[Efficiency assessment of preoperative preparatory programs in pediatric patients in dentistry].
Research objective was to compare the efficiency of different preoperative preparatory programs which had been used for anxiety decrease in Pediatric patients before oral cavity sanation with general anaesthesia. Two preparatory programs were used. In the first program patients were informed about the treatment they were undergoing. Patients visited the operating unit and watched the videos about forthcoming procedure (group of Information Technologies (IT), n = 82). The second program included the tutorials (face mask use, acquaintance with equipment alarms etc.) in addition to Information Technologies (group of lnformation Technologies and tutorials (ITT) n = 83). Information Technologies and tutorials were not used in the control group (n = 86). Both used programs were effective. ITT program was the most effective.


Attitudes toward 'Disorders of Sex Development' nomenclature among physicians, genetic counselors, and mental health clinicians.
In 2006, nomenclature referencing atypical sex development (i.e., 'intersex') was updated, and the term disorder of sex development (DSD) was formally introduced. Clinicians, patients, and parents, however, have not universally accepted the new terminology, and some continue to use different nomenclature. This inconsistency in terminology can lead to confusion among clinicians and patients, affect clinician-patient relationships, and interfere with the recommended multidisciplinary model for DSD care. This study sought to (1) evaluate frequency of use and comfort with specific DSD terminology, (2) assess why clinicians are not using specific terms, and (3) determine what terms are being heard within the medical community and by the public in a sample of physicians, genetic counselors, and licensed mental health clinicians. A Web-based survey assessing the use of DSD terminology was distributed to endocrinologists, urologists, genetic counselors, and mental health clinicians. The survey assessed frequency of use and comfort with specific terms, negative experiences related to specific nomenclature use, and the context in which terms are used (e.g. case conference, literature, patient/parents, and media). A qualitative analysis of open-ended responses was conducted to characterize reasons for avoiding specific terms. The survey was completed by 286 clinicians. There were significant differences between specialties in comfort and frequency of use of specific terms, and significant differences were based on clinician gender, patient volume, length of time in practice, and practice setting. The study results also showed a difference in the nomenclature used within the medical community versus the media. Study findings are consistent with previous research exploring medical professionals' use of the new term: disorder of sex development. However, there continues to be inconsistency in the uptake of this new terminology. Words that have been purposed in the literature to replace disorder, such as difference and variation, would be accepted by clinicians, and the word divergent would not. This study expands on the existing literature documenting high uptake of disorder of sex development nomenclature among medical professionals. In addition, this study demonstrates that the most common diagnostic terms used by the medical community are not the same terms being presented to the public by the media. Medical professionals have varying preferences for terminology use when describing DSD, which can affect patient care. These results can be used in the future to compare with what patients and advocates prefer to develop a more universally accepted approach to nomenclature.


Prevalence of myopia and its risk factors in urban school children in Delhi: the North India Myopia Study (NIM Study).
Assess prevalence of myopia and identify associated risk factors in urban school children. This was a cross-sectional study screening children for sub-normal vision and refractive errors in Delhi. Vision was tested by trained health workers using ETDRS charts. Risk factor questionnaire was filled for children with vision <6/9.5, wearing spectacles and for a subset (10%) of randomly selected children with normal vision. All children with vision <6/9.5 underwent cycloplegic refraction. The prevalence of myopia <-0.5 diopters was assessed. Association of risk factors and prevalence of myopia was analyzed for children with myopia and randomly selected non myopic children and adjusted odds ratio values for all risk factors were estimated. A total number of 9884 children were screened with mean age of 11.6 + 2.2 years and 66.8% boys. Prevalence of myopia was 13.1% with only 320 children (24.7%) wearing appropriate spectacles. Mean myopic spherical error was -1.86 + 1.4 diopters. Prevalence of myopia was higher in private schools compared to government schools (p<0.001), in girls vs. boys (p = 0.004) and among older (> 11 years) children (p<0.001). There was a positive association of myopia with studying in private schools vs. government schools (p<0.001), positive family history (p< 0.001) and higher socio-economic status (p = 0.037). Positive association of presence of myopia was observed with children studying/reading > 5 hours per day (p < 0.001), watching television > 2 hours / day (p < 0.001) and with playing computer/video/mobile games (p < 0.001). An inverse association with outdoor activities/playing was observed with children playing > 2 hours in a day. Myopia is a major health problem in Indian school children. It is important to identify modifiable risk factors associated with its development and try to develop cost effective intervention strategies.


KIF18B is a cell type-specific regulator of spindle orientation in the epidermis.
Proper spindle orientation is required for asymmetric cell division and the establishment of complex tissue architecture. In the developing epidermis, spindle orientation requires a conserved cortical protein complex of LGN/NuMA/dynein-dynactin. However, how microtubule dynamics are regulated to interact with this machinery and properly position the mitotic spindle is not fully understood. Furthermore, our understanding of the processes that link spindle orientation during asymmetric cell division to cell fate specification in distinct tissue contexts remains incomplete. We report a role for the microtubule catastrophe factor KIF18B in regulating microtubule dynamics to promote spindle orientation in keratinocytes. During mitosis, KIF18B accumulates at the cell cortex, colocalizing with the conserved spindle orientation machinery. In vivo we find that KIF18B is required for oriented cell divisions within the hair placode, the first stage of hair follicle morphogenesis, but is not essential in the interfollicular epidermis. Disrupting spindle orientation in the placode, using mutations in either KIF18B or NuMA, results in aberrant cell fate marker expression of hair follicle progenitor cells. These data functionally link spindle orientation to cell fate decisions during hair follicle morphogenesis. Taken together, our data demonstrate a role for regulated microtubule dynamics in spindle orientation in epidermal cells. This work also highlights the importance of spindle orientation during asymmetric cell division to dictate cell fate specification.


Ipsilateral Healthy-segment Response to Leg Length Discrepancy.
Few studies address frequency or magnitude of healthy lower-extremity segment response to ipsilateral companion segment shortening. We sought to document and quantify this occurrence in a variety of pediatric etiologies. We reviewed the medical record and radiographs of patients undergoing epiphysiodesis to manage leg length discrepancy. Inclusion criteria for this study were leg length discrepancy of a single lower-extremity segment by identifiable cause and adequate scanograms to allow accurate measurement of all 4 lower-extremity segments before any surgical treatment for the discrepancy. We recorded the etiology of shortening, age of onset of disorder, the length of the lower-extremity segments on scanograms, and age at the time of radiographs. We considered ipsilateral healthy-segment difference from the contralateral ≥ 0.5 cm. as clinically significant. Two hundred nine patients met inclusion criteria (126 boys, 83 girls). The average age was 12.5 years. 16/60 patients with avascular necrosis of the hip demonstrated ipsilateral tibial shortening averaging 1.2 cm whereas 6/60 demonstrated ipsilateral tibial overgrowth averaging 0.6 cm. 11/30 Legg-Perthés patients demonstrated ipsilateral tibial shortening averaging 0.7 cm; none had ipsilateral tibial overgrowth. 10/42 posteromedial bow patients had ipsilateral femoral shortening averaging 0.8 cm, whereas 6/42 had ipsilateral overgrowth averaging 0.8 cm. 13/48 with distal femoral physeal injury demonstrated ipsilateral tibial shortening averaging 1.2 cm, whereas 6/48 demonstrated ipsilateral tibial overgrowth averaging 0.8 cm. 8/29 tibial physeal injuries (proximal or distal) demonstrated ipsilateral femoral shortening averaging 1.1 cm. whereas 7/29 demonstrated ipsilateral femoral overgrowth averaging 0.7 cm. Although there are individual exceptions, the ipsilateral healthy segment does not grow appreciably more than the contralateral in patients with avascular necrosis of the hip, Legg-Perthés disease, or physeal trauma. The femur is not a significant component of shortening in patients with posteromedial bow. Level III, retrospective review.


[Metastatic ability occurs already early on in pancreatic cancer].
Metastatic ability occurs already early on in pancreatic cancer Pancreatic cancers are associated with poor survival and only some 10 per cent are resectable, but even in this subgroup recurrence is very frequent. The traditional view of sequential development of pancreatic cancer has been challenged by novel molecular biological findings, where the tumor quite rapidly might turn metastatic. In about 60 000 patients with diagnosed pancreatic cancer the association between tumor size, metastatic spread and survival was analyzed. Even the smallest tumors (<0.5 cm) had remote metastases in more than 30 per cent. Tumor biology seems more important than size per se as regards disease course and outcome and thus also sets new demands on how to define an early pancreatic cancer. The data require novel types of biomarkers/panels in serum and cancer tissue in order to take tumor biology into consideration to achieve improved personalized and more effective management of pancreatic cancer patients.


Cocaine-induced heart disease: mechanisms and pathology.
Cocaine use has increased in recent years, in part as a result of the increased availability of "crack," the inexpensive freebase form. Although it is used medicinally and initially was considered a relatively safe street drug, cocaine clearly has addictive potential as well as adverse health consequences even in low doses. Some of its most serious adverse effects involve the cardiovascular system. Understanding the cellular mechanisms of the action of cocaine on the heart allows insight into the pathophysiology of its adverse effects. Blockade of sodium channels accounts for cocaine's anesthetic effects and acts directly on myocytes to impair action potential generation and conduction, predisposing to dysrhythmias. Blockade of neurotransmitter reuptake has many deleterious effects, including dysrhythmogenesis via increased intracellular calcium, myocardial ischemia via vasospasm and increased myocardial oxygen demand, and contraction band necrosis also via increased intracellular calcium. In addition, alterations in platelet-endothelial cell function predispose to coronary artery thrombosis and ischemia. Alterations in immune function of natural killer cells may, among other effects, predispose to the development of myocarditis, the etiology of which is probably multifactoral. Finally, a direct toxic effect of cocaine on myocytes may, in some cases, produce heart muscle dysfunction. These multiple mechanisms of action combined with the deleterious effects of often-present adulterants give rise to an unpredictable, variable, and potentially life-threatening cardiovascular response to cocaine administration.


Endovascular therapy for ischemic stroke: Save a minute-save a week.
To quantify the patient lifetime benefits gained from reduced delays in endovascular therapy for acute ischemic stroke. We used observational prospective data of consecutive stroke patients treated with IV thrombolysis in Helsinki (1998-2014; n = 2,474) to describe distributions of age, sex, stroke severity, onset-to-treatment times, and 3-month modified Rankin Scale (mRS) in routine clinical practice. We used treatment effects by time of endovascular therapy in large vessel occlusion over and above thrombolysis as reported by the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study to model the shift in 3-month mRS distributions with reducing treatment delays. From the 3-month outcomes we derived patient-expected lifetimes and cumulative long-term disability with incremental treatment delay reductions. Each minute saved in onset-to-treatment time granted on average 4.2 days of extra healthy life, with a 95% prediction interval 2.3-5.4. Women gained slightly more than men due to their longer life expectancies. Patients younger than 55 years with severe strokes of NIH Stroke Scale score above 10 gained more than a week per each minute saved. In the whole cohort, every 20 minutes decrease in treatment delays led to a gain of average equivalent of 3 months of disability-free life. Small reductions in endovascular delays lead to marked health benefits over patients' lifetimes. Services need to be optimized to reduce delays to endovascular therapy.


Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer.
The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.


Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia.
l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.


Sleep Modulation Alleviates Axonal Damage and Cognitive Decline after Rodent Traumatic Brain Injury.
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment. Here, we investigated whether sleep modulation after trauma has an impact on DAI and memory outcome. We assessed cognition with the novel object recognition test and stained for amyloid precursor protein, a DAI marker. We found that both sleep induction and restriction acutely after TBI enhanced encephalographic slow-wave activity, markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved memory impairment 2 weeks after trauma. These results suggest that enhancing slow-wave sleep acutely after trauma may have a beneficial disease-modifying effect in subjects with acute TBI. Traumatic brain injury (TBI) is a clinically important entity. Cognitive deficits belong to the most prevalent chronic posttraumatic symptoms, most likely due to diffuse axonal injury (DAI). A growing body of evidence suggests a role of sleep in the clearance of waste products in the brain, possibly including amyloid precursor protein (APP), a marker of DAI. In this study, we provide evidence that enhancement of slow-wave oscillatory activity in the delta-frequency range decreases the APP-immunoreactivity and preserves cognitive abilities after trauma, potentially offering novel, noninvasive treatment options for traumatic injury.


Touch-screen technology for the dynamic display of -2D spatial information without vision: promise and progress.
Many developers wish to capitalize on touch-screen technology for developing aids for the blind, particularly by incorporating vibrotactile stimulation to convey patterns on their surfaces, which otherwise are featureless. Our belief is that they will need to take into account basic research on haptic perception in designing these graphics interfaces. We point out constraints and limitations in haptic processing that affect the use of these devices. We also suggest ways to use sound to augment basic information from touch, and we include evaluation data from users of a touch-screen device with vibrotactile and auditory feedback that we have been developing, called a vibro-audio interface.


The prevalence of internuclear ophthalmoparesis in a population-based cohort of individuals with multiple sclerosis.
Internuclear ophthalmoparesis (INO) occurs in 15-52% of individuals with multiple sclerosis (MS) and is reliably detected by infrared oculography. Methods for diagnosing INO with infrared oculography and the association between INO and MS characteristics need confirmation. We aimed to describe INO prevalence and the clinical characteristics of individuals with MS and INO in a population-based cohort of individuals with MS born in the year 1966 (Project Y). Previously described thresholds for the versional dysconjugacy index (VDI), assessed with standardized infrared oculography, were used to detect INO in participants of project Y. Clinical characteristics, visual functioning and complaints were compared between individuals with MS with INO and individuals with MS without INO. Two-hundred-twenty individuals with MS and 110 healthy controls were included. VDI values exceeding the threshold for INO presented in 53 (24%) individuals with MS and 19 controls (13%). INO was associated with male sex, greater disability, worse cognition and worse arm function in individuals with MS. There was no association with disease duration, visual functioning or complaints. INO is prevalent among individuals with MS aged fifty-three and related to clinical characteristics of MS. INO was more frequently detected in healthy controls than previous studies, implying that oculography based diagnosis of INO requires further refinement.


Diabetes Care in India.
Diabetes has become a major health care problem in India with an estimated 66.8 million people suffering from the condition, representing the largest number of any country in the world. The rising burden of diabetes has greatly affected the health care sector and economy in India. The goal of health care experts in India is to transform India into a diabetes care capital in the world. An expert detailed review of the medical literature with an Asian Indian context was performed. Recent epidemiologic studies from India point to a great burden from diabetes. Diabetes control in India is far from ideal with a mean hemoglobin A1c of 9.0%-at least 2.0% higher than suggested by international bodies. Nearly half of people with diabetes remain undetected, accounting for complications at the time of diagnosis. Screening can differentiate an asymptomatic individual at high risk from one at low risk for diabetes. Despite the large number of people with diabetes in India, awareness is low and needs to be addressed. Other challenges include balancing the need for glycemic control with risk reduction due to overly tight control, especially in high-risk groups and taking into account health care professional expertise, attitudes, and perceptions. Pharmacologic care should be individualized with early consideration of combination therapy. Regular exercise, yoga, mindful eating, and stress management form a cornerstone in the management of diabetes. Considering the high cost incurred at various steps of screening, diagnosis, monitoring, and management, it is important to realize the cost-effective measures of diabetes care that are necessary to implement. Result-oriented organized programs involving patient education, as well as updating the medical fraternity on various developments in the management of diabetes, are required to combat the current diabetes epidemic in India.


MEN1 Surveillance Guidelines: Time to (Re)Think?
Clinical practice guidelines for patients with multiple endocrine neoplasia type 1 (MEN1) recommend a variety of surveillance options. Given progress over the past decade in this area, it is timely to evaluate their ongoing utility. MEN1 is characterized by the development of synchronous or asynchronous tumors affecting a multitude of endocrine and nonendocrine tissues, resulting in premature morbidity and mortality, such that the rationale for undertaking surveillance screening in at-risk individuals appears robust. Current guidelines recommend an intensive regimen of clinical, biochemical, and radiological surveillance commencing in early childhood for those with a clinical or genetic diagnosis of MEN1, with the aim of early tumor detection and treatment. Although it is tempting to assume that such screening results in patient benefits and improved outcomes, the lack of a strong evidence base for several aspects of MEN1 care, and the potential for iatrogenic harms related to screening tests or interventions of unproven benefit, make such assumptions potentially unsound. Furthermore, the psychological as well as economic burdens of intensive screening remain largely unstudied. Although screening undoubtedly constitutes an important component of MEN1 patient care, this perspective aims to highlight some of the current uncertainties and challenges related to existing MEN1 guidelines with a particular focus on the role of screening for presymptomatic tumors. Looking forward, a screening approach that acknowledges these limitations and uncertainties and places the patient at the heart of the decision-making process is advocated.


The urban environment from the health perspective: the case of Belo Horizonte, Minas Gerais, Brazil.
This study aims to determine spatial patterns of mortality and morbidity for five health problems in an urban environment: homicides, adolescent pregnancy, asthma hospitalization, and two vector-borne diseases, dengue and visceral leishmaniasis. All events were obtained through the city health database and geoprocessed using residential addresses and 80 planning units consisting of census tracts. We used thematic maps, proportionate mortality/morbidity ratios by planning unit, and the overlapped rank of the 20th worse planning unit rates for each event. A spatial pattern of high rates of homicides, proportion of young mothers, and hospitalization due to asthma overlapped in socially and economically disadvantaged areas. For the two vector-borne diseases, high rates with great dispersion were found in underprivileged areas, in contrast with very low rates among higher income areas. The results indicated the coexistence of heavier disease burden for residents of urban areas where poverty and lack of effective public health policies may be modulating social health problems. For the two vector-borne diseases, an environmental intervention in one mosquito-borne disease might be playing a role in the other's incidence.


Inflammation and Mental Health Disorders: Immunomodulation as a Potential Therapy for Psychiatric Conditions.
Mood disorders are the leading cause of disability worldwide and their incidence has significantly increased after the COVID-19 pandemic. Despite the continuous surge in the number of people diagnosed with psychiatric disorders, the treatment methods for these conditions remain limited. A significant number of people either do not respond to therapy or discontinue the drugs due to their severe side effects. Therefore, alternative therapeutic interventions are needed. Previous studies have shown a correlation between immunological alterations and the occurrence of mental health disorders, yet immunomodulatory therapies have been barely investigated for combating psychiatric conditions. In this article, we have reviewed the immunological alterations that occur during the onset of mental health disorders, including microglial activation, an increased number of circulating innate immune cells, reduced activity of natural killer cells, altered T cell morphology and functionality, and an increased secretion of pro-inflammatory cytokines. This article also examines key studies that demonstrate the therapeutic efficacy of anti-inflammatory medications in mental health disorders. These studies suggest that immunomodulation can potentially be used as a complementary therapy for controlling psychiatric conditions after careful screening of candidate drugs and consideration of their efficacy and side effects in clinical trials.


Identification of a novel mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency.
A novel mutation was identified in two unrelated patients with medium-chain acyl-CoA dehydrogenase deficiency. First, a 19-year-old Caucasian female presented with a devastating illness, resulting in sudden death in adulthood which is unusual. The second patient, now a 3.5-year-old male, presented at 17 months of age with a hypoglycemic seizure and dehydration. Sequence analysis revealed a novel mutation G617T in exon 8 resulting in an arginine to leucine substitution at codon 206 (R206L). Both patients were compound heterozygous for this G617T and the common mutation A985G.


Resting-state fMRI activity predicts unsupervised learning and memory in an immersive virtual reality environment.
In the real world, learning often proceeds in an unsupervised manner without explicit instructions or feedback. In this study, we employed an experimental paradigm in which subjects explored an immersive virtual reality environment on each of two days. On day 1, subjects implicitly learned the location of 39 objects in an unsupervised fashion. On day 2, the locations of some of the objects were changed, and object location recall performance was assessed and found to vary across subjects. As prior work had shown that functional magnetic resonance imaging (fMRI) measures of resting-state brain activity can predict various measures of brain performance across individuals, we examined whether resting-state fMRI measures could be used to predict object location recall performance. We found a significant correlation between performance and the variability of the resting-state fMRI signal in the basal ganglia, hippocampus, amygdala, thalamus, insula, and regions in the frontal and temporal lobes, regions important for spatial exploration, learning, memory, and decision making. In addition, performance was significantly correlated with resting-state fMRI connectivity between the left caudate and the right fusiform gyrus, lateral occipital complex, and superior temporal gyrus. Given the basal ganglia's role in exploration, these findings suggest that tighter integration of the brain systems responsible for exploration and visuospatial processing may be critical for learning in a complex environment.


Small-cell carcinomas of the gastrointestinal tract: a review.
To improve our understanding of the entity of small-cell carcinoma (SmCC) of the gastrointestinal (GI) tract. A MEDLINE search was done, using the terms "small cell carcinoma" or "oat cell carcinoma" combined with "gastrointestinal" or with any of the GI sites, for the period 1970 to 2003. The 138 eligible reports identified in this way were reviewed for clinical data. To date, approximately 544 cases of GI SmCC have been reported. The disease represents 0.1% to 1% of all GI malignancies, with the esophagus being the most common primary site. A majority of patients present with overt distant metastases. Systemic symptoms are common; ectopic hormonal secretion may occur. By light microscopy, GI SmCCs are essentially indistinguishable from primary pulmonary SmCC. The presence of non-SmCC components is common. Data from molecular analysis of the disease has identified some similarities to pulmonary SmCC. Chemotherapy represents the main treatment option, with modest impact on survival. In locoregional disease, the literature suggests that treatment be initiated using chemoradiotherapy and then, if metastatic disease is still excluded, surgical resection be considered. The disease is highly aggressive, and survival is in the range of several weeks for untreated patients and of 6 to 12 months for those receiving therapy. SmCC of the GI tract is a rare and lethal disease. Although there are many similarities to pulmonary SmCC, some differences between the two entities are suggested. While chemotherapy can achieve significant palliation, surgery may have a potential impact on long-term survival of patients with locoregional disease.


Template to Perpetrate: An Update on Violence in Autism Spectrum Disorder.
For the past two decades, researchers have been using various approaches to investigate the relationship, if any, between autism spectrum disorder (ASD) and violence. The need to clarify that relationship was reinforced by the tragic mass shooting at Sandy Hook Elementary School in Newtown, Connecticut, in December 2012 by an individual diagnosed with Asperger's syndrome. The purpose of this article is (1) to provide an updated review of the literature on the association between ASD and violence, and (2) to examine implications for treating, and for preventing violence by, individuals with ASD. A review of all published literature regarding ASD and violence from 1943 to 2014 was conducted using electronic and paper searches. Although some case reports have suggested an increased violence risk in individuals with ASD compared to the general population, prevalence studies have provided no conclusive evidence to support this suggestion. Among individuals with ASD, however, generative (e.g., comorbid psychopathology, social-cognition deficits, emotion-regulation problems) and associational (e.g., younger age, Asperger's syndrome diagnosis, repetitive behavior) risk factors have been identified or proposed for violent behavior. While no conclusive evidence indicates that individuals with ASD are more violent than those without ASD, specific generative and associational risk factors may increase violence risk among individuals with ASD. Further research would help to clarify or confirm these findings, suggest potential directions for evaluation, treatment, and prevention, and potentially provide compelling empirical support for forensic testimony regarding defendants with ASD charged with violent crimes.


Association of two polymorphisms of tumor necrosis factor gene with acute biliary pancreatitis.
To investigate TNF-alpha-308 and TNFB polymorphisms in acute biliary pancreatitis (ABP) and to related them to the plasma TNF-alpha levels. Genomic DNA was prepared from peripheral blood leukocytes. Genotypes and allele frequencies were determined in patients (n=127) and healthy controls (n=102) using restriction fragment length polymorphism analysis of polymerase chain reaction (PCR) products. Reading the size of digested bands from polyacrylamide gel demonstrated the two alleles TNF1 and TNF2, or the two alleles TNFB1 and TNFB2. The frequencies of TNF2 polymorphism and TNFB2 polymorphism were both similar in patients with mild or severe pancreatitis, so were in pancreatitis patients and in controls. Patients with septic shock showed a significantly higher prevalence of the TNF2 than those without. No significant differences were found in the genotype distribution of TNF-alpha-308 and TNFB among different groups. Plasma TNF-alpha levels did not differ significantly in ASBP patients displaying different alleles of the TNF gene studied. Results indicate that TNF gene polymorphisms studied play no part in determination of disease severity or susceptibility to acute biliary pancreatitis; however, TNF2 polymorphism is associated with septic shock from ASBP. Genetic factors are not important in determining plasma TNF-alpha levels in ASBP.


Interventions to Improve Follow-up of Positive Results on Fecal Blood Tests: A Systematic Review.
Fecal immunochemical testing is the most commonly used method for colorectal cancer screening worldwide. However, its effectiveness is frequently undermined by failure to obtain follow-up colonoscopy after positive test results. To evaluate interventions to improve rates of follow-up colonoscopy for adults after a positive result on a fecal test (guaiac or immunochemical). English-language studies from the Cochrane Central Register of Controlled Trials, PubMed, and Embase from database inception through June 2017. Randomized and nonrandomized studies reporting an intervention for colonoscopy follow-up of asymptomatic adults with positive fecal test results. Two reviewers independently extracted data and ranked study quality; 2 rated overall strength of evidence for each category of study type. Twenty-three studies were eligible for analysis, including 7 randomized and 16 nonrandomized studies. Three were at low risk of bias. Eleven studies described patient-level interventions (changes to invitation, provision of results or follow-up appointments, and patient navigators), 5 provider-level interventions (reminders or performance data), and 7 system-level interventions (automated referral, precolonoscopy telephone calls, patient registries, and quality improvement efforts). Moderate evidence supported patient navigators and provider reminders or performance data. Evidence for system-level interventions was low. Seventeen studies reported the proportion of test-positive patients who completed colonoscopy compared with a control population, with absolute differences of -7.4 percentage points (95% CI, -19 to 4.3 percentage points) to 25 percentage points (CI, 14 to 35 percentage points). More than half of studies were at high or very high risk of bias; heterogeneous study designs and characteristics precluded meta-analysis. Patient navigators and giving providers reminders or performance data may help improve colonoscopy rates of asymptomatic adults with positive fecal blood test results. Current evidence about useful system-level interventions is scant and insufficient. National Cancer Institute. (PROSPERO: CRD42016048286).


Ten Years Progress of Electrical Detection of Heavy Metal Ions (HMIs) Using Various Field-Effect Transistor (FET) Nanosensors: A Review.
Heavy metal pollution remains a major concern for the public today, in line with the growing population and global industrialization. Heavy metal ion (HMI) is a threat to human and environmental safety, even at low concentrations, thus rapid and continuous HMI monitoring is essential. Among the sensors available for HMI detection, the field-effect transistor (FET) sensor demonstrates promising potential for fast and real-time detection. The aim of this review is to provide a condensed overview of the contribution of certain semiconductor substrates in the development of chemical and biosensor FETs for HMI detection in the past decade. A brief introduction of the FET sensor along with its construction and configuration is presented in the first part of this review. Subsequently, the FET sensor deployment issue and FET intrinsic limitation screening effect are also discussed, and the solutions to overcome these shortcomings are summarized. Later, we summarize the strategies for HMIs' electrical detection, mechanisms, and sensing performance on nanomaterial semiconductor FET transducers, including silicon, carbon nanotubes, graphene, AlGaN/GaN, transition metal dichalcogenides (TMD), black phosphorus, organic and inorganic semiconductor. Finally, concerns and suggestions regarding detection in the real samples using FET sensors are highlighted in the conclusion.


[Features of the homotopical and transcallosal potentials of the somatosensory and parietal cortex in the cat].
Multiple recording of EPs from analogous areas of cerebral hemispheres was performed with symmetrical relocation of stimulating and recording electrodes. The right hemisphere was shown to prevail by the amplitude of positive component of the somatosensory area EPs whereas an individual asymmetry of this phase of EPs was observed in the parietal cortex. The homotopic transcallosal responses of the somatosensory cortex seem to reflect local processes induced, mainly, by callosal effects whereas the parietal area response seems to be an integrative index of processes stemming from the local convergence of effects spreading over and intracortical projections.


Harnessing β-Lactam Antibiotics for Illumination of the Activity of Penicillin-Binding Proteins in Bacillus subtilis.
Selective chemical probes enable individual investigation of penicillin-binding proteins (PBPs) and provide critical information about their enzymatic activity with spatial and temporal resolution. To identify scaffolds for novel probes to study peptidoglycan biosynthesis in Bacillus subtilis, we evaluated the PBP inhibition profiles of 21 β-lactam antibiotics from different structural subclasses using a fluorescence-based assay. Most compounds readily labeled PBP1, PBP2a, PBP2b, or PBP4. Almost all penicillin scaffolds were coselective for all or combinations of PBP2a, 2b, and 4. Cephalosporins, on the other hand, possessed the lowest IC50 values for PBP1 alone or along with PBP4 (ceftriaxone, cefoxitin) and 2b (cefotaxime) or 2a, 2b, and 4 (cephalothin). Overall, five selective inhibitors for PBP1 (aztreonam, faropenem, piperacillin, cefuroxime, and cefsulodin), one selective inhibitor for PBP5 (6-aminopenicillanic acid), and various coselective inhibitors for other PBPs in B. subtilis were discovered. Surprisingly, carbapenems strongly inhibited PBP3, formerly shown to have low affinity for β-lactams and speculated to be involved in β-lactam resistance in B. subtilis. To investigate the specific roles of PBP3, we developed activity-based probes based on the meropenem core and utilized them to monitor the activity of PBP3 in living cells. We showed that PBP3 activity localizes as patches in single cells and concentrates as a ring at the septum and the division site during the cell growth cycle. Our activity-based approach enabled spatial resolution of the transpeptidation activity of individual PBPs in this model microorganism, which was not possible with previous chemical and biological approaches.


PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.
Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.


A Blood Biomarker for Duchenne Muscular Dystrophy Shows That Oxidation State of Albumin Correlates with Protein Oxidation and Damage in Mdx Muscle.
Duchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disease with no cure. While the precise mechanisms of progressive dystropathology remain unclear, oxidative stress caused by excessive generation of oxidants is strongly implicated. Blood biomarkers that could track oxidant levels in tissues would be valuable to measure the effectiveness of clinical treatments for DMD; our research has focused on developing such biomarkers. One target of oxidants that has the potential to be harnessed as a clinical biomarker is the thiol side chain of cysteine 34 (Cys34) of the blood protein albumin. This study using the mdx mouse model of DMD shows that in plasma, albumin Cys34 undergoes thiol oxidation and these changes correlate with levels of protein thiol oxidation and damage of the dystrophic muscles. A comparison with the commonly used biomarker protein carbonylation, confirmed that albumin thiol oxidation is the more sensitive plasma biomarker of oxidative stress occurring in muscle tissue. We show that plasma albumin oxidation reflects muscle dystropathology, as increased after exercise and decreased after taurine treatment of mdx mice. These data support the use of albumin thiol oxidation as a blood biomarker of dystropathology to assist with advancing clinical development of therapies for DMD.


Beyond expectations: The responses of the autonomic nervous system to visual food cues.
Self-report measures rely on cognitive and rational processes and may not, therefore, be the most suitable tools to investigate implicit or unconscious factors within a sensory experience. The responses from the autonomic nervous system (ANS), which are not susceptible to bias due to their involuntary nature, may provide a better insight. Expectations are important for the consumer-product interaction and should be considered. However, research using ANS responses has not focused thoroughly on expectations. Our aim was to investigate the mechanisms underlying ANS responses by evaluating the reactions to different images when expectations about a product are created (before tasting the product) and when they are confirmed and disconfirmed (after tasting the product). In a first study, seventy-five participants tasted four drinks (three identical soy-based drinks and one rice-based drink) and were told that they would be shown their main ingredient either before or after tasting. For the three identical drinks, the images shown were: worms, chocolate, and soy. Heart rate and skin conductance were measured during the procedure. The results showed that ANS responses followed similar patterns when images were presented before or after tasting. Heart rate decreased for all images, with the largest decrease found for chocolate and worms. Skin conductance increased, with the largest increase found for worms. To test whether the effects were solely caused by image perception, a second study was done in which forty participants only saw the images. The responses obtained were smaller and did not completely match those of the first study. In conclusion, it could be said that the ANS responses of the first study were a result of the sensory processing and defense mechanisms happening during the creation and (dis)confirmation of expectations. The second study confirmed that visual perception alone could not account for these effects and that it led to smaller changes. Hence, it seems that the context of use influences the patterns and magnitude of ANS responses to food cues.


Human erythrocytes are not suitable for determination of intravascular volume of perfused rat liver.
Homologous or heterologous erythrocytes have been widely used for the estimation of intravascular volume of the liver. However, cross-species blood mediates immune response in the organ, and foreign cells are rapidly cleared from the plasma, indicating that heterologous erythrocytes may not be a suitable marker for determination of vascular space. This aspect was investigated in the perfused rat liver preparation following bolus administration of human (heterologous) erythrocytes into the portal vein. To compare the extent of its distribution within the liver, rat (homologous) erythrocytes and Evans blue were chosen as the reference vascular and extracellular markers, respectively. Hepatic distribution of human erythrocytes was influenced by the perfusion medium (with and without protein) and injection number (first and second injections). Mean transit time and hence volume of distribution decreased in the presence of protein and repetition of the injection. Even in the presence of protein, the volume of distribution obtained for human erythrocytes was larger than that of the extracellular volume of the liver obtained with Evans blue (0.22 +/- 0.01 vs. 0.20 +/- 0.02 ml/g), indicating that they are not suitable for determination of intravascular volume of the perfused rat liver preparation.


Regional disparities in the incidence of elevated blood pressure among young adults: the CARDIA study.
Within the United States, little is known about regional disparities in blood pressure (BP), their changes over time, or explanations for their existence. A population-based cohort of 5115 black and white men and women, 18 to 30 years old in 1985-1986 (balanced on age, race, sex, and education), was followed up for 7 years in four centers: Birmingham, Ala; Chicago, Ill; Minneapolis, Minn; and Oakland, Calif. Differences in elevated BP (EBP) prevalence among centers at years 0, 2, 5, and 7 and in 7-year incidence of EBP were assessed. Sociodemographic and dietary variables, physical activity, weight, smoking, and alcohol were considered. At year 0, no regional differences were seen. Seven years later, there was marked variability in prevalence of EBP overall and for both black and white men, from a low in Chicago (9% for black men and 5% for white men) to a high in Birmingham (25% for black men and 14% for white men). Birmingham also had the highest 7-year incidence (11%) and overall prevalence at year 7 (14%). The adjusted odds ratios, with Birmingham as referent (95% CIs), for 7-year incidence of EBP overall were 0.38 (0.24, 0.60) for Chicago, 0.37 (0.24, 0.57) for Minneapolis, and 0.74 (0.52, 1.07) for Oakland. Regional disparities are absent at baseline but become apparent as the cohort ages. These differences are not fully explained by the available behavioral and sociodemographic characteristics.


Modified constraint-induced movement therapy for a 12-month-old child with hemiplegia: a case report.
This case report describes the use of modified constraint-induced movement therapy (CIMT) to improve upper-limb function in a 12-month-old child with right hemiplegia. It also describes parent concerns about CIMT and documents the short- and long-term effects of modified CIMT. The participant was assessed 5 times over a 7.5-month period using the Peabody Developmental Motor Scales-2, Pediatric Motor Activity Log, Toddler Amount of Use Test, and Knox Parent Questionnaire. CIMT included a nonremovable cast worn on the unaffected arm and approximately 8 hr per week of occupational and physical therapy for 2 weeks. Benefits of improved upper-limb function measured immediately after CIMT were sustained at 6 months' follow-up. No adverse events related to cast use were reported. The findings from this case report suggest that CIMT was a safe intervention associated with improving upper-limb function for this young child with hemiplegia.


Development of a selective molecularly imprinted polymer-based solid-phase extraction for indomethacin from water samples.
A selective molecularly imprinted solid-phase extraction (MISPE) for indomethacin (IDM) from water samples was developed. Using IDM as template molecule, acrylamide (AM) or methacrylic acid (MAA) as functional monomer, ethylene dimethacrylate (EDMA) as crosslinker, and bulk or suspension polymerization as the synthetic method, three molecularly imprinted polymers (MIPs) were synthesized and characterized with a rebinding experiment. It was found that the MIP of AM-EDMA produced by bulk polymerization showed the highest binding capacity for IDM, and so it was chosen for subsequent experiments, such as those testing the selectivity and recognition binding sites. Scatchard analysis revealed that at least two kinds of binding sites formed in the MIP, with the dissociation constants of 7.8 micromol L(-1) and 127.2 micromol L(-1), respectively. Besides IDM, three structurally related compounds--acemetacin, oxaprozin and ibuprofen--were employed for selectivity tests. It was observed that the MIP exhibited the highest selective rebinding to IDM. Accordingly, the MIP was used as a solid-phase extraction sorbent for the extraction and enrichment of IDM in water samples. The extraction conditions of the MISPE column for IDM were optimized to be: chloroform or water as loading solvent, chloroform with 20% acetonitrile as washing solution, and methanol as eluting solvent. Water samples with or without spiking were extracted by the MISPE column and analyzed by HPLC. No detectable IDM was observed in tap water and the content of IDM in a river water sample was found to be 1.8 ng mL(-1). The extraction efficiencies of the MISPE column for IDM in spiked tap and river water were acceptable (87.2% and 83.5%, respectively), demonstrating the feasibility of the prepared MIP for IDM extraction.


Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. 13C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.


Cationically Substituted Bi0.7Fe0.3OCl Nanosheets as Li Ion Battery Anodes.
Cation substitution of Bi3+ with Fe3+ in BiOCl leads to the formation of ionically layered Bi0.7Fe0.3OCl nanosheets. The synthesis follows a hydrolysis route using bismuth(III) nitrate and iron(III) chloride, followed by postannealing at 500 °C. Room temperature electrical conductivity improves from 6.11 × 10-8 S/m for BiOCl to 6.80 × 10-7 S/m for Bi0.7Fe0.3OCl. Correspondingly, the activation energy for electrical conduction reduces from 862 meV for pure BiOCl to 310 meV for Bi0.7Fe0.3OCl. These data suggest improved charge mobility in Bi0.7Fe0.3OCl nanosheets. Density functional theory calculations confirm this behavior by predicting a high density of states near the Fermi level for Bi0.7Fe0.3OCl. The improvement in electrical conductivity is exploited in the electrochemical performance of Bi0.7Fe0.3OCl nanosheets. The insertion capacity of Li+ ions shows an increase of 2.5×, from 215 mAh·.g-1 for undoped BiOCl to 542 mAh·g-1 for Bi0.7Fe0.3OCl after 50 cycles at a current density of 50 mA·g-1. Thus, the direct substitution of Bi3+ sites with Fe3+ in BiOCl results in nanosheets of an ionically layered ternary semiconductor compound which is attractive for Li ion battery anode applications.


Obstacles to getting ahead: how assimilation mechanisms impact undocumented mexican immigrant families.
This study explores the roles played by U.S. schools, workplaces, churches, and peers in the acculturation process of immigrant adolescents. Qualitative interviews were conducted with members of 10 undocumented Mexican families (12 adolescents and 14 of their parents) who had immigrated within the past 7 years. Results indicated that assimilation was prompted by two powerful mechanisms: monolingualism and discrimination. Monolingualism and discrimination in interpersonal interactions and social policies directed Mexican adolescents and their parents to learn English and to conform to host culture norms, appearance, and behaviors to advance in school and in their work. These assimilation mechanisms contributed to female adolescents' and parents' feelings of anxiety and depression. Male adolescents reported feeling angry and ready to physically defend themselves. Mexican families found a refuge from assimilation stress in church. Churches valued biculturalism and religious faith was used to handle daily assimilation stress. Implications for social policy were discussed.


[Fractures of the L5 transverse process in pelvic ring injury].
The aim of the study was to record the frequency of L5 transverse process fractures associated with pelvic injuries and to find out whether in unstable pelvic fractures the frequency is significantly higher. The group evaluated comprised 106 patients (38 women and 68 men; average age, 43.4 years; range, 16 to 95 years) treated for pelvic ring fractures at two trauma centres in the period from January 1 to December 31, 2007. Their radiographs and CT scans were retrospectively reviewed in order to identify fractures of the L5 transverse processes and to obtain exact descriptions of injuries to the dorsal pelvic structures. The results were statistically analysed using the Chi-square test with a 5 % level of significance. The evaluation of radiographs and CT scans identified L5 process fractures in 21 patients; none of these had type A pelvic fracture. An L5 transverse process fracture was found in 10 (15 %) of 69 patients with type B pelvic fracture and in 11 (73 %) of 15 patients with type C pelvic fracture, i.e., only in the patients with unstable injury to the pelvis classified as type C or type B. The occurrence of L 5 transverse process fractures was significantly higher in completely unstable, type C pelvic trauma than in partially unstable, type B pelvic injury (p < 0.001). Our results showed that evaluation of the radiographs was not sufficient for the identification of L5 transverse process fractures and trauma to the dorsal pelvic structures. The reason was either poor quality or incorrect positioning. This gives support to the recommendations of many authors that CT scans should be the standard method for identification of all pelvic injuries. The study also confirmed that L5 transverse process fractures are associated with unstable pelvic injuries. Their significantly high occurrence is in agreement with other relevant studies which, however, have reported the results without statistical evaluation. The study shows a significantly higher occurrence of L5 transverse process fractures in patients with unstable pelvic ring injuries. The finding of such a fracture should focus attention to looking for trauma to the dorsal pelvic structures.


Exclusive and Combined Use of Statins and Aspirin and the Risk of Pancreatic Cancer: a Case-Control Study.
Data on the association between aspirin and statin use and Pancreatic Ductal AdenoCarcinoma (PDAC) risk are conflicting. These drugs are often co-prescribed, but no studies evaluated the potential combined or confounding effect of the two at the same time. We aimed to investigate the association between aspirin and statin exclusive and combined use and PDAC occurrence. Data on environmental factors, family and medical history were screened in a case-control study. PDAC cases were matched to controls for age and gender. Power calculation performed ahead. Odds ratios (OR) and 95% confidence intervals(CI) were obtained from multivariable logistic regression analysis. In 408 PDAC patients and 816 matched controls, overall statin (OR 0.61; 95%CI,0.43-0.88), but not aspirin use was associated to reduced PDAC risk. Compared to non-users, exclusive statin (OR 0.51; 95%CI,0.32-0.80) and exclusive aspirin users (OR 0.64; 95%CI,0.40-1.01) had reduced PDAC risk. Concomitant statin and aspirin use did not further reduce the risk compared with statin use alone and no interaction was evident. Statin protective association was dose-dependent, and consistent in most subgroups, being stronger in smokers, elderly, obese and non-diabetic patients. The present study suggests that statin use is associated to reduced PDAC risk, supporting a chemopreventive action of statins on PDAC.


[Acute and recurrent otitis media. Prevention and treatment in the light of current knowledge].
Acute otitis media refers to a clinically identifiable infection of the middle ear with sudden onset and of short duration. By two years of age, approximately 40% of children have had at least one attack of acute otitis media. Of these, 5-10% subsequently experience recurrent infections. Evidence suggests that frequent attacks of acute otitis media may adversely affect neurocognitive and language development and necessitate repeated medical and surgical treatment. Efforts have been made to identify early risk factors associated with this proneness to otitis in order to give the affected children optimal medical care and prophylactic treatment. Based on existing literature, guidelines for prophylaxis and treatment of acute and recurrent acute otitis media are discussed in this paper.


Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.
Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.


Simple luminescence method for estimation of benzo[a]pyrene in a complex mixture of polycyclic aromatic hydrocarbons without a pre-separation procedure.
Benzo[a]pyrene causes cancer at cellular level and is widely present in the environment. Conventional spectroscopic methods for analysis of this compound need a pre-separation procedure due to severe spectral overlap from other polycyclic aromatic hydrocarbons. We report a simple method that avoids spectral overlap of benzo[a]pyrene from other impurities or polycyclic aromatic hydrocarbons (PAHs), thus it can easily identify benzo[a]pyrene in a complex PAH mixture. The method could easily identify benzo[a]pyrene in an 18-component PAH mixture. Calibration plots in methanol solution and in micellar media show a good linearity (R > 0.9997) in the benzo[a]pyrene concentration range generally found in the environment. The method gives a detection limit of 1.52 x 10(-9) mol/L in CTAB micellar medium and 2.55 x 10(-9) mol/L in methanol solution. The proposed method is selective, sensitive and fast. The fluorescence response of benzo[a]pyrene is found to be a potential candidate to sense the critical micellar concentration (CMC) of CTAB micelles.


Purification, stability, and immunogenicity analyses of five bluetongue virus proteins for use in development of a subunit vaccine that allows differentiation of infected from vaccinated animals.
Bluetongue virus (BTV) causes bluetongue disease, a vector-borne disease of ruminants. The recent northerly spread of BTV serotype 8 in Europe resulted in outbreaks characterized by clinical signs in cattle, including unusual teratogenic effects. Vaccination has been shown to be crucial for controlling the spread of vector-borne diseases such as BTV. With the aim of developing a novel subunit vaccine targeting BTV-8 that allows differentiation of infected from vaccinated animals, five His-tagged recombinant proteins, VP2 and VP5 of BTV-8 and NS1, NS2, and NS3 of BTV-2, were expressed in baculovirus or Escherichia coli expression systems for further study. Optimized purification protocols were determined for VP2, NS1, NS2, and NS3, which remained stable for detection for at least 560 to 610 days of storage at +4°C or -80°C, and Western blotting using sera from vaccinated or experimentally infected cattle indicated that VP2 and NS2 were recognized by BTV-specific antibodies. To characterize murine immune responses to the four proteins, mice were subcutaneously immunized twice at a 4-week interval with one of three protein combinations plus immunostimulating complex ISCOM-Matrix adjuvant or with ISCOM-Matrix alone (n = 6 per group). Significantly higher serum IgG antibody titers specific for VP2 and NS2 were detected in immunized mice than were detected in controls. VP2, NS1, and NS2 but not NS3 induced specific lymphocyte proliferative responses upon restimulation of spleen cells from immunized mice. The data suggest that these recombinant purified proteins, VP2, NS1, and NS2, could be an important part of a novel vaccine design against BTV-8.


Molecular Diversity Within Melanomys caliginosus (Rodentia: Oryzomyini): Evidence for Multiple Species.
Nucleotide sequences from the mitochondrial DNA cytochrome-b gene were used to infer phylogenetic relationships and estimate genetic distances from 10 individuals of Melanomys caliginosus and to explore the hypothesis that this taxon is comprised of multiple species. Individuals of four geographic populations of M. caliginosus from Central America (Nicaragua and Costa Rica), Panama, Venezuela, and Ecuador, respectively, were included in this analysis. Topologies obtained from maximum parsimony and Bayesian inference analyses were identical and produced clades referable to each of the geographic populations. Genetic distances between any pair-wise comparisons of the four groups (except between Panamanian and Venezuelan samples) were comparable to values estimated from comparisons of sister species in the closely related genus Nectomys. Distances between samples from Panama and Venezuela were greater than those of samples within the Ecuadorian and Central American clades, but less than that between species of Nectomys. Based on results from the sequence data, it appears that all four of the populations should be elevated to species level; however, additional data are needed to resolve the nomenclature of the Panamanian and Venezuelan populations.


Conditional Recruitment to a DNA-Bound CRISPR-Cas Complex Using a Colocalization-Dependent Protein Switch.
To spatially control biochemical functions at specific sites within a genome, we have engineered a synthetic switch that activates when bound to its DNA target site. The system uses two CRISPR-Cas complexes to colocalize components of a de novo-designed protein switch (Co-LOCKR) to adjacent sites in the genome. Colocalization triggers a conformational change in the switch from an inactive closed state to an active open state with an exposed functional peptide. We prototype the system in yeast and demonstrate that DNA binding triggers activation of the switch, recruitment of a transcription factor, and expression of a downstream reporter gene. This DNA-triggered Co-LOCKR switch provides a platform to engineer sophisticated functions that should only be executed at a specific target site within the genome, with potential applications in a wide range of synthetic systems including epigenetic regulation, imaging, and genetic logic circuits.


[Lavomax in outpatient treatment of urogenital chlamidiasis in males].
Sixty four males (age 21-45 years) with urogenital chlamidiasis were divided into two groups. 34 patients of the study group received interferon inductor and lavomax. 30 patients of the control group--interferon inductor and cycloferon. Treatment efficacy in the study group was higher.


A teleradiology case conference system.
To investigate the use of teleradiology in the quality assurance programme of a multicentre radiotherapy practice, we installed image acquisition and display workstations at each of two affiliated radiation oncology clinics. A commercial diagnostic teleradiology system was successfully modified to suit the requirements of the radiotherapy subspecialty. The system allowed intersite transmission of images, access to high-resolution images from each site and, by use of laser film scanners, made accessible all types of radiation therapy image. Transmission speed and storage capacity were better than expected. Using the system, radiation oncology residents and staff reviewed 83 complex cases over eight months. Case presentation and discussion were enhanced. In the same period, 276 cases were reviewed by conference in person. Case conferences for quality assurance conducted with the teleradiology system influenced changes in treatment planning as effectively as those conducted in person. Equivalent treatment outcomes were produced. The teleradiology system facilitated quality assurance through review of patients' radiation treatments by allowing natural interactive consultation.


Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease.
Recent studies show that mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the cause of the most common inherited and some sporadic forms of Parkinson's disease (PD). The molecular mechanism underlying the pathogenic role of LRRK2 mutations in PD remains unknown. Using affinity purification and mass spectrometric analysis, we investigated phosphorylation sites and binding proteins of LRRK2 purified from mouse brain. We identified multiple phosphorylation sites at N-terminus of LRRK2 including S910, S912, S935 and S973. Focusing on the high stoichiometry S935 phosphorylation site, we developed an anti-pS935 specific antibody and showed that LRRK2 is constitutively phosphorylated at S935 in various tissues (including brain) and at different ages in mice. We find that 14-3-3 proteins (especially isoforms γ and η) bind LRRK2 and this binding depends on phosphorylation of S935. The binding of 14-3-3, with little effect on dimer formation of LRRK2, confers protection of the phosphorylation status of S935. Furthermore, we show that protein kinase A (PKA), but not LRRK2 kinase itself, can cause the phosphorylation of LRRK2 at S935 in vitro and in cell culture, suggesting that PKA is a potential upstream kinase that regulates LRRK2 function. Finally, our study indicates that the common PD-related mutations of LRRK2, R1441G, Y1699C and G2019S, decrease homeostatic phosphorylation levels of S935 and impair 14-3-3 binding of LRRK2. LRRK2 is extensively phosphorylated in vivo, and the phosphorylation of specific sites (e.g. S935) determines 14-3-3 binding of LRRK2. We propose that 14-3-3 is an important regulator of LRRK2-mediated cellular functions. Our study suggests that PKA, a cAMP-dependent kinase involved in regulating dopamine physiology, is a potential upstream kinase that phosphorylates LRRK2 at S935. Furthermore, the reduction of phosphorylation/14-3-3 binding of LRRK2 due to the common familial PD-related mutations provides novel insight into the pathogenic mechanism of LRRK2-linked PD.


Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. In Vietnam, knowledge regarding N. gonorrhoeae prevalence and AMR is limited, and data concerning genetic characteristics of N. gonorrhoeae is totally lacking. Herein, we investigated the phenotypic AMR (previous, current and possible future treatment options), genetic resistance determinants for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolated in 2011 in Hanoi, Vietnam. N. gonorrhoeae isolates from Hanoi, Vietnam isolated in 2011 (n = 108) were examined using antibiograms (Etest for 10 antimicrobials), Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST), and sequencing of ESC resistance determinants (penA, mtrR and penB). The levels of in vitro resistance were as follows: ciprofloxacin 98%, tetracycline 82%, penicillin G 48%, azithromycin 11%, ceftriaxone 5%, cefixime 1%, and spectinomycin 0%. The MICs of gentamicin (0.023-6 mg/L), ertapenem (0.002-0.125 mg/L) and solithromycin (<0.016-0.25 mg/L) were relatively low. No penA mosaic alleles were found, however, 78% of the isolates contained an alteration of amino acid A501 (A501V (44%) and A501T (34%)) in the encoded penicillin-binding protein 2. A single nucleotide (A) deletion in the inverted repeat of the promoter region of the mtrR gene and amino acid alterations in MtrR was observed in 91% and 94% of the isolates, respectively. penB resistance determinants were detected in 87% of the isolates. Seventy-five different NG-MAST STs were identified, of which 59 STs have not been previously described. In Vietnam, the highly diversified gonococcal population displayed high in vitro resistance to antimicrobials previously recommended for gonorrhoea treatment (with exception of spectinomycin), but resistance also to the currently recommended ESCs were found. Nevertheless, the MICs of three potential future treatment options were low. It is essential to strengthen the diagnostics, case reporting, and epidemiologic surveillance of gonorrhoea in Vietnam. Furthermore, the surveillance of gonococcal AMR and gonorrhoea treatment failures is imperative to reinforce. Research regarding novel antimicrobial treatment strategies (e.g., combination therapy) and new antimicrobials is crucial for future treatment of gonorrhoea.


Effect of Face Masks and Speech Style on Speech Intelligibility and Listener Effort in Parkinson's Disease.
The aim of this study was to quantify the combined effects of face masks and effortful speech styles on listener intelligibility and perceived listener effort in talkers with and without Parkinson's disease (PD). Ten people with PD and 10 healthy, older controls read aloud sentences in two face mask and three speech style conditions. Masks included no mask and KN95 masks. Speech styles included habitual, clear, and loud. Listener participants were tasked with listening to each sentence mixed with background noise and then transcribing what they heard and rating how effortful it was to understand. Listener accuracy and effort were each modeled as a function of speaker group, face mask, and speech style using mixed-effects regression models. Listeners were less accurate and reported greater listening effort for the PD group and for the mask condition. Listeners were more accurate and reported less effort when listening to clear and loud compared to habitual speech. Listener accuracy and listener effort were strongly negatively correlated across all conditions. Face masks were also associated with a steeper decline in speech intelligibility and an increase in listener effort for talkers with PD. Face masks resulted in steeper speech intelligibility decline for talkers with PD compared to controls. Speaking more loudly or more clearly when wearing a face mask improved intelligibility for talkers with PD compared to habitual speech, and both speech styles resulted in speech intelligibility levels that approximated talkers' baseline intelligibility levels without a mask.


Metabolism of norepinephrine during nerve stimulation in dog trachea.
We determined the relative importance of neuronal and extraneuronal uptake in the metabolism of norepinephrine (NE) released during electrical stimulation (ES) of isolated canine tracheal smooth muscle (TSM). Strips of TSM were labeled with L-[3H]NE (2 X 10(-7) M) and mounted for superfusion. Superfusate was collected continuously before, during, and after ES (15 V, 0.5 ms, 5 Hz). Measurements were made of [3H]NE and its metabolites in superfusate and in tissue. Neuronal uptake followed by metabolism was estimated by measuring the amount of 3,4-dihydroxyphenylglycol (DOPEG). Extraneuronal uptake was estimated by measuring O-methylated metabolites (OMM). ES caused large increases in the efflux of NE, DOPEG, and OMM from TSM. However, the overflow of OMM was six times greater than that of DOPEG. Cocaine (10(-5) M) abolished the increased efflux of DOPEG during ES and enhanced the overflow of NE and OMM. We conclude that extraneuronal uptake constitutes the primary metabolic pathway for NE released from adrenergic nerves innervating TSM.


Nurses' expert opinions of workplace interventions for a healthy working environment: a Delphi survey.
Much has been written about interventions to improve the nursing work environment, yet little is known about their effectiveness. A Delphi survey of nurse experts was conducted to explore perceptions about workplace interventions in terms of feasibility and likelihood of positive impact on nurse outcomes such as job satisfaction and nurse retention. The interventions that received the highest ratings for likelihood of positive impact included: bedside handover to improve communication at shift report and promote patient-centred care; training program for nurses in dealing with violent or aggressive behaviour; development of charge nurse leadership team; training program focused on creating peer-supportive atmospheres and group cohesion; and schedule that recognizes work balance and family demands. The overall findings are consistent with the literature that highlights the importance of communication and teamwork, nurse health and safety, staffing and scheduling practices, professional development and leadership and mentorship. Nursing researchers and decision-makers should work in collaboration to implement and evaluate interventions for promoting practice environments characterized by effective communication and teamwork, professional growth and adequate support for the health and well-being of nurses.


Spontaneous Regression of Advanced Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The tumor carries poor prognosis with curative therapeutic options limited to surgical resection, tumor ablation, and liver transplantation. Rarely, there is spontaneous regression of the tumor. We describe the case of a 74-year-old male with cirrhosis from non-alcoholic steatohepatitis who developed advanced HCC that was associated with tumor invasion of the portal vein and marked elevation of serum alfa-fetoprotein level. The patient received no cancer-specific therapy. However, 1 year after the initial diagnosis, he was noted to have complete regression of the tumor. In this report, we discuss possible mechanisms of spontaneous tumor regression and its therapeutic implications.


The energy-enhancing potential of participatory performance-based arts activities in the care of people with a diagnosis of cancer: an integrative review.
Cancer in all its forms and stages is accompanied by a range of emotional, social and spiritual impacts. Pharmacological interventions have limited success with these issues and a range of interventions are needed to support people with a cancer diagnosis. We seek to understand the benefits of participatory performance-based arts activities, such as music, singing, drama and dance, in the care of people with cancer. We use the emerging Energy Restoration Framework, based on Kaplan's Attention Restoration Theory to explore the potentially energy-enhancing aspects of participation in such activities. An integrative review is used to explore existing research on the use of participatory performance-based arts in cancer care. Existing research is summarized and critically appraised. Results are analysed thematically and mapped to the attributes of the Energy Restoration Framework. Eight studies (four qualitative, three quantitative and one mixed-methods study) published between 2001 and 2016 met the search criteria. Findings from the thematic analysis resonated with the attributes of the Energy Restoration Framework. Research on the topic is very limited. When examined through the lens of the Energy Restoration Framework, the literature hints at the potential value of participatory performance-based arts activities for enhancing energy in the cancer care context.


The urea cycle of Helicobacter pylori.
The presence and activities of the enzymes of the urea cycle in the bacterium Helicobacter pylori were investigated employing one- and two-dimensional NMR spectroscopy and radioactive tracer analysis. Cell suspensions, lysates and membrane preparations generated L-ornithine and ammonium at high rates in incubations with L-arginine, indicating the presence of arginase activity. Anabolic ornithine transcarbamoylase (OTCase) activity was identified by the formation of heat-stable products in incubations of cell-free extracts with ornithine and radiolabelled carbamoyl phosphate. The heat-labile product that resulted from incubations of cell-free extracts with citrulline radiolabelled in the guanidino moiety revealed the presence of catabolic OTCase activity. Argininosuccinate formation and catalysis indicated the presence of argininosuccinate synthetase and argininosuccinase activities. The findings suggested that H. pylori has a urea cycle which acts as an effective mechanism to extrude excess nitrogen from cells.


Applications of RNA from circulating tumor cells.
Circulating tumour cells (CTCs) are shed into the bloodstream from both primary and secondary tumours and provide a non-invasive means to study tumor progression and response to treatment. Assessment of ribonucleic acid (RNA) and monitoring dynamic changes in gene expression profiles of CTCs extends their clinical and prognostic power and establish their role in guiding treatment. Among these methods, droplet digital (RT-ddPCR) technique provides a high sensitivity and detectibility of CTCs. RNA-sequencing (RNAseq) is the most comprehensive method, that would allow the simultaneous measurement of a large number of genes and theoretically the whole transcriptome. Since CTCs are heterogeneous in nature, single cell RNAseq methods are very valuable in assessing population dynamics and functional states of CTCs. While RNA in situ hybridization (RNA-ISH) is used relatively less frequently, it also allows for the assessment of expression of multiple genes within individual CTCs. Epithelial to Mesenchymal Transition (EMT) is a major contributor to metastasis, providing a mechanism to allow cells to become migratory and invasive, and to survive in the bloodstream. Monitoring CTCs undergoing EMT may lead to improvement in their prognostic and predictive power. Here, we review various RNA analysis of CTCs and those that undergo EMT and their application in diagnosis, prognosis and treatment of cancers.


Targeting Staphylococcus aureus Toxins: A Potential form of Anti-Virulence Therapy.
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria's ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria's acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S. aureus toxin production and potential anti-virulence strategies that target S. aureus toxins.


Ethical lapses: staff's perception of abuse in health care.
Objective. Studies have shown high lifetime prevalence of abuse in health care (AHC) in Nordic gynaecological patients. For patients AHC implies feeling disempowered, dehumanised and devalued. The aim of our study was to apprehend health care staff's perceptions of AHC. Study design. Qualitative interviews with staff at a Swedish gynaecological clinic analysed by Constant comparative analysis (N = 21). Results. The two categories - ethical failures against a patient and staff members avoid responsibility - gives two disparate pictures of what AHC is. The interviews showed that these pictures can exist alongside even if they contradict each other. The core category 'ethical lapses' brings staff's contradictory reflections on AHC together in one picture. Notable is that the dualistic notion of AHC did not result in a moral conflict within staff members. Conclusion. Health care staff perceives AHC primarily as ethical lapses. Avoiding responsibility for AHC might lead to a failing recognition of AHC, implying that the problem is not properly dealt with. Our study highlights the need for a more open attitude in health care staff toward AHC. To counteract AHC, staff members need to accept that AHC occurs also in their own units, bringing in moral conflicts in the everyday work.


Altered plasma membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes.
The intraerythrocytic development of the malaria parasite is accompanied by distinct morphological and biochemical changes in the host cell membrane, yet little is known about development-related alterations in the transbilayer organization of membrane phospholipids in parasitized cells. This question was examined in human red cells infected with Plasmodium falciparum. Normal red cells were infected with strain FCR3 or with clonal derivatives that either produce (K+) or do not produce (K-) knobby protuberances on the infected red cells. Parasitized cells were harvested at various stages of parasite development, and the bilayer orientation of red cell membrane phospholipids was determined chemically using 2,4,6-trinitrobenzene sulphonic acid (TNBS) or enzymatically using bee venom phospholipase A2 (PLA2) and sphingomyelinase C (SMC). We found that parasite development was accompanied by distinct alterations in the red cell membrane transbilayer distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Increases in the exoplasmic membrane leaflet exposure of PE and PS were larger in the late-stage parasitized cells than in the early-stage parasitized cells. Similar results were obtained for PE membrane distribution using either chemical (TNBS) or enzymatic (PLA2 plus SMC) methods, although changes in PS distribution were observed only with TNBS. Uninfected cohort cells derived from mixed populations of infected and uninfected cells exhibited normal patterns of membrane phospholipid organization. The observed alterations in P falciparum-infected red cell membrane phospholipid distribution, which is independent of the presence or absence of knobby protuberances, might be associated with the drastic changes in cell membrane permeability and susceptibility to early hemolysis observed in the late stages of parasite development.


Dampening Ab responses using proteasome inhibitors following in vivo B cell activation.
Upon encounter with Ag, B lymphocytes undergo terminal differentiation into plasma cells, highly specialized Ab secretors that mediate humoral immune responses. Profound changes adapt cellular morphology and proteome to the new secretory functions. Although a massive secretory activity is expected to require an efficient ubiquitin-proteasome degradation system, recent in vitro studies have surprisingly revealed that the proteasome function sharply decreases during plasma cell development, thereby limiting the proteolytic capacity. We challenged this paradigm in mouse models of B cell activation, and observed that following polyclonal activation, proteasome activity decreases more than previously reported in vitro. This decrease is linked to enhanced apoptosis after treatment with the potent anti-myeloma proteasome inhibitor PS-341. Accordingly, in vivo treatment with PS-341 decreases Ab titres in T-dependent and -independent mouse immunization models. This study provides the rationale for limiting the activity of Ab-secreting cells in vivo by impacting proteasome function.


[Bone alloplasty: its place and role in the system of modern osteosynthesis methods].
The experience with alloplasty carried out upon 265 patients with fractures and pseudoarthrosis of long tubular bones is generalized in this work. In 87 cases the osteosynthesis with bone angular and T-bars was performed. The analysis of the results of surgical treatment of fractures and pseudoarthrosis has proved the advantages of the bone bar osteosynthesis over other surgical procedures, especially from the technical and biological points of view, which are the following: its simplicity and non-traumatic effect, good fracture stability, prevention from angular and rotational displacement of the fragments through the external plaster cast immobilization, shortening of the operation time, freedom from repeated operations for the removal of metallic constructions.


Pulmonary invasive mucinous adenocarcinoma.
Invasive mucinous adenocarcinoma (IMA) is a relatively rare subtype of lung adenocarcinoma, composed of goblet and/or columnar tumour cells containing abundant intracytoplasmic mucin vacuoles. While a majority of IMAs are driven by KRAS mutations, recent studies have identified distinct genomic alterations, such as NRG1 and ERBB2 fusions. IMAs also more frequently present as a pneumonic-like pattern with multifocal and multilobar involvement, and comparative genomic profiling predominantly shows a clonal relationship, suggesting intrapulmonary metastases rather than synchronous primary tumours. Accordingly, these unique features require different therapeutic approaches when compared to nonmucinous adenocarcinomas in general. In this article, we review recent updates on the histopathological, clinical, and molecular features of IMAs, and also highlight some unresolved issues for future studies.


Relationships between plasma insulin-like growth factor-I and insulin-like growth factor binding protein-3 and second breast cancer risk in a prevention trial of fenretinide.
High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women </=50 years of age. Within a Phase III trial, we measured baseline and 1-year levels of IGF-I, IGFBP-3, and their ratio in 302 subjects on fenretinide and 220 controls who provided plasma samples. The prognostic effect of IGF-I and IGFBP-3, and the surrogate effect of IGF-I during fenretinide were assessed by Cox models after 9.4 years. Among controls, high IGF-I and low IGFBP-3 were associated with elevated second breast cancer risk [top versus bottom tertile, IGF-I, hazard ratio (HR) = 1.94, 95% confidence interval (CI), 0.87-4.31, P = 0.105; and IGFBP-3, HR = 0.40, 95% CI, 0.18-0.93, P = 0.033]. Fenretinide induced reductions of IGF-I, IGFBP-3, and IGF-I:IGFBP-3 of 8% (95% CI, 2-12%; P = 0.004), 3% (95% CI, 1-5%; P = 0.002), and 5% (95% CI, 0-10%; P = 0.050), respectively. Second breast cancer risk was reduced by 39% (HR = 0.61; 95% CI, 0.40-0.94; P = 0.026). The percentage of treatment effect explained by IGF-I and IGF-I:IGFBP-3 reductions were 4.8% (95% CI, 0.8-28.9%) and 3.1% (95% CI, 0.5-20.8%), respectively. Fenretinide induced a moderate reduction of IGF-I, which marginally explains observed cancer risk reductions in women </=50 years of age. In this age group high IGF-I and particularly low IGFBP-3 levels predict second breast cancer risk.


Sour Cherry (Prunus cerasus L) Anthocyanins as Ingredients for Functional Foods.
In the recent years many studies on anthocyanins have revealed their strong antioxidant activity and their possible use as chemotherapeutics. The finding that sour cherries (Prunus cerasus L) (also called tart cherries) contain high levels of anthocyanins that possess strong antioxidant and anti-inflammatory properties has attracted much attention to this species. Here we report the preliminary results of the induction of anthocyanin biosynthesis in sour cherry callus cell cultures. The evaluation and characterization of the in vitro produced pigments are compared to those of the anthocyanins found in vivo in fruits of several sour cherry cultivars. Interestingly, the anthocyanin profiles found in whole fruit extracts were similar in all tested genotypes but were different with respect to the callus extract. The evaluation of antioxidant activity, performed by ORAC and TEAC assays, revealed a relatively high antioxidant capacity for the fruit extracts (from 1145 to 2592 $\mu $ mol TE/100 g FW) and a lower one for the callus extract (688 $\mu $ mol TE/100 g FW).


Parental smoking and passive smoking in infants: fathers matter too.
This study examines mothers' and fathers' smoking patterns in different kinds of smoking households, and assesses their relative contribution to infants' exposure to environmental tobacco smoke. It uses data from a cross-sectional survey of 314 smoking households (infants: mean age 10 weeks) in Coventry and Birmingham, England, examining reported tobacco consumption and objective measures of exposure: the study infant's urinary cotinine:creatinine ratios and their mother's salivary cotinine. The study shows that both mothers' and fathers' tobacco smoke make substantial contributions to infant exposure to tobacco smoke. Households were more likely to contain a smoking father than mother, with over two-thirds of households including a smoking father. In households where both parents smoke, fathers' tobacco consumption was found to be significantly higher than in households where only the father smokes. This suggests that the interaction between parents needs to be considered rather than focusing on mothers' or fathers' smoking behaviour in isolation. The implications for health promotion programmes are discussed, particularly the need to place more emphasis on tackling fathers' smoking. Currently, fathers' smoking receives far less research or health promotion attention than mothers' smoking. Protecting infants from fathers' as well as mothers' smoking is key to reducing environmental tobacco exposure in early infancy, when the risk of Sudden Infant Death is highest.


Quality of life and other outcome measures in caregivers of patients with schizophrenia.
There is a growing concern about caregivers of individuals with schizophrenia who assume almost the totality of the patient care. This responsibility exposes them to an intense burden with negative consequences for them and indirectly for patients' health. The aim of this study was to provide an overview of the content and psychometric properties of instruments assessing the experience of caregivers of individuals with schizophrenia. Of the 460 articles screened from 1990 to 2013, 16 instruments were identified focusing on caregivers' burden (8), coping strategies (3), perception of need (3) and quality of life (2). These instruments were based primarily on experts' opinions, except two which were based exclusively on caregivers' view. The psychometric properties were poorly documented for a number of them and no information was published about responsiveness. Future works are needed to involve caregivers in the development of instruments and to explore psychometric properties of these instruments.