores con fractura de radio distal Fernández III. Tratamiento no complicado quirúrgico y no quirúrgico.
Las fracturas de radio distal Fernández III (FRDF III) son una urgencia muy frecuente. Las indicaciones quirúrgicas y no quirúrgicas persisten controversiales, así como el impacto funcional. Comparar la evolución clínica de los trabajadores con FRDF III, con manejo quirúrgico frente a no quirúrgico, no complicados, en un hospital especializado. Estudio comparativo, observacional y longitudinal en trabajadores con FRDF III unilateral cerrada, de ambos sexos, con evolución menor de 5 días. Se excluyeron pacientes con comorbilidad afectante de consolidación ósea y polifracturados. Se eliminaron aquellos con información incompleta, con complicaciones, con aparato de yeso modificado 5 días después de su colocación, con mala reducción-estabilización acorde a la AO. Se aplicó la Escala Funcional de Mayo para Muñeca (EFMM) a los 3 y 6 meses del tratamiento. Se utilizó la prueba t de Student. 159 pacientes, 34% mujeres, 66% hombres. Edad promedio 40.18 años. Manejo quirúrgico 42,5% (placa 8.7%, fijador 29%, fijador + clavillo 8.7%); no quirúrgico 33%. Diferencias significativas (p ≤ 0.05): EFMM 3 y 6 meses; a 3 meses: dolor, prensión; a 6 meses: movilidad; y días totales de incapacidad. El tratamiento quirúrgico muestra mejores resultados funcionales, destacando el dolor y la prensión a 3 meses, y la movilidad a 6 meses, con reincorporación laboral en menos tiempo. This fracture is a very frequent emergency. Surgical and non-surgical management are still controversial, such as functional impact. To compare clinical evolution of Fernandez III distal radius fractures, managed with surgically vs no surgical treatment, in a specialized hospital. Comparative, observational, longitudinal study, released on workers with unilateral Fernandez III closed distal radius fractures, both sex, with evolution less than 5 days. Those patients with pathologies getting difficult in bone consolidation, and with several fractures were excluded. Those with incomplete information, complicated, and whom paste were modified after 5 days, and with bad reduction or stabilization fracture according AO were eliminated. Mayo Functional Wrist Scale (EFMM) was applied at 3 and 6 months. Student-t test was applied. 159 patients recruited, 34% females, 66% males. Medium age 40 years old. Surgical treatment 42.5% (plaque 8.7%, external fixation 29%, external fixation and nails 8.7%). Non-surgical treatment 33%. Significative differences (p≤0.05): EFMM at 3 and 6 months; pain, grasp at 3 months; mobility at 6 months; total laboral inhability days. Surgical treatment shows better functional results, specially pain and grasp at 3 months, mobility at 6 months, and faster returning to work.


Apraxia, pantomime and the parietal cortex.
Apraxia, a disorder of higher motor cognition, is a frequent and outcome-relevant sequel of left hemispheric stroke. Deficient pantomiming of object use constitutes a key symptom of apraxia and is assessed when testing for apraxia. To date the neural basis of pantomime remains controversial. We here review the literature and perform a meta-analysis of the relevant structural and functional imaging (fMRI/PET) studies. Based on a systematic literature search, 10 structural and 12 functional imaging studies were selected. Structural lesion studies associated pantomiming deficits with left frontal, parietal and temporal lesions. In contrast, functional imaging studies associate pantomimes with left parietal activations, with or without concurrent frontal or temporal activations. Functional imaging studies that selectively activated parietal cortex adopted the most stringent controls. In contrast to previous suggestions, current analyses show that both lesion and functional studies support the notion of a left-hemispheric fronto-(temporal)-parietal network underlying pantomiming object use. Furthermore, our review demonstrates that the left parietal cortex plays a key role in pantomime-related processes. More specifically, stringently controlled fMRI-studies suggest that in addition to storing motor schemas, left parietal cortex is also involved in activating these motor schemas in the context of pantomiming object use. In addition to inherent differences between structural and functional imaging studies and consistent with the dedifferentiation hypothesis, the age difference between young healthy subjects (typically included in functional imaging studies) and elderly neurological patients (typically included in structural lesion studies) may well contribute to the finding of a more distributed representation of pantomiming within the motor-dominant left hemisphere in the elderly.


Retinoblastoma associated with orbital pseudocellulitis and high-risk retinoblastoma: a study of 32 eyes.
To study the correlation between retinoblastoma (RB) associated with orbital pseudocellulitis and high-risk histopathology features. Retrospective study of 32 patients who underwent primary enucleation for RB presenting with orbital pseudocellulitis. All RB patients presented with orbital pseudocellulitis. The mean age at presentation of RB was 30 months (median, 24 months; range, 3-70 months). There were 14 (44%) males and 18 (56%) females. All patients were referred with a diagnosis of RB with orbital pseudocellulitis. Tumor was bilateral in 12 (38%) patients but orbital pseudocellulitis was unilateral in all cases. The pseudocellulitis features included proptosis (n = 9; 28%), eyelid edema (n = 22; 69%), conjunctival congestion (n = 23; 72%), and conjunctival chemosis (n = 15; 47%). Based on clinical features and orbital imaging, all patients were diagnosed to have group E intraocular RB. All patients received intravenous steroids prior to enucleation. On histopathology, tumor necrosis was present in all cases with a mean % necrosis of 60% (median, 60%; range, 10% to 90%). Most tumors (72%) were poorly differentiated. High-risk histopathology features were noted in 23 (72%) cases and adjuvant chemotherapy was advised for all these patients. The most common high-risk histopathology features included post-laminar optic nerve infiltration (34%) and scleral infiltration (22%). Over a mean follow-up period of 34 months (median, 9 months; range, < 1-188 months), there was no event of metastasis or death in any patient. RB presenting with orbital pseudocellulitis is associated with high incidence of high-risk histopathology features.


Autologous hematopoietic stem cell transplantation-what determines the outcome: an experience from North India.
Limited information is available from developing countries about complications, pattern of infections, and long-term outcome of patients following high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ASCT). Between April, 1990 and December 2009, 228 patients underwent ASCT. Patients' median age was 48 years, ranging from 11 to 68 years. There were 158 males and 70 females. Indications for transplant included multiple myeloma, n = 143; lymphoma, n = 44 (Hodgkin's, n = 25 and non-Hodgkin's, n = 19); leukemia, n = 22; and solid tumors, n = 18. Patients received HDCT as per standard protocols. Following ASCT, 175 (76.7%) patients responded; complete, 98 (43%); very good partial response, 37 (16.2%); and partial response, 40 (17.5%). Response rate was higher for patients with good Eastern Cooperative Oncology Group (ECOG) performance status (0-2 vs. 3-4, p < 0.001), pretransplant chemo-sensitive disease (p < 0.001) and those with diagnosis of hematological malignancies (p < 0.003). Mucositis, gastrointestinal, renal, and liver dysfunctions were major nonhematologic toxicities, 3.1% of patients died of regimen-related toxicities. Infections accounted for 5.3% of deaths seen before day 30. At a median follow-up of 66 months (range, 9-234 months), median overall (OS) and event-free survival (EFS) were 72 months (95% CI 52.4-91.6) and 24 months (95% CI 17.15-30.9), respectively. For myeloma, OS and EFS were 79 months (95% CI 52.3-105.7) and 30 months (95% CI 22.6-37.4), respectively. Pretransplant good performance status and achievement of significant response following transplant were major predictors of survival. Our analysis demonstrates that such procedure can be successfully performed in a developing country with results comparable to developed countries.


Combined effect of buthionine sulfoximine and cyclophosphamide upon murine tumours and bone marrow.
Two and four treatments of 5 mmol kg-1 of buthionine sulfoximine (BSO) at an interval of 12 h depleted the glutathione (GSH) content in NFSa tumours of C3H/He mice, respectively, to 24.0 and 1.78 percent of the untreated controls. BSO pre-treatments every 12 h enhanced the cytotoxicity of cyclophosphamide (CYC) towards artificial lung micrometastases of NFSa tumours giving enhancement ratios (ERs) ranging from 1.75 to 1.83 and from 2.41 to 2.73, for two and four BSO pretreatments respectively. Large ERs were obtained at low CYC doses (high cell survival). Four BSO pre-treatments at an interval of 12 h did not increase the cytotoxicity of CYC to bone marrow stem cells. Our results suggest a clinical applicability of the combination of BSO and CYC.


Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature.
Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential DDIs in Iran in both inpatient and outpatient settings was relatively high, there is still no evidence of the incidence of actual DDIs. More extensive research is needed to identify and minimize factors associated with incidence of DDIs, and to evaluate the effects of preventive interventions especially those that utilize information technology.


Identification of the sequence motif of glycoside hydrolase 13 family members.
A bioinformatics analysis of sequences of enzymes of the glycoside hydrolase (GH) 13 family members such as α-amylase, cyclodextrin glycosyltransferase (CGTase), branching enzyme and cyclomaltodextrinase has been carried out in order to find out the sequence motifs that govern the reactions specificities of these enzymes by using hidden Markov model (HMM) profile. This analysis suggests the existence of such sequence motifs and residues of these motifs constituting the -1 to +3 catalytic subsites of the enzyme. Hence, by introducing mutations in the residues of these four subsites, one can change the reaction specificities of the enzymes. In general it has been observed that α -amylase sequence motif have low sequence conservation than rest of the motifs of the GH13 family members.


Involvement of endoplasmic reticulum stress response and IRE1-mediated ASK1/JNK/Mcl-1 pathways in silver nanoparticle-induced apoptosis of human retinal pigment epithelial cells.
Silver nanoparticles (AgNPs) have cytotoxic effects on various human cell types. The endoplasmic reticulum (ER) is very sensitive to cytotoxic damage. Retina tissue is easily affected by internal and external stimuli. However, the effect of AgNPs on human retinal cells is not known. This study examined the effect of AgNPs on ER stress induction and their mechanism of action in human retinal pigment epithelium (RPE) ARPE-19 cells. We found that AgNPs significantly increased ARPE-19 cell cytotoxicity and stimulated caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, as well as mitochondrial membrane potential (MMP) depolarization, in ARPE-19 cells in a dose-dependent manner (0.2-5 μg/mL for 18 h). AgNPs (5 μg/mL for 18 h) induced several signature ER stress markers, as indicated by the upregulated expressions of CCAAT/enhancer-binding protein-homologous protein (CHOP), phosphorylated protein kinase RNA-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), and inositol-requiring protein 1 (IRE1), and cleaved activating transcription factor 6 (ATF6). AgNPs also activated ASK1 and JNK in ARPE-19 cells, and induced increases in Bax and Puma expressions, as well as a decrease in Mcl-1 expression. However, inhibition of the ER stress response by pretreatment with 4-PBA included apparently and dose-dependently reduced levels of p-PERK, p-IRE1, CHOP, cleaved ATF6, p-ASK1, p-JNK, cleaved caspase-3, procaspase-12, and MMP depolarization in AgNP-treated ARPE-19 cells; it also led to significantly increased Mcl-1 protein levels in a dose-dependent manner in ARPE-19 cells. Pretreatment with JNK inhibitor SP600125 significantly attenuated caspase-3 cleavage and MMP depolarization and increased Mcl-1 protein levels in AgNPs-treated ARPE-19 cells in a dose-dependent manner. Hence, our study demonstrated that AgNPs induced apoptosis in human RPE ARPE-19 cells by ER stress response and ER stress-dependent mitochondrial apoptosis via the IRE1/ASK1/JNK/Mcl-1 pathways.


Highly Sensitive Fluorescent pH Microsensors Based on the Ratiometric Dye Pyranine Immobilized on Silica Microparticles.
Invited for the cover of this issue are Anil Chandra, Loretta L. del Mercato and co-workers at the Institute of Nanotechnology of National Research Council and the University of Salento. The image depicts how negatively charged pH-sensitive pyranine (HPTS) molecules were successfully immobilized on silica microparticles (SMPs) without compromising the molecules' pH sensitivity. These resulting sensors can be used to measure pH in vitro and in vivo due to the cytocompatibility of HPTS molecules and SMPs. Read the full text of the article at 10.1002/chem.202101568.


19-Hydroxybufalin inhibits non-small cell lung cancer cell proliferation and promotes cell apoptosis via the Wnt/β-catenin pathway.
Bufadienolides derived from the skin of toads are often regarded as the main active components with antitumor effects. 19-Hydroxybufalin (19-HB) is a monomer of bufadienolides; however, its effects and underlying molecular mechanisms on tumor growth remain to be ascertained. In this report, we focused on the antitumor effects of 19-HB on non-small cell lung cancer to provide a scientific basis for its further development and utilization. The antitumor effects of 19-HB on the human NSCLC cell lines NCI-H1299 and NCI-H838 were examined in vitro. The cells were treated with different concentrations of 19-HB, and the inhibition of cell growth was measured by CCK-8 and colony formation assays. Furthermore, cell apoptosis was analyzed by flow cytometry, TUNEL staining, JC-1 staining, and western blotting. The effects on migration and invasion were evaluated by wound-healing assay, transwell assay, and western blotting. Finally, the antitumor effects of 19-HB were evaluated in vivo using a xenograft mouse model. 19-HB-treated NSCLC cells showed inhibited cell viability and increased apoptosis. The expression levels of cleaved caspase-3, cleaved-PARP, and Bax/Bcl-2 were upregulated, while the mitochondrial membrane potential decreased. In contrast, migration, invasion, as well as the expression of MMP2, MMP7, MMP9, the epithelial-mesenchymal transition-related proteins N-cadherin and Vimentin, and the transcription factors Snail and Slug were inhibited. Furthermore, the expression levels of the key molecules in the Wnt/β-catenin signaling pathway (CyclinD1, c-Myc, and β-catenin) were decreased. In vivo, the growth of xenograft tumors in nude mice was also significantly inhibited by 19-HB, and there were no significant changes in biochemical indicators of hepatic and renal function. 19-HB inhibited the proliferation, migration, and invasion, and promoted the apoptosis of NSCLC cells via the Wnt/β-catenin pathway. In addition, 19-HB inhibited the growth of xenograft tumors in nude mice with little toxicity to the liver and kidney. Thus, 19-HB may be a potential antitumor agent for treating NSCLC.


High temperatures trigger suicide mortality in Brussels, Belgium: A case-crossover study (2002-2011).
Temperature may trigger the risk of suicide, however, the extent and shape of the associations show geographical variation. Here, we investigate the short-term effects of temperature on suicide deaths occurring in Brussels between January 1st, 2002 and December 31st, 2011. We conducted a bidirectional time-stratified case-crossover study with cases being suicide deaths occurring among Brussels residents aged 5 years or older. Cases were matched by day of the week with control days from the same month and year. The exposure was the daily average temperature measured at the Uccle station (Brussels) and obtained from the Belgian Royal Meteorological Institute. We combined conditional logistic regression with distributed lag non-linear models (DLNM) to obtain one week (lag 0-6) cumulative risk ratios (RR) and their 95% confidence intervals (CI) for the effects of moderate and extreme cold (5th and 1st percentiles of temperature, respectively) and moderate and extreme heat (95th and 99th percentiles of temperature, respectively), relative to the median temperature. In total, 1891 suicide deaths were included. The median temperature was 11.6 °C, moderate and extreme cold temperatures were 0 and -3.1 °C, respectively, and moderate and extreme high temperatures were 20.9 and 24.4 °C, respectively. The cumulative risk of suicide mortality was almost twice higher among lags 0 to 6 for both moderate and extreme heat, relative to the period median temperature (e.g. moderate heat RR = 1.80 CI:1.27-2.54). No statistically significant associations were observed for cold temperatures. In Brussels, a western European city with temperate climate, high temperatures may trigger suicide deaths up to one week later. In the context of climate change, adaptation strategies must take into consideration the effects of temperature on mental health.


Quantitative analysis of dendritic branching. I. Simple formulae for the quantitative analysis of dendritic branching.
Dendritic branching of neurons may be quantitatively studied using applications of graph theory. Dendritic ramifications may be considered as 'forests' of planted, stemmed, binary 'trees' with simple mathematical properties. Two fundamental numbers, that of dendritic tips and that of dendritic stems, usually suffice to quantify the dendritic branching of one neuron as, in most cases, they allow the computation of all other numbers of dendritic points and segments.


A functional ecological network based on metaproteomics responses of individual gut microbiomes to resistant starches.
Resistant starches (RS) are dietary compounds processed by the gut microbiota into metabolites, such as butyrate, that are beneficial to the host. The production of butyrate by the microbiome appears to be affected by the plant source and type of RS as well as the individual's microbiota. In this study, we used in vitro culture and metaproteomic methods to explore individual microbiome's functional responses to RS2 (enzymatically-resistant starch), RS3 (retrograded starch) and RS4 (chemically-modified starch). Results showed that RS2 and RS3 significantly altered the protein expressions in the individual gut microbiomes, while RS4 did not result in significant protein changes. Significantly elevated protein groups were enriched in carbohydrate metabolism and transport functions of families Eubacteriaceae, Lachnospiraceae and Ruminococcaceae. In addition, Bifidobacteriaceae was significantly increased in response to RS3. We also observed taxon-specific enrichments of starch metabolism and pentose phosphate pathways corresponding to this family. Functions related to starch utilization, ABC transporters and pyruvate metabolism pathways were consistently increased in the individual microbiomes in response to RS2 and RS3. Given that these taxon-specific responses depended on the type of carbohydrate sources, we constructed a functional ecological network to gain a system-level insight of functional organization. Our results suggest that while some microbes tend to be functionally independent, there are subsets of microbes that are functionally co-regulated by environmental changes, potentially by alterations of trophic interactions.


The effects of treadmill exercise in animal models of Parkinson's disease: A systematic review.
Parkinson's disease (PD) is a progressive disabling brain disorder. Physical exercise has been shown to alleviate the symptoms of PD and, consequently, improve patient quality of life. Exercise mechanisms involved in beneficial effects on PD have been widely investigated. This study aims to systematically review the literature on the use of treadmill exercise in PD animal models. The study was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Searches were conducted in MEDLINE, EMBASE, and ISI databases. In total, 78 studies were included. The dopaminergic system, behavior, neuroplasticity, neuroinflammation, mitochondria, and musculoskeletal systems were some of the outcomes evaluated by the selected studies. Based on the systematic review center for laboratory animal experimentation (SYRCLE) RoB tool, the methodologies revealed a high risk of bias and lack of information about study design, which needs attention for data reproducibility. This review can guide future studies that aim to fill existing gaps regarding the effects of treadmill exercise in PD animal models.


Evaluation of the effects of herpes simplex glycoprotein B on complement system and cytokines in in vitro models of Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder that causes memory loss and dementia and is characterized by a decline in cognitive functions. Brain infections, especially induced by herpes simplex virus type-1 (HSV-1), are suggested to play a key role in the pathogenesis of AD. Within the scope of this study, two different AD models (Tau model and amyloid beta [Aβ]) were created in the SH-SY5Y cell line, and HSV glycoprotein B (gB) was applied to the cell line and on the generated AD models. Study groups (n = 3) were designed as (1) control, (2) HSV-gB group, (3) retinoic acid (RA) and brain derived neurotrophic factor (BDNF) induced Alzheimer's model (AD), (4) RA and BDNF induced Alzheimer's model + HSV-gB (ADH), (5) Aβ 1-42 peptide-induced Alzheimer's model (Aβ), and (6) Aβ 1-42 peptide-induced Alzheimer's model + HSV-gB (AβH). Levels of complement proteins and cytokines were determined comparatively. In addition, specific markers of AD (hyperphosphorylated Tau proteins, Aβ 1-40 peptide and amyloid precursor protein) were measured in all groups. HSV-gB administration was found to increase Aβ and hyperphosphorylated Tau levels, similar to AD models. In addition, our data confirmed that the immune system and chronic inflammation might have a crucial role in AD development and that HSV-1 infection might also be an underlying factor of AD.


Resonant oscillators with carbon-nanotube torsion springs.
We report on the characterization of nanometer-scale resonators. Each device incorporates one multiwalled carbon nanotube (MWNT) as a torsional spring. The devices are actuated electrostatically, and their deflections, both low frequency and on resonance, are detected optically. These are some of the smallest electromechanical devices ever created and are a demonstration of practical integrated MWNT-based oscillators. The results also show surprising intershell mechanical coupling behavior in the MWNTs.


[Intestinal angiodysplasia as a cause of severe intestinal hemorrhage--report of 4 cases].
Angiodysplasia of the small intestine alone cannot be differentiated histologically from hereditary hemorrhagic telangiectasia (Morbus Rendu-Osler-Weber). Isolated localisation in the small intestine is rare and requires surgery in the event of massive bleeding. Four cases of bleeding from angiodysplasias of the small intestine in patients having undergone surgery at our institution over a ten-year period are presented. In three patients the particular intestine was resected. Two of these patients had an uneventful follow-up of even and ten years, one patient relapsed and was rehospitalized for surgical treatment. The fourth patient, who showed angiodysplasias scattered over the entire small intestine, had no further bleeding over a three-year period after transmural ligations of the lesions found by intraoperative endoscopical diaphany.


Prediction and evaluation of brainstem function by auditory brainstem responses in patients with uncal herniation.
Serial measurements of auditory brainstem-evoked responses (BERs) were conducted in 15 patients with supratentorial mass lesions. Significant prolongation of the latency of wave V BERs, which originates in the inferior colliculus, occurred when the intracranial pressure (ICP) approached 30 mmHg. In four of five patients whose BERs were measured before pupillary changes, a significant lengthening of wave V latency was observed prior to clinical manifestation of uncal herniation. These results suggest that immediate medical or surgical decompression of ICP should be performed when ICP approaches 30 mmHg with significant prolongation of wave V latency.


Gut hormones, adipokines, and pro- and anti-inflammatory cytokines/markers in loss of control eating: A scoping review.
Loss of control (LOC) eating is the defining feature of binge-eating disorder, and it has particular relevance for bariatric patients. The biomarkers of LOC eating are unclear; however, gut hormones (i.e., ghrelin, cholecystokinin [CCK], peptide YY [PYY], glucagon-like peptide 1 [GLP-1], and pancreatic polypeptide [PP]), adipokines (i.e., leptin, adiponectin), and pro- and anti-inflammatory cytokines/markers (e.g., high-sensitivity C-reactive protein [hsCRP]) are candidates due to their involvement in the psychophysiological mechanisms of LOC eating. This review aimed to synthesize research that has investigated these biomarkers with LOC eating. Because LOC eating is commonly examined within the context of binge-eating disorder, is sometimes used interchangeably with subclinical binge-eating, and is the latent construct underlying disinhibition, uncontrolled eating, and food addiction, these eating behaviors were included in the search. Only studies among individuals with overweight or obesity were included. Among the identified 31 studies, 2 studies directly examined LOC eating and 4 studies were conducted among bariatric patients. Most studies were case-control in design (n = 16) and comprised female-dominant (n = 13) or female-only (n = 13) samples. Studies generally excluded fasting total ghrelin, fasting CCK, fasting PYY, and fasting PP as correlates of the examined eating behaviors. However, there was evidence that the examined eating behaviors were associated with lower levels of fasting acyl ghrelin (the active form of ghrelin) and adiponectin, higher levels of leptin and hsCRP, and altered responses of postprandial ghrelin, CCK, and PYY. The use of GLP-1 analog was able to decrease binge-eating. In conclusion, this review identified potential biomarkers of LOC eating. Future studies would benefit from a direct focus on LOC eating (especially in the bariatric population), using longitudinal designs, exploring potential mediators and moderators, and increased inclusion of the male population.


Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.
In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patient's hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. Thirty-two of the 172 patients (19%) had GI bleeding after 63 ± 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory-Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive-line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention.


An ectopic ureter of a duplicated system presenting as a pelvic collection following laparoscopic radical prostatectomy.
Radical prostatectomy remains the gold-standard surgical treatment for clinically localized prostate cancer. Contrast imaging of the upper urinary tract is not part of the routine work-up of the patient before radical prostatectomy. This may lead to rare, albeit serious complications when anatomical anomalies are present. This article reports a case of delayed anastomotic leakage following radical prostatectomy due to an unrecognized duplex system on the left side and inclusion of the ureteric orifice draining the upper moiety in the anastomosis, which caused failure of healing and persistent leakage.


From basic science to life-saving therapy: the rationale, and drug discovery efforts that led to the direct factor Xa inhibitor eliquis.
Over the past few decades, drug discovery directed at the treatment and prevention of thromboembolic diseases has been challenged by the need to balance robust efficacy with improved safety relative to the standard of care. To this end, the most impactful advance to date has been the discovery and development of oral factor Xa inhibitors. In this essay, a brief account of the program that culminated in the discovery of Eliquis (apixaban) and the commitment to identify a compound with an optimal profile are described.


Prevalence and clinical characteristics of allergic rhinitis in the elderly Korean population.
The proportion of elderly people aged ≥ 65 years is increasing worldwide. Although the reported prevalence of sinonasal disease can vary according to the diagnostic methods used, differences in allergic rhinitis prevalence in the elderly according to diagnostic method have not been reported. We thus aimed to evaluate allergic rhinitis prevalence in the elderly according to diagnostic criteria obtained from questionnaires, physician diagnoses, and allergy tests. We compared the allergic rhinitis prevalence in the elderly aged ≥ 65 years with adults aged 19-64 years, using data from the Korean National Health and Nutrition Examination Survey 2008-2012. Total serum IgE and IgE levels specific to allergens of Dermatophagoides farina, cockroach, and dog dander were examined, and factors affecting specific IgE levels were investigated. Allergic rhinitis prevalence according to the questionnaire responses, physician diagnoses, and allergy test results was 35.02%, 14.89%, and 17.56%, respectively. The prevalence based on all diagnostic methods assessed was significantly lower in the elderly than in the general adult group (p < 0.001). Rhinorrhea incidence was significantly increased in the elderly (p = 0.018). Sensitization to Dermatophagoides farina was significantly decreased in the elderly (p = 0.006) and did not correlate with socioeconomic status and/or general health factors. The elderly population has a distinct clinical presentation, including a low prevalence of allergic rhinitis, and an increased incidence of rhinorrhea symptoms, compared with the general adult population. The management of allergic rhinitis in elderly patients may therefore require a different therapeutic approach to improve rhinorrhea rather than nasal obstruction.


Comparison of acid-lowering drugs for endoscopy negative reflux disease: Systematic review and network Meta-Analysis.
The comparative efficacy and safety of medical therapies for gastro-esophageal reflux symptoms in endoscopy-negative reflux disease is unclear. We conducted a network meta-analysis to evaluate efficacy and safety of proton pump inhibitors (PPIs), histamine-2-receptor antagonists, potassium-competitive acid blockers (PCABs), and alginates in patients with endoscopy-negative reflux disease. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to February 1, 2022. We included randomized controlled trials (RCTs) comparing efficacy of all drugs versus each other, or versus a placebo, in adults with endoscopy-negative reflux disease. Results were reported as pooled relative risks with 95% confidence intervals to summarize effect of each comparison tested, with treatments ranked according to P-score. We identified 23 RCTs containing 10,735 subjects with endoscopy-negative reflux disease. Based on failure to achieve complete relief of symptoms between ≥2 and <4 weeks, omeprazole 20 mg o.d. (P-score 0.94) ranked first, with esomeprazole 20 mg o.d. or 40 mg o.d. ranked second and third. In achieving adequate relief, only rabeprazole 10 mg o.d. was significantly more efficacious than placebo. For failure to achieve complete relief at ≥4 weeks, dexlansoprazole 30 mg o.d. (P-score 0.95) ranked first, with 30 ml alginate q.i.d. combined with omeprazole 20 mg o.d., and 30 ml alginate t.i.d. second and third. In terms of failure to achieve adequate relief at ≥4 weeks, dexlansoprazole 60 mg o.d. ranked first (P-score 0.90), with dexlansoprazole 30 mg o.d. and rabeprazole 20 mg o.d. second and third. All drugs were safe and well-tolerated. Our results confirm superiority of PPIs compared with most other drugs in treating endoscopy-negative reflux disease. Future RCTs should aim to better classify patients with endoscopy-negative reflux disease, and to establish the role of alginates and PCABs in achieving symptom relief in both the short- and long-term.


Transforming growth factorβ1 L10P variant plays an active role on the breast cancer susceptibility in Caucasian: evidence from 10,392 cases and 11,697 controls.
In view of the essential role of transforming growth factorβ1 (TGFB1) on both inhibiting the development of early benign breast tumors as well as promoting tumor invasion, the association of TGFB1 L10P polymorphism and breast cancer risk has been widely reported, but results of previous studies were somewhat contradictory and underpowered. To overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis towards the association between TGFB1 L10P polymorphism and breast cancer. Through retrieving MEDLINE, PubMed, Embase, and Web of Science, a total of 16 studies with 10,392 cases and 11,697 controls were identified. The results showed that significant association was found in the recessive genetic model for Caucasian (OR = 1.152, 95% CI = 1.020-1.301). However, we did not find any associations in additive genetic model (PP vs. LL for total: OR = 1.026, 95% CI = 0.940-1.121), allele contrast (L vs. P for total: OR = 1.004, 95% CI = 0.966-1.044), and dominant genetic model (PP + LP vs. LL for total: OR = 1.001, 95% CI = 0.946-1.061). Conclusively, this meta-analysis strongly suggests that TGFB1 L10P polymorphism may play a low penetrance role in breast cancer susceptibility in Caucasian. Large well-designed epidemiological studies will be necessary to validate the risk identified in the current meta-analysis.


Cytoskeletal regulation guides neuronal trafficking to effectively supply the synapse.
The development and proper function of the brain requires the formation of highly complex neuronal circuitry. These circuits are shaped from synaptic connections between neurons and must be maintained over a lifetime. The formation and continued maintenance of synapses requires accurate trafficking of presynaptic and postsynaptic components along the axon and dendrite, respectively, necessitating deliberate and specialized delivery strategies to replenish essential synaptic components. Maintenance of synaptic transmission also requires readily accessible energy stores, produced in part by localized mitochondria, that are tightly regulated with activity level. In this review, we focus on recent developments in our understanding of the cytoskeletal environment of axons and dendrites, examining how local regulation of cytoskeletal dynamics and organelle trafficking promotes synapse-specific delivery and plasticity. These new insights shed light on the complex and coordinated role that cytoskeletal elements play in establishing and maintaining neuronal circuitry.


Correlation between dental plaque accumulation and gingival health in periodontal maintenance patients using short or extended personal oral hygiene intervals.
To evaluate the correlation between bacterial dental plaque accumulation and gingival health in subjects with history of periodontitis attending a maintenance programme including personal oral hygiene measures (pOH) at short and extended intervals. This study is a secondary analysis of a randomized clinical trial. Forty-two subjects were randomized into groups performing pOH at 12-, 24- or 48-h intervals. The Plaque Index (PlI), Gingival Index (GI) and bleeding on probing (BoP) were recorded at baseline, 30 and 90 days. For the analysis, pOH groups were collapsed into subjects performing pOH at daily (G12/24) or extended (G48) intervals. Summary statistics and Spearman correlations between plaque accumulation and gingival inflammation are presented. G12/24 and G48 subjects showed significant increases in plaque scores and percentage sites with gingival inflammation over the course of study. At 90 days, G48 subjects showed significantly greater GI and BoP scores than G12/24 subjects. While PlI/GI correlations were not affected by pOH interval, PlI/BoP correlations remained unchanged with short to increase with extended pOH intervals. pOH interval influences the correlation between bacterial dental plaque accumulation and gingival inflammation. Subjects using extended pOH intervals exhibit an increased correlation allowing accumulation of bacterial dental plaque to the detriment of gingival health. (ClinicalTrials.gov: 50208115.9.0000.5346). Clinical Trials: ClinicalTrials.gov: NCT02684682.


Sudden infant death syndrome and superoxide/nitric oxide.
In a sudden infant death syndrome review Valdès-Dapena describes Naeye's report of increased medial muscle mass in walls of small pulmonary arteries and increased weight of cardiac right ventricles. These findings point to cardiorespiratory insufficiency, a problem in fast growing chicks raised at high altitudes. The vascular epithelium lining all blood vessels synthesises nitric oxide which induces relaxation of smooth muscle in vessel walls, and is possibly an important neurotransmitter. Others demonstrate that nitric oxide is involved in regulating vessel calibre, blood pressure and blood flow, as well as falls in ventricular outputs. Superoxide interacts with nitric oxide and removes it from the circulation. Superoxide is thus a vasoconstrictor. Superoxide is produced by activated phagocytes and possibly lymphocytes and other cell types in the immune response. Elevated immunoglobulins in mucus secretions are a hallmark in sudden infant death syndrome and hypoxic chicks. Our approach therefore is that cardiorespiratory insufficiency may be induced by superoxide in small pulmonary arteries preventing nitric oxide from acting as a muscle relaxant in vascular walls.


Mid-term outcomes of rapid deployment aortic prostheses in patients with small aortic annulus.
The Edwards Intuity valve is a rapid deployment aortic prosthesis that favours less invasive approaches. However, evidence about the clinical behaviour of their smaller sizes is scarce. Herein, we studied haemodynamic behaviours and clinical outcomes of small Intuity prostheses (19-21 mm) in comparison to larger Intuity prostheses (>21 mm). This is an observational study including patients implanted with an Edwards Intuity rapid deployment aortic prosthesis. Patients with prosthesis sizes 19-21 and >21 mm were included. Baseline and perioperative variables, as well as adverse events during the follow-up were recorded and compared between groups. A total of 122 patients (37% female, mean age 75 ± 4.5 years) were included, of whom 54 (45%) were implanted with a small prosthesis and 68 (55%) with a prosthesis >21 mm. There were no significant differences between patients with small Intuity prostheses and patients with larger prostheses regarding in-hospital mortality (2% vs 4%, P = 0.43) or mortality during the follow-up (3.41 vs 2.45 per 100 patients-years; P = 0.58). Survival in the small Intuity valve group was 95% at 1 year and 83% at 6 years, whereas in the larger Intuity valve group was 96% at 1 year and 78% at 6 years. The presence of a small prosthesis did not influence mid-term survival (log-rank P-value = 0.62). This study showed good clinical performance of Intuity aortic prostheses with appropriate mid-term survival in patients with the small aortic annulus. Thus, the Edwards Intuity rapid deployment aortic prosthesis may be considered as a potential option in patients with the small aortic annulus.


Induction of mouse brain ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate is independent of TPA receptor concentration.
Ornithine decarboxylase (ODC, E.C. 220.127.116.11) activity was measured in a 35,000 X g brain supernatant fraction, prepared 5 h after intracisternal injection of 12-O-tetradecanoylphorbol-13-acetate (TPA) into developing mouse brain. TPA-dependent induction of ODC activity was maximal on days 5 and 9 postnatally while on day 7, the developmental (endogenous) level of ODC in brain was high and, concurrently, the ability of TPA to induce ODC was reduced. Both TPA-dependent and developmental increases in mouse brain ODC activity were significantly reduced by intracisternal injection of retinoic acid (RA). The efficacy of TPA in elevating ODC activity at postnatal ages 1-220 days-old was independent of both soluble-and particulate-associated TPA receptor concentration. These observations suggest that although TPA receptor activation may be an obligatory event in ODC induction, TPA receptor activation and its concentration per se, are not sufficient determinants for ODC induction and tumorigenesis. Furthermore, the endogenous mechanism of ODC induction is distinct from that of the TPA-dependent increase in ODC enzyme activity.


Chenopodium polyploidy inferences from Salt Overly Sensitive 1 (SOS1) data.
Single-copy nuclear loci can provide powerful insights into polyploid evolution. Chenopodium (Amaranthaceae) is a globally distributed genus composed of approximately 50-75 species. The genus includes several polyploid species, some of which are considered noxious agricultural weeds, and a few are domesticated crops. Very little research has addressed their evolutionary origin to date. We construct a phylogeny for Chenopodium based on two introns of the single-copy nuclear locus Salt Overly Sensitive 1 (SOS1) to clarify the relationships among the genomes of the allotetraploid and allohexaploid species, and to help identify their genome donors. Diploid species were sequenced directly, whereas homeologous sequences of polyploid genomes were first separated by plasmid-mediated cloning. Data were evaluated in maximum likelihood and Bayesian phylogenetic analyses. Homeologous sequences of polyploid species were found in four clades, which we designate as A-D. Two distinct polyploid lineages were identified: one composed of American tetraploid species with A and B class homeologs and a second composed of Eastern Hemisphere hexaploid species with B, C, and D class homeologs. We infer that the two polyploid lineages arose independently and that each lineage may have originated only once. The American diploid, C. standleyanum, was identified as the closest living diploid relative of the A genome donor for American tetraploids, including domesticated C. quinoa, and is of potential importance for quinoa breeding. The east Asian diploid species, C. bryoniifolium, groups with American diploid species, which suggests a transoceanic dispersal.


Association of Clinical Assessments of Hand Function and Quantitative Ultrasound Metrics in First Carpometacarpal Osteoarthritis.
Thumb carpometacarpal (CMC) osteoarthritis (OA), a degenerative condition affecting hand use, is typically evaluated through radiographs and clinical examination. Although this can determine treatment, it is difficult to evaluate functional limitations. Shear wave elastography (SWE) is a quantitative ultrasound technique that characterizes tissue stiffness. This pilot study aimed to establish data of the SWE findings in the thenar eminence muscles in patients with first CMC OA and correlate these findings with the clinical tests of hand function. This cross-sectional study correlated the SWE stiffness of thenar eminence muscles to clinical tests of hand function in patients with first CMC OA and in asymptomatic control subjects, using Spearman's correlation coefficient. Mean SWE values of the thenar eminence muscles in patients were compared with those in control subjects. The study was performed in a non-profit tertiary care hospital setting. Patients and control subjects were recruited on a volunteer basis. SWE values in the abductor pollicis brevis and flexor pollicis brevis muscles showed moderate to very strong correlation with multiple measures of hand function. Mean SWE values of the thenar eminence muscles in first CMC OA patients were lower than those in asymptomatic control subjects. Correlations between mean SWE values in the thenar eminence muscles and clinical measures of hand function suggest decreased function in subjects with less stiff thenar eminence muscles.


Modulation of quail oviduct adenylate cyclase activity by estradiol and progesterone.
Oviduct adenylate cyclase activity of the quail was measured by radiochemical analysis following different hormonal treatments. A single injection of estradiol benzoate (EB) to immature female quails resulted in a prereplicative surge of adenylate cyclase activity. A second surge of enzyme activity was observed during the proliferative phase induced by EB. Estradiol-17 alpha, estrone, estriol and testosterone were ineffective. Tamoxifen completely inhibits the growth-promoting effect of EB and the second surge of adenylate cyclase activity but does not inhibit the prereplicative increase of enzyme activity. This prereplicative increase of adenylate cyclase activity was also observed, even in the absence of increased plasma estradiol, when estradiol-17 beta (E2) was perfused through the hepatic portal vein. Moreover, E2 had no effect on enzyme activity when added directly to the oviduct homogenate preparation, at concentrations ranging from 10(-9) to 10(-7) M. In response to progesterone injection, oviduct adenylate cyclase activity followed a different pattern, beginning its increase after 3 h and remaining elevated up to 24 h. The activation by estradiol was independent of the presence of guanylylimidodiphosphate. Moreover, the enzyme was more sensitive to forskolin at submaximal concentration in estradiol treated birds than in control. These results demonstrate that transient activation of adenylate cyclase at the early stages of the action of estradiol does not occur through the classic nuclear receptor-gene activation pathway or a membrane receptor mediated process, but involves an indirect pathway, yet to be defined.


Complications of loop ileostomy closure in patients with rectal tumor.
Loop ileostomy is customary after very low rectal anastomosis to reduce the rate of pelvic sepsis that can result from anastomotic leakage. To evaluate complications of stoma closure is important to maximize the benefit of making the defunctioning stoma. The aim of this study was to examine possible risk factors associated with complications, especially wound infections, after loop ileostomy closure in patients with rectal tumor. Data from 125 consecutive patients who underwent an elective closure of loop ileostomy after primary rectal tumor resection from January 2005 and October 2009 at a single institution were prospectively collected. Nineteen independent clinical variables were examined by univariate and multivariate analyses. Postoperative complications developed in 21 (16.8%) patients, including 20 (16%) wound infections, 1 (0.8%) ileus, and 1 (0.8%) anastomotic bleeding. There was no postoperative mortality. Risk factors for wound infection included male gender (odds ratio = 5.30; 95% confidence interval 1.14-24.8; p = 0.0339) and surgical site infection (SSI) after primary surgery (odds ratio = 5.00; 95% confidence interval 1.24-20.1; p = 0.0234). Mean length of postoperative hospital stay was significantly longer in patients with complications than in patients without them (14.0 versus 11.0 days; p = 0.0078). The present study showed that most complications associated with ileostomy closure in a homogeneous group of patients with rectal tumor were wound infections. Male gender and SSI after primary surgery were independent risk factors for the development of wound infections. Surgeons should be aware of such high-risk patients, and techniques other than primary closure might need to be considered in high-risk patients to reduce wound infections.