Defining Digital Public Health and the Role of Digitization, Digitalization, and Digital Transformation: Scoping Review.
The recent proliferation and application of digital technologies in public health has spurred interest in digital public health. However, as yet, there appears to be a lack of conceptual clarity and consensus on its definition. In this scoping review, we seek to assess formal and informal definitions of digital public health in the literature and to understand how these definitions have been conceptualized in relation to digitization, digitalization, and digital transformation. We conducted a scoping literature search in Ovid MEDLINE, Embase, Google Scholar, and 14 government and intergovernmental agency websites encompassing 6 geographic regions. Among a total of 409 full articles identified, we reviewed 11 publications that either formally defined digital public health or informally described the integration of digital technologies into public health in relation to digitization, digitalization, and digital transformation, and we conducted a thematic analysis of the identified definitions. Two explicit definitions of digital public health were identified, each with divergent meanings. The first definition suggested digital public health was a reimagination of public health using new ways of working, blending established public health wisdom with new digital concepts and tools. The second definition highlighted digital public health as an asset to achieve existing public health goals. In relation to public health, digitization was used to refer to the technical process of converting analog records to digital data, digitalization referred to the integration of digital technologies into public health operations, and digital transformation was used to describe a cultural shift that pervasively integrates digital technologies and reorganizes services on the basis of the health needs of the public. The definition of digital public health remains contested in the literature. Public health researchers and practitioners need to clarify these conceptual definitions to harness opportunities to integrate digital technologies into public health in a way that maximizes their potential to improve public health outcomes. RR2-10.2196/preprints.27686.


Impacts of Environmental Regulation on the Green Transformation and Upgrading of Manufacturing Enterprises.
Since environmental problems are becoming increasingly prominent, macro policies and social development have placed higher requirements on manufacturing enterprises to promote green transformation and upgrading (GTU) in China. Considering that different manufacturing enterprises choose different green technology innovation levels for GTU under environmental regulation, a game model between manufacturing enterprises and the government is constructed. The relationship between the green technology innovation level (GTIL) and the environmental regulation intensity is analyzed. Through numerical examples, the influences of environmental regulation and consumer preference on system decisions are further examined. Moreover, an econometric model is constructed to explore the influence that the environmental regulation exerts on the GTIL using panel data from the Chinese manufacturing industry. Our results show that the increase in environmental regulation intensity contributes to improving GTIL and promoting the GTU of manufacturing enterprises. Furthermore, as the environmental regulation is enhanced, the sales price decreases, benefiting consumers. Consumers' preference for high-GTIL products is conducive to GTU under environmental regulation. Empirical analysis shows that there is a U-shaped relationship between environmental regulation and the GTIL. Only when the intensity reaches a threshold can the environmental regulation be beneficial to improve the GTIL and promote the GTU of Chinese manufacturing enterprises.


CARD11 alteration as a candidate biomarker of skin cutaneous melanoma treated with immune checkpoint blockade.
Immune checkpoint inhibitors (ICIs) can be problematic, including a lack of sustained clinical response, in the treatment of skin cutaneous melanoma (SKCM) patients; therefore, predictive biomarkers are urgently needed. Recently, gene mutations identified by melanoma genomic analysis have shown great predictive potential. We collected an immunotherapy cohort and The Cancer Genome Atlas (TCGA)-SKCM cohort from published studies and tested the predictive function of the CARD11 mutation. We then further studied the association between the CARD11 mutation and tumor immunogenicity by studying related genes and pathways in the tumor microenvironment (TME). In the immunotherapy and TCGA-SKCM cohorts, patients with CARD11-mutant (MT) tumors had longer overall survival (OS) and a better prognosis than those with CARD11-wild-type (WT) tumors. CARD11-MT tumors had higher immunogenicity, and gene expression related to immunosuppression was significantly downregulated in CARD11-MT tumors. We found that immunosuppression-related pathways were significantly downregulated in CARD11-MT tumors, while immune activation-related pathways were significantly upregulated. Additionally, CARD11-MT tumors had more DNA damage response and repair (DDR) pathway mutations. CARD11 mutation is associated with longer OS and a better prognosis after ICI treatment. Therefore, the CARD11 gene can be used as a biomarker for predicting the efficacy of ICIs in SKCM patients.


Psychological and biological resilience modulates the effects of stress on epigenetic aging.
Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed "epigenetic clocks" such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e-4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.


7T MR spectroscopic imaging in the localization of surgical epilepsy.
With the success that surgical approaches can provide for localization-related epilepsy, accurate seizure localization remains important. Although magnetic resonance (MR) spectroscopy has had success in earlier studies in medial temporal lobe epilepsy, there have been fewer studies evaluating its use in a broader range of localization-related epilepsy. With improvements in signal-to-noise with ultra-high field MR, we report on the use of high resolution 7T MR spectroscopic imaging (MRSI) in 25 surgically treated patients studied over a 3.5-year period. Patients were included in this analysis if the region of MRSI study included the surgical resection region. Concordance between region of MRSI abnormalities and of surgical resection was classified into three groups (complete, partial, or no agreement) and outcome was dichotomized by International League Against Epilepsy (ILAE) I-III and IV-VI groups. MRSI was performed with repetition time/echo time 1.5 s/40 msec in two-dimensional (2D) or three-dimensional (3D) encoding for robust detection of singlets N-acetyl aspartate (NAA), creatine (Cr), and choline with abnormalities in NAA/Cr determined with correction for tissue content of gray matter. The concordance between MRSI-determined abnormality and surgical resection region was significantly related to outcome: Outcome was better if the resected tissue was metabolically abnormal. All 14 patients with complete resection of the region with the most severe metabolic abnormality had good outcome, including five requiring intracranial electroencephalography (EEG) analysis, whereas only 3/11 without complete resection of the most severe metabolic abnormality had good outcome (p < 0.001). This is consistent with the seizure-onset zone being characterized by metabolic dysfunction and suggests that high resolution MRSI can help define these regions for the purposes of outcome prediction.


Atrial natriuretic peptide and plasma renin levels in assessment of mineralocorticoid replacement in Addison's disease.
Assessment of mineralocorticoid replacement therapy in Addison's disease relies on clinical features and laboratory measurements, including plasma renin and potassium. Previous studies have questioned the value of measuring the plasma renin concentration (PRC), particularly in the setting of fludrocortisone overreplacement. The aim of this study was to evaluate the usefulness of plasma atrial natriuretic peptide (ANP) measurements as a marker of sodium and volume status in Addison's disease. Fourteen patients with Addison's disease receiving their usual glucocorticoid doses were placed on various doses of fludrocortisone (FC; 0 mg, 0.05 mg, 0.1 mg and 0.2 mg) in random order for four 2-week periods. At the end of each period, blood pressure and clinical symptoms were assessed, and blood was drawn for measurement of PRC and ANP levels. PRC was significantly elevated in patients receiving placebo (54.2 +/- 57.9 ng/mL x h) compared with PRC in those receiving baseline FC (24.7 +/- 42.4 ng/mL x h), 0.1 mg FC (15.2 +/- 25.9 ng/mL x h), and 0.2 mg FC (5.5 +/- 5.7 ng/mL x h). ANP levels were measured by either an extraction method (ANP(ext)) or directly from plasma (ANP(dir)). ANP(dir) was significantly elevated at 0.2 mg FC (87.1 +/- 20.1 pg/mL) compared with baseline (63.3 +/- 8.1 pg/mL), placebo (56.1 +/- 5.5 pg/mL), 0.05 mg FC (60.5 +/- 16.0 pg/mL), and 0.1 mg FC (65.4 +/- 13.7 pg/mL) values. ANP(ext) was elevated in patients receiving 0.2 mg FC (42.7 +/- 41.8 pg/mL) compared with that in patients receiving placebo (7.9 +/- 5.4 pg/mL), 0.05 mg FC (16.2 +/- 11.2 pg/mL), or 0.1 mg FC (19.7 +/- 11.1 pg/mL). Our data suggest that PRC is of value in determining mineralocorticoid underreplacement, whereas ANP is a more sensitive index of FC overreplacement. ANP levels may, therefore, be complementary to PRC in adjustment of mineralocorticoid doses in the upper dose range, where clinical symptoms and signs appear to be of little value.


Chronic food restriction alters mu and kappa opioid receptor binding in the parabrachial nucleus of the rat: a quantitative autoradiographic study.
Using quantitative autoradiography, it was previously observed that chronic food restriction alters mu and kappa receptor binding in several regions of the rat forebrain. The present autoradiographic study was designed to investigate whether food restriction affects regional mu and kappa binding in the brainstem. [3H]DAGO (mu) and-mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 21 brainstem regions. A significant decrease in mu binding was observed in the external lateral and external medial subnuclei of the parabrachial nucleus while a significant increase in kappa binding was observed in the external lateral subnucleus. The possible functional significance of these changes is discussed.


RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome.
Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY. Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated. Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type. This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status.


The Impact of Poverty on Partner Violence Against Women Under Regional Effects: The Case of Turkey.
Violence against women has been the subject of scientific literature in many fields and poverty has been one of the most important companions in this field. It can be found lots of empirical studies about violence against women for countries as Turkey too. However, regional considerations relating to people's socioeconomic condition have not been considered in these investigations although it has been indicated that these factors are important in terms of violence against women. Therefore, the main motivation of this study to investigate the impact of poverty on partner violence against women under the regional impacts in Turkey. The multinomial logit analysis preferred since the violence against women considered under three groups which are physical, sexual violence, and never experienced. The dataset received from the Survey on Domestic Violence Against Women in Turkey which was performed by Turkish Statistical Institute (TURKSTAT). This survey is performed in both 2008 and 2014 years. For this study, the 2008 data is chosen as it carries the information of "having a green card" which is a formal demonstration of being poor. Also, NUTS 2 (Nomenclature of territorial units for statistics) regions for Turkey are considered during the analysis. Based on the general results, the poverty status and regional effects of women, showed quite different results in terms of physical and sexual violence types. The poverty has a positive effect only on physical violence, not on sexual violence. Further, all regions have an important role on physical violence, while only less developed regions have a dominant impact on sexual violence. Also, the findings show that the intimate partners' bad habits make women more vulnerable to violence. According to the results, it can be suggested that developing policies based on regional effects and types of violence would be more effective.


Effect of Chokeberry (Aronia melanocarpa) juice on the metabolic activation and detoxication of carcinogenic N-nitrosodiethylamine in rat liver.
Chokeberry is a rich source of polyphenols, which may counteract the action of chemical carcinogens. The aim of this study was to examine the effect of chokeberry juice alone or in combination with N-nitrosodiethylamine (NDEA) on phase I and phase II enzymes and DNA damage in rat liver. The forced feeding with chokeberry juice alone decreased the activities of enzymatic markers of cytochrome P450, CYP1A1 and 1A2. NDEA treatment also decreased the activity of CYP2E1 but enhanced the activity of CYP2B. Pretreatment with chokeberry juice further reduced the activity of these enzymes. Modulation of P450 enzyme activities was accompanied by the changes in the relevant proteins levels. Phase II enzymes were increased in all groups of animals tested. Chokeberry juice augmented DNA damage and aggravated the effect of NDEA. These results indicate that chokeberry may protect against liver damage; however, in combination with chemical carcinogens it might enhance their effect.


Type 1 diabetes mellitus and its oral tolerance therapy.
As a T cell-mediated autoimmune disease, type 1 diabetes mellitus (T1DM) is marked by insulin defect resulting from the destruction of pancreatic β-cells. The understanding of various aspects of T1DM, such as its epidemiology, pathobiology, pathogenesis, clinical manifestations, and complications, has been greatly promoted by valuable research performed during the past decades. However, these findings have not been translated into an effective treatment. The ideal treatment should safely repair the destroyed immune balance in a long-lasting manner, preventing or stopping the destruction of β-cells. As a type of immune hypo-responsiveness to the orally administrated antigen, oral tolerance may be induced by enhancement of regulatory T cells (Tregs) or by anergy/deletion of T cells, depending on the dosage of orally administrated antigen. Acting as an antigen-specific immunotherapy, oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing. Based on the review of the proposed mechanism of the development of T1DM and oral tolerance, we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.


Morphoclinical aspects of the human paraprostethic gingival mucosa.
The multiple and various changes that the human gingival mucosa undergoes when coming into contact with a denture, require a histopathological study correlated with that of clinical manifestations. The highlighting of the histological lesions of the prosthetic field's mucosa is extremely important in the study concerning the tolerance of the oral cavity tissues towards the materials of dentures, because it has been observed that different materials can cause the same type of clinical changes. The clinical research has been carried out having as a basis a group of patients, carriers of fixed dentures made of different materials, the study method consisting in their clinical evaluation. The investigation of microscopic preparations, obtained through drawing mucosa from those patients under study, has been made by using both usual colorations for an overall examination of the tissue architecture, as well as special colorations for pointing out certain structures. The results of the investigation have made clear the fact that the clinical changes of the prosthetic field's mucosa can be adaptable to the denture or can react pathologically to the various possibilities of denture aggression. The histopathological picture of the paraprosthetic mucosa lesions is polymorphous due to the morphofunctional complexity as well as to the reacting capacity of the oral mucosa when interfering with a fixed denture.


Considerations for the definitions and classification of households and families and related variables for the 1990 round of censuses.
Questions related to the definition and classification of households and families in the 1990 census round in the Economic Commission for Europe (ECE) region are discussed. The author concludes that "the recommendations for the 1980 censuses of population and housing in the ECE region were largely adequate and should not be substantially revised other than a need to more precisely and concisely state the definition....While there is a demonstrated need to close some information gaps, such as through the provision of longitudinal family data using retrospective surveys, there is also a great need to more effectively use currently available cross-sectional data bases."


The diaries of Dr. Samuel Patton Hand 1911-1917. Part I.
Dr. Samuel Patton Hand practiced medicine in Demopolis, Alabama, for many years before his death in 1917. During the last seven years of his life he kept detailed diaries. These diaries have been passed down through the family since his death. These papers review the diaries, which present an intimate look at the life of an Alabama small-town doctor during this period. This first paper deals with the doctor's daily personal and social life, and looks at the transportation in Dr. Hand's day and its effect on his medical practice. The next paper will examine purely medical matters. A third paper will look at excerpts from a notebook or "Pearl book" the doctor kept.


Primary burkitt lymphoma of the brain in an immunocompetent patient. Case report.
Primary central nervous system (CNS) lymphoma is rare and is most often seen in immunodeficient patients. The majority of these tumors are the non-Hodgkin type and are high grade. Primary Burkitt lymphoma of the CNS in immunocompetent individuals has rarely been reported. The authors treated a 49-year-old woman who presented with left-sided weakness that had lasted 1.5 months. Magnetic resonance imaging revealed an oval mass in the left parietal region. with central necrosis and peripheral edema, and no attachment to the leptomeninges or ependyma. Pathological examination yielded a diagnosis of typical Burkitt lymphoma. Six months postoperatively, the patient is ambulatory and has improving neurological signs. This is a typical case of primary Burkitt lymphoma of the brain in an immunocompetent patient, which is a very rare event. The imaging pattern of the lesion is not typical of brain lymphomas and can result in an incorrect preoperative diagnosis of other brain tumors, such as glioblastoma multiforme. The patient's treatment and follow-up review are discussed.


Invasion growth rate and its relevance to persistence: a response to Technical Comment by Ellner et al.
Ellner et al. (2020) state that identifying the mechanisms producing positive invasion growth rates (IGR) is useful in characterising species persistence. We agree about the importance of the sign of IGR as a binary indicator of persistence, but question whether its magnitude provides much information once the sign is given.


Cryoballoon Atrial Fibrillation Ablation in a Patient with an Atrial Septal Defect Closure Device.
Atrial fibrillation (AF) is the most commonly treated arrhythmia in clinical practice and is often found in association with an atrial septal defect (ASD). However, ASD closure rarely confers complete arrhythmia control. A 23-year-old man presented to our center with frequent episodes of palpitations. AF was documented in 12-lead electrocardiography, and echocardiography showed a secundum-type ASD, 14 mm in size, with a significant left-to-right shunt. ASD closure was performed successfully with an ASD occluder device with no residual shunting. During follow-up, the patient experienced several episodes of AF. Thirteen months after the ASD closure, cryoballoon pulmonary vein isolation was done successfully with no complications. During a 12-month follow-up, he had no symptoms or AF recurrences, and echocardiography showed no residual shunting. This study showed that cryoballoon pulmonary vein isolation could be performed successfully without residual shunts in patients with ASD closure devices.


Molecular heterogeneity of angiotensin converting enzyme in human cerebrospinal fluid.
Three different molecular forms of angiotensin converting enzyme (ACE) (approximately Mr 150,000, 80,000 and 40,000, respectively), have been recovered from human cerebrospinal fluid. All three enzymes were inhibited by captopril and enalapril and their activity was potentiated by chloride ions. They were capable of degrading Leu-enkephalin-Arg6 and substance -P, but gave no conversion of neurokinin A. In all these aspects, the CSF enzymes were identical with the human pulmonary enzyme. The Mr 40,000 form of ACE is the smallest active form of the enzyme hitherto reported and is likely to represent a fragment of the C-terminal part of native ACE, where its active center is located.


Similarities and Differences of Hsp70, hsc70, Grp78 and Mortalin as Cancer Biomarkers and Drug Targets.
Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies.


Children (but not adults) can inhibit false memories.
The role of inhibition in children's (5-, 7-, and 11-year-olds') false memory illusions in the Deese-Roediger-McDermott (DRM) paradigm was examined using a list-wise directed-forgetting procedure. Children studied either a single DRM list (control) or two DRM lists in succession with a directed-remembering instruction or a directed-forgetting instruction between list presentations. The findings indicated that, like adults, children effectively suppressed the output of true memories when given a directed-forgetting instruction. Unlike adults, whose false memories are not attenuated in directed-forgetting conditions, children suppressed false memories at recall in the directed-forgetting condition. Because recognition data indicated that the children did generate false memories regardless of instruction, it appears that although adults' false memories are generated automatically and do not become part of their conscious experience, children's false memories are produced with greater effort and conscious processing, and as a result are easier to suppress at output.


Accelerated development of the first and second mandibular molars after distraction osteogenesis of the mandible in patients with hemifacial microsomia.
Although distraction osteogenesis of the mandible in patients with hemifacial microsomia (HFM) before the mixed dentition period is widely performed, long-term follow-up information on dental problems is limited. We evaluated the long-term effect of distraction osteogenesis on dental development by comparing Nolla's developmental stages of the first and second molars between the affected and unaffected sides of the mandible. Forty-five patients with unilateral HFM who received distraction osteogenesis of the mandible between the ages of 5 and 8 years and whose dental status was followed for more than 2 years were selected for this study. The patients were divided into 2 groups: group I (n = 28) consisted of patients with Pruzansky types I and IIA and group II (n = 17) consisted of patients with types IIB and III. Panoramic radiographs at T0 (1 month before distraction), T1 (6 months to 1 year after distraction), T2 (2-3 years after distraction) were reviewed. Nolla's stages for the first and second molars were compared at each of the abovementioned times between the affected and unaffected sides using Wilcoxon signed-rank test. In group I, there was no differences observed in Nolla's stages of the first and second molars in comparisons between the affected and unaffected sides of the mandible. However, in group II, at T0, there was a significant difference in Nolla's stage of the first and second molars in comparisons between the affected and unaffected sides. Over time, tooth development was accelerated, and eventually, there was no difference in Nolla's stage between the affected and unaffected sides at T1 and T2. Patients with severe HFM can benefit from distraction osteogenesis of the mandible. The results of this study showed that this procedure could normalize the delayed development and eruption of the first and second molars.


Protein Synthesis in Isolated Mitochondria of Rice (Oryza sativa L.) Seedlings.
For studies of in organello mitochondrial protein synthesis in rice, Oryza sativa L., conventional surface-sterilization procedures were demonstrated to be ineffective. Because of the over-whelmingly efficient [(35)S]methionine utilization by contaminating bacteria, even "essentially bacteria-free" rice mitochondria were shown to be unsuitable for the study of in organello protein synthesis. We developed a procedure to obtain a bacteria-free preparation of rice mitochondria. Such mitochondria favored a membrane-dependent ATP-generating system over an external ATP-generating system as the energy supplement for in organello protein synthesis. Two distinct classes of [(35)S]methionine-labeled, cycloheximide-insensitive products were detected: an electrophoretically unresolved population and a set of some 22 to 27 discrete polypeptide species, each with a characteristic electrophoretic mobility and relative abundance.


Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins.
Leptospirosis is an infectious disease of public health importance. To successfully colonize the host, pathogens have evolved multiple strategies to escape the complement system. Here we demonstrate that the culture supernatant of pathogenic but not saprophytic Leptospira inhibit the three complement pathways. We showed that the proteolytic activity in the supernatants of pathogenic strains targets the central complement molecule C3 and specific proteins from each pathway, such as factor B, C2, and C4b. The proteases cleaved α and β chains of C3 and work in synergy with host regulators to inactivate C3b. Proteolytic activity was inhibited by 1,10-phenanthroline, suggesting the participation of metalloproteases. A recombinant leptospiral metalloprotease from the thermolysin family cleaved C3 in serum and could be one of the proteases responsible for the supernatant activity. We conclude that pathogenic leptospiral proteases can deactivate immune effector molecules and represent potential targets to the development of new therapies in leptospirosis.


Laboratory strength measures of talented and less talented Greek children ages 9 to 10 years.
The purpose was twofold: (1) to assess whether laboratory tests can distinguish talented groups and less talented groups of children identified by their total scores in a battery of field tests and (2) to evaluate whether scores in field and laboratory tests are correlated. 36 children (ages 9 to 10 years) were divided into groups of higher and lower total scores on standing long jump, medicine ball throw, and sprint. Both groups were tested for maximum isometric force, force produced at the initial 100 msec., reactive force index, drop jump height, squat jump height, and maximum pedaling rate. Analysis showed the talented group had significantly (p < or = .05) higher scores on maximum isometric force, force produced in the initial 100 msec., and drop jump height than less talented children. Moderate to high correlations were found among scores for field performance tests with maximum pedaling rate. In conclusion, the laboratory tests distinguished the talented and less talented children in maximal isometric force, the force produced at the initial 100 msec., the reactive force index, and the drop jump height.


Victimization, substance use, and HIV risk behaviors among gay/bisexual/two-spirit and heterosexual American Indian Men in New York City.
secondary aims included describing condom-use attitudes, beliefs about HIV/AIDS in the Indian community, HIV knowledge, HIV status, and preference for and access to HIV prevention services in this population. A survey was mailed to all members of an American Indian community organization in New York City. The 20 men self-identifying as gay, two-spirit, or bisexual (hereafter, "two-spirit") were more likely to report being victimized and engaging in HIV risk behaviors than the 51 heterosexual respondents, although they reported comparable levels of recent substance use. Overall, victimization was associated with lifetime HIV risk behaviors (even after control for sexual orientation) but not with substance use or unsafe sex in the past 12 months. The percentage of HIV infection was surprisingly high (10% of two-spirit men and 6% of heterosexual men). Two-spirit men are a vulnerable population whose victimization must be understood within an appropriate historical and political context.


Comparative Evaluation of Changes in Physiological and Psychomotor Effects in Pediatric Patients during Extraction under Different Concentrations of Nitrous Oxide-Oxygen Inhalation Sedation.
Nonpharmacological behavioral management techniques are routinely used to create an environment that facilitates and builds a rapport between the child and the dentist to carry out procedures with minimal disruption. However, the discomfort associated with oral injections produces varying degrees of stress in all patients. Nitrous oxide (N2O)-oxygen (O2) inhalation sedation is one of the most widely used modalities for the management of fear and anxiety in children. The objective was to evaluate changes in physiological and psychomotor effects in pediatric patients during extraction under different concentrations of N2O-O2 inhalation sedation. A total of 300 healthy patients in the age range of 6-12 years (mean 8.9 years), who needed extraction of primary tooth, were included in the study. Pulse rate, SpO2, blood pressure (BP), and temperature were recorded at baseline, 30% N2O concentration, 50% N2O concentration, and again postoperatively. In addition, anxiety levels and neuromuscular coordination were recorded at the respective intervals. The results revealed a mean decrease in pulse rate and BP from baseline and an increase in temperature and O2 saturation during the sedation procedure. The findings were statistically significant. Significant impairment of coordination and psychomotor ability was seen at each step. Anxiety had significantly reduced after the onset of sedation due to the anxiolytic effect of N2O. N2O-O2 inhalation sedation under different concentrations reduces the anxiety of the patient and produces adequate sedation with vital signs within normal limits along with temporary impairment of psychomotor ability and coordination.


Development and validation of a new bitumen fume generation system which generates polycyclic aromatic hydrocarbon concentrations proportional to fume concentrations.
Bitumen fumes emitted during road paving and roofing contain polycyclic aromatic compounds (PACs) of potential health concern. Little information is available for an experimental device devoted to inhalation experiments with animals exposed to bitumen fumes, and in all studies the systems were never validated for a range of fume concentrations, which prohibited their use for toxicological concentration-effect studies. Therefore, the purpose of this study was to validate a new experimental device able to generate bitumen fumes at different total particulate matter (TPM) concentrations with a linear correlation between TPM and the concentrations of different PACs, thus allowing toxicological dose-response studies with fumes representative of those in the field. Atmosphere samples collected from an animal exposure chamber allowed the determination of TPM, toluene soluble matter, polycyclic aromatic hydrocarbons (PAHs) and semi-volatiles. The particulate size distributions were determined in order to assess the deposition pattern in the respiratory tract. The temperature of 170 degrees C was chosen by analogy with the upper range of the temperature used during paving operations. The temperature of the air passing over the fume emission area was regulated to 20 degrees C and stirring of the heated bitumen was restricted to 90 r.p.m. The data show that the objective of developing a static fume generation system that reproducibly produces fumes in the inhalation chamber for specified target concentrations (TPM) were successful. The within-day variation coefficients for TPM were between 2.5 and 6.1%. The day-to-day variations for TPM concentration were between 4.1 and 5.8%. The concentrations of the 4-5 ring PAHs and the polycyclic aromatic sulphur heterocycles were proportional to the TPM concentration. The 2 and 3 ring PAH concentrations showed a deviation from proportionality with the TPM, probably due to their re-evaporation during sampling. The mass median aerodynamic diameter of airborne particles varied from 1.4 micro m at a fume concentration of 5 mg/m(3) to 3.2 micro m at 100 mg/m(3). In conclusion, this equipment was suitable for nose-only inhalation studies in the 5-100 mg/m(3) range of TPM. Bitumen fumes were generated with a good reproducibility under well-controlled conditions. Finally, the PAH profiles from atmospheric samples were in good agreement with those measured during road paving.


Structural and functional studies of the yeast class II Hda1 histone deacetylase complex.
Yeast class II Hda1 histone deacetylase (HDAC) complex is an H2B- and H3-specific HDAC in Saccharomyces cerevisiae consisting of three previously identified subunits, the catalytic subunit scHda1p and two non-catalytic structural subunits scHda2p and scHda3p. We co-expressed and co-purified recombinant yeast class II HDAC complex from bacteria as a functionally active and trichostatin-A-sensitive hetero-tetrameric complex. According to an extensive analysis of domain organization and interaction of all subunits (or domains), the N-terminal domain of scHda1p associates through the C-terminal coiled-coil domains (CCDs) of the scHda2p-scHda3p sub-complex, yielding a truncated scHda1pHDAC-scHda2pCCD2-scHda3pCCD3 complex with indistinguishable deacetylase activity compared to the full-length complex in vitro. We characterized the interaction of the HDAC complex with either single-stranded or double-stranded DNA and identified the N-terminal halves of scHda2p and scHda3p as binding modules. A high-resolution structure of the scHda3p DNA-binding domain by X-ray crystallography is presented. The crystal structure shows an unanticipated structural homology with the C-terminal helicase lobes of SWI2/SNF2 chromatin-remodeling domains of the Rad54 family enzymes. DNA binding is unspecific for nucleotide sequence and structure, similar to the Rad54 enzymes in vitro. Our structural and functional analyses of the budding yeast class II Hda1 HDAC complex provide insight into DNA recognition and deacetylation of histones in nucleosomes.


High-throughput sequencing reveals landscapes of female germ cell development.
Female germ cell development is a highly complex process that includes meiosis initiation, oocyte growth recruitment, oocyte meiosis retardation and resumption and final meiotic maturation. A series of coordinated molecular signaling factors ensure successful oogenesis. The recent rapid development of high-throughput sequencing technologies allows for the dynamic omics in female germ cells, which is essential for further understanding the regulatory mechanisms of molecular events comprehensively. In this review, we summarize the current literature of multi-omics sequenced by epigenome-, transcriptome- and proteome-associated technologies, which provide valuable information for understanding the regulation of key events during female germ cell development.


Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture.
Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.


Interplay of electron-lattice interactions and superconductivity in superconductivity in Bi2Sr2CaCu2O8+delta.
Formation of electron pairs is essential to superconductivity. For conventional superconductors, tunnelling spectroscopy has established that pairing is mediated by bosonic modes (phonons); a peak in the second derivative of tunnel current d2I/dV2 corresponds to each phonon mode. For high-transition-temperature (high-T(c)) superconductivity, however, no boson mediating electron pairing has been identified. One explanation could be that electron pair formation and related electron-boson interactions are heterogeneous at the atomic scale and therefore challenging to characterize. However, with the latest advances in d2I/dV2 spectroscopy using scanning tunnelling microscopy, it has become possible to study bosonic modes directly at the atomic scale. Here we report d2I/dV2 imaging studies of the high-T(c) superconductor Bi2Sr2CaCu2O8+delta. We find intense disorder of electron-boson interaction energies at the nanometre scale, along with the expected modulations in d2I/dV2 (refs 9, 10). Changing the density of holes has minimal effects on both the average mode energies and the modulations, indicating that the bosonic modes are unrelated to electronic or magnetic structure. Instead, the modes appear to be local lattice vibrations, as substitution of 18O for 16O throughout the material reduces the average mode energy by approximately 6 per cent--the expected effect of this isotope substitution on lattice vibration frequencies. Significantly, the mode energies are always spatially anticorrelated with the superconducting pairing-gap energies, suggesting an interplay between these lattice vibration modes and the superconductivity.


tan and ebony genes regulate a novel pathway for transmitter metabolism at fly photoreceptor terminals.
In Drosophila melanogaster, ebony and tan, two cuticle melanizing mutants, regulate the conjugation (ebony) of beta-alanine to dopamine or hydrolysis (tan) of the beta-alanyl conjugate to liberate dopamine. beta-alanine biosynthesis is regulated by black. ebony and tan also exert unexplained reciprocal defects in the electroretinogram, at ON and OFF transients attributable to impaired transmission at photoreceptor synapses, which liberate histamine. Compatible with this impairment, we show that both mutants have reduced histamine contents in the head, as measured by HPLC, and have correspondingly reduced numbers of synaptic vesicles in their photoreceptor terminals. Thus, the histamine phenotype is associated with sites of synaptic transmission at photoreceptors. We demonstrate that when they receive microinjections into the head, wild-type Sarcophaga bullata (in whose larger head such injections are routinely possible) rapidly (<5 sec) convert exogenous [3H]histamine into its beta-alanine conjugate, carcinine, a novel metabolite. Drosophila tan has an increased quantity of [3H]carcinine, the hydrolysis of which is blocked; ebony lacks [3H]carcinine, which it cannot synthesize. Confirming these actions, carcinine rescues the histamine phenotype of ebony, whereas beta-alanine rescues the carcinine phenotype of black;tan double mutants. The equilibrium ratio between [3H]carcinine and [3H]histamine after microinjecting wild-type Sarcophaga favors carcinine hydrolysis, increasing to only 0.5 after 30 min. Our findings help resolve a longstanding conundrum of the involvement of tan and ebony in photoreceptor function. We suggest that reversible synthesis of carcinine occurs in surrounding glia, serving to trap histamine after its release at photoreceptor synapses; subsequent hydrolysis liberates histamine for reuptake.


Site-Specific N-Glycan Characterization of Grass Carp Serum IgM.
Immunoglobulin M (IgM) is the major antibody in teleost fish and plays an important role in humoral adaptive immunity. The N-linked carbohydrates presenting on IgM have been well documented in higher vertebrates, but little is known regarding site-specific N-glycan characteristics in teleost IgM. In order to characterize these site-specific N-glycans, we conducted the first study of the N-glycans of each glycosylation site of the grass carp serum IgM. Among the four glycosylation sites, the Asn-262, Asn-303, and Asn-426 residues were efficiently glycosylated, while Asn-565 at the C-terminal tailpiece was incompletely occupied. A striking decrease in the level of occupancy at the Asn-565 glycosite was observed in dimeric IgM compared to that in monomeric IgM, and no glycan occupancy of Asn-565 was observed in tetrameric IgM. Glycopeptide analysis with liquid chromatography-electrospray ionization tandem mass spectrometry revealed mainly complex-type glycans with substantial heterogeneity, with neutral; monosialyl-, disialyl- and trisialylated; and fucosyl-and non-fucosyl-oligosaccharides conjugated to grass carp serum IgM. Glycan variation at a single site was greatest at the Asn-262 glycosite. Unlike IgMs in other species, only traces of complex-type and no high-mannose glycans were found at the Asn-565 glycosite. Matrix-assisted laser desorption ionization analysis of released glycans confirmed the overwhelming majority of carbohydrates were of the complex-type. These results indicate that grass carp serum IgM exhibits unique N-glycan features and highly processed oligosaccharides attached to individual glycosites.


HIV Infection: Assessment of Sexual Risk, Knowledge, and Attitudes Towards Prevention in 1,586 High School Students in the Toulouse Education Authority Area.
Abstract In view of the spread of the AIDS epidemic in France, knowledge of the disease and sexual behavior, particularly use of condoms, was examined in 1,586 high school pupils in the Toulouse area. Modes of HIV transmission were found to be well known. However, some misconceptions existed, including the possibility of contagion from drinking utensils or from being around someone with AIDS. One third of the pupils had had sexual intercourse with more than one partner, and of these, 42 percent had never used condoms. A total of 65 percent of those questioned were in favor of condom use, but nearly 25 percent of students who had already used condoms found them difficult to use. Use of condoms appeared more likely if students felt personally at risk.


Development of a fluorogenic polymerase chain reaction assay (TaqMan) for the detection and quantitation of varicella zoster virus.
A TaqMan based polymerase chain reaction (PCR) assay was developed for the detection and quantitation of varicella zoster virus (VZV). This method enables simple, reproducible, sensitive and specific detection and quantification of VZV. The TaqMan assay was able to detect four copies of VZV and did not cross-react with other herpesviruses DNA. The assay has several advantages over conventional PCR. First, in the TaqMan assay there is no need for gel electrophoresis and contact with hazardous chemicals. Second, the method is rapid allowing the analysis of 92 samples within minutes after completion of PCR. Finally, the incorporation of a specific probe into the PCR reaction enhances the sensitivity and specificity of the method compared with conventional PCR. The TaqMan system could, therefore, be a useful tool for the epidemiological and diagnostic investigation of VZV.


Early-life origins of chronic respiratory diseases: understanding and promoting healthy ageing.
Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease often originate early in life. In addition to a genetic predisposition, prenatal and early-life environmental exposures have a persistent impact on respiratory health. Acting during a critical phase of lung development, these factors may change lung structure and metabolism, and may induce maladaptive responses to harmful agents, which will affect the whole lifespan. Some environmental factors, such as exposure to cigarette smoke, type of childbirth and diet, may be modifiable, but it is more difficult to influence other factors, such as preterm birth and early exposure to viruses or allergens. Here, we bring together recent literature to analyse the critical aspects involved in the early stages of lung development, going back to prenatal and perinatal events, and we discuss the mechanisms by which noxious factors encountered early on may have a lifelong impact on respiratory health. We briefly comment on the need for early disease biomarkers and on the possible role of "-omic" technologies in identifying risk profiles predictive of chronic respiratory conditions. Such profiles could guide the ideation of effective preventive strategies and/or targeted early lifestyle or therapeutic interventions.


A case-control study of gastric cancer and nutritional factors in Marseille, France.
A case-control study was conducted in Marseille (France) to investigate the relationship between usual diet and risk of gastric cancer. Patients with histologically confirmed gastric adenocarcinoma were identified in 8 major centres for gastric surgery. Controls were selected in specialized medical centres from patients undergoing functional reeducation for injuries or trauma, according to the age and sex distributions of the cases. The study involved 92 cases and 128 controls who were interviewed with a dietary history questionnaire on their usual diet during the year preceding first symptoms for cases, or preceding interview for controls. Odds ratios for specific foods were calculated after adjustment for age, sex, occupation and energy intake. A reduced risk was observed for consumption of raw vegetables (OR2: 0.55; OR3: 0.41 for the second and third tertiles, respectively), fresh fruit (OR2: 0.63; OR3: 0.50), vegetable oil (OR2: 0.60; OR3: 0.52), pasta and rice (OR2: 1.06; OR3: 0.50) whereas consumption of cakes and pastries (OR2: 1.02; OR3: 2.96), sugar and confectionery (OR2: 0.96; OR3: 1.68) was associated with an increased risk. An increased risk was found for intake of saturated fat (OR2: 1.49; OR3: 1.67), simple sugars (OR2: 1.18; OR3: 1.78) and calcium (OR2: 1.84; OR3: 2.57). A decreased risk was observed with intake of fiber (OR2: 0.49; OR3: 0.59), fibre from vegetables and fruit (OR2: 0.83; OR3: 0.53) and iron (OR2: 0.70; OR3: 0.41).


Knowledge of a patient-dependant phase of acute myocardial infarction in Polish adults: the role of physician's advice.
Effective management of acute myocardial infarction (AMI) is limited by patient delay in calling an ambulance. We aimed to assess knowledge related to a patient-dependant phase of AMI and its determinants in adults. Questionnaire survey was conducted among a random sample of 942 men (48%) and women (52%) aged 63.50 ± 6.50 selected from population registers in Cracow (Poland). Questions from the Behavioral Risk Factor Surveillance System were used to assess knowledge of AMI symptoms. The respondents were further asked about the first thing they would do in response to AMI symptoms, the emergency phone number and whether a doctor advised them about AMI. All suggested AMI symptoms were recognized by 51 (5.4%) respondents. More persons would call an ambulance in response to AMI symptoms in another person than if they appear in themselves (87.4% vs. 74.4%, P = 0.02). Only 644 (68%) participants knew the emergency phone number and 104 (11%) were advised about AMI by their doctors. Such advice was associated with higher rates of knowledge of AMI symptoms and the emergency phone number but not with a declaration of the appropriate reaction to AMI symptoms. Participants after AMI did not represent better knowledge of a patient-dependant phase of AMI but paradoxically less frequently than other persons declared calling an ambulance in response to AMI symptoms. Improvement in knowledge and attitudes related to a patient-dependant phase of AMI is needed in adults even if they experienced AMI before. A routine advice from a doctor may contribute significantly to this improvement.


Time-Resolved Detection of Surface Oxide Formation at Individual Gold Nanoparticles: Role in Electrocatalysis and New Approach for Sizing by Electrochemical Impacts.
Nanoparticle (NP) impacts on electrode surfaces has become an important method for analyzing the properties and activity of individual NPs, by either (i) electrocatalytic reactions or (ii) volumetric (dissolution) analyses. Using Au NPs as an exemplar system, this contribution shows that it is possible to detect surface oxide formation at individual NPs, which can occur on a rapid time scale (few μs). The charge associated with this "surface oxidation method" can be used for sizing (with results that are comparable to TEM) despite charges of only fC being measured. This platform further allows the role of surface oxides in electrocatalysis to be elucidated, with the time scale of oxide formation being controllable (i.e., "tunable") via the applied potential, as illustrated through studies of borohydride and hydrazine electro-oxidation. Finally, all of these studies are carried out on an oxide-covered Au substrate, which can be prepared and regenerated straightforwardly on an Au electrode, through the applied potential.


Metastatic breast cancer masquerading as a pituitary macroadenoma: A case report.
The purpose of this manuscript is to report a case of symptomatic breast cancer metastasis to the pituitary gland, a described yet exceedingly rare phenomenon. A 52-year-old woman with a known history of stage-IV breast cancer treated 3 years prior with chemotherapy presented to the emergency department with 2 weeks of right-sided periorbital headache and 1 week of right-sided ptosis. Magnetic resonance imaging showed a 1.9 cm × 2.8 cm × 2.8 cm mass in the pituitary with mass effect on the right optic chiasm. Endocrine laboratory studies were largely normal, including prolactin, thyroid-stimulating hormone, insulin-like growth factor, and a minimally decreased cortisol. She underwent endoscopic transnasal transsphenoidal resection 4 days later to remove the mass without complication. Postoperative pathologic studies were positive for breast cancer metastasis, and she was subsequently started on adjuvant radiation and oral chemotherapy. While breast cancer metastases to the sella have been described in the literature before, symptomatic spread to the pituitary represents a small percentage of all breast cancer metastases, and we thus feel is worthy of further discussion.


Activating Aging Stereotypes Increases Source Recollection Confusions in Older Adults: Effect at Encoding but Not Retrieval.
Activating aging stereotypes can impair older adult performance on episodic memory tasks, an effect attributed to stereotype threat. Here, we report the first study comparing the effects of explicitly activating aging stereotypes at encoding versus retrieval on recollection accuracy in older adults. During the encoding phase, older adults made semantic judgments about words, and during the retrieval phase, they had to recollect these judgments. To manipulate stereotype activation, participants read about aging-related decline (stereotype condition) or an aging-neutral passage (control condition), either before encoding or after encoding but before retrieval. We also assessed stereotype effects on metacognitive beliefs and two secondary tasks (working memory, general knowledge) administered after the recollection task. Stereotype activation at encoding, but not retrieval, significantly increased recollection confusion scores compared to the control condition. Stereotype activation also increased self-reports of cognitive decline with aging, but it did not reliably impact task-related metacognitive assessments or accuracy on the secondary tasks. Explicitly activating aging stereotypes at encoding increases the likelihood of false recollection in older adults, potentially by diminishing encoding processes. Stereotype activation also influenced global metacognitive assessments, but this effect may be unrelated to the effect of stereotypes on recollection accuracy.


Resonant Dipolar Collisions of Ultracold Molecules Induced by Microwave Dressing.
We demonstrate microwave dressing on ultracold, fermionic ^{23}Na^{40}K ground-state molecules and observe resonant dipolar collisions with cross sections exceeding 3 times the s-wave unitarity limit. The origin of these interactions is the resonant alignment of the approaching molecules' dipoles along the intermolecular axis, which leads to strong attraction. We explain our observations with a conceptually simple two-state picture based on the Condon approximation. Furthermore, we perform coupled-channel calculations that agree well with the experimentally observed collision rates. The resonant microwave-induced collisions found here enable controlled, strong interactions between molecules, of immediate use for experiments in optical lattices.


Msx1 is present in thyrotropic cells and binds to a consensus site on the glycoprotein hormone alpha-subunit promoter.
Our studies are aimed at identifying the transcription factors that activate the glycoprotein hormone alpha-subunit promoter. Therefore, we performed a Southwestern screening of a thyrotropic (alphaTSH) cDNA expression library, using the region of the promoter from -490 to -310 that contains sequences critical for expression in thyrotrope cells. A clone was isolated corresponding to part of the coding sequence of Msx1, which is a homeodomain-containing transcription factor that has been found to play an important role in the development of limb buds and craniofacial structures. Northern blot analysis, using the cloned Msx1 cDNA fragment as a probe, demonstrated that alpha-subunit-expressing thyrotrope cells (alphaTSH cells and TtT97 tumors) contained Msx1 RNA transcripts of 2.2 kb, while somatomammotrope (GH3) cells that do not produce the alpha-subunit had barely detectable levels. The presence of Msx1 protein was demonstrated by Western blot analysis in alphaTSH cells. We also demonstrated that transcripts encoding the closely related Msx2 factor were not detectable by Northern blot analysis in either thyrotrope or somatomammotrope-derived cells. Subfragments of the region from -490 to -310 of the alpha-subunit promoter were used in a Southwestern blot assay using bacterially produced Msx1 and demonstrated that binding was localized specifically to the region from -449 to -421. Deoxyribonuclease I protection analysis, using purified Msx1 homeodomain, demonstrated structurally induced differences in DNA digestion patterns between -436 and -413, and sequence analysis of this region revealed a direct repeat of the sequence GXAATTG, which is similar to the Msx1 consensus-binding site. When nucleotides at both sites were mutated, Msx1 binding was dramatically reduced, and the activity of an alpha-subunit promoter construct decreased by approximately 50% in transfected thyrotrope (alphaTSH) cells. These studies suggest that Msx1 may play a role in the expression of the alpha-subunit gene in thyrotrope cells.


Decisional involvement: staff nurse and nurse manager perceptions.
Enhancing involvement in organizational decisions is one strategy to improve the work environment of registered nurses and to increase their recruitment and retention. Little is known about the type of decision making and the level of involvement nurses desire. This was a descriptive study exploring staff nurse and nurse manager ratings of actual and preferred decisional involvement and differences between staff nurses and nurse managers. A sample of 320 RNs from a Midwestern health care network was surveyed using the Decisional Involvement Scale. Nurse managers and staff nurses had statistically significant differences in their perceptions of who was involved in actual decision making in the areas of unit governance and leadership and collaboration or liaison activities. There were statistically significant differences in preferred decisional involvement between staff nurses and nurse managers in the overall DIS scale and the subscales of unit governance and leadership and quality of support staff practice.


Does cognitive dysfunction correlate with neurofilament light polypeptide levels in the CSF of patients with multiple sclerosis?
To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS. This observational case-control study included patients with MS. CSF levels of NfL were determined using enzyme-linked immunosorbent assay. Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population. Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (-0.34 ± 1.13). Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72). An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = -0.944). This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples.


Effect of age at feedlot entry on performance and carcass characteristics of bulls and steers.
Seventy Angus x Simmental calves (BW = 166.3 +/- 4.2 kg) were used in a 3 x 2 factorial arrangement to determine the effect of age at feedlot entry and castration on growth, performance, and carcass characteristics. At 82 d of age, steers were castrated. Calves were placed in the feedlot at 111 (early-weaned), 202, or 371 (yearling) d of age. Steers were implanted with Synovex-S followed 93 d later with Revalor-S. Calves were harvested on an individual basis when fat thickness was estimated to be 1.27 cm. During the feedlot phase, yearlings gained faster (P < 0.01) than calves placed in the feedlot at 202 or 111 d of age (1.88, 1.68, and 1.62 kg/d, respectively); however, from 111 d of age until harvest, ADG was greatest for early-weaned calves, intermediate for cattle placed in the feedlot at 202 d of age, and lowest for yearlings (1.62, 1.47, and 1.21 kg/d, respectively; P < 0.01). Early-weaned calves spent the most days in the feedlot, followed by calves placed in the feedlot at 202 d of age; yearlings spent the fewest days in the feedlot (221, 190, and 163 d, respectively; P < 0.01). Total DMI when in the feedlot was similar (P = 0.22) among age groups; however, daily DMI was lowest for early-weaned calves, intermediate for calves placed in the feedlot at 202 d of age, and the highest for yearlings (7.1, 8.1, 10.5 kg/ d, respectively; P < 0.01). Early-weaned calves were the most efficient, followed by calves placed in the feedlot at 202 d of age; yearlings were the least efficient (227, 207, 180 g gain/kg feed, respectively; P < 0.01). Weight at harvest (682, 582, 517 kg, respectively; P < 0.01) and hot carcass weight (413, 358, 314 kg, respectively; P < 0.01) were greatest for yearlings, intermediate for cattle placed in the feedlot at 202 d of age, and lowest for early-weaned calves. Early-weaned calves had the smallest longissimus area, followed by calves placed in the feed-lot at 202 d of age; yearlings had the largest longissimus area (77, 86, 88 cm2, respectively; P < 0.01). Calves placed in the feedlot at 111 and 202 d of age had lower yield grades (3.2, 3.1, 3.5, respectively; P < 0.04), and produced fewer select carcasses than yearlings (25, 13, 48%, respectively; P < 0.01). Bulls and implanted steers both had an ADG of 1.7 kg/d when in the feedlot; however, bulls had a greater (P < 0.09) hot carcass weight (370 vs 354 kg) and a larger (P < 0.01) longissimus area (85.8 vs 81.3 cm2) than steers. Earlier feedlot placement resulted in greater quality grades but lower carcass weights.


State parity laws and access to treatment for substance use disorder in the United States: implications for federal parity legislation.
The passage of the 2008 Mental Health Parity and Addiction Equity Act and the 2010 Affordable Care Act incorporated parity for substance use disorder (SUD) treatment into federal legislation. However, prior research provides us with scant evidence as to whether federal parity legislation will hold the potential for improving access to SUD treatment. To examine the effect of state-level SUD parity laws on state-aggregate SUD treatment rates and to shed light on the impact of the recent federal SUD parity legislation. We conducted a quasi-experimental study using a 2-way (state and year) fixed-effect method. We included all known specialty SUD treatment facilities in the United States and examined treatment rates from October 1, 2000, through March 31, 2008. Our main source of data was the National Survey of Substance Abuse Treatment Services, which provides facility-level information on specialty SUD treatment. State-level SUD parity laws during the study period. State-aggregate SUD treatment rates in (1) all specialty SUD treatment facilities and (2) specialty SUD treatment facilities accepting private insurance. The implementation of any SUD parity law increased the treatment rate by 9% (P < .001) in all specialty SUD treatment facilities and by 15% (P = .02) in facilities accepting private insurance. Full parity and parity only if SUD coverage is offered increased the SUD treatment rate by 13% (P = .02) and 8% (P = .04), respectively, in all facilities and by 21% (P = .03) and 10% (P = .04), respectively, in facilities accepting private insurance. We found a positive effect of the implementation of state SUD parity legislation on access to specialty SUD treatment. Furthermore, the positive association is more pronounced in states with more comprehensive parity laws. Our findings suggest that federal parity legislation holds the potential to improve access to SUD treatment.


Risk of second primary cancer among women with breast cancer: a population-based study in Granada (Spain).
The higher risk of developing new cancers in breast cancer survivors is a public health concern. Our aim was to examine risk of second primary cancers among women diagnosed with breast cancer. We studied two cohorts of female cancer patients identified in a population-based cancer registry in Granada (Spain): women first diagnosed with a primary breast cancer (n=5897) and those with a primary cancer in another site (n=22,814), followed during 1985-2007 for second cancers and breast cancer occurrence, respectively. We used Standardized Incidence Ratios (SIRs) to estimate second cancer risk by age (<50y, ≥50y), time since diagnosis (≤5y, >5y) and calendar periods (≤1995, >1996). SIR for breast cancer was calculated in the second cohort. The risk of developing second cancers (n=314) was 39% higher (95% CI=1.23-1.54) among breast cancer patients, and particularly high among women under 50 (SIR=1.96, 95% CI=1.48-2.44). Excess risk for endometrial cancer (SIR=3.04, 95% CI=2.14-3.94) was statistically significant and remained so in women over 50. Younger women were at higher risk of second ovarian cancer (SIR=4.90, 95% CI=1.27-8.53). Increased SIRs were observed during the first five years after breast cancer diagnosis, whereas SIRs decreased thereafter. Breast cancer incidence (n=171) was not higher among women previously diagnosed with other cancer types (SIR=0.86, 95% CI=0.74-1.00). Women diagnosed with breast cancer have a higher incidence of second primary cancers, particularly of endometrial cancer in women over 50 at diagnosis, and ovarian cancer in younger women. These findings may be explained by treatment-related effects or shared risk factors.


Newly identified aspects of tumor suppression by RB.
The retinoblastoma (RB) tumor suppressor belongs to a cellular pathway that plays a crucial role in restricting the G1-S transition of the cell cycle in response to a large number of extracellular and intracellular cues. Research in the last decade has highlighted the complexity of regulatory networks that ensure proper cell cycle progression, and has also identified multiple cellular functions beyond cell cycle regulation for RB and its two family members, p107 and p130. Here we review some of the recent evidence pointing to a role of RB as a molecular adaptor at the crossroads of multiple pathways, ensuring cellular homeostasis in different contexts. In particular, we discuss the pro- and anti-tumorigenic roles of RB during the early stages of cancer, as well as the importance of the RB pathway in stem cells and cell fate decisions.


Retest learning in the absence of item-specific effects: does it show in the oldest-old?
This study examined whether the nonitem-specific retest learning effects, previously shown with young-old adults primarily in their 60s and 70s, could be extended to oldest-old adults aged 80 and onward. Twenty-one oldest-olds participated in an 8-session retest training program with three ability domains: perceptual speed, inductive reasoning, and visual attention. Their data were compared with the data of 30 young-olds collected in a previous work (Yang, Reed, Russo, & Wilkinson, 2009). The two age groups showed largely equivalent retest learning effects. In addition, only young-olds were able to benefit from item-specific retest learning, specifically in reasoning and perceptual speed tests.


International migration and gestational diabetes mellitus: a systematic review of the literature and meta-analysis.
Influxes of migrant women of childbearing age to receiving countries have made their perinatal health status a key priority for many governments. The international research collaboration Reproductive Outcomes And Migration (ROAM) reviewed published studies to assess whether migrants in countries of resettlement have a greater risk of gestational diabetes mellitus (GDM) than women in receiving countries. A systematic review of the literature from Medline, Embase, PsychInfo and CINAHL from 1990 to 2009 included studies of migrant women and GDM. Studies were excluded if there was no cross-border movement or comparison group or if the receiving country was not the country of resettlement. Studies were assessed for quality, analysed descriptively and meta-analysed. Twenty-four reports (representing >120,000 migrants) met our inclusion criteria. Migrants were described primarily by geographic origin; other relevant aspects (e.g. time in country, language fluency) were rarely studied. Migrants' results for GDM were worse than those for receiving-country women in 79% of all studies. Meta-analyses showed that, compared with receiving-country women, Caribbean, African, European and Northern European women were at greater risk of GDM, while North Africans and North Americans had risks similar to receiving-country women. Although results of the 31 comparisons of Asians, East Africans or non-Australian Oceanians were too heterogeneous to provide a single GDM risk estimate for migrant women, only one comparison was below the receiving-country comparison group, all others presented a higher risk estimate. The majority of women migrants to resettlement countries are at greater risk for GDM than women resident in receiving countries. Research using clear, specific migrant definitions, adjusting for relevant risk factors and including other aspects of migration experiences is needed to confirm and understand these findings.


Estimation of Levodopa in the Unani Drug Mucuna pruriens Bak. and Its Marketed Formulation by High-Performance Thin-Layer Chromatographic Technique.
Mucuna pruriens Bak. Syn. Mucuna prurita Hook. seed is the rich source of levodopa (L-dopa) and has been used in traditional medicines to treat diseases resembling Parkinson's disease. In the present study, a new HPTLC method was developed and validated for estimation of L-dopa from M. pruriens (black- and white-colored seeds) collected from two different locations in India. TLC aluminum plates precoated with silica gel were used as the stationary phase. The plates were developed to a distance of 60 mm at a temperature of 22 ± 4°C in a twin glass chamber saturated with ethyl acetate-methanol-formic acid-water (15+3+3+4.5, v/v/v/v), as the mobile phase. The Rf value of L-dopa was found to be 0.45. L-dopa was quantified at 282 nm, the wavelength of maximum absorbance by a densitometric scanner. The TLC plate was derivatized by ninhydrin reagent and photodocumented. L-dopa showed a good linearity in the concentration range 400-1000 ng/spot. The linear regression analysis of calibration plot showed good linear relationship between peak area and peak height (r2 = 0.997). The method was validated for precision, repeatability, and accuracy. Recovery was determined by spiking L-dopa with samples and was found to be 96.10%. L-dopa was found to be present at concentration 3.02-4.72% in samples and its formulation.


Protein Synthesis and Degradation Inhibitors Potently Block Mycobacterium tuberculosis type-7 Secretion System ESX-1 Activity.
Mycobacterium tuberculosis (M. tb) uses its type-7 secretion system ESX-1 to translocate key virulence effector proteins. Taking a chemical genetics approach, we demonstrate for the first time the importance of mycobacterial proteostasis to ESX-1. We show that individual treatment with inhibitors of protein synthesis (chloramphenicol and kanamycin) and protein degradation (lassomycin and bortezomib), at concentrations that only reduce M. tb growth by 50% and less, specifically block ESX-1 secretion activity in the tubercle bacillus. In contrast, the mycobacterial cell-wall synthesis inhibitor isoniazid, even at a concentration that reduces M. tb growth by 90% has no effect on ESX-1 secretion activity. We also show that chloramphenicol but not isoniazid at subinhibitory concentrations specifically attenuates ESX-1-mediated M. tb virulence in macrophages. Taken together, the results of our study identify a novel vulnerability in the ESX-1 system and offer new avenues of anti-TB drug research to neutralize this critical virulence-mediating protein secretion apparatus.


Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins.
Fic proteins that are defined by the ubiquitous FIC (filamentation induced by cyclic AMP) domain are known to catalyse adenylylation (also called AMPylation); that is, the transfer of AMP onto a target protein. In mammalian cells, adenylylation of small GTPases through Fic proteins injected by pathogenic bacteria can cause collapse of the actin cytoskeleton and cell death. It is unknown how this potentially deleterious adenylylation activity is regulated in the widespread Fic proteins that are found in all domains of life and that are thought to have critical roles in intrinsic signalling processes. Here we show that FIC-domain-mediated adenylylation is controlled by a conserved mechanism of ATP-binding-site obstruction that involves an inhibitory α-helix (α(inh)) with a conserved (S/T)XXXE(G/N) motif, and that in this mechanism the invariable glutamate competes with ATP γ-phosphate binding. Consistent with this, FIC-domain-mediated growth arrest of bacteria by the VbhT toxin of Bartonella schoenbuchensis is intermolecularly repressed by the VbhA antitoxin through tight binding of its α(inh) to the FIC domain of VbhT, as shown by structure and function analysis. Furthermore, structural comparisons with other bacterial Fic proteins, such as Fic of Neisseria meningitidis and of Shewanella oneidensis, show that α(inh) frequently constitutes an amino-terminal or carboxy-terminal extension to the FIC domain, respectively, partially obstructing the ATP binding site in an intramolecular manner. After mutation of the inhibitory motif in various Fic proteins, including the human homologue FICD (also known as HYPE), adenylylation activity is considerably boosted, consistent with the anticipated relief of inhibition. Structural homology modelling of all annotated Fic proteins indicates that inhibition by α(inh) is universal and conserved through evolution, as the inhibitory motif is present in ∼90% of all putatively adenylylation-active FIC domains, including examples from all domains of life and from viruses. Future studies should reveal how intrinsic or extrinsic factors modulate adenylylation activity by weakening the interaction of α(inh) with the FIC active site.


Mirror, mirror on my desk.
Physician executives, perhaps more than typical business managers, are often generally cognizant of their own personalities and their relative strengths and weaknesses. However, as with most matters with which one has intimate familiarity, we are less clear about the specifics of our personality styles and their most effective use. This article discusses a model for using personality assessment and developmental and historical interviewing in the education of physician executives. Examples show how personality assessment can be used by physician executives in a voluntary and safe way to enhance professional development and career decision making.


Complementary effect of Phloxine B on the insecticidal efficacy of Isaria fumosorosea SFP-198 wettable powder against greenhouse whitefly, Trialeurodes vaporariorum West.
Insecticidal activities of five photoactive dyes against greenhouse whitefly (GWF), Trialeurodes vaporariorum West., in tomatoes were investigated to improve the control efficacy of an entomopathogenic fungal product, Isaria fumosorosea SFP-198 wettable powder (WP). Azorubine, Eosin B, Erythrosine, Brilliant Green and Phloxine B were used in this work, accompanying pyriproxyfen emulsifiable concentrate (EC) as a commercial standard for comparison. Phloxine B had the highest control efficacy in glasshouse conditions. The most suitable dose of Phloxine B was determined as 0.005 g L(-1) , given the dosage-dependent control efficacy and phytotoxicity of the dye, and its influence on the germination of SFP-198 conidia. In field conditions, SFP-198 WP + Phloxine B (2 + 0.005 g L(-1) ; tank mix) showed 89.1 and 95.3% control efficacy 7 and 14 days post-application, which was significantly higher than the efficacy of SFP-198 WP alone (43.5 and 64.0%), Phloxine B (47.5 and 30.7%) or pyriproxyfen EC (67.7 and 80.2%). Phloxine B cooperates with SFP-198 WP complementarily, possibly in the order of killing action (early: Phloxine B; late: SFP-198 WP). The dye can be incorporated into SFP-198 WP to improve its efficacy and applied to other Hypocrelean entomopathogenic fungal products.


Cortisol and growth hormone: clinical implications of a complex, dynamic relationship.
Children with Cushing syndrome (CS), whether CS is iatrogenic or caused by endocrine tumors, have short stature and suffer from excess adiposity and lower bone mineral density. These clinical observations are well entrenched in the minds of pediatricians and pediatric endocrinologists. It is then surprising when one discovers that patients with cortisol-secreting adrenal tumors actually do not have completely suppressed growth hormone levels unless they are obese. Adequate adrenocortical glucocorticoid secretion is necessary for normal function of the somatotropic axis, at least in rodents. Furthermore, glucocorticoids appear to play a regulatory role in skeletal bone accumulation that goes far beyond the well known suppressive effects of excess cortisol on osteoblastic function. To add to the complexity, endocrine and paracrine cortisol levels and actions depend much on the activity of metabolizing enzymes, such as 11-beta-hydroxysteroid dehydrogenase type-1 and CYP3A. The text that follows reviews the complex and dynamic state of the relationship between two of the most important hormones that regulate growth and development in childhood as revealed from clinical, physiologic, and basic science studies. The message is clear: although excess cortisol inhibits growth and the skeleton, normal cortisol levels are part of the mix that ensures both normal growth hormone secretion and bone accumulation in childhood.


PAI-1 inhibits neutrophil efferocytosis.
Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical for the resolution of inflammation. Plasma and tissue levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, are elevated in inflammatory conditions, including sepsis and acute lung injury, in which activated neutrophils accumulate in tissues and contribute to organ dysfunction. In this study, we explored the potential involvement of PAI-1 in modulating neutrophil efferocytosis. We found enhanced phagocytosis of viable PAI-1 deficient (PAI-1(-/-)) and of wild-type neutrophils treated with anti-PAI-1 antibodies. PAI-1 levels were decreased on the surface of apoptotic neutrophils and the enhanced phagocytosis of apoptotic wild-type neutrophils or of viable PAI-1(-/-) neutrophils was diminished by preincubation with PAI-1. The increased phagocytosis associated with PAI-1 deficiency or blockade depended on both the lipoprotein receptor-related protein (LRP) and its ligand, calreticulin (CRT), because the LRP-mediated increase in phagocytosis of viable neutrophils induced by blockade of CD 47 was abrogated by PAI-1. CRT levels are increased on viable PAI-1(-/-) neutrophils. While CRT colocalizes with PAI-1 on viable neutrophils, markedly diminished colocalization of PAI-1 and CRT was present on apoptotic neutrophils. Our data therefore indicate that PAI-1 serves as a novel "don't eat me" signal for viable and apoptotic neutrophils.


Paediatric Salmonellosis-Differences between Tropical and Sub-Tropical Regions of Queensland, Australia.
Salmonellosis is an important cause of morbidity in tropical regions.This study aims to describe the epidemiology of non-typhoidal Salmonellae (NTS) in children presenting to public hospitals in Queensland, Australia, over the past 20 years, with a focus on differences between tropical and sub-tropical zones in the region. This is a retrospective and descriptive cohort study of 8162 NTS positive samples collected in 0-17-year-olds from the Queensland public hospital pathology database (Auslab) over a 20-year period from 1997 to 2016. There were 2951 (36.2%) positive NTS samples collected in tropical zones and 5211 (63.8%) in the sub-tropical zones of Queensland, with a total of 8162 over the region. The tropical zone contributed a disproportionately higher number of positive NTS samples by population sub-analysis. Of the specimens collected, 7421 (90.92%) were faecal, 505 (6.2%) blood, 161 (1.97%) urine, 13 (0.16%) cerebrospinal fluid (CSF) and 62 of other origin. Other categories of specimen types isolated include swab, fluid, aspirate, lavage, bone, tissue, isolate and pus, and these were not included in sub-analysis. The most commonly identified serovars were Salmonella Typhimurium, Salmonella Virchow and Salmonella Saintpaul. This is the first and largest study that emphasises the high burden of invasive and non-invasive NTS infections resulting in hospital presentations in the paediatric population of tropical north Queensland, compared to the sub-tropics.


[Lumbar lordosis: radiological classification and biomechanical consequences].
Various radiological parameters were measured on a lateral film taken in erect position of the lumbar spine in 55 patient with low back pain. These various parameters had inter-, intra-observer and inter-study variation coefficients of less than 3%. In patients with a positive Fergusson index ("low" or inferior lordosis), mean values of the angle of lordosis and of obliqueness of the lower vertebral plateau of L5 in relation to the horizontal were higher than in patients with a negative Fergusson index ("high" or superior lordosis), this being statistically significant. In view of the correlations found between the various parameters measured and this classification, the biomechanical consequences, which have their role to play in the management of patients with low back pain, are discussed.


WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells.
The sorting of soluble secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex is mediated by coat protein complex II (COPII) vesicles and thought to required specific ER membrane cargo-receptor proteins. However, these receptors remain largely unknown. Herein, we show that ER to Golgi transfer of vesicular cargo proteins requires WFS1, an ER-associated membrane protein whose loss of function leads to Wolfram syndrome. Mechanistically, WFS1 directly binds to vesicular cargo proteins including proinsulin via its ER luminal C-terminal segment, whereas pathogenic mutations within this region disrupt the interaction. The specific ER export signal encoded in the cytosolic N-terminal segment of WFS1 is recognized by the COPII subunit SEC24, generating mature COPII vesicles that traffic to the Golgi complex. WFS1 deficiency leads to abnormal accumulation of proinsulin in the ER, impeding the proinsulin processing as well as insulin secretion. This work identifies a vesicular cargo receptor for ER export and suggests that impaired peptide hormone transport underlies diabetes resulting from pathogenic WFS1 mutations.


Haptic breakage following neonatal IOL implantation in a nonhuman primate model.
To evaluate the long-term safety of implanting intraocular lenses (IOLs) in neonatal eyes using a nonhuman primate model, a one-piece all-polymethylmethacrylate (PMMA) IOL was implanted into the posterior chamber of 21 neonatal Rhesus monkey eyes following a lensectomy and anterior vitrectomy. These monkeys then were monitored for 26 to 40 months for complications. The eyes from seven monkeys were studied histopathologically. One or both haptics broke on 7 of the 21 (33%) IOLs in a mean of 21 months (range 6 to 31 months) after their implantation. Only one of the haptics from these seven eyes was found to be in the capsular bag when these eyes were studied histopathologically. Nine haptics had eroded into the iris leaflets, two into the ciliary body, and one into the anterior chamber. One additional haptic was in the sulcus. The haptics of one-piece all-PMMA IOLs may break if implanted in neonatal eyes. A number of factors likely contributed to haptic breakage in these eyes, including an increased number of reoperations, malpositioning of IOL haptics, rapid circumferential and axial growth, and the formation of large Soemmerring's rings.


Altered sphingolipid metabolism in N-(4-hydroxyphenyl)-retinamide-resistant A2780 human ovarian carcinoma cells.
In the present work, we studied the effects of fenretinide (N-(4-hydroxyphenyl)retinamide (HPR)), a hydroxyphenyl derivative of all-trans-retinoic acid, on sphingolipid metabolism and expression in human ovarian carcinoma A2780 cells. A2780 cells, which are sensitive to a pharmacologically achievable HPR concentration, become 10-fold more resistant after exposure to increasing HPR concentrations. Our results showed that HPR was able to induce a dose- and time-dependent increase in cellular ceramide levels in sensitive but not in resistant cells. This form of resistance in A2780 cells was not accompanied by the overexpression of multidrug resistance-specific proteins MDR1 P-glycoprotein and multidrug resistance-associated protein, whose mRNA levels did not differ in sensitive and resistant A2780 cells. HPR-resistant cells were characterized by an overall altered sphingolipid metabolism. The overall content in glycosphingolipids was similar in both cell types, but the expression of specific glycosphingolipids was different. Specifically, our findings indicated that glucosylceramide levels were similar in sensitive and resistant cells, but resistant cells were characterized by a 6-fold lower expression of lactosylceramide levels and by a 6-fold higher expression of ganglioside levels than sensitive cells. The main gangliosides from resistant A2780 cells were identified as GM3 and GM2. The possible metabolic mechanisms leading to this difference were investigated. Interestingly, the mRNA levels of glucosylceramide and lactosylceramide synthases were similar in sensitive and resistant cells, whereas GM3 synthase mRNA level and GM3 synthase activity were remarkably higher in resistant cells.


Comparative structural and functional studies of avian and mammalian hemoglobins.
Thermal stabilities of chicken, grey lag goose (Anser anser), turkey as avian hemoglobins (Hbs); and human, bovine, sheep and horse as mammalian Hbs in hemolysate form were investigated and compared with oxygen affinities taken from literature. The thermal stability was obtained from thermal profiles using temperature scanning spectrophotometry. The buffer conditions were 50 mM Tris, pH 7.2, and 1 mM EDTA. The average of the inverse temperature transitions, average hydrophobicity, total van der Waals volume, partial molal volume and hydration potential were calculated by computational methods. The hemolysed avian Hbs have a lower oxygen affinity, higher thermal stability and higher self association than the mammalian Hbs. These observations are based on amino-acid composition, influence of ionic effectors, and the presence of Hb D in several avian Hbs. The results indicate that the avian Hbs have a more tense (T) conformation than the mammalian Hbs.


Plasma catecholamine concentrations are a reliable index of sympathetic vascular tone in patients with cirrhosis.
In patients with cirrhosis, the significance of elevated plasma catecholamine concentrations is unclear. Thus we investigated the relationship between plasma catecholamine concentrations and the hemodynamic effect of pindolol (an index of sympathetic vascular tone) in 10 patients with cirrhosis. Systemic and splanchnic hemodynamics and plasma catecholamine concentrations in the pulmonary artery and the splanchnic veins (hepatic and azygos veins) were studied before and after the oral administration of pindolol (20 mg). In basal conditions patients exhibited a hyperkinetic circulatory syndrome and elevated plasma catecholamine concentrations. Alterations in basal hemodynamics were correlated with plasma epinephrine concentrations but not with norepinephrine. Pindolol administration significantly decreased heart rate and increased right atrial pressure. After pindolol administration, individual hemodynamic changes (cardiac index, systemic vascular resistance, wedged hepatic venous pressure) were significantly correlated with plasma catecholamine concentrations. In conclusion, this study shows that in cirrhotic patients epinephrine may play a role in hemodynamic alterations, and plasma catecholamine concentrations are an index of sympathetic vascular tone.


[Association of polymyositis, myasthenia, and thymoma. A case and review of the literature].
We report the case of a 51 years old woman with myositis, myasthenia gravis and thymoma. First apparent sign is myositis in 1976 but chest X ray show a mediastinal opacity and the patient reports an intermittent diplopia since 1973. The evolution of myositis occurs in two bouts in 1976 and 1981, Myasthenia gravis restricted to diplopia from 1973 to 1979 grow worse first alone then in association with increase of myositis signs in 1981. The mediastinal opacity seen on chest X ray in 1976 don't change and is revealed to be a thymoma at operation in 1981. After thymoma ablation myasthenic and myositis signs decrease. This pathologic association is found 24 times in literature and involves "giant cells" in muscle biopsy in about 50 p. 100 of cases and a myocarditis also with "giant cells". Those "giant cells" unusual in common myositis appears to have a prognostic value.


Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice.
Slc17a5-/- mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10-p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5-/- mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5-/- mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders.


Cancer Needs a Robust "Metadata Supply Chain" to Realize the Promise of Artificial Intelligence.
Profound advances in computational methods, including artificial intelligence (AI), present the opportunity to use the exponentially growing volume and complexity of available cancer measurements toward data-driven personalized care. While exciting, this opportunity has highlighted the disconnect between the promise of compute and the supply of high-quality data. The current paradigm of ad-hoc aggregation and curation of data needs to be replaced with a "metadata supply chain" that provides robust data in context with known provenance, that is, lineage and comprehensive data governance that will allow the promise of AI technology to be realized to its full potential in clinical practice.


Rosiglitazone and pioglitazone alter aromatase kinetic properties in human granulosa cells.
We have previously reported that, in human granulosa cells, thiazolidinediones rosiglitazone and pioglitazone inhibit estrogen synthesis by interfering with androgen binding to aromatase, without an effect on aromatase mRNA or protein expression. In the current paper, we explore the effects of rosiglitazone and pioglitazone on the aromatase enzyme kinetic properties in human granulosa cells. The cells were incubated with various concentrations of testosterone or androstenedione, with or without rosiglitazone or pioglitazone. Estradiol and estrone concentrations in the conditioned tissue culture medium were measured by radioimmunoassay or immunosorbent assay. When testosterone was used as substrate, rosiglitazone or pioglitazone inhibited the V(max) by 35% (P < 0.001) and 24% (P < 0.001), respectively. When androstenedione was used as substrate, both rosiglitazone or pioglitazone inhibited V(max) by 13% (P < 0.007). We conclude that rosiglitazone or pioglitazone has no effect on K(m) but inhibits V(max) of aromatase in human granulosa cells, therefore, acting as noncompetitive inhibitors.