A novel protein localized to the fibrillar compartment of the nucleolus and to the brush border of a secretory cell.
We report the identification and molecular characterization of a novel abundant nucleolar protein of the dipteran Chironomus tentans. As shown by Western blot analysis, this protein is present in nuclear extracts in a phosphorylated form with a mobility corresponding to 100 kDa. Therefore, the protein has been termed Chironomus tentans p100, or p100 for short. Analysis of the cDNA-derived primary structure of p100 indicates a protein that contains a combination of structural domains which could be involved in interactions with proteins and nucleic acids: twelve alternating acidic and basic repeats, a glycine-arginine-rich domain and a region with two zinc fingers of the C4-type. Acidic and basic repeats are typical for a group of nonribosomal nucleolar proteins. The best-studied representatives of this group are Nopp140 and nucleolin, proteins with structural and regulatory functions in rDNA transcription. Immunocytology and immunoelectron microscopy of Chironomus tentans salivary gland cells have shown that the p100 protein is located in the fibrillar compartment of the nucleolus, while it is almost absent from the granular compartment and from the nucleoplasm. The p100 protein remains in the nucleolus after removal of RNA and DNA by digestion with nucleases. This indicates that p100 might be a constituent of the nucleolar proteinaceous framework. Remarkably, p100 is also localized in the brush border in the apical part of the salivary gland cell. The presence of p100 both in the nucleolus and at the apical plasma membrane suggests that it could be involved in coordination of the level of protein production and export from the cell through regulation of the level of rRNA production in the nucleolus.


Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia.
Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.


Fundus autofluorescence features in the inflammatory maculopathies.
To describe the fundus autofluorescence (FAF) features of the inflammatory maculopathies and develop a quantification method for FAF analysis. This is a retrospective, consecutive case series of patients with inflammatory maculopathies from two tertiary centers. The clinical findings, demographics, and FAF imaging characteristics were reviewed. Foveal autofluorescence (AF) was analyzed. Median and standard deviation (SD) of foveal AF intensity were measured. Thirty eyes of 15 patients were evaluated with both qualitative and quantitative FAF analysis. In acute macular neuroretinopathy, the active phase showed foveal hypoautofluorescence, which became hypoautofluorescent with resolution. In acute posterior multifocal placoid pigment epitheliopathy, multiple lesions with hypoautofluorescent centers with hyperautofluorescent borders were observed in active disease and became hypoautofluorescent with disease convalescence. In multifocal choroiditis and punctate inner choroiditis, the active hyperautofluorescent lesions progressed to inactive, hypoautofluorescent scars. Active serpiginous choroiditis showed hyperautofluorescent borders adjacent to a helicoid-shaped, hypoautofluorescent scar. Active unilateral acute idiopathic maculopathy (UAIM) showed a complex pattern of hypo- and hyperautoflourescence in the macula. The median foveal AF was the greatest in acute macular neuroretinopathy and UAIM among the maculopathies, while the greatest SD of foveal AF intensity was observed in UAIM. The active phase of the majority of inflammatory maculopathies was characterized by hyperautofluorescent lesions. Increased SD of foveal AF correlated with a mixture of hypo-and hyperautoflourescence. Median and SD may be useful metrics in foveal AF and quantifiable values that may be assessed over time as a disease process evolves. Improvements in quantification methods of FAF imaging may allow us to objectively evaluate posterior uveitis.


Duodenal chemosensing.
Luminal chemosensing is a term used to describe how small molecules in the gut lumen interact with the host through surface receptors or via transport into the submucosa. In this review, we have summarized recent advances of understanding luminal chemosensing in the gastroduodenal mucosa, with a particular emphasis on how chemosensing affects mucosal protective responses and the metabolic syndrome. In the past decade, data have supported the hypothesis that gut luminal chemosensing not only is important for the local or remote regulation of gut function but also contributes to the systemic regulation of metabolism, energy balance and food intake. We have provided examples of how luminal nutrients such as long-chain fatty acids (LCFAs), endogenous compounds such as bile acids, bacterial metabolites such as short-chain fatty acids (SCFAs) and bacterial components such as lipopolysaccharide (LPS) activate cognate receptors expressed on key effector cells such as enteroendocrine cells and inflammatory cells in order to profoundly affect organ function through the initiation or suppression of inflammatory pathways, altering gut barrier function and nutrient uptake, altering gut motility and visceral pain pathways, and preventing mucosal injury. These recent discoveries in this area have provided new possibilities for identifying novel molecular targets for the treatment of mucosal injury, metabolic disorders and abnormal visceral sensation. Understanding luminal chemosensory mechanisms may help to identify novel molecular targets for the treatment and prevention of mucosal injury, metabolic disorders and abnormal visceral sensation.


Utilization of paramagnetic relaxation enhancements for structural analysis of actin-binding proteins in complex with actin.
Actin cytoskeleton dynamics are controlled by various actin binding proteins (ABPs) that modulate the polymerization of the monomeric G-actin and the depolymerization of filamentous F-actin. Although revealing the structures of the actin/ABP complexes is crucial to understand how the ABPs regulate actin dynamics, the X-ray crystallography and cryoEM methods are inadequate to apply for the ABPs that interact with G- or F-actin with lower affinity or multiple binding modes. In this study, we aimed to establish the alternative method to build a structural model of G-actin/ABP complexes, utilizing the paramagnetic relaxation enhancement (PRE) experiments. Thymosin β4 (Tβ4) was used as a test case for validation, since its structure in complex with G-actin was reported recently. Recombinantly expressed G-actin, containing a cysteine mutation, was conjugated with a nitroxyl spin label at the specific site. Based on the intensity ratio of the 1H-15N HSQC spectra of Tβ4 in the complex with G-actin in the paramagnetic and diamagnetic states, the distances between the amide groups of Tβ4 and the spin label of G-actin were estimated. Using the PRE-derived distance constraints, we were able to compute a well-converged docking structure of the G-actin/Tβ4 complex that shows great accordance with the reference structure.


Fat maintenance is a predictor of the murine lifespan response to dietary restriction.
Dietary restriction (DR), one of the most robust life-extending manipulations, is usually associated with reduced adiposity. This reduction is hypothesized to be important in the life-extending effect of DR, because excess adiposity is associated with metabolic and age-related disease. Previously, we described remarkable variation in the lifespan response of 41 recombinant inbred strains of mice to DR, ranging from life extension to life shortening. Here, we used this variation to determine the relationship of lifespan modulation under DR to fat loss. Across strains, DR life extension correlated inversely with fat reduction, measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63, P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan. We identified two significant quantitative trait loci (QTLs) affecting fat mass under DR in males but none for lifespan, precluding the confirmation of these loci as coordinate modulators of adiposity and longevity. Our data also provide evidence for a QTL previously shown to affect fuel efficiency under DR. In summary, the data do not support an important role for fat reduction in life extension by DR. They suggest instead that factors associated with maintaining adiposity are important for survival and life extension under DR.


Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.
Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.


Ocular biometric measurements in cataract surgery candidates in Portugal.
Describe the ocular biometric parameters and their associations in a population of cataract surgery candidates. A cross-sectional study of 13,012 eyes of 6,506 patients was performed. Biometric parameters of the eyes were measured by optical low-coherence reflectometry. The axial length (AL), mean keratometry (K) and astigmatism, anterior chamber depth (ACD) (epithelium to lens), lens thickness (LT), and Corneal Diameter (CD) were evaluated. The mean age was 69 ± 10 years (44-99 years). Mean AL, Km, and ACD were 23.87 ± 1.55 mm (19.8-31.92 mm), 43.91 ± 1.71 D (40.61-51.14 D), and 3.25 ± 0.44 mm (2.04-5.28 mm), respectively. The mean LT was 4.32 ± 0.49 mm (2.73-5.77 mm) and the mean CD was 12.02 ± 0.46 mm (10.50-14.15 mm). The mean corneal astigmatism was 1.08 ± 0.84 D (0.00-7.58 D) and 43.5% of eyes had astigmatism ≥ 1.00 D. Male patients had longer AL and ACDs (p < .001) and flatter corneas (p < .001). In regression models considering age, gender, Km, ACD, LT, and CD, a longer AL was associated with being male and having higher ACD, LT and CD. These data represent normative biometric values for the Portuguese population. The greatest predictor of ocular biometrics was gender. There was no significant correlation between age and AL, ACD, or Km. These results may be relevant in the evaluation of refractive error and in the calculation of intraocular lens power.


Connecting with social and emotional well-being in rural Australia: An evaluation of 'We-Yarn', an Aboriginal gatekeeper suicide prevention workshop.
This evaluation considered the potential of We-Yarn, a suicide prevention gatekeeper training workshop, to contribute to Aboriginal suicide prevention in rural New South Wales. A mixed methods approach included surveys, in-depth interviews and workshop observations. Aboriginal suicide prevention training in rural New South Wales, Australia. Attendees at We-Yarn training. We-Yarn provided culturally safe suicide prevention skills training for Aboriginal people and for those who work with Aboriginal communities and persons in rural New South Wales. Training workshops were delivered across multiple locations for 6 hours in one day. Workshops were facilitated by two facilitators with lived and professional experience; one Aboriginal and one non-Aboriginal facilitator. We-Yarn content was developed by staff from the Centre for Rural and Remote Mental Health, and in consultation with Aboriginal Elders and representatives of Aboriginal Medical Services to ensure relevance and cultural appropriateness. Pre and post-workshop surveys captured capacity and participants' confidence in identifying and responding to a person at risk of suicide. Interviews explored participants' experiences of workshops, implementation of learning, and attitudes regarding social and emotional wellbeing and suicide. Observations detailed the workshop environment, participants' engagement, and participants' responses to facilitators and content. We-Yarn was considered culturally appropriate. Participants responded to facilitators' lived experiences. Participants reported significant improvements in understanding the links between cultural strengths, social and emotional wellbeing and suicide prevention. However, health professionals with existing knowledge wanted a stronger focus on clinical training. We-Yarn promoted discussion of suicide prevention within a holistic health framework, building on participants' pre-existing knowledge about social and emotional wellbeing. Importantly, skilful facilitators with lived experience were vital to the success of the workshops. Consideration should be given to attracting people with low suicide prevention knowledge to the workshops, developing tailored workshops for health professionals and ensuring prolonged engagement with communities. Multifaceted and long term responses in addition to this type of training are important.


COVID-19 Testing Among US Children, Parental Preferences for Testing Venues, and Acceptability of School-Based Testing.
Testing remains critical for identifying pediatric cases of COVID-19 and as a public health intervention to contain infections. We surveyed US parents to measure the proportion of children tested for COVID-19 since the start of the pandemic, preferred testing venues for children, and acceptability of school-based COVID-19 testing. We conducted an online survey of 2074 US parents of children aged ≤12 years in March 2021. We applied survey weights to generate national estimates, and we used Rao-Scott adjusted Pearson χ2 tests to compare incidence by selected sociodemographic characteristics. We used Poisson regression models with robust SEs to estimate adjusted risk ratios (aRRs) of pediatric testing. Among US parents, 35.9% reported their youngest child had ever been tested for COVID-19. Parents who were female versus male (aRR = 0.69; 95% CI, 0.60-0.79), Asian versus non-Hispanic White (aRR = 0.58; 95% CI, 0.39-0.87), and from the Midwest versus the Northeast (aRR = 0.76; 95% CI, 0.63-0.91) were less likely to report testing of a child. Children who had health insurance versus no health insurance (aRR = 1.38; 95% CI, 1.05-1.81), were attending in-person school/daycare versus not attending (aRR = 1.67; 95% CI, 1.43-1.95), and were from households with annual household income ≥$100 000 versus income <$50 000-$99 999 (aRR = 1.19; 95% CI, 1.02-1.40) were more likely to have tested for COVID-19. Half of parents (52.7%) reported the pediatrician's office as the most preferred testing venue, and 50.6% said they would allow their youngest child to be tested for COVID-19 at school/daycare if required. Greater efforts are needed to ensure access to COVID-19 testing for US children, including those without health insurance.


Codevelopment of ADHD and externalizing behavior from childhood to adulthood.
Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with externalizing disorders, but a clear understanding of the etiologic underpinnings is hampered by the limited understanding of the codevelopment of the traits from childhood into early adulthood. Using a birth cohort of 2600 twins, the Swedish Twin study of Child and Adolescent Development study, assessed at ages 8-9, 13-14, 16-17, and 19-20, we investigated the codevelopment of ADHD and externalizing behavior from childhood to adulthood. The analyses examined ADHD-like and externalizing traits, as rated by twins and their parents using the Attention Problems scale and Externalizing scale of the Child Behavior Checklist, and estimated cross-lagged effects (one trait at one time-point predicting the other at the next). The covariation between the traits were decomposed into stable (effects carried over from the prior time-points) and innovative (new effects for each time-point) sources; each source was further decomposed into additive genetics, shared and nonshared environment. The analysis suggested that externalizing traits in middle childhood (age 8-9) predicted ADHD-like traits in early adolescence (age 13-14), whereas the reverse association was nonsignificant. In contrast, ADHD-like traits in lateadolescence (age 16-17) predicted externalizing traits in early adulthood (age 19-20). The correlation between ADHD-like and externalizing traits increased over time. At all time-points, innovative sources contributed substantially to maintained comorbidity. Genetic effects explained 67% of the covariation at each time-point; importantly, nearly 50% of these effects were innovative. This study challenges the belief that ADHD generally precedes externalizing behaviors; rather, change in the etiologic factors across the development is the rule. The effects were due to both new genetic and environmental factors emerging up to young adulthood. Clinicians and researchers needs to consider complex etiologic and developmental models for the comorbidity between ADHD and externalizing behaviors.


Ferroportin downregulation promotes cell proliferation by modulating the Nrf2-miR-17-5p axis in multiple myeloma.
Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using a microRNA target-scan algorithm, we identified miR-17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis-both in vitro and in vivo. miR-17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR-17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5'-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR-17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.


Synaptic activation and membrane potential changes modulate the frequency of spontaneous elementary Ca2+ release events in the dendrites of pyramidal neurons.
In most neurons postsynaptic [Ca(2+)](i) changes result from synaptic activation opening voltage gated channels, ligand gated channels, or mobilizing Ca(2+) release from intracellular stores. In addition to these changes that result directly from stimulation we found that in pyramidal cells there are spontaneous, rapid, Ca(2+) release events, predominantly, but not exclusively localized at dendritic branch points. They are clearest on the main apical dendrite but also have been detected in the finer branches and in the soma. Typically they have a spatial extent at initiation of approximately 2 microm, a rise time of <15 ms, duration <100 ms, and amplitudes of 10-70% of that generated by a backpropagating action potential at the same location. These events are not caused by background electrical or synaptic activity. However, their rate can be increased by repetitive synaptic stimulation at moderate frequencies, mainly through metabotropic glutamate receptor mobilization of IP(3). In addition, their frequency can be modulated by changes in membrane potential in the subthreshold range, predominantly by affecting Ca(2+) entry through L-type channels. They resemble the elementary events ("sparks" and "puffs") mediated by IP(3) receptors and ryanodine receptors that have been described primarily in non-neuronal preparations. These spontaneous Ca(2+) release events may be the fundamental units underlying some postsynaptic signaling cascades in mature neurons.


Treatment advances in adult immune thrombocytopenic purpura.
Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by autoantibody-mediated destruction of platelets. The disease generally runs a mild clinical course, though significant morbidity and mortality can occur. Steroids and/or splenectomy are effective in treating the disease in approximately 70% of patients. These treatments have been well established with approximately 50 years of clinical experience. While open splenectomy is the traditional surgical procedure, laparoscopic splenectomy, splenic artery embolization, and splenic irradiation are viable alternatives. For patients who relapse after the above therapies, treatment is more difficult and seldom results in a cure. The goals of therapy involve maintaining a safe platelet count while minimizing toxicities from the treatment. Multiple treatment options exist including corticosteroids, androgens, immunomodulatory drugs, cytotoxic chemotherapy, immunoglobulin preparations, bone marrow transplantation, Helicobacter pylori eradication, and others. While the standard treatment of steroids and splenectomy has changed little over the past decades, a number of promising new therapies on the horizon may soon join the armamentarium upon which the clinician can draw to fight the disease. In this review, we will examine treatment for chronic ITP in adults in the pre-splenectomy, splenectomy, and post-splenectomy settings.


Polarization-maintaining optical microfiber.
We have successfully demonstrated a polarization-maintaining (PM) fused silica microfiber by adiabatically tapering a conventional PM fiber. Compared to standard single-mode microfibers, the proposed PM microfibers exhibit robust polarization, preserving characteristics under the presence of external perturbations, such as bending. A polarization-extinction ratio of 16 dB is typically obtained through the device with a corresponding excess loss of 0.2 dB.


Construct validity of the BESTest, mini-BESTest and briefBESTest in adults aged 50 years and older.
The Balance Evaluation Systems Test (BESTest) and its two abbreviated versions (mini-BESTest and briefBESTest) are functional balance tools that have yet to be validated in middle aged and elderly people living in the community. Determine the construct validity of the three BESTest versions by comparing them with commonly-used measures of balance, balance confidence and physical activity, and examining their ability to discriminate between groups with respect to falls and fall risk. This was a secondary analysis of data from 79 adults (mean age 68.7±10.57 years). Pearson correlation coefficients were used to examine the relationships between each BESTest measure and the Activities-Specific Balance Confidence (ABC) scale, the Physical Activity Scale for the Elderly (PASE), the Timed Up and Go (TUG) and the Single Leg Stance (SLS) test. Independent t-tests were used to examine differences in balance between fallers (≥1 fall in previous year) and non-fallers and individuals classified at low versus high fall risk using the Elderly Falls Screening Test (EFST). The BESTest measures showed moderate associations with the ABC scale and TUG (r=0.62-0.67 and -0.60 to -0.68 respectively), fair associations (r=0.33-0.40) with the PASE and moderate to high associations (r=0.67-0.77) with the SLS. Fallers showed a trend (p=0.054) for lower scores on the original BESTest, and people at high risk for falls had significantly lower scores on all BESTest versions. These findings support the construct validity of the BESTest, mini-BESTest and briefBESTest in adults over 50 years old.


[Use of the Coombs' test and the fluorescent antibody technic in order to detect incomplete antibodies in brucellosis patients].
The serological data obtained in the survey of persons working on cattle-breeding farms with registered cases of brucellosis and chronic brucellosis patients are presented. The survey was made with the use of the Coombs test and the indirect immunofluorescent method. The high diagnostic value of the Coombs antiglobulin test was confirmed. The data obtained by the Coombs test and the indirect immunofluorescent method in the detection of incomplete antibodies were found to be correlated.


Oxidative damage and DNA damage in lungs of an ovalbumin-induced asthmatic murine model.
Asthma is characterized to chronic airway inflammation. However, the role of oxidative damage and DNA damage in the pathophysiology of asthma have rarely been studied. On the other hand, there are evidences that DNA-dependent protein kinase (DNA-PK) participates in DNA damage repair and regulates innate immune responses and proinflammatory signaling pathways. After ovalbumin (OVA)-induced asthmatic murine model was established, airway hyper-responsiveness (AHR), total and differential bronchoalveolar lavage fluid (BALF) cell counts. IL-4, IL-8, IL-13 and TNF-α were chosen to evaluate the airway inflammation, and oxidative damage indicators levels (8-isoprostane and 8-OhdG) in BALF were measured. Alkaline comet assay was conducted to detected DNA damage. Histological analysis was conducted after hematoxylin and eosin (HE) straining, and proteins were extracted for 3-nitrotyrosine (3-NT) detection and immunoblotting. AHR, infiltration of inflammatory cells and pro-inflammatory cytokine levels in lungs were significantly higher in asthmatic mice. OVA challenge resulted in robust increase in 3-NT, 8-isoprostane and 8OHdG in lungs, which represented oxidative damage level. DNA damage and repair proteins levels in asthma were also increased. NU7441 aggravated the DNA damage level. However, it suppressed infiltration of lung inflammatory cells and inflammatory cytokine levels, suggesting that DNA-PK may be a potential target for treatment of allergic asthma. Our study showed that oxidative damage and DNA damage existed in the airway of asthmatic mice. NU7441 augmented DNA damage level, and moreover, it also attenuated infiltration of inflammatory cells and pro-inflammatory cytokine levels in asthmatic lungs.


Role of antispasmodics in the treatment of irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.


Target, purging magnet and electron collector design for scanned high-energy photon beams.
A new method for producing very narrow and intense 50 MV bremsstrahlung beams with a half-width as low as 35 mm at a distance of 1 m from the target is presented. Such a beam is well suited for intensity modulation using scanned photon beams. An algorithm has been developed to minimize the width of the bremsstrahlung beam generated in a multilayer target by varying the individual layer thicknesses and atomic numbers under given constraints on the total target thickness and the mean energy of the transmitted electrons. Under such constraints the narrowest possible bremsstrahlung beam is obtained with a target composed of layers of monotonically increasing atomic number starting with the lowest possible value at the entrance side where the electrons impinge. It is also shown that the narrowest photon beam profile is associated with the highest possible forward photon yield. To be able to use the optimized target clinically it is desirable to be able to collect and stop all the electrons that are transmitted through the target. The electrons are most efficiently collected if they are kept close together, i.e. by minimizing the multiple scatter of the electrons and consequently the half-width of the generated bremsstrahlung beam. This is achieved by a thin low-atomic-number target. A dedicated electron stopper has been developed and integrated with the purging magnet. When the electron stopper is combined with a purging magnet, a primary photon collimator and a multileaf collimator, almost all of the transmitted electrons and their associated bremsstrahlung contamination can effectively be collected. The narrow photon beams from thin low-atomic-number targets have the additional advantage of producing the hardest and most penetrative photon spectrum possible, which is ideal for treating large deep-seated tumours.


Comparison between 1-needle technique versus 2-needle technique for bone marrow aspiration and biopsy procedures.
Bone marrow examination is essential for diagnosis and staging of hematologic disorders. Traditionally, the bone marrow biopsy and aspirate are obtained with 2 needles at 2 separate sites. This approach is associated with significant discomfort, procedural time, and occasionally, morbidity. Although previous observations had suggested that a single-needle technique at one site is a simpler and less-painful procedure, there had been concern that the 1-needle technique may yield a suboptimal biopsy for diagnosis. To conduct a systematic comparison of multiple parameters of bone marrow biopsy specimens obtained by the traditional 2-needle technique versus the 1-needle technique for bone marrow collection. We retrospectively evaluated 20 biopsy specimens obtained by each of the 2 mentioned techniques by comparing the morphologic quality of the biopsy, biopsy length, and biopsy cellularity. We found that the 1-needle technique yielded an adequate biopsy for diagnosis. The measured parameters of the samples obtained by the 1-needle versus 2-needle techniques were similar. This study suggests that the 1-needle technique may be preferred for bone marrow aspirate and biopsy.


Lead modulation of macrophages causes multiorgan detrimental health effects.
The environmental toxicant lead (Pb) has detrimental effects on a number of organ systems, including the immune system. Pb exposure decreases host immune defenses against numerous microorganisms and cancer. Although Pb effects on humoral and cell-mediated immunity as well as on erythrocyte, neural, and renal pathophysiology have been well documented, there are few reports regarding Pb's impact on innate immunity, which can affect multiorgan processes. This review focuses on Pb modulation of a key innate immune cell, the macrophage. The impact of Pb on macrophages in different organs, on immature versus mature macrophages, and on low versus high Pb concentrations is discussed. Pb decreases phagocytosis and chemotaxis of macrophages and affects nitric oxide production and eicosanoid metabolism in mature macrophages. Pretreatment of macrophages with Pb increases TNF-α secretion after in vitro stimulation with lipopolysaccharide; however, Pb exposure decreases in vivo intracellular pathogen killing. More recent evidence from mouse studies indicates that even low, environmentally relevant, blood concentrations of Pb result in increased phagocytosis of erythrocytes and decreased expression of interferon-gamma-inducible GTPases, p65-GBP, and p47-IRG, which are necessary for intracellular pathogen killing. Taking into account the effects of Pb on macrophages, the review describes posited mechanisms to account for Pb-altered health effects; Pb effects on heme levels may play a key role as well as Pb's preferential induction of helper type-2 T (Th2) cells and M2 macrophages, which is related to oxidative stress. The discussion links old findings with new, thereby adding new insight into the effects of Pb on macrophages and the resultant compromised immunity and health.


[Genetic divergence of rice cultivars for resistance to Tibraca limbativentris Stål (Hemiptera: Pentatomidae)].
The genetic divergence of sixteen rice cultivars regarding their resistance to the rice stem bug, Tibraca limbativentris Stål, was estimated by multivariate analysis techniques. The experiment was carried out in greenhouse, in randomized block design with eight replications. Eight plant resistance related traits were evaluated. Genetic divergence was evaluated by multivariate procedures: generalized Mahalanobis (D(2)) distance, the Tocher's grouping optimization method and canonical variables. The most dissimilar cultivars were Bico Ganga and Marabá Branco, while Agulha and Branco Tardão were the most similar. Five clusters were formed by the Tocher's optimization method. Three canonic variables explained 88.5% of the observed variation. We concluded that the multivariate analysis techniques are suitable for analyzing the genetic divergence among rice cultivars, indicating Bico Ganga and Marabá Branco as the most promising for future breeding programs of resistance to the rice stem bug.


Antioxidant, Antimicrobial, and Curing Potentials of Micronized Celery Powders added to Pork Sausages.
Meat industries utilize plant material such as celery in cured meat products. Extraction of valuable bioactive compounds, nitrates and nitrites often involves processes that increase cost or lack sustainability. Thus, this study investigated the effect of ball-milled celery powders (CP) on the physicochemical, antioxidant, and antimicrobial properties along with curing efficiency in comminuted meat product. Pork sausages loaded with CPs with different average particle sizes: 265 μm (T1), 68 μm (T2) and 7 μm (T3) were compared to those added without and with sodium nitrite (150 ppm). The a* values were increased for sausages with larger particle size. The L* values decreased for all CPs. Residual nitrite for all particle sizes increased in the earlier stages and decreased at the end of storage period. The curing efficiency also increased for larger size particles with an increase until day 9 followed by a gradual decrease. Superfine CP had a tendency to improve the antioxidant activities. The antimicrobial activity of CPs was not comparable with nitrite added sausages. The textural parameters remained unaffected by particle size. Thus, instead of extracts or juices, micronized CPs could be used to improve the antioxidant activities and curing efficiency of label friendly reformulated meat products.


Coffee consumption and coronary artery calcium in young and middle-aged asymptomatic adults.
To investigate the association between regular coffee consumption and the prevalence of coronary artery calcium (CAC) in a large sample of young and middle-aged asymptomatic men and women. This cross-sectional study included 25 138 men and women (mean age 41.3 years) without clinically evident cardiovascular disease who underwent a health screening examination that included a validated food frequency questionnaire and a multidetector CT to determine CAC scores. We used robust Tobit regression analyses to estimate the CAC score ratios associated with different levels of coffee consumption compared with no coffee consumption and adjusted for potential confounders. The prevalence of detectable CAC (CAC score >0) was 13.4% (n=3364), including 11.3% prevalence for CAC scores 1-100 (n=2832), and 2.1% prevalence for CAC scores >100 (n=532). The mean ±SD consumption of coffee was 1.8±1.5 cups/day. The multivariate-adjusted CAC score ratios (95% CIs) comparing coffee drinkers of <1, 1-<3, 3-<5, and ≥5 cups/day to non-coffee drinkers were 0.77 (0.49 to 1.19), 0.66 (0.43 to 1.02), 0.59 (0.38 to 0.93), and 0.81 (0.46 to 1.43), respectively (p for quadratic trend=0.02). The association was similar in subgroups defined by age, sex, smoking status, alcohol consumption, status of obesity, diabetes, hypertension, and hypercholesterolaemia. In this large sample of men and women apparently free of clinically evident cardiovascular disease, moderate coffee consumption was associated with a lower prevalence of subclinical coronary atherosclerosis.


Impact of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump on prognostically important clinical outcomes in patients undergoing high-risk percutaneous coronary intervention (from the PROTECT II randomized trial).
A periprocedural myocardial infarction, defined as the advent of new Q-waves or a creatine kinase-MB elevation >83 normal has been previously validated as predictive of subsequent mortality. We examined the effects of using this clinically relevant definition of periprocedural myocardial infarction instead of the original protocol definition on outcomes in the recent PROTECT II [A Prospective, Multi-center, Randomized Controlled Trial of the IMPELLA RECOVER LP 2.5 System Versus Intra Aortic Balloon Pump (IABP) in Patients Undergoing Non Emergent High Risk PCI] trial. In this trial, patients who were undergoing high-risk percutaneous coronary intervention (PCI) were randomized to either an intraaortic balloon pump (IABP, n[211) or a left ventricular assist device (Impella, n[216). All eligible patients per study protocol were included in the analysis. Patient outcomes were compared up to 90 days, the longest available follow-up, on the composite end points of major adverse events (MAE) and major adverse cardiac and cerebral events (MACCE [ death, stroke, myocardial infarction, and repeat revascularization). At 90 days, the rates of both composite end points were lower in the Impella group compared with the IABP group (MAE, 37% vs 49%, p [ 0.014 respectively; MACCE, 22% vs 31%, p [ 0.034 respectively). There were no differences in death or large myocardial infarction between the 2 arms. By multivariable analysis, treatment with Impella as opposed to IABP was an independent predictor for freedom from MAE (odds ratio[0.75 [95% confidence interval 0.61 to 0.92], p[0.007) andMACCE (odds ratio[0.76 [95% confidence interval 0.61 to 0.96], p[0.020) at 90 days postprocedure. In conclusion, hemodynamic support with Impella compared with IABP during high-risk PCI in the PROTECT-II trial resulted in improved event-free survival at 3-month follow-up; this finding was further supported by multivariate analyses.


Synthesis and properties of star-comb polymers and their doxorubicin conjugates.
We describe a six-step synthesis to water-soluble doxorubicin (DOX)-loaded biodegradable PEGylated star-comb polymers with favorable pharmaceutical properties by atom transfer radical polymerization (ATRP) starting with a commercially available tripentaerythritol carrying eight reactive sites. The low polydispersity polymers degrade in a stepwise manner into lower molecular weight (MW) fragments by 15 days at 37 °C at either pH 5.0 or pH 7.4. The half-life of the star-comb polymers in blood is dependent upon the molecular weight; the 44 kDa star-comb has a t(1/2, β) of 30.5 ± 2.1 h, which is not significantly changed (28.6 ± 2.7 h) when 6.6 wt % of DOX is attached to it via a pH-sensitive hydrazone linker. The star-comb polymers have low accumulation in organs but a high accumulation in C26 flank tumors implanted in Balb/C mice. The hydrodynamic diameter of polymer-DOX conjugates measured by dynamic light scattering increases from 8 to 35 to 41 nm as the loading is increased from 6.6 to 8.4 to 10.2 wt %. Although there is no significant difference in the t(1/2, β) or in the accumulation of polymer-DOX in C-26 tumors, the uptake of polymer in the spleen is significantly higher for polymers with DOX loadings greater than 6.6 wt %. Polymer accumulation in other vital organs is independent of the DOX loading. The facile synthesis, biodegradability, long circulation time, and high tumor accumulation of the attached drug suggests that the water-soluble star-comb polymers have promise in therapeutic applications.


[Fine-needle aspiration biopsy under CT-guidance--usefulness in diagnosis of malignant lung tumors].
Aim of the study was to evaluate the usefulness of fine-needle aspiration biopsy (FNAB) in diagnosis of malignant lung tumors. The results of 438 CT guided FNAB of lung lesions performed between Sep. 1st 1999 and Feb. 20th 2004 were evaluated. In 295 cases (67.35%) the cytological diagnosis of lung tumours were established by FNAB. The most common type of the tumours were: non-small cell lung cancer: 222 (50.69%) and small cell lung cancer: 49 (11.19%). 104 of these results were histologically verified and two false positive results were detected. In 143 cases (32.65%) however, the results established by FNAB were non-diagnostic. 63 of the lesions were verified and in 36 cases (57.1%) the malignant tumours were proved. The specificity of the method regarding malignant lesions reached 93.10%, and its sensitivity for patients with malignancy was 73.91%. The average diameter of the malignant tumour was 5.4+/-1.3 cm whereas in case of non-diagnostic results the diameter of the tumour was 4.1+/-1.6 cm. However, there was no significant difference between the two groups. The most common complication of FNAB was pneumothorax, which occurred in 22 patients (5.02%) and in 13 cases (2.97%) required drainage of the chest cavity. FNAB is a safe diagnostic method with high specificity and moderate sensitivity in detecting of malignant lung lesions.


Transduction of c-src coding and intron sequences by a transformation-defective deletion mutant of Rous sarcoma virus.
The mechanism of cellular src (c-src) transduction by a transformation-defective deletion mutant, td109, of Rous sarcoma virus was studied by sequence analysis of the recombinational junctions in three td109-derived recovered sarcoma viruses (rASVs). Our results show that two rASVs have been generated by recombination between td109 and c-src at the region between exons 1 and 2 defined previously. Significant homology between td109 and c-src sequences was present at the sites of recombination. The viral and c-src sequence junction of the third rASV was formed by splicing a cryptic donor site at the 5' region of env of td109 to exon 1 of c-src. Various lengths of c-src internal intron 1 sequences were incorporated into all three rASV genomes, which resulted from activation of potential splice donor and acceptor sites. The incorporated intron 1 sequences were absent in the c-src mRNA, excluding its being the precursor for recombination with td109 and implying that initial recombinations most likely took place at the DNA level. A potential splice acceptor site within the incorporated intron 1 sequences in two rASVs was activated and was used for the src mRNA synthesis in infected cells. The normal env mRNA splice acceptor site was used for src mRNA synthesis for the third rASV.


Effects of a polyphenol present in olive oil, oleuropein aglycone, in a murine model of intestinal ischemia/reperfusion injury.
Dietary olive oil supplementation and more recently, olive oil phenols have been recommended as important therapeutic interventions in preventive medicine. Ole has several pharmacological properties, including antioxidant, anti-inflammatory, antiatherogenic, anticancer, antimicrobial, and antiviral and for these reasons, is becoming an important subject of study in recent years. The aim of this study was to investigate the effects of Ole aglycone on the modulation of the secondary events in mice subjected to intestinal IRI. This was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by release of the clamp, allowing reperfusion for 1 h. After 60 min of reperfusion, animals were killed for histological examination of the ileum tissue and immunohistochemical localization of proinflammatory cytokines (TNF-α and IL-1β) and adhesion molecules (ICAM-1 and P-sel); moreover, by Western blot analysis, we investigated the activation of NF-κB and IκBα. In addition, we evaluated the apoptosis process, as shown by TUNEL staining and Bax/Bcl-2 expressions. The results obtained by the histological and molecular examinations showed in Ole aglycone-treated mice, a decrease of inflammation and apoptosis pathway versus SAO-shocked mice. In conclusion, we propose that the olive oil compounds, in particular, the Ole aglycone, could represent a possible treatment against secondary events of intestinal IRI.


[COMPARATIVE ASSESSMENT OF MASS-SPECTROMETRY AND INFRARED SPECRTROMETRY USED IN 13C-UREA BREATH TEST FOR HELICOBACTER PYLORI].
At present, mass-spectrometry is the most accurate and efficient method for measuring carbon isotope ratio in 13C-urea breath test for H. pylori infection but its wide application is restricted by the high cost of equipment and operational complexity. IR spectrometry is one of the less expensive techniques recently proposedfor the purpose. To compare the effectiveness of the two methods, we undertook a study including 20 volunteers (6 men and 14 women) aged 18-60 years with parallel measurements by IR and mass-spectrometry. IR spectrometry was shown to be highly accurate (94-96%), sensitive (up to 100%), and specific (87.5%) which makes it a promising alternative to mass-spectrometry to be used in urea breath test for mass examination especially in outpatient facilities.


Mexiletine and lidocaine suppress the excitability of dorsal horn neurons.
Spinal sensitization and facilitatory processes in dorsal horn neurons after nerve injury alter spinal outflow leading to enhanced pain perception and chronic pain syndromes. Clinically used Na+ channel blockers at doses which do not block conduction can relieve such chronic pain. Although much attention has been paid to their effect upon afferents, less work has been done with their effect on the excitability of central sensory neurons. Thus, we investigated the effects of the Na+ channel blockers mexiletine and lidocaine on sensory spinal dorsal horn neurons. Patch-clamp recordings were directly performed in visualized neurons of the substantia gelatinosa in the spinal cord of young rats to investigate the effect of mexiletine and lidocaine in different types of dorsal horn neurons (tonically firing, adapting-firing, and single spike neurons). All three different types of neurons responded dose-dependently to mexiletine and lidocaine. Both local anesthetics reversibly inhibited Na+ and K+ currents. The half-maximal inhibitory concentration for Na+ conductance block was 89 +/- 2 or 54 +/- 6 microM and for delayed-rectifier K+ conductance block was 582 +/- 36 or 398 +/- 14 microM for lidocaine and mexiletine, respectively. The inhibition of Na+ and K+ currents consecutively altered the properties of single action potentials and reduced the firing rate of tonically firing and adapting-firing neurons. In clinically relevant concentrations, lidocaine and mexiletine reduced the excitability of sensory dorsal horn neurons via a blockade of Na+ and K+ channels. Our work confirms that, in addition to the peripheral effects of lidocaine and mexiletine, modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs used in pain therapy.


Usability of Virtual Visits for the Routine Clinical Care of Trans Youth during the COVID-19 Pandemic: Youth and Caregiver Perspectives.
We evaluated families' perspectives on the usability of virtual visits for routine gender care for trans youth during the COVID-19 pandemic. An online survey, which included a validated telehealth usability questionnaire, was sent to families who had a virtual Gender Clinic visit between March and August 2020. A total of 87 participants completed the survey (28 trans youth, 59 caregivers). Overall, usability was rated highly, with mean scores between "quite a bit" and "completely" in all categories (usefulness, ease of use, interface and interaction quality, reliability, and satisfaction). Caregivers reported higher usability scores compared to trans youth [mean (SD) 3.43 (0.80) vs. 3.12 (0.93), p = 0.01]. All families felt that virtual visits provided for their healthcare needs. A total of 100% of youth and caregivers described virtual appointments as safer or as safe as in-person visits. A total of 94% of participants would like virtual visits after the pandemic; families would choose a mean of two virtual and one yearly in-person visit with a multidisciplinary team. Overall, virtual gender visits for trans youth had impressive usability. Participants perceived virtual visits to be safe. For the future, a combination of virtual and in-person multidisciplinary visits is the most desired model.


The inhibition of pepsin-catalysed reactions by structural and stereochemical product analogues.
1. The inhibition of pepsin-catalysed hydrolysis of N-acetyl-l-phenylalanyl-l-phenylalanylglycine by products and product analogues was studied. 2. Inhibitors of the l-configuration give rise to linear non-competitive inhibition, whereas those of the d-configuration show linear competitive behaviour. 3. Non-competitive inhibition by the product N-acetyl-l-phenylalanine indicates an ordered release of products, which supports a common mechanism (involving an ;amino-enzyme') for pepsin-catalysed transpeptidation and hydrolysis reactions. 4. The differences in the types of inhibition caused by product analogues of the l- and d-series emphasize the stereospecificity of the binding of these inhibitors to free enzyme and to the putative amino-enzyme intermediate. 5. The results suggest that it is the anion of the acyl product that is released first in the hydrolytic reaction (see Kitson & Knowles, 1971).


Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.
Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.


The impact of greenspace and condition of the neighbourhood on child overweight.
Childhood overweight/obesity has been associated with environmental, parenting and socioeconomic status (SES) factors. This paper assesses the influence of the amount of green space, accessibility to a garden and neighbourhood condition on being overweight/obese. It investigates whether parental behaviours moderate or mediate this influence and evaluates the interaction of SES with environmental context. 6467 children from the UK Millennium Cohort Study living in England were analysed. We estimated logistic regressions to examine the initial association between environment and overweight. Subsequently, parenting determinants comprising: food consumption, physical activity, rules and regularity were evaluated as moderators or mediators. Lastly SES related variables were tested as moderators or mediators of the associations. Statistically significant associations were found between low levels of green space, no access to a garden, run down area and childhood overweight/obesity [odds ratio (OR) [95% confidence interval (CI)] respectively: 1.14 (1.02-1.27), 1.35 (1.16-1.58), 1.22 (1.05-1.42)]. None of the parental constructs mediated or moderated the relationships between environment and childhood overweight/obesity. Including SES, parental education moderated the effect of environmental context. Specifically, among lower educated households lack of garden access and less green space was associated with overweight/obesity; and among higher educated households poor neighbourhood condition influenced the probability of overweight/obesity respectively: 1.38 (1.12-1.70) OR 1.38, 95% CI (1.21-1.70). This study suggests that limits on access to outdoor space are associated with future childhood overweight/obesity although the ways in which this occurs are moderated by parental education level.


MicroRNA gene dosage alterations and drug response in lung cancer.
Chemotherapy resistance is a key contributor to the dismal prognoses for lung cancer patients. While the majority of studies have focused on sequence mutations and expression changes in protein-coding genes, recent reports have suggested that microRNA (miRNA) expression changes also play an influential role in chemotherapy response. However, the role of genetic alterations at miRNA loci in the context of chemotherapy response has yet to be investigated. In this study, we demonstrate the application of an integrative, multidimensional approach in order to identify miRNAs that are associated with chemotherapeutic resistance and sensitivity utilizing publicly available drug response, miRNA loci copy number, miRNA expression, and mRNA expression data from independent resources. By instigating a logical stepwise strategy, we have identified specific miRNAs that are associated with resistance to several chemotherapeutic agents and provide a proof of principle demonstration of how these various databases may be exploited to derive relevant pharmacogenomic results.


BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex.
BMP-induced chemotaxis of mesenchymal progenitors is fundamental for vertebrate development, disease and tissue repair. BMP2 induces Smad and non-Smad signalling. Whereas signal transduction via Smads lead to transcriptional responses, non-Smad signalling induces both, transcriptional and immediate/early non-transcriptional responses. However, the molecular mechanisms by which BMP2 facilitates planar cell polarity, cortical actin rearrangements, lamellipodia formation and chemotaxis of mesenchymal progenitors are poorly understood. Our aim was to uncover the molecular mechanism by which BMP2 facilitates chemotaxis via the BMP2-dependent activation of PI3K and spatiotemporal control of PIP3 production important for actin rearrangements at the mesenchymal cell cytocortex. We unveiled the molecular mechanism by which BMP2 induces non-Smad signalling by PI3K and the role of the second messenger PIP3 in BMP2-induced planar cell polarity, cortical actin reorganisation and lamellipodia formation. By using protein interaction studies, we identified the class Ia PI3K regulatory subunit p55γ to act as a specific and non-redundant binding partner for BMP receptor type II (BMPRII) in concert with the catalytic subunit p110α. We mapped the PI3K interaction to a region within the BMPRII kinase. Either BMP2 stimulation or increasing amounts of BMPRI facilitated p55γ association with BMPRII, but BMPRII kinase activity was not required for the interaction. We visualised BMP2-dependent PIP3 production via PI3K p55γ/p110α and were able to localise PIP3 to the leading edge of intact cells during the process of BMP2-induced planar cell polarity and actin dependent lamellipodia formation. Using mass spectrometry, we found the highly PIP3-sensitive PH-domain protein LL5β to act as a novel BMP2 effector in orchestrating cortical actin rearrangements. By use of live cell imaging we found that knock-down of p55γ or LL5β or pharmacological inhibition of PI3K impaired BMP2-induced migratory responses. Our results provide evidence for an important contribution of the BMP2-PI3K (p55γ/p110α)- PIP3-LL5β signalling axis in mesenchymal progenitor cell chemotaxis. We demonstrate molecular insights into BMP2-induced PI3K signalling on the level of actin reorganisation at the leading edge cytocortex. These findings are important to better understand BMP2-induced cytoskeletal reorganisation and chemotaxis of mesenchymal progenitors in different physiological or pathophysiological contexts.


Endophthalmitis caused by Pantoea agglomerans: clinical features, antibiotic sensitivities, and outcomes.
To report the clinical findings, antibiotic sensitivities, and visual outcomes associated with endophthalmitis caused by Pantoea agglomerans. A consecutive case series of patients with vitreous culture-positive endophthalmitis caused by P. agglomerans from January 1, 1990 to December 31, 2012 at a large university referral center. Findings from the current study were compared to prior published studies. Of the three study patients that were identified, clinical settings included trauma (n=2) and post-cataract surgery (n=1). Presenting visual acuity was hand motion or worse in all three cases. All isolates were sensitive to ceftazidime, gentamicin, imipenem, and fluoroquinolones. All isolates were resistant to ampicillin. Initial treatment strategies were vitreous tap and intravitreal antibiotic injection (n=1) and pars plana vitrectomy with intravitreal antibiotic injection (n=2). At last follow-up, one patient had no light perception vision, while the other two had best-corrected visual acuity of 20/200 and 20/400. All Pantoea isolates were sensitive to ceftazidime, gentamicin, imipenem, and fluoroquinolones. All patients in the current study received at least one intravitreal antibiotic to which P. agglomerans was shown to be sensitive in vitro. In spite of this, the visual outcomes were generally poor.


Glucocorticoid-Induced Myopathy in a Patient with Systemic Lupus Erythematosus (SLE): A Case Report and Review of the Literature.
BACKGROUND Chronic intake of high-dose corticosteroids is associated with multiple adverse clinical effects, including hypertension, insulin resistance, impaired wound healing, immunosuppression, myopathy, and osteoporosis. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy to limit these side effects. Glucocorticoid-induced myopathy is a less common side effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40-60 mg/day can induce clinically significant myopathy and weakness. CASE REPORT A 35-year-old woman with a past medical history of hypothyroidism, systemic lupus erythematosus (SLE), and end-stage renal disease secondary to lupus nephritis, on hemodialysis, presented to the local emergency department with progressive bilateral proximal lower extremity weakness. Three months before admission, when her insurance company prematurely discontinued her monthly cyclophosphamide injections, at which time, she was treated with prednisone 60 mg daily. Two months before hospital admission, she reported increasing fatigue, weight gain, difficulty in standing from a seated position and climbing stairs. CONCLUSIONS Elucidating the etiology of progressive neuromotor deficit in immunosuppressed patients can be difficult. The management of SLE and other autoimmune diseases with chronic high-dose steroids is associated with recognized side effects. Differentiating natural disease progression from iatrogenic etiologies is important in this subset of patients, particularly to reduce prolonged clinical management and hospital admissions.


Ethiopia: between Sub-Saharan Africa and western Eurasia.
Ethiopia is central to population genetic studies investigating the out of Africa expansion of modern humans, as shown by Y chromosome and mtDNA studies. To address the level of genetic differentiation within Ethiopia, and its relationship to Sub-Saharan Africa and Eurasia, we studied an 8 kb segment of the X-chromosome from 72 chromosomes from the Amhara, Oromo and Ethiopian Jews, and compared these results with 804 chromosomes from Middle Eastern, African, Asian and European populations, and 22 newly typed Saharawi. Within Ethiopia the two largest ethnic groups, the Amhara and Oromo, were not found to be statistically distinct, based on an exact test of haplotype frequencies. The Ethiopian Jews appear as an admixed population, possibly of Jewish origin, though the data remain equivocal. There is evidence of a close relationship between Ethiopian and Yemenite Jews, likely a result of indirect gene flow. Within an African and Eurasian context, the distribution of alleles of a variable T(n) repeat, and the spread of haplotypes containing Africa-specific alleles, provide evidence of a genetic continuity from Sub-Saharan Africa to the Near East, and furthermore suggest that a bottleneck occurred in Ethiopia associated with an out of Africa expansion. Ethiopian genetic heterogeneity, as evidenced by principal component analysis of haplotype frequencies, most likely resulted from periods of subsequent admixture. While these results are from the analysis of one locus, we feel that in association with data from other marker systems they add a complementary perspective on the history of Ethiopia.


Hypercalcemia and elevated serum calcitriol in a patient with seminoma.
This report describes a 49-year-old man with hypercalcemia and seminoma. His serum calcitriol (1,25-dihydroxy-vitamin D) level was markedly elevated. Additional endocrine evaluation revealed a normal serum phosphate level, hypercalciuria, and normal serum levels of immunoreactive parathyroid hormone. Serum calcium and calcitriol levels returned to normal following partial resection and successful combination chemotherapy. The association of hypercalcemia and elevated serum calcitriol levels has been previously described in a few patients with malignant lymphoma, but, to our knowledge, not in patients with solid tumors. The mechanism of hypercalcemia in this patient is not proved, but available evidence suggests calcitriol as the mediator.


Biodistribution of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar, without integration, despite differing plasmid backbones or gene inserts.
The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies have been performed in mice or rabbits to determine where in the body these plasmid vaccines would biodistribute and how rapidly they would clear. In the course of these studies, it has been observed that regardless of the gene insert (expressing the vaccine immunogen or cytokine adjuvant) and regardless of the promoter used to drive expression of the gene insert in the plasmid backbone, the plasmid vaccines do not biodistribute widely and remain essentially in the site of injection, in the muscle and overlying subcutis. Even though approximately 10(14) molecules are inoculated in the studies in rabbits, by day 8 or 9 ( approximately 1 week postinoculation), already all but on the order of 10(4)-10(6) molecules per microgram of DNA extracted from tissue have been cleared at the injection site. Over the course of 2 months, the plasmid clears from the site of injection with only a small percentage of animals (generally 10-20%) retaining a small number of copies (generally around 100 copies) in the muscle at the injection site. This pattern of biodistribution (confined to the injection site) and clearance (within 2 months) is consistent regardless of differences in the promoter in the plasmid backbone or differences in the gene insert being expressed by the plasmid vaccine. In addition, integration has not been observed with plasmid vaccine candidates inoculated i.m. by Biojector 2000 or by needle and syringe. These data build on the repeated-dose toxicology studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.


The nature and properties of the inducible sodium-plus-potassium ion-dependent adenosine triphosphatase in the gills of eels (Anguilla anguilla) adapted to fresh water and sea water.
1. Gill tissue from eels adapted to fresh water or to sea water was disrupted in 0.32m-sucrose containing 0.1% (w/v) sodium deoxycholate and the subcellular distribution of (Na(+)+K(+))-dependent adenosine triphosphatase was determined. 2. About 70% of the recovered enzyme was in a fraction sedimenting between 225000g(av.)-min and 6000000g(av.)-min; the specific activities of enzymes from tissues of freshwater and seawater eels were 16 and 51 mumol of phosphate/h per mg of protein respectively. 3. The enzymes from gills of freshwater and seawater eels were indistinguishable on the basis of a number of parameters. These included phosphorylation by [gamma-(32)P]ATP, the binding of [(3)H]ouabain, the extent to which bound [(3)H]ouabain was displaced by increasing concentrations of KCl and pH optima. 4. Electrophoresis on polyacrylamide gels in sodium dodecyl sulphate showed that enzyme preparations from both sources had an identical number of protein components. 5. The higher specific activity of (Na(+)+K(+))-dependent adenosine triphosphatase from tissue of seawater eels was accompanied by increased amounts of two protein components. One of these proteins retained (32)P after treatment of the enzyme with [gamma-(32)P]ATP and had mol.wt. 97000; the other component was a glycoprotein with mol.wt. approx. 46000. 6. The results are discussed in terms of the nature of the transepithelial NaCl pumps in the gills of freshwater and seawater fish.


[Prevalence and risk factors of Enterobius vermicularis among preschool children in kindergartens in Luohu District, Shenzhen City].
To understand the prevalence and risk factors of Enterobius vermicularis among preschool children in kindergartens in Luohu District, Shenzhen City. A total of 489 children in 6 kindergartens were selected by the stratified sampling method and investigated for E. vermicularis infection by the cellophane anal swab technique. The information of sanitary condition of the kindergartens, personal hygiene, and family hygiene were investigated by questionnaire. The infection rate of E. vermicularis was 10.2% (50/489). The single factor analysis indicated that the following factors might related to the infection: the different classes of kindergartens, grades, ground of bed ioom, private toilet, types of taps and beds, bed management, education levels of parents, frequency of shower and washing anus, and washing hands before meal and after WC. The multivariate Logistic analysis indicated that the bed management, education level of mothers, frequency of washing anus, and private toilet were independent risk factors for E. vermicularis infection. To control the infection of E. vermicularis, the circumstance and management of kindergartens, parents' knowledge of E. vernicularis infection, and children's healthy habit need improve.


Germanium nanocrystals as luminescent probes for rapid, sensitive and label-free detection of Fe3+ ions.
Luminescent water-soluble germanium nanocrystals (Ge NCs) have been developed as a fluorescent sensing platform for the highly selective and sensitive detection of Fe3+ via quenching of their strong blue luminescence, without the need for analyte-specific labelling groups. The amine-terminated Ge NCs were separated into two discrete size fractions with average diameters of 3.9±0.4 nm and 6.8±1.8 nm using centrifugation. The smaller 3.9 nm NCs possessed a strong blue luminescence, with an average lifetime of 6.1 ns and a quantum yield (QY) of 21.5%, which is strongly influenced by solution pH. In contrast, 6.8 nm NCs exhibited a green luminescence with a longer lifetime of 7.8 ns and lower QY (6.2%) that is insensitive to pH. Sensitive detection of Fe3+ was successfully demonstrated, with a linear relationship between luminescence quenching and Fe3+ concentration observed from 0-800 μM, with a limit of detection of 0.83 μM. The Ge NCs show excellent selectivity toward Fe3+ ions, with no quenching of the fluorescence signal induced by the presence of Fe2+ ions, allowing for solution phase discrimination between ions of the same element with different formal charges. The luminescence quenching mechanism was confirmed by static and time-resolved photoluminescence spectroscopies, while the applicability for this assay for detection of Fe3+ in real water samples was successfully demonstrated.


Characterization of transcription start sites of putative non-coding RNAs by multifaceted use of massively paralleled sequencer.
On the basis of integrated transcriptome analysis, we show that not all transcriptional start site clusters (TSCs) in the intergenic regions (iTSCs) have the same properties; thus, it is possible to discriminate the iTSCs that are likely to have biological relevance from the other noise-level iTSCs. We used a total of 251,933,381 short-read sequence tags generated from various types of transcriptome analyses in order to characterize 6039 iTSCs, which have significant expression levels. We analyzed and found that 23% of these iTSCs were located in the proximal regions of the RefSeq genes. These RefSeq-linked iTSCs showed similar expression patterns with the neighboring RefSeq genes, had widely fluctuating transcription start sites and lacked ordered nucleosome positioning. These iTSCs seemed not to form independent transcriptional units, simply representing the by-products of the neighboring RefSeq genes, in spite of their significant expression levels. Similar features were also observed for the TSCs located in the antisense regions of the RefSeq genes. Furthermore, for the remaining iTSCs that were not associated with any RefSeq genes, we demonstrate that integrative interpretation of the transcriptome data provides essential information to specify their biological functions in the hypoxic responses of the cells.


Spatio-temporal mapping of breast and prostate cancers in South Iran from 2014 to 2017.
The most common gender-specific malignancies are cancers of the breast and the prostate. In developing countries, cancer screening of all at risk is impractical because of healthcare resource limitations. Thus, determining high-risk areas might be an important first screening step. This study explores incidence patterns of potential high-risk clusters of breast and prostate cancers in southern Iran. This cross-sectional study was conducted in the province of Kerman, South Iran. Patient data were aggregated at the county and district levels calculating the incidence rate per 100,000 people both for cancers of the breast and the prostate. We used the natural-break classification with five classes to produce descriptive maps. A spatial clustering analysis (Anselin Local Moran's I) was used to identify potential clusters and outliers in the pattern of these cancers from 2014 to 2017. There were 1350 breast cancer patients (including, 42 male cases) and 478 prostate cancer patients in the province of Kerman, Iran during the study period. After 45 years of age, the number of men with diagnosed prostate cancer increased similarly to that of breast cancer for women after 25 years of age. The age-standardised incidence rate of breast cancer for women showed an increase from 29.93 to 32.27 cases per 100,000 people and that of prostate cancer from 13.93 to 15.47 cases per 100,000 during 2014-2017. Cluster analysis at the county level identified high-high clusters of breast cancer in the north-western part of the province for all years studied, but the analysis at the district level showed high-high clusters for only two of the years. With regard to prostate cancer, cluster analysis at the county and district levels identified high-high clusters in this area of the province for two of the study years. North-western Kerman had a significantly higher incidence rate of both breast and prostate cancer than the average, which should help in designing tailored screening and surveillance systems. Furthermore, this study generates new hypotheses regarding the potential relationship between increased incidence of cancers in certain geographical areas and environmental risk factors.


Dosimetric Comparison of Different Planning Techniques in Left-sided Whole-Breast Irradiation: A Planning Study.
This planning study compared the various dosimetric parameters of different types of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques for left-sided breast cancer radiotherapy. Treatment of 22 left-sided breast cases was planned using two IMRT and VMAT techniques for the prescription of 40 Gy in 15 fractions. For tangential IMRT (Tan_IMRT), five beams were placed as conventional tangential beams. For equally spaced IMRT (Equi_IMRT), six beams were placed equidistantly at 40° interval from 300° to 140°. For tangential VMAT (Tan_VMAT), two arcs were used with the avoidance sector in such a way that the beam covered like tangential fields. For full-arc VMAT (Full_VMAT), similar arcs as Tan_VMAT were used, without avoidance sector. All treatment plans were generated using Eclipse planning system for TrueBeam STx linear accelerator. For planning target volume (PTV), dose parameters including D95%, D99%, V105% homogeneity index (HI), and conformity index (CI) were analyzed. Different dose parameters for the left lung, heart, left anterior descending artery (LAD), right lung, and right breast were also analyzed. In addition, low-dose spillage in the normal tissues and the number of monitor units (MUs) required for the treatment were compared. IMRT technique exhibited superior D95% and D99% for PTV compared with VMAT techniques. VMAT plans provided more V105% (6%) compared with that of IMRT plans (approximately 1%). HI was better in IMRT plans (Tan_IMRT, 0.085 ± 0.015; Equi_IMRT, 0.094 ± 0.011) than in VMAT plans. CI was better in VMAT plans. The mean lung dose (7.7 Gy ± 1.788 Gy) and V5Gy (34.99% ± 6.799%) were better achieved in Tan_IMRT plan than other plans. Right lung, heart, and right breast sparing were better achieved in Tan_IMRT plan. Moreover, low-dose spillage was very less in the Tan_IMRT compared with all other techniques. Dosimetric comparison in this study showed that tangential IMRT technique is superior in terms of target coverage, sparing of lung, heart, and right breast, and low-dose spillage control in the left-sided breast-only radiotherapy.


Impacts of Embryonic Thermal Programming on the Expression of Genes Involved in Foie gras Production in Mule Ducks.
Embryonic thermal programming has been shown to improve foie gras production in overfed mule ducks. However, the mechanisms at the origin of this programming have not yet been characterized. In this study, we investigated the effect of embryonic thermal manipulation (+1°C, 16 h/24 h from embryonic (E) day 13 to E27) on the hepatic expression of genes involved in lipid and carbohydrate metabolisms, stress, cell proliferation and thyroid hormone pathways at the end of thermal manipulation and before and after overfeeding (OF) in mule ducks. Gene expression analyses were performed by classic or high throughput real-time qPCR. First, we confirmed well-known results with strong impact of OF on the expression of genes involved in lipid and carbohydrates metabolisms. Then we observed an impact of OF on the hepatic expression of genes involved in the thyroid pathway, stress and cell proliferation. Only a small number of genes showed modulation of expression related to thermal programming at the time of OF, and only one was also impacted at the end of the thermal manipulation. For the first time, we explored the molecular mechanisms of embryonic thermal programming from the end of heat treatment to the programmed adult phenotype with optimized liver metabolism.


Oral midodrine does not expedite liberation from protracted vasopressor infusions: A case-control study.
Vasopressor dependence is a common problem affecting patients in the recovery phase of critical illness, often necessitating intensive care unit (ICU) admission and other interventions which carry associated risks. Midodrine is an orally administered vasopressor which is commonly used off-label to expedite weaning from vasopressor infusions and facilitate discharge from ICU. We performed a single-centre, case-control study to assess whether midodrine accelerated liberation from vasopressor infusions in patients who were vasopressor dependent. Cases were identified at the discretion of treating intensivists and received 20 mg oral midodrine every eight h from enrolment. Controls received placebo. Data on duration and dose of vasopressor infusion, haemodynamics and adverse events were collected. Between 2012 and 2019, 42 controls and 19 cases were recruited. Cases had received vasopressor infusions for a median of 94 h versus 29.3 h for controls, indicating prolonged vasopressor dependence amongst cases. Midodrine use in cases was not associated with faster weaning of intravenous (IV) vasopressors (26 h versus 24 h for controls, P = 0.51), ICU or hospital length of stay after adjustment for confounders. Midodrine did not affect mean heart rate but was associated with bradycardia. This case-control study demonstrates that midodrine has limited efficacy in expediting weaning from vasopressor infusions in patients who have already received relatively prolonged courses of these infusions.


A Scoping Review of Behavioral Interventions Addressing Medical Financial Hardship.
Little information has been compiled across studies about existing interventions to mitigate issues of medical financial hardship, despite growing interest in health care delivery. The purpose of this qualitative systematic scoping review was to examine content and outcomes of interventions to address medical financial hardship. PRISMA guidelines were applied to present results using PubMed, Scopus, and CINAHL, published between January 1980 and August 2020. Additional studies were identified through reference lists of selected papers. Included studies focused on mitigating medical financial hardship from out-of-pocket (OOP) health care expenses as an intervention strategy with at least 1 evaluation component. Screening 2412 articles identified 339 articles for full-text review, 12 of which met inclusion criteria. Variation was found regarding targets and outcome measurement of intervention. Primary outcomes were in the following categories: financial outcomes (eg, OOP expenses), behavioral outcomes, psychosocial, health care utilization, and health status. No included studies reported significant reduction in OOP expenses, perceptions of financial burden/toxicity, or health status. However, changes were observed for behavioral outcomes (adherence to treatment, patient needs addressed), some psychosocial outcomes (mental health symptoms, perceived support, patient satisfaction), and care utilization such as routine health care. No patterns were observed in the achievement of outcomes across studies based on intensity of intervention. Few rigorous studies exist in this emerging field, and studies have not shown consistent positive effects. Future research should focus on conceptual clarity of the intervention, align outcome measurement and achieve consensus around outcomes, and employ rigorous study designs, measurement, and outcome follow-up.


Differential effects of eicosapentaenoic acid and oleic acid on lipid synthesis and secretion by HepG2 cells.
The effects of eicosapentaenoic acid and oleic acid on lipid synthesis and secretion by HepG2 cells were examined to identify fatty acid specific changes in lipid metabolism that might indicate a basis for the hypolipidemic effect attributed to eicosapentaenoic acid and related n-3 fatty acids. Cellular glycerolipid synthesis, as determined by [3H]glycerol incorporation, increased in a concentration-dependent manner in cells incubated 4 h with either eicosapentaenoic acid or oleic acid at concentrations between 10 and 300 microM. [3H]Glycerol-labeled triglyceride was the principal lipid formed and increased approximately fourfold with the addition of 300 microM oleic acid or eicosapentaenoic acid. Both fatty acids also produced a 20-40% increase in the total cellular triglyceride mass. Although both fatty acids increased triglyceride synthesis to similar extents, eicosapentaenoic acid-treated cells secreted 40% less [3H]glycerol-labeled triglyceride than cells fed oleic acid. Cellular synthesis of [3H]glycerol-labeled phosphatidylethanolamine and phosphatidylcholine was also reduced by 40% and 30%, respectively, in cells given eicosapentaenoic acid versus cells given oleic acid. Similar results were obtained in determinations of radiolabeled oleic acid and eicosapentaenoic acid incorporation. At a fatty acid concentration of 300 microM, incorporation of radiolabeled eicosapentaenoic acid into cellular triglycerides was greater than the incorporation obtained with radiolabeled oleic acid, while the reverse relationship was observed for the formation of phosphatidylcholine from the same fatty acids. Eicosapentaenoic acid is as potent as oleic acid in inducing triglyceride synthesis but eicosapentaenoic acid is a poorer substrate than oleic acid for phospholipid synthesis. The intracellular rise in de novo-synthesized triglyceride in eicosapentaenoic acid-treated cells without corresponding increases in triglyceride secretion suggests that eicosapentaenoic acid is less effective than oleic acid in promoting the transfer of de novo-synthesized triglyceride to nascent very low density lipoproteins.


[Psychological counselling and motivational psychotherapy in the treatment of drug dependence: assessment of interventions with the CEDRO Lugar de Escucha Program].
The objective of the present research is to assess perception of and levels of satisfaction with the Lugar de Escucha program, as well as its brief interventions using counseling and motivational sessions. The study is of a pre-experimental type, with a single-group pretest-posttest measurement design. The sample was made up of 128 participants (9.4% females and 90.6% males), aged 15 to 51 (mean= 23.65; standard deviation = 7.92), users of cannabis, cocaine base paste, cocaine, inhalants and alcohol who attended the program. Data collection was carried out using Attention Forms (FdA); the University of Rhode Island Change Assessment Scale (URICA); the Treatment Satisfaction Questionnaire (CST); and the Cases Follow-up Survey (ESC). In order to evaluate the effectiveness of the Lugar de Escucha Program, we assessed participants' motivational phases during the first interview and at referral, their level of satisfaction with the service received and the percentage of entrance to different treatment programs of the referred participants. The results on perception and satisfaction confirm a predominance of the program's strengths. With regard to the motivational phases, the findings show that the motivational induction interventions help to establish and maintain the patient's motivation for attitude change and for cessation of the abuse. In this sense, according to the findings, such interventions tend to be more effective when applied to patients in the Precontemplational and Contemplational phases. This suggests the need to work with more homogeneous groups, considering type of drugs, age and gender, and to use pre and post instruments. Likewise, the results suggest the need to classify patients in phases of change; such classification could be a useful tool for the improvement of treatment programs for drug users.


Muscle injury: the role of imaging in prognostic assignment and monitoring of muscle repair.
Muscle injury is common among athletes, and imaging is increasingly being used to confirm injury, to assess its location, extent, and severity, and on occasion to make inferences regarding prognosis and timing of return to sports. Ultrasound and magnetic resonance imaging (MRI) are accurate for diagnosis of acute injuries, but measurements of the extent of injury (cross-sectional area and longitudinal extent of muscle injury adjacent to the musculotendinous junction) have also been shown to correlate with athlete prognosis and recovery time. Specifically, normal MRI studies shortly after injury are associated with rapid (1- to 2-week) recovery and low risk of recurrent injury. Abnormal muscle cross-sectional area >55% is associated with a convalescence interval of >6 weeks, but larger measurements are not clearly associated with higher recurrence risk. The clinical value of follow-up imaging before return to competition is not established, but residual muscle abnormality is often present at this time.


Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury.
Oxidized low density lipoprotein (LDL), formed in vivo from presently unknown reactions, may play a role in atherogenesis. In vitro, transition metals such as iron and copper will facilitate LDL oxidation, but these metals are unlikely to exist in free form in normal body fluids. We have explored the possibility that LDL oxidation may be promoted by heme, a physiologically ubiquitous, hydrophobic, iron-containing compound. Indeed, during several-hour incubation, heme caused extensive oxidative modification of LDL; however, such modification requires only minutes in the presence of small amounts of H2O2 or preformed lipid hydroperoxides within the LDL. Oxidative interactions between heme, LDL, and peroxides lead to degradation of the heme ring and consequent release of heme iron, which further accelerates heme degradation. Coupled (evidently iron-catalyzed) heme degradation and LDL oxidation are both effectively inhibited by hydrophobic antioxidants and iron chelators. That such hemin-induced LDL oxidation may be involved in atherogenesis is supported by the finding that LDL oxidized by hemin is extremely cytotoxic to cultured aortic endothelial cells. Overall, these investigations not only lend support to the idea that LDL oxidation by physiological substances such as heme may play a role in the process of atherogenesis but also may have broader implications, as similar oxidative reactions between heme and unsaturated fatty acids may occur consequent to hemorrhagic injury.


Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts.
Sodium-channel blockers act by slowing sodium influx into myocytes through voltage gated channels. Many substances have sodium-channel blocking properties and many others show this effect when taken in overdose. Sodium-channel blocker poisoning, associated with a high death rate, is characterized by a variety of clinical presentation, depending on the pharmaceutical agent involved. Sodium bicarbonate or lactate, increasing serum pH and extracellular concentration of the ion, displace the drug from its receptor sites and can be used for the treatment of cardiac toxicity in the setting of sodium-channel blocker poisoning. In spite of this theoretical assumption, the role played by hypertonic sodium salts is not well elucidated and conflicting results have been reported. Authors review the pathophysiologic mechanisms of sodium-channel blocker poisoning and the evidences in literature concerning the efficacy of hypertonic sodium salts in the treatment of the related toxicity.


Mainstem bronchial atresia: a lethal anomaly amenable to fetal surgical treatment.
The purpose of this study was to review the unique imaging characteristics, prenatal course, and outcomes for fetuses with mainstem bronchial atresia (MBA). The records of all patients referred for a fetal lung malformation from 2001 to 2012 and the medical literature were reviewed to identify cases of MBA. Of 129 fetuses evaluated, 3 were diagnosed prenatally with right-sided MBA. The first had a CCAM-volume ratio (CVR) of 9, hydrops, mirror syndrome, and preterm delivery of a nonviable fetus. The second (CVR 2.6) had ascites, preterm delivery at 34-weeks, and neonatal demise. The third fetus (CVR 5.7) presented with hydrops at 21-weeks, prompting fetal pneumonectomy. Postoperatively, hydrops resolved, and the contralateral lung grew dramatically, but preterm delivery occurred 3 weeks later. Ventilation could not be sustained, and the infant died. Four similar cases of MBA were in the literature, all right-sided. Two fetuses with hydrops delivered at 25-weeks and died immediately. One pregnancy was terminated. One fetus underwent pneumonectomy at 24-weeks but died intraoperatively. MBA is a rare and lethal lesion that must be distinguished from other right-sided lung masses. Fetal pneumonectomy can be performed with resolution of hydrops and compensatory contralateral lung growth, but remains limited by complications of preterm birth.


Deterministic global optimization for FNN training.
This paper addresses the issue of training feedforward neural networks by global optimization. The main contributions include characterization of global optimality of a network error function, and formulation of a global descent algorithm to solve the network training problem. A network with a single hidden-layer and a single-output unit is considered. By means of a monotonic transformation, a sufficient condition for global optimality of a network error function is presented. Based on this, a penalty-based algorithm is derived directing the search towards possible regions containing the global minima. Numerical comparison with benchmark problems from the neural network literature shows superiority of the proposed algorithm over some local methods, in terms of the percentage of trials attaining the desired solutions. The algorithm is also shown to be effective for several pattern recognition problems.


Pattern of clinical features of chronic simple rhinosinusitis in Port Harcourt.
To evaluate the symptoms, signs and types of chronic simple rhino-sinusitis. This is prospective work done over a 2-year period. All the patients had symptoms of more than 8 weeks duration. Only patients with symptoms indicative of chronic rhino-sinusitis were included in the study. All the patients had plain x-rays of the paranasal sinuses done and a radiologist reported such. One hundred and fifteen patients were studied. The male to female ratio was 1:1.4 age range 15 years to 70 years. The mean duration of symptoms was 32.03 months. Rhinorrhoea 100%, stuffy nose 97.4%, sneezing 67.6%, anosmia 54.8% and headache 54.8% were the common symptoms while engorged inferior turbinates 79.1%, anterior nasal discharge 63.5% and postnasal discharge 39.1% were the common findings on examination. The clinical diagnosis was chronic infective sinusitis 72.7%, vasomotor rhinitis 17.4% and allergic rhinitis 10.4%. Engorged turbinate was the commonest radiological comment. Chronic infective rhino-sinusitis is the commonest type of chronic rhino-sinusitis seen in this study.


Further characterization of human eosinophil peroxidase.
The large and the small subunits (Mr 50 000 and 10 500 respectively) of human eosinophil peroxidase were isolated by gel filtration under reducing conditions. The subunits were very strongly associated but not apparently cross-linked by disulphide bridges. During storage, the large subunit tended to form aggregates, which required reduction to dissociate them. Amino acid analysis of the performic acid-treated large subunit showed the presence of 19 cysteic acid residues. The small subunit of eosinophil peroxidase had the same Mr value as the small subunit of myeloperoxidase. However, although these subunits have very similar amino acid compositions, they showed different patterns of peptide fragmentation after CNBr treatment. The carbohydrate of eosinophil peroxidase seemed associated exclusively with the large subunit and comprised mannose (4.5%, w/w) and N-acetylglucosamine (0.8%, w/w). The far-u.v.c.d. spectrum of the enzyme indicated the presence of relatively little ordered secondary structure.