MIN6 beta-cell-beta-cell interactions influence insulin secretory responses to nutrients and non-nutrients.
Insulin-secreting MIN6 cells show greatly enhanced secretory responsiveness to nutrients when grown as islet-like structures (pseudoislets). Since beta-cells use different mechanisms to respond to nutrient and non-nutrient stimuli, we have now investigated the role of homotypic beta-cell interactions in secretory responses to pharmacological or receptor-operated non-nutrient stimuli in MIN6 pseudoislets. In addition to an enhanced secretory responsiveness to glucose, insulin secretion from MIN6 pseudoislets was also enhanced by non-nutrients, including carbachol, tolbutamide, PMA, and forskolin. The improved secretory responsiveness was dependent on the cells being configured as pseudoislets and was lost on dispersal of the pseudoislets into single cells and regained on the re-formation of pseudoislet structures. These observations emphasise the importance of islet anatomy on secretory responsiveness, and demonstrate that homotypic beta-cell interactions play an important role in generating physiologically appropriate insulin secretory responses to both nutrient and non-nutrient stimuli.


Leisure-time physical activity in São Paulo adults: a trend analysis from 2006 to 2016.
To investigate the temporal trend of practicing physical exercise and sports during leisure time in adults in São Paulo between 2006 to 2016. Time series analysis study using the VIGITEL System. Adding up the number of people who participated each year, a total 21,357 people were studied. Analyzes of the physical exercises and sports practiced during leisure time (yes or no) stratified by sex, age and education were performed. The prevalences and the differences for all of the years were calculated using the Prains-Winster regression. Practice of physical exercises or sports increased by 7.9 percentage points in the period (p = 0.003) (from 39.9% 95%CI 37.4 - 42.4 to 47.8% 95%CI 45.2 - 50.4). There was a significant increase for women (p = 0.011), for people between 18-24 years old (p = 0.001), 25-34 years old (p = 0.003), 45-54 years old (p = 0.003), and for people with up to eight years of schooling (p = 0.010). There was a decrease in walking and playing soccer and there was an increase in doing gymnastics. There was an increase in the practice of physical exercise and sports during leisure time in adults from São Paulo. These increases were observed mainly in women, in people between 18 and 34 years old, between 45 and 54 years old, and in people with up to eight years of schooling. These results are important, as they have shown an increase in general and in more vulnerable groups, and may be related to environmental changes and interventions that have occurred in the city in the last 15 years.


Severe weight gain induced by combination treatment with risperidone and paroxetine.
Successful combination therapy with atypical antipsychotics and selective serotonin reuptake inhibitors has been reported for several psychiatric conditions. However, great attention should be paid to the possible adverse effects. In this retrospective chart review, we focused on the drug-drug interaction of paroxetine and risperidone. Retrospectively, we identified two patients treated with a combination of risperidone and paroxetine therapy, and analyzed their medical records. During a 3-month period of monotherapy with risperidone, the changes in body weight were +/- 0.0 kg in Patient 1 and -2.0 kg in Patient 2. In contrast, during combination therapy with paroxetine and risperidone, the body-weight changes were +14.0 kg in Patient 1 (after 4 months) and +13.5 kg in Patient 2 (after 5 months). In addition, diabetes mellitus was observed in Patient 2. Regarding the mechanism of severe weight gain in these two patients, we speculate a drug-drug interaction involving inhibition of the cytochrome P450 enzyme 2D6 (CYP4502D6) by paroxetine.


Antiphase dynamics and chaos in self-pulsing erbium-doped fiber lasers.
We present experimental evidence of antiphase dynamics in self-pulsing erbium-doped fiber lasers operating simultaneously at 1.536- and 1.55-microm wavelengths. Autonomous chaos is also observed for several ranges of pumping rates. The fractal dimension of the chaotic attractor, calculated from experimental data by use of the Procaccia method, is found to depend on the pumping ratio but always remains smaller than 4.1, regardless of the chaotic regime considered.


MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells.
To improve regeneration of the injured myocardium, it is necessary to enhance the intrinsic capacity of the heart to regenerate itself and/or replace the damaged tissue by cell transplantation. Cardiomyocyte progenitor cells (CMPCs) are a promising cell population, easily expanded and efficiently differentiated into beating cardiomyocytes. Recently, several studies have demonstrated that microRNAs (miRNAs) are important for stem cell maintenance and differentiation via translational repression. We hypothesize that miRNAs are also involved in proliferation/differentiation of the human CMPCs in vitro. Human fetal CMPCs were isolated, cultured, and efficiently differentiated into beating cardiomyocytes. miRNA expression profiling demonstrated that muscle-specific miR-1 and miR-499 were highly upregulated in differentiated cells. Transient transfection of miR-1 and -499 in CMPC reduced proliferation rate by 25% and 15%, respectively, and enhanced differentiation into cardiomyocytes in human CMPCs and embryonic stem cells, likely via the repression of histone deacetylase 4 or Sox6. Histone deacetylase 4 and Sox6 protein levels were reduced, and small interference RNA (siRNA)-mediated knockdown of Sox6 strongly induced myogenic differentiation. miRNAs regulate the proliferation of human CMPC and their differentiation into cardiomyocytes. By modulating miR-1 and -499 expression levels, human CMPC function can be altered and differentiation directed, thereby enhancing cardiomyogenic differentiation.


Outcome of thoracoscopic repair of type-C esophageal atresia: a single-center experience from North Africa.
Thoracoscopic repair of esophageal atresia is gaining popularity worldwide attributable to availability and advances in minimally invasive instruments. In this report, we presented our experience with thoracoscopic esophageal atresia/tracheoesophageal fistula (EA/TEF) repair in our tertiary care institute. A prospective study on short-gap type-C EA/TEF was conducted at Cairo University Specialized Pediatric Hospital between April 2016 and 2018. Excluded were cases with birth weight < 1500 gm, inability to stabilize physiologic parameters, or major cardiac anomalies. The technique was standardized in all cases and was carried out by operating team concerned with minimally invasive surgery at our facility. Primary outcome evaluated was successful primary anastomosis. Secondary outcomes included operative time, conversion rate, anastomotic leakage, recurrent fistula, postoperative stricture, and time till discharge. Over the inclusion period of this study, 136 cases of EA/TEF were admitted at our surgical NICU. Thoracoscopic repair was attempted in 76 cases. In total, 30 cases were pure atresia/long gap type-C atresia and were excluded from the study. Remaining 46 cases met the inclusion criteria and were enrolled in the study. Mean age at operation was 8.7 days (range 2-32), and mean weight was 2.6 Kg (range 1.8-3.6). Apart from five cases (10.8%) converted to thoracotomy, the mean operative time was 108.3 minutes (range 80-122 minute). A tension-free primary anastomosis was possible in all thoracoscopically managed cases (n = 41) cases. Survival rate was 85.4% (n = 35). Anastomotic leakage occurred in seven patients (17%). Conservative management was successful in two cases, while esophagostomy and gastrostomy were judged necessary in the other for five. Anastomotic stricture developed in five cases (16.6%) of the 30 surviving patients who kept their native esophagus. Despite the fact that good mid-term presented results may be due to patient selection bias, thoracoscopic approach proved to be feasible for management of short-gap EA/TEF. Authors of this report believe that thoracoscopy should gain wider acceptance and pediatric surgeons should strive to adopt this procedure.


Skin-derived precursors generate myelinating Schwann cells for the injured and dysmyelinated nervous system.
Although neural stem cells hold considerable promise for treatment of the injured or degenerating nervous system, their current human sources are embryonic stem cells and fetally derived neural tissue. Here, we asked whether rodent and human skin-derived precursors (SKPs), neural crest-related precursors found in neonatal dermis, represent a source of functional, myelinating Schwann cells. Specifically, cultured SKPs responded to neural crest cues such as neuregulins to generate Schwann cells, and these Schwann cells proliferated and induced myelin proteins when in contact with sensory neuron axons in culture. Similar results were obtained in vivo; 6 weeks after transplantation of naive SKPs or SKP-derived Schwann cells into the injured peripheral nerve of wild-type or shiverer mutant mice (which are genetically deficient in myelin basic protein), the majority of SKP-derived cells had associated with and myelinated axons. Naive rodent or human SKPs also generated Schwann cells that myelinated CNS axons when transplanted into the dysmyelinated brain of neonatal shiverer mice. Thus, neonatal SKPs generate functional neural progeny in response to appropriate neural crest cues and, in so doing, provide a highly accessible source of myelinating cells for treatment of nervous system injury, congenital leukodystrophies, and dysmyelinating disorders.


Reporting of the translation and cultural adaptation procedures of the Addenbrooke's Cognitive Examination version III (ACE-III) and its predecessors: a systematic review.
The ACE-III, a gold standard for screening cognitive impairment, is restricted by language and culture, with no uniform set of guidelines for its adaptation. To develop guidelines a compilation of all the adaptation procedures undertaken by adapters of the ACE-III and its predecessors is needed. We searched EMBASE, Medline and PsychINFO and screened publications from a previous review. We included publications on adapted versions of the ACE-III and its predecessors, extracting translation and cultural adaptation procedures and assessing their quality. We deemed 32 papers suitable for analysis. 7 translation steps were identified and we determined which items of the ACE-III are culturally dependent. This review lists all adaptations of the ACE, ACE-R and ACE-III, rates the reporting of their adaptation procedures and summarises adaptation procedures into steps that can be undertaken by adapters.


Effectiveness of Asteraceae extracts on Trichostrongylidae eggs development in sheep.
Data on in vitro evaluation of extracts of three species of the Asteraceae family on the development of Trichostrongylidae eggs in sheep are presented. Egg hatchability was tested using herbal extracts prepared in a Soxhlet extractor, and using hydrolate prepared by means of hydrodistillation. The laboratory tests showed that the ethanol extract from flowers of the species Aster lanceolatus presented high activity against Trichostrongylidae eggs development in sheep, inhibiting larva formation by 91% within 48 hours, and maintaining similar rates after 72 hours.


Influence of sex on the radiation-induced life span modifications in Drosophila melanogaster.
Drosophila melanogaster is exposed to 0, 25, 50, 75 kr of 60Co gamma-irradiation at 1,000 r/min, on the 4th day of its imaginal life. As a result, the life span of the flies is reduced for both sexes. Females, however, are more radiosensitive than males. In females, the radiation-induced life span shortening does not vary with the doses administered; in males, on the contrary, the life expectancy decreases as the dose is increased.


Asthma across the lifespan: Time for a paradigm shift.
We have a unique opportunity to significantly reduce the worldwide burden of asthma in children and affect respiratory outcomes in adults. However, this will require a paradigm shift that is directed at altering the natural history of asthma, reducing asthma exacerbations, and preventing long-term adverse outcomes of childhood asthma. Attention should continue to be directed toward minimizing risk, as well as impairment, with a goal to achieve optimal control. Based on several National Institutes of Health studies conducted over the last 10 years, we now have the tools necessary to accomplish this goal. The tools include assessment of lung function over time or defining trajectories of lung growth, the Composite Asthma Severity Index score, a panel of useful biomarkers, the Seasonal Asthma Exacerbation Prediction Index score, and rapidly advancing technology that includes adherence monitoring. Future guideline revisions should consider incorporating recommendations to follow spirometry over time and defining trajectories of lung growth to assess risk for reduced lung growth and early decline, asthma burden by using biomarkers to select and monitor therapy, assessment of social determinants of health, evaluation of risk for seasonal exacerbations, and consideration of electronic adherence monitoring for difficult-to-manage asthma. Guidelines should continue to include a core dedicated to the diagnosis and treatment of intermittent and mild and moderate persistent asthma and include additional sections dedicated to the management of severe asthma.


Tumorlike eosinophilic granuloma of the skin.
In 1952, Kuske reported on a patient with a peculiar tumor on the dorsum of the right hand; histological analysis revealed a dense dermal infiltrate with numerous eosinophils. Not aware of any similar case report in the literature, he coined the descriptive term "tumor-like eosinophilic granuloma of the skin." In 1995, a 55-year-old white man with cancer of the prostate presented with a 4-month history of two reddish-brown, solid skin tumors on his left forearm and on the right side of his abdomen, respectively. Histologic examination revealed a dense, superficial and deep, tumorlike dermal inflammatory infiltrate consisting mainly of eosinophils as well as neutrophils and in part epithelioid, in part foamy histiocytes. Flame figures were absent. Immunohistochemical analysis was negative for S-100 protein, whereas sporadic cells in the infiltrate were CD1a positive and many mononuclear-histiocytic cells reacted with MAC 387. Stains as well as cultures for bacteria, mycobacteria, and fungi were negative. The descriptive diagnosis of tumorlike eosinophilic granuloma of the skin was made. Seven weeks after prostatectomy, both tumors resolved spontaneously and so far has not recurred. In our opinion, this is the second report of Kuske's tumorlike eosinophilic granuloma of the skin. Perhaps tumorlike eosinophilic granuloma of the skin, eosinophilic ulcer of the mucosa, and transient eosinophilic nodulomatosis should be considered a mucocutaneous reaction pattern as is seen in cats. In humans, hypersensitivity reactions or atopy could emerge as an etiological link.


Structure and function of the two tandem WW domains of the pre-mRNA splicing factor FBP21 (formin-binding protein 21).
Human FBP21 (formin-binding protein 21) contains a matrin-type zinc finger and two tandem WW domains. It is a component of the spliceosomes and interacts with several established splicing factors. Here we demonstrate for the first time that FBP21 is an activator of pre-mRNA splicing in vivo and that its splicing activation function and interaction with the splicing factor SIPP1 (splicing factor that interacts with PQBP1 and PP1) are both mediated by the two tandem WW domains of group III. We determined the solution structure of the tandem WW domains of FBP21 and found that the WW domains recognize peptide ligands containing either group II (PPLP) or group III (PPR) motifs. The binding interfaces involve both the XP and XP2 grooves of the two WW domains. Significantly, the tandem WW domains of FBP21 are connected by a highly flexible region, enabling their simultaneous interaction with two proline-rich motifs of SIPP1. The strong interaction between SIPP1 and FBP21 can be explained by the conjugation of two low affinity interactions with the tandem WW domains. Our study provides a structural basis for understanding the molecular mechanism underlying the functional implication of FBP21 and the biological specificity of tandem WW domains.


[Intracorporeal injection of papaverine for diagnosis of impotence: clinical evaluation of 120 patients].
Intracorporeal papaverine injections were performed for evaluation of penile erection on 120 patients with sexual impotence. This diagnostic technique was found to be simple, objective, realistic, and more precise in the differentiation of sexual dysfunction in men. In addition to observing the onset and duration of erection after papaverine injection, we could also classify the erectile rigidity by measuring the erectile angle while standing. The penile deformity after erection that possibly contributed to the etiology of patient's impotence could also easily be detected after papaverine injection. Thus we could differentiate 120 cases of impotence into the following types: psychogenic (26 cases), neurogenic (2 cases), mild vasculogenic (including physiologic) (33 cases), severe vasculogenic (54 cases) and pure venous leakage syndrome (5 cases). None of our patients developed fatal complications during or after the papaverine intracorporeal injection test; however, we experienced 5 cases of priapism requiring emergency management. Therefore, the injection must be done under the supervision of an experienced urologist.


Pathogenesis of nonsteroidal antiinflammatory drug-induced asthma.
To summarize recent findings related to the pathogenic mechanisms of aspirin-induced asthma with emphasis on molecular genetic mechanisms. The overproduction of cysteinyl leukotrienes with the increased expression of cysteinyl leukotriene receptor 1 (CYSLTR1) is a consistent finding in aspirin-induced asthma patients. Recent data have suggested a dysregulation of cyclooxygenase-2 and prostaglandin E2, increased levels of 15-hydroxyeicosatetranoic acid, and decreased lipoxin generation as characteristics of the condition. The HLA allele DPB10301 was documented as a strong genetic marker for susceptibility in an Asian population. Leukotriene C4 synthase has been established as a key genetic determinant of aspirin-induced asthma, but recent studies have demonstrated that several single nucleotide polymorphisms in the promoters of prostaglandin E2 receptor subtype 2, CYSLTR1 and CYSLTR2 and T-box expressed in T cells (TBX21) could increase risk for the condition. Although cyclooxygenase-2 and thromboxane A2 receptor polymorphisms were not associated with aspirin-induced asthma phenotype, they may exert functional effects. The identification of genetic markers for aspirin-induced asthma susceptibility along with in-vitro functional studies would help to elucidate the pathogenesis of the condition. Further studies of the interactions among genes and between genes and the environment will be essential.


Early action and gesture "vocabulary" and its relation with word comprehension and production.
Data from 492 Italian infants (8-18 months) were collected with the parental questionnaire MacArthur Bates Communicative Development Inventories to describe early actions and gestures (A-G) "vocabulary" and its relation with spoken vocabulary in both comprehension and production. A-G were more strongly correlated with word comprehension than word production. A clear developmental pattern for the different types of A-G was found. These findings are similar to those of different Western languages, indicating a common biological and cultural basis. The analysis of individual A-G and their relations with early words with a related meaning showed interesting similarities between the production of A-G with and without object manipulation and the comprehension and production of corresponding words. Results indicate that the transition from A-G to spoken language is mediated by word comprehension.


Interleukin-1beta expression in murine J774A.1 macrophages exposed to platinum compounds: the role of p38 and ERK 1/2 mitogen-activated protein kinases.
Although skin and respiratory sensitizing properties of platinum compounds have been proved in humans and mice, little is known about signal transduction pathways leading to cytokine production in the induction phase. It is generally assumed that induction of skin sensitization, but not skin irritation, is associated with a rapid increase in the IL-1beta mRNA expression. In this study, IL-1beta expression and a role of mitogen-activated protein kinases (MAPKs) in this process were investigated in murine macrophages J774A.1 exposed to four platinum compounds. Potassium tetrachloroplatinate (K(2)PtCl(4); TCPP), ammonium tetrachloroplatinate ((NH(4))(2)PtCl(4); TCPA), ammonium hexachloroplatinate ((NH(4))(2)PtCl(6); HCPA) showed a very similar range of cytotoxic concentrations (IC(50) values: 238 microM+/-30; 269 microM+/-39 and 245 microM+/-31, respectively) as assessed in the 24-h MTT reduction test. Cytotoxicity of cis-diammineplatinum dichloride (cisplatin) was considerably higher (IC(50) of 23 microM+/-4). While increased expression of IL-1beta mRNA was observed in the macrophages exposed to each test compound, IL-1beta protein production was detected in cell lysates after treatment with TCPP, TCPA and HCPA for 24h (concentration range of 150-350 microM) as well as for 2h (450-650 microM). The treatment with each compound resulted in the phosphorylation of both p38 MAPK and ERK 1/2 (p44/42). Blocking the activation of p38 MAPK as well as ERK 1/2 with specific inhibitors (SB203580 and U0126, respectively) down-regulated the IL-1beta expression. Interestingly, the skin irritant sodium dodecyl sulfate did not trigger phosphorylation of these kinases, nor induced IL-1beta production. These data suggest that p38 MAPK and ERK 1/2 play an important role in induction of IL-1beta expression in J774A.1 macrophages exposed to test platinum compounds.


Three decades of Omaha System research: Providing the map to discover new directions.
The Omaha System is a classification system or standardized terminology designed to enhance practice, documentation, and information management. Fifty unique studies were identified that focused on the Omaha System's Problem Classification Scheme, the Intervention Scheme, and the Problem Rating Scale for Outcomes. A computerized search of the research literature used CINAHL, MEDLINE, and Dissertation Abstracts databases for the years 1982 to 2003 on the keyword, Omaha System. Nursing studies predominated and were organized into eight categories. Based on the review, recommendations were made for future Omaha System research.


Clinical and laboratory monitoring of dogs naturally infected by Leishmania infantum.
The clinical evolution of Leishmania infantum infection in dogs is largely influenced by the host's individual immune response. Few studies have investigated the time course and clinical evolution of the infection both under experimental and natural conditions. In the present investigation, the time course of L. infantum infection was studied by monitoring clinical and laboratory features in naturally infected dogs sheltered in southern Italy. Twenty-three dogs that had one or more positive diagnostic tests for L. infantum were enrolled in the study and followed up every 4 months. A clinical score was assigned at each visit after assessing the presence of clinical signs suggestive of leishmaniosis. L. infantum-infected dogs were classified into three different categories based on their clinical score and serological and parasitological test results. Based on data from diagnostic tests and clinical scores, the time course of infection was defined as transient asymptomatic infection (11 dogs), persistent asymptomatic infection (2 dogs), and symptomatic infection (8 dogs). Two dogs were lost after the first sand fly season. The results of the present study provide a framework for assessing the clinical status of L. infantum infection in dogs and suggest that infected animals should be monitored over time to expedite therapeutic decisions and plan appropriate control interventions.


Single-molecule high-resolution colocalization of single probes.
Colocalization of fluorescent probes is commonly used in cell biology to discern the proximity of two proteins in the cell. Considering that the resolution limit of optical microscopy is on the order of 250 nm, there has not been a need for high-resolution colocalization techniques. However, with the advent of higher resolution techniques for cell biology and single-molecule biophysics, colocalization must also improve. For diffraction-limited applications, a geometric transformation (i.e., translation, scaling, and rotation) is typically applied to one color channel to align it with the other; however, to achieve high-resolution colocalization, this is not sufficient. Single-molecule high-resolution colocalization (SHREC) of single probes uses the local weighted mean transformation to achieve a colocalization resolution of at least 10 nm. This protocol describes the acquisition of registration data and the analysis required to obtain a high-resolution mapping between imaging channels. The total internal reflection fluorescence microscope (TIRFM) system described is designed to excite and image the fluorescent probes Cy3 and Cy5. Modifications may be required depending on the requirements of the individual study.


The primacy of vital signs--acute care nurses' and midwives' use of physical assessment skills: a cross sectional study.
Registered nurses and midwives play an essential role in detecting patients at risk of deterioration through ongoing assessment and action in response to changing health status. Yet, evidence suggests that clinical deterioration frequently goes unnoticed in hospitalised patients. While much attention has been paid to early warning and rapid response systems, little research has examined factors related to physical assessment skills. To determine a minimum data set of core skills used during nursing assessment of hospitalised patients and identify nurse and workplace predictors of the use of physical assessment to detect patient deterioration. The study used a single-centre, cross-sectional survey design. The study included 434 registered nurses and midwives (Grades 5-7) involved in clinical care of patients on acute care wards, including medicine, surgery, oncology, mental health and maternity service areas, at a 929-bed tertiary referral teaching hospital in Southeast Queensland, Australia. We conducted a hospital-wide survey of registered nurses and midwives using the 133-item Physical Assessment Skills Inventory and the 58-item Barriers to Registered Nurses' Use of Physical Assessment Scale. Median frequency for each physical assessment skill was calculated to determine core skills. To explore predictors of core skill utilisation, backward stepwise general linear modelling was conducted. Means and regression coefficients are reported with 95% confidence intervals. A p value <.05 was considered significant for all analyses. Core skills used by most nurses every time they worked included assessment of temperature, oxygen saturation, blood pressure, breathing effort, skin, wound and mental status. Reliance on others and technology (F=35.77, p<.001), lack of confidence (F=5.52, p=.02), work area (F=3.79, p=.002), and clinical role (F=44.24, p<.001) were significant predictors of the extent of physical assessment skill use. The increasing acuity of the acute care patient plausibly warrants more than vital signs assessment; however, our study confirms nurses' physical assessment core skill set is mainly comprised of vital signs. The focus on these endpoints of deterioration as dictated by early warning and rapid response systems may divert attention from and devalue comprehensive nursing assessment that could detect subtle changes in health status earlier in the patient's hospitalisation.


AtATG genes, homologs of yeast autophagy genes, are involved in constitutive autophagy in Arabidopsis root tip cells.
In Arabidopsis root tips cultured in medium containing sufficient nutrients and the membrane-permeable protease inhibitor E-64d, parts of the cytoplasm accumulated in the vacuoles of the cells from the meristematic zone to the elongation zone. Also in barley root tips treated with E-64, parts of the cytoplasm accumulated in autolysosomes and pre-existing central vacuoles. These results suggest that vacuolar and/or lysosomal autophagy occurs constitutively in these regions of cells. 3-Methyladenine, an inhibitor of autophagy, inhibited the accumulation of such inclusions in Arabidopsis root tip cells. Such inclusions were also not observed in root tips prepared from Arabidopsis T-DNA mutants in which AtATG2 or AtATG5, an Arabidopsis homolog of yeast ATG genes essential for autophagy, is disrupted. In contrast, an atatg9 mutant, in which another homolog of ATG is disrupted, accumulated a significant number of vacuolar inclusions in the presence of E-64d. These results suggest that both AtAtg2 and AtAtg5 proteins are essential for autophagy whereas AtAtg9 protein contributes to, but is not essential for, autophagy in Arabidopsis root tip cells. Autophagy that is sensitive to 3-methyladenine and dependent on Atg proteins constitutively occurs in the root tip cells of Arabidopsis.


Histiocytic sarcoma in the tarsus of a cat.
A 12-year-old Persian cat was examined for a firm swelling of the right tarsal region and enlargement of the corresponding right popliteal lymph node. Cytologic evaluation demonstrated a population of malignant cells consistent with large cell lymphoma. Necropsy revealed a multi-lobulated subcutaneous mass involving the tarsus with some extension into adjacent deep muscular tissue. Histologically, the mass was composed of round cells with eosinophilic cytoplasm and pleomorphic anisokaryotic nuclei. Evidence of articular and nodal infiltration by these cells was observed. Differential diagnoses included synovial sarcoma and histiocytic sarcoma. Neoplastic cells were negative for cytokeratin, CD79a, and CD3 and positive for CD18, vimentin, lysozyme, and alpha-1-antitrypsin, most consistent with a diagnosis of histiocytic sarcoma. This is the first report of a histiocytic sarcoma involving a joint of a cat. The final diagnosis was based on the light microscopic appearance in combination with the immunohistochemical stains.


Recurrent mitral regurgitation due to ruptured artificial chordae: case report and review of the literature.
The use of expanded polytetrafluoroethylene (ePTFE) sutures has become an established method to correct mitral regurgitation due to elongated or ruptured mitral chordae. Mitral valve repair using artificial chordae has demonstrated excellent long-term results, particularly as ePTFE retains its flexibility with time and is highly resistant to mechanical stress. On conducting a literature review, four cases were found of recurrent mitral regurgitation due to the late (6-14 years postoperatively) rupture of ePTFE chordae. Herein, the case is described of artificial chordal rupture that required reoperation at 11 years after the initial mitral valve repair. In all previously reported cases, chordal rupture was related to the calcification of ePTFE, whereas in the present case only minimal calcification was observed at histology, and chordal rupture was most likely due to ePTFE fatigue-induced lesion. Although rare, rupture of the artificial chordae may cause recurrent mitral regurgitation; hence, the continuous monitoring of these patients, especially when the follow up extends beyond 10 years, appears mandatory.


Vasoactive peptides in the lung, with special reference to vasoactive intestinal peptide.
Numerous biologically active peptides are present in normal lung. Some of these, like vasoactive intestinal peptide (VIP) and substance P, are neuropeptides that may function as neurotransmitters or neuromodulators. The activities of lung peptides include relaxation or contraction of airway and pulmonary vascular smooth muscle, modification of bronchial water and mucus secretion, and stimulation of adenylate cyclase activity. Much remains to be learned about active peptides in the lung: their full identities, their localization, their physiologic roles, and their participation in disease processes. One of these peptides, VIP, widely distributed in other organ systems, may mediate the nonadrenergic relaxation of airways and pulmonary vessels. It may also regulate bronchial secretion and, through its promotion of cyclic adenosine monophosphate accumulation in the lung, may modulate the immunologic release of mediators from mast cells.


Ascorbic Acid Attenuates Multifidus Muscles Injury and Atrophy After Posterior Lumbar Spine Surgery by Suppressing Inflammation and Oxidative Stress in a Rat Model.
A rat model of multifidus muscles injury and atrophy after posterior lumbar spine surgery. We determined the effect of ascorbic acid (AA) on the postoperative multifidus muscles in rat model. Previous studies show oxidative stress and inflammation are two main molecular mechanisms in multifidus muscle injury and atrophy after posterior lumbar surgery. AA may have a protective effect in postoperative multifidus muscles. Rats were divided into sham surgery, control surgery, and surgery plus AA groups. Multifidus muscles of the control and AA groups were excised from the osseous structures. The muscles were retracted continuously for 2 hours. In the sham and AA groups, AA was administered via oral gavage daily in the first week. In each group, the oxidative stress was evaluated by measuring malondialdehyde (MDA) and Total superoxide dismutase (T-SOD). The inflammation, fat degeneration, or fibrosis of multifidus muscle were evaluated by quantitative real-time polymerase chain reaction (q-PCR), histology, or immunohistochemical analysis. T-SOD activity was significantly lower in the control group than that in the AA group in the first week. MDA levels were significantly higher in the AA group. Interleukin-6 and tumor necrosis factor-α in multifidus muscles also showed significant differences when treated with AA. The inflammation score on histology was significantly lower in the AA group postoperatively in the first week. In the long run, marker genes for fibrosis and fat degeneration, and fibrosis and fat degeneration scores, were significantly lower in the AA than the control group on days 14 and 28 postoperatively. In conclusion, AA attenuated the oxidative stress and inflammation response in the postoperative multifidus muscles, and remarkable differences were observed from the histological assessment and related marker genes expression. Our results provided important insight into the anti-inflammatory and anti-oxidative effects of AA in the postoperative multifidus muscles. N/A.


Dislocation Networks in Folded-Chain Polyethylene Crystals.
Interaction between the fold surfaces of polymer crystals can be strong enough to concentrate any mismatch in orientation into a network of dislocations. Direct observation of these networks by diffraction contrast electron microscopy yields strong evidence in favor of polymer crystallization by a regular chain-folding mechanism.


Successful Treatment of a Pacemaker Infection with Intraperitoneal Daptomycin.
We investigated the pharmacokinetics of intraperitoneal administration of daptomcyin in a peritoneal dialysis (PD) patient treated for a pacemaker infection with Staphylococcus epidermidis. After initial start of intravenous daptomycin at 9 mg/kg body weight every 48 hours, the therapy was switched to intraperitoneal administration of 5.3 mg/kg body weight in 1 L icodextrin 7.5% with a dwell time of 12 hours overnight every 48 hours. Therapeutic drug monitoring (TDM) was performed at 4 hours and 24 hours after dose administration. Due to high peak concentration above target peak concentration, the dose was reduced to a final maintenance dose of 3.2 mg/kg body weight. Data from this single case suggest that serum drug concentration above the minimal inhibitory concentration (MIC) can be easily achieved with intraperitoneal administration of daptomycin every 48 hours even with a lower dose, as recommended for the intravenous administration, but measurement of serum concentration and dose adjustments are mandatory in such cases.


IMMUNOSUPPRESSION AND RECOVERY OF DRUG-IMPAIRED HOST RESISTANCE AGAINST CANDIDA ALBICANS INFECTION BY OXOGLAUCINE.
The immunosuppressive action of aporphinoid alkaloid oxoglaucine was studied in experimental Candida albicans (C. albicans) infection in mice. The alkaloid augmented host resistance to pathogen applied to mice (6-8 weeks of age) at a low dose of 2 mg kg(-1)in 3 days and impaired it at a high dose of 10 mg kg(-1). The suppressive activity observed under the latter schedule correlated with the inhibited proliferative response of splenic cells to mitogens and with decreased popliteal lymph node (PLN) reaction to C. albicans. Treatment of mice with oxoglaucine (at the age of 5 days) at a dose of 5 mg kg(-1)in 3 consecutive days increased the susceptibility to Candida inoculation at the age of 6 weeks. Delayed type hypersensitivity (DTH) response to C. albicans was enhanced after pretreatment of adult mice and was suppressed after administration to newborn mice. Long-time treatment (10 days) with oxoglaucine, cyclophoshamide or prednisolone at a dose of 10 mg kg(-1)increased the rate of mortality of Candida -infected mice. Combined pretreatment of mice with cyclophosphamide or prednisolone (5 days at a dose of 5 mg kg(-1)) followed by oxoglaucine (5 days at a dose of 5 mg kg(-1)), prolonged the survival of infected mice. 2000 Academic Press@p$hr Copyright 2000 Academic Press.


Technologies for diabetes genomics.
The genetic risk for diabetes largely depends on the type of diabetes and the penetrance and severity of the effect of the contributing genes. This ranges from the high-risk mutations of neonatal diabetes and maturityonset diabetes of the young to the lower, but still significant, risk conferred by common human leukocyte antigen alleles in type 1 diabetes to the still-lower risk conferred by the common variants associated with type 2 diabetes. There are many new molecular technologies, each with their own set of methodological issues, that have been used for genome-wide association studies and that can be used for determining the genetic risk for these various types of diabetes. These technologies include whole genome single nucleotide polymorphism microarrays, high-throughput polymorphism analyzers, next-generation sequencers, and copy-number variant technologies.


Merging the fields of mental health and social enterprise: lessons from abroad and cumulative findings from research with homeless youths.
Despite the growing integration of supported employment within the mental health system in the United States as well as the widespread use of social enterprises abroad, the fields of mental health and social enterprises remain largely separate in the USA. The mental health field currently lacks a response that strengthens homeless youths' existing human and social capital, provides them with marketable job skills and employment, and impacts their mental health. To address this gap, this paper establishes a case for using social enterprises with homeless youths, drawing on both global precedents and findings from a mixed-methods study of a social enterprise intervention with homeless youths. Recommendations are offered for how to integrate social enterprises with mental health treatment as well as how to evaluate their impact on mental health outcomes.


[Inhibition of the peroxidase-catalyzed oxidation of chromogenic substrates by alkyl-substituted diphenols].
A comparative kinetic study of the peroxidase oxidation of three chromogenic substrates--2,2'-azino-bis(3-ethyl-2,3-dihydrobenzothiazoline-6-sulfonic acid), o-phenylenediamine (PDA), and 3,3',5,5'-tetramethylbenzidine--inhibited by trimethylhydroquinone and six tert-butylated pyrocatechols (InH) was carried out at 20 degrees C in 0.015 M phosphate-citrate buffer (pH 6.0) containing organic cosolvents (0-10% ethanol or DMF). The inhibitors were quantitatively characterized by the inhibition constants (Ki), the duration of the lag period in the oxidation product formation (delta tau), and the stoichiometric coefficient of inhibition that specifies the number of radicals terminated by one InH molecule (f). The inhibition could be competitive, noncompetitive, mixed, or uncompetitive, which depended on the nature and structure of the chromogenic substrate-diatomic phenol pair. Various substrate-diatomic phenol pairs exhibited Ki values within the range of 11-240 microM and f values from 0.7 to 2.6. The absence of a lag period was characteristic of oxidation of the substituted o-phenylenediamine-substituted pyrocatechol. The total kinetic parameters and properties of the components allowed us to suggest six chromogenic substrate-substituted diatomic phenol pairs for use in test systems for the determination of antioxidant activity in human body fluids, natural biological preparations, and food. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.


Oscillatory activity regulation in an ensemble of autonomous mercury beating heart oscillators.
Collective behavior of an ensemble of directly or indirectly coupled oscillators can be a function of population density. Experiments using autonomous mercury beating heart (MBH) oscillators coupled through their surroundings are employed, to study the existence of quorum-like (population dependent) phenomena. Two coupling mechanisms are used, namely, static and dynamic coupling. For the static coupling scheme, the transitions of a subset of the coupled oscillators occur from active (oscillatory) to inactive (quiescent) state and vice versa. A continuous variation of collective dynamics was observed as the population of the oscillators increased. For the dynamic coupling scheme, the time for which the coupled oscillators are active changes sharply as the population increases beyond a certain threshold.


Investigating Deviance Distraction and the Impact of the Modality of the To-Be-Ignored Stimuli.
It has been suggested that deviance distraction is caused by unexpected sensory events in the to-be-ignored stimuli violating the cognitive system's predictions of incoming stimuli. The majority of research has used methods where the to-be-ignored expected (standards) and the unexpected (deviants) stimuli are presented within the same modality. Less is known about the behavioral impact of deviance distraction when the to-be-ignored stimuli are presented in different modalities (e.g., standard and deviants presented in different modalities). In three experiments using cross-modal oddball tasks with mixed-modality to-be-ignored stimuli, we examined the distractive role of unexpected auditory deviants presented in a continuous stream of expected standard vibrations. The results showed that deviance distraction seems to be dependent upon the to-be-ignored stimuli being presented within the same modality, and that the simplest omission of something expected; in this case, a standard vibration may be enough to capture attention and distract performance.


Epidural blood patch: A narrative review.
The epidural blood patch (EBP) is one of the most effective treatments for intracranial hypotension. Anesthesiologists are familiar with performing EBPs for the treatment of dural puncture-associated intracranial hypotension following spinal anesthesia, complicated epidural analgesia, and diagnostic lumbar puncture. Increasingly, EBPs are used to treat patients with spontaneous intracranial hypotension. However, the treatment of these non-iatrogenic conditions presents new therapeutic challenges. The purpose of this narrative review is to discuss both procedural and diagnostic considerations of EBP for the various presentations of intracranial hypotension and allow the clinician to tailor treatment for the patient, especially in the setting of diagnostic dilemmas. After discussing EBP history and relevant anatomy, we review mechanisms of action and clinical indications for this intervention. The contraindications, complications, and treatment alternatives to the blood patch are examined in detail. Finally, objective methods to evaluate the effectiveness of the EBP, such as MRI or Doppler ultrasound, are presented as novel methods that may improve future diagnostic accuracy and treatment success.


Modeling of Non-Ferrous Metallurgy Waste Disposal with the Production of Iron Silicides and Zinc Distillation.
This paper presents studies on the possibility of utilization of technogenic waste from the metallurgical industry by the method of complex processing in order to reduce the anthropogenic load on the environment of the region with the example of the zinc silicate-magnetite-carbon system. The selected sample of clinker dump from welting was subjected to chemical and scanning electron microscopic analyses and thermodynamic modeling. Thermodynamic studies were carried out in the temperature range 1600-2200 K and pressure p = 0.1 MPa, modeling the process of electric melting of clinker from welting in an arc furnace using the software application Astra 4 developed at the Bauman Moscow State Technical University (Moscow, Russian Federation). As a result of the thermodynamic modeling, the optimal temperature range was established, which was 1800-1900 K. Thermodynamic studies established that it is possible to drive away zinc from the system under study by 99-100% in the entire temperature range under study. The maximum degree of silicon extraction (αSi) in the alloy is up to 69.44% at T = 1900 K, and the degree of iron extraction (αFe) in the alloy is up to 99.996%. In particular, it was determined and proved that clinker waste from welting can act as a secondary technogenic raw material when it is processed as a mono mixture to produce iron silicides with a silicon content of 18 to 28%.


[Lack of association between blood pressure variability and left ventricular hypertrophy in essential hypertension].
Blood pressure (BP) fluctuations may contribute to the development of target organ damage in essential hypertension. However, a possible relationship with left ventricular hypertrophy (LVH) is controversial. The aim of the present study was to analyze the association between BP variability, defined through different instrument measures, and LVH in a group of essential hypertensive patients. Forty-three untreated hypertensive patients were studied. BP variability was evaluated by using both non-invasive, beat-to-beat finger 24-hour monitoring (Portapres) and discontinuous oscillometric ambulatory blood pressure monitoring (ABPM). All patients underwent echocardiography in order to detect the presence or absence of LVH. Thirty out of 43 patients studied (70%) exhibited LVH. Office [167.7 (19.5) versus 156.7 (14.9) mmHg; p = 0.032], 24-hour ambulatory [146.6 (15.7) versus 131.9 (15.1) mmHg; p = 0.003] and 24-hour continuous finger [147.5 (21.3) versus 135.7 (14.2) mmHg; p = 0.046] systolic BP were significantly higher in patients with LVH with respect to those without cardiac hypertrophy. No differences were observed in terms of nocturnal BP fall, ABPM 24-h standard deviation of BP or continuous finger BP variability estimates. Left ventricular hypertrophy is mainly correlated with the severity of systolic BP elevation, but not with BP variability, neither long-term nor short-term.


Gestational Tissue-Derived Human Mesenchymal Stem Cells Use Distinct Combinations of Bioactive Molecules to Suppress the Proliferation of Human Hepatoblastoma and Colorectal Cancer Cells.
Cancer has been considered a serious global health problem and a leading cause of morbidity and mortality worldwide. Despite recent advances in cancer therapy, treatments of advance stage cancers are mostly ineffective resulting in poor survival of patients. Recent evidences suggest that multipotent human mesenchymal stem cells (hMSCs) play important roles in growth and metastasis of several cancers by enhancing their engraftment and inducing tumor neovascularization. However, the effect of hMSCs on cancer cells is still controversial because there are also evidences demonstrating that hMSCs inhibited growth and metastasis of some cancers. In this study, we investigated the effects of bioactive molecules released from bone marrow and gestational tissue-derived hMSCs on the proliferation of various human cancer cells, including C3A, HT29, A549, Saos-2, and U251. We also characterized the hMSC-derived factors that inhibit cancer cell proliferation by protein fractionation and mass spectrometry analysis. We herein make a direct comparison and show that the effects of hMSCs on cancer cell proliferation and migration depend on both hMSC sources and cancer cell types and cancer-derived bioactive molecules did not affect the cancer suppressive capacity of hMSCs. Moreover, hMSCs use distinct combination of bioactive molecules to suppress the proliferation of human hepatoblastoma and colorectal cancer cells. Using protein fractionation and mass spectrometry analysis, we have identified several novel hMSC-derived factors that might be able to suppress cancer cell proliferation. We believe that the procedure developed in this study could be used to discover other therapeutically useful molecules released by various hMSC sources for a future in vivo study.


Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching.
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (hemodynamic) pressure on VSMCs. Thereby, we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze the molecular mechanism in stiffness and pressure sensing and identify a regulation through different but overlapping pathways culminating in the regulation of the actin cytoskeleton through cofilin. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.


Association of Glycated Hemoglobin Level with Self-Reported Chewing Problems in Elderly Community-Dwelling Individuals in Japan.
Chewing problems are associated with increased mortality, geriatric syndromes and poor activities of daily living. Starting in 2018, in Japan, a self-reported questionnaire investigating chewing status was implemented in the annual health checkup program. Considering the bidirectional association between hyperglycemia and poor oral health, it is hypothesized that people with self-reported chewing problems will have relatively poor glycemic profiles. We investigated the metabolic characteristics of elderly community dwellers with self-reported chewing problems, as well as the association between the problems and HbA1c levels. This was a retrospective, cross-sectional study. We reviewed the data of 1018 adults ≥ 65 years of age who had undergone an annual health checkup at Nihon University Hospital during the period from January 2019 through December 2019. The presence of chewing problems was investigated using a self-reported questionnaire constructed based on guidance provided by the Japanese government. In the 1018 participants, the overall prevalence of chewing problems was 10.4%. Participants with chewing problems showed significantly higher levels and worse categories of HbA1c than those without such problems (HbA1c < 6.0%, 42.5% vs 54.8%; HbA1c 6.0-6.9%, 41.5% vs 37.0%; HbA1c ≥ 7.0%, 16.0% vs 8.2%, p = 0.008). Participants with HbA1c ≥ 7.0% have a significantly increased risk of chewing problems as compared to those with HbA1c < 6.0% (odds ratio 2.76, p = 0.002), even after adjusting for the effects of age, sex, body mass index, eating behaviors, and history of diabetes mellitus. HbA1c ≥ 7.0% is associated with self-reported chewing problems in elderly Japanese community-dwellers. We thus recommend a proactive assessment of oral conditions for this population.


Restriction/Modification systems and restriction endonucleases are more effective on lactococcal bacteriophages that have emerged recently in the dairy industry.
Recently, eight lytic small isometric-headed bacteriophages were isolated from cheese-manufacturing plants throughout North America. The eight phages were different, but all propagated on one strain, Lactococcus lactis NCK203. On the basis of DNA homology, they were classified in the P335 species. Digestion of their genomes in vitro with restriction enzymes resulted in an unusually high number of type II endonuclease sites compared with the more common lytic phages of the 936 (small isometric-headed) and c2 (prolate-headed) species. In vivo, the P335 phages were more sensitive to four distinct lactococcal restriction and modification (R/M) systems than phages belonging to the 936 and c2 species. A significant correlation was found between the number of restriction sites for endonucleases (purified from other bacterial genera) and the relative susceptibility of phages to lactococcal R/M systems. Comparisons among these three phage species indicate that the P335 species may have emerged most recently in the dairy industry.


[Treatment of hepatic trauma. Our experience with 14 surgically treated cases].
The authors report their experience of 14 cases of hepatic trauma that underwent surgical treatment. During the period 1987-1990, 42 patients were admitted with diagnosis of hepatic injuries to the surgical department of Ravenna Hospital. 28 of the 42 patients were subjected to repeated abdominal echography and didn't undergo surgical treatment. The authors consider the importance of the abdominal echography whether of the surgical treatment or nonoperative management. Prognosis is always serious, and it is influenced by three factors: the kind of trauma, the concomitant lesions and the general conditions of the patient. The authors, in conclusion, report the per cent of survive and of complications that they have found.


Blocking memory reconsolidation reverses memory-associated changes in glutamate receptor expression.
It has been reported that consolidated memories can return to a labile state when reactivated and undergo a process of re-storage, termed reconsolidation, required for later recall. We investigated memory for a nonassociative learning task (habituation) and found that memory for this task also undergoes reconsolidation after recall. To investigate reconsolidation, we first demonstrated that adult Caenorhabditis elegans are capable of reliable memory 48 h after habituation training (p < 0.05). When heat shock was administered immediately after a reminder, response magnitudes of trained animals matched response levels of untrained animals: the inhibitory effects of heat shock on protein synthesis disrupted memory reconsolidation. Pharmacological blockade of non-NMDA-type glutamate receptors during reminder also eliminated 48 h retention. When expression levels of a specific glutamate receptor subunit (GLR-1) (40% homology to mammalian AMPA-type glutamate receptors) (Hart et al., 1995; Maricq et al., 1995) were measured 48 h after training, there was a significant decrease in trained compared with untrained controls. If trained worms were given a reminder followed immediately by heat shock, the effect of training on GLR-1 levels was reversed. From these studies, we conclude that both the behavioral expression of long-term memory for habituation and a cellular correlate of that memory (the alteration in expression levels of GLR-1) in C. elegans can be altered after retrieval. Furthermore, conditions that impair memory consolidation similarly disrupt memory reconsolidation, suggesting that similar mechanisms are involved.


Stability of frozen 1% voriconazole eye-drops in both glass and innovative containers.
To assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera). Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20 °C in amber glass (n = 32), classical LDPE (n = 32) or innovative LDPE (n = 31) bottles. Stability-indicating (HPLC-UV-DAD) and chiral chromatography methods were developed. The stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D - (2S,3R)-voriconazole) were assessed at the beginning and end of the study. Results are expressed as mean ± standard deviation. Statistical analyses were performed using non-parametric tests (α < 5%) to compare containers. When stored frozen, concentration was between 95.2 ± 1.4% and 103.6 ± 1.3% of the initial concentration (C0) with no difference between the three containers (p = 0.564; non-significant). Fifteen days after thawing, concentration was between 97.1 ± 1.6% and 98.6 ± 0.8% of C0 with no difference between containers (p = 0.278 and 0.368 for VED thawed at room temperature and at 2-8 °C, respectively). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ± 8.93 mOsm/Kg) than in plastic containers (522.17±3.31mOsm/Kg, classical LDPE; 517.5 ± 12.42 mOsm/Kg, innovative LDPE) (p = 0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected. We have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability does not differ from that of amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.


Inherited Moderate Factor X Deficiency Presenting as Cardiac Tamponade.
Factor X deficiency is a rare bleeding disorder that varies in the severity of its clinical manifestations. The symptoms of this disorder can occur at any age, although most severe cases appear in childhood. The rarity of this condition has not allowed for the establishment of evidence-based management guidelines, and thus, individuals afflicted with factor X deficiency are treated based on limited literature and the opinions of clinicians with extensive experience. In this case report, we discuss a unique presentation of a 38-year-old male who was found to have cardiac tamponade as a result of his newly diagnosed inherited moderate factor X deficiency. This was discovered by obtaining a factor X activity assay and confirmed with genetic testing which demonstrated a missense variant on the factor X gene on chromosome 13. His management involved correction of his factor X deficiency with fresh frozen plasma, a pericardiocentesis, and placement of a pericardial window. He has been asymptomatic and without hemorrhagic episodes for the 10 months following his discharge.


Rotating sample magnetometer for cryogenic temperatures and high magnetic fields.
We report on the design and implementation of a rotating sample magnetometer (RSM) operating in the variable temperature insert (VTI) of a cryostat equipped with a high-field magnet. The limited space and the cryogenic temperatures impose the most critical design parameters: the small bore size of the magnet requires a very compact pick-up coil system and the low temperatures demand a very careful design of the bearings. Despite these difficulties the RSM achieves excellent resolution at high magnetic field sweep rates, exceeding that of a typical vibrating sample magnetometer by about a factor of ten. In addition the gas-flow cryostat and the high-field superconducting magnet provide a temperature and magnetic field range unprecedented for this type of magnetometer.


Spin-liquid state in the S=1/2 hyperkagome antiferromagnet Na4Ir3O8.
A spinel related oxide, Na(4)Ir(3)O(8), was found to have a three dimensional network of corner shared Ir(4+) (t(2g)(5)) triangles. This gives rise to an antiferromagnetically coupled S = 1/2 spin system formed on a geometrically frustrated hyperkagome lattice. Magnetization M and magnetic specific heat C(m) data showed the absence of long range magnetic ordering at least down to 2 K. The large C(m) at low temperatures is independent of applied magnetic field up to 12 T, in striking parallel to the behavior seen in triangular and kagome antiferromagnets reported to have a spin-liquid ground state. These results strongly suggest that the ground state of Na(4)Ir(3)O(8) is a three dimensional manifestation of a spin liquid.


Correction: Eliciting an immune hot tumor niche with biomimetic drug-based multi-functional nanohybrids augments immune checkpoint blockade-based breast cancer therapy.
Correction for 'Eliciting an immune hot tumor niche with biomimetic drug-based multi-functional nanohybrids augments immune checkpoint blockade-based breast cancer therapy' by Wei Du et al., Nanoscale, 2020, 12, 3317-3329, https://doi.org/10.1039/C9NR09835F.


Physiological and Molecular Mechanisms of Differential Sensitivity of Palmer Amaranth (Amaranthus palmeri) to Mesotrione at Varying Growth Temperatures.
Herbicide efficacy is known to be influenced by temperature, however, underlying mechanism(s) are poorly understood. A marked alteration in mesotrione [a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor] efficacy on Palmer amaranth (Amaranthus palmeri S. Watson) was observed when grown under low- (LT, 25/15 °C, day/night temperatures) and high (HT, 40/30° C) temperature compared to optimum (OT, 32.5/22.5 °C) temperature. Based on plant height, injury, and mortality, Palmer amaranth was more sensitive to mesotrione at LT and less sensitive at HT compared to OT (ED50 for mortality; 18.5, 52.3, and 63.7 g ai ha-1, respectively). Similar responses were observed for leaf chlorophyll index and photochemical efficiency of PSII (Fv/Fm). Furthermore, mesotrione translocation and metabolism, and HPPD expression data strongly supported such variation. Relatively more mesotrione was translocated to meristematic regions at LT or OT than at HT. Based on T50 values (time required to metabolize 50% of the 14C mesotrione), plants at HT metabolized mesotrione faster than those at LT or OT (T50; 13, 21, and 16.5 h, respectively). The relative HPPD:CPS (carbamoyl phosphate synthetase) or HPPD:β-tubulin expression in mesotrione-treated plants increased over time in all temperature regimes; however, at 48 HAT, the HPPD:β-tubulin expression was exceedingly higher at HT compared to LT or OT (18.4-, 3.1-, and 3.5-fold relative to untreated plants, respectively). These findings together with an integrated understanding of other interacting key environmental factors will have important implications for a predictable approach for effective weed management.


Enabling BioSharing - a report on the Annual Spring Workshop of the HUPO-PSI April 11-13, 2011, EMBL-Heidelberg, Germany.
The Annual Spring workshop of the HUPO-PSI was this year held at the EMBL International Centre for Advanced Training (EICAT) in Heidelberg, Germany. Delegates briefly reviewed the successes of the group to date. These include the wide spread implementation of the molecular interaction data exchange formats, PSI-MI XML2.5 and MITAB, and also of mzML, the standard output format for mass spectrometer output data. These successes have resulted in enhanced accessibility to published data, for example the development of the PSICQUIC common query interface for interaction data and the development of databases such as PRIDE to act as public repositories for proteomics data and increased biosharing, through the development of consortia, for example IMEx and ProteomeXchange which will both share the burden of curating the increasing amounts of data being published and work together to make this more accessible to the bench scientist. Work then started over the three days of the workshop, with a focus on advancing the draft format for handling quantitative mass spectrometry data (mzQuantML) and further developing TraML, a standardized format for the exchange and transmission of transition lists for SRM experiments.


Offered Support and Knowledge about the Menstrual Cycle in the Athletic Community: A Cross-Sectional Study of 1086 Female Athletes.
Many female athletes perceive that symptoms related to the menstrual cycle such as dysmenorrhea, premenstrual symptoms, amenorrhea or side-effects of hormonal contraceptives negatively impact their training, performance, and general well-being. Knowledge and communication about female athletes' health is therefore important in the sport community. The aims of this study were to explore the level of knowledge and communication about menstrual cycle issues and use of hormonal contraceptives in the athletic community and to describe the kinds of medical support offered to female athletes. A total of 1086 Swedish and Norwegian athletes from 57 different sports responded to a web-based questionnaire. Of these, 58% (n = 627) practiced team sports and 42% (n = 459) individual sports. Twenty-six percent (n = 278) of the athletes perceived their knowledge about female athlete health to be poor/very poor and the knowledge was most often acquired from medical staff. Fifty-three percent (n = 572) of the athletes perceived the knowledge acquired of their coaches as poor/very poor, even though a significantly (p < 0.001) higher proportion of athletes with a female coach (30%, n = 31) rated their coach's knowledge as very good/good, compared to athletes with a male coach (5%, n = 31). Only 11% (n = 116) of the athletes discussed female health issues with their coach. The majority (81%, n = 842) of the athletes partly to strongly agreed that female athlete health is considered a taboo topic in the athletic community. Forty-seven percent (n = 510) of the athletes had access to a physiotherapist, while only three percent (n = 29) had access to a gynecologist. Low perceived knowledge, lack of communication and support demonstrate the need for a multi-professional medical team and enhanced educational efforts focused on female athlete health in the athletic community.


Creating the web-based intensive care unit safety reporting system.
In an effort to improve patient safety, researchers at the Johns Hopkins University designed and implemented a comprehensive Web-based Intensive Care Unit Safety Reporting System (ICUSRS). The ICUSRS collects data about adverse events and near misses from all staff in the ICU. This report reflects data on 854 reports from 18 diverse ICUs across the United States. Reporting is voluntary, and data collected is confidential, with patient, provider, and reporter information deidentified. Preliminary data include system factors reported, degree of patient harm, reporting times, and evaluations of the system. Qualitative and quantitative data are reported back to the ICU site study teams and frontline staff through monthly reports, case discussions, and a quarterly newsletter.


Systemic capsaicin treatment impairs the micturition reflex in the rat.
Filling the urinary bladder via a urethral cannula and preventing its voiding in anaesthetized rats led to rhythmic contractions of the detrusor muscle, which lasted for more than 1 h. This rhythmic activity ceased about 30 min after a s.c. injection of 50 mg kg-1 capsaicin. The contractile response of the detrusor to topically applied capsaicin was lost after systemic administration of the toxin, whereas no change in the sensitivity to acetylcholine was observed. Urinary bladders of normal rats had a capacity of about 1 ml. Bladders of rats treated with capsaicin as neonates held a volume of more than 5 ml without contracting. Such bladders were insensitive to topically applied capsaicin but they contracted to acetylcholine as strongly as the bladders of control rats. During an observation period of 3 days control rats gained weight at night and lost weight by day. Rats treated with capsaicin as neonates showed little fluctuation in body weight. Such rats hardly excreted any urine by day although at night they excreted as much as controls. A water load of 5 ml 100 g-1 was excreted by control rats within 3 h. Rats treated with capsaicin as neonates excreted only half as much. In addition, 50% of the water load was excreted far later by capsaicin treated rats than by controls. Few changes were observed in rats treated with capsaicin as adults. It is concluded that all primary afferent fibres mediating the sensation of a full bladder are capsaicin-sensitive. An additional effect of capsaicin on renal mechanisms cannot be excluded.


Direct in situ measurement of cell turgor in grape (Vitis vinifera L.) berries during development and in response to plant water deficits.
Vitis vinifera L. berries are non-climacteric fruits that exhibit a double-sigmoid growth pattern, and at the point known as 'veraison', which is just before the beginning of the second period of rapid fruit growth, these berries undergo several abrupt physiological changes. Cell pressure probe was used to examine the in situ turgor (P) of cells in the mesocarp during berry development and in response to plant water deficits. Initial tests comparing attached and detached berries demonstrated that cell P was stable for up to 48 h after detachment from the vine, provided that water loss from the berry was prevented. Cell P at pre-dawn was on the order of 0.25 MPa pre-veraison (PreV) and was reduced by an order of magnitude to 0.02 MPa post veraison (PostV). Cell P declined slightly but significantly with depth from the berry surface PreV, but not PostV. When water was withheld from potted vines, cell P declined about 0.2 Mpa, as pre-dawn vine water potential declined about 0.6 MPa over 12 d, whereas cell P was completely insensitive to a 1.10 MPa decrease in pre-dawn vine water potential after veraison. Rewatering of stressed plants also resulted in a 24 h recovery of cell P before, but not after veraison. The substantial decline in cell P around veraison is consistent with the decline in berry firmness that is known to occur at this time, and the PostV insensitivity of P to changes in vine water status is consistent with current hypotheses that the PostV berry is hydraulically isolated from the vine. The fact that a measurable P of about 0.02 MPa and typical cell hydraulic/osmotic behaviour were exhibited in PostV berries, however, indicates that cell membranes remain intact after veraison, contrary to many current hypotheses that veraison is associated with a general loss of membrane function and cellular compartmentation in the grape berry. We hypothesize that cell P is low in the PostV berry, and possibly other fleshy fruits, because of the presence of regulated quantities of apoplastic solutes.


Confocal microscopy of corneal nerve plexus as an early marker of eye involvement in patients with type 2 diabetes.
To measure the thickness and length of corneal nerves and the peri-papillary retinal nerve fiber layer (RNFL) thickness in patients recently diagnosed with diabetes mellitus (DM). Twenty-two eyes of 22 patients recently diagnosed with type 2 DM and 22 eyes of 22 healthy individuals were consecutively enrolled. Central corneal sensitivity was measured using a Cochet-Bonnet esthesiometer, and corneal nerve length (CNL) and thickness (CNT) were evaluated through in vivo confocal microscopy. The confocal images were examined using software that could semi-automatically trace the corneal nerve pathway. Spectral domain optical coherence tomography (SD-OCT) was performed to quantify the overall and sectorial RNFL thickness. Mean DM duration was 3.5 ± 1.7 months, whereas the mean glycemia and HbA1c levels were 180.5 ± 73.13 mg/dl and 8.6 ± 1.7% (65.2 ± 19.7 mmol/mol), respectively. Corneal sensation threshold was significantly lower in the DM group compared to control group (p = 0.003). CNL and CNT were reduced in the DM group (p = 0.043 and p = 0.004, respectively). Significant correlations were found between CNT and HbA1c levels (p = 0.04; r = -0.47), and between CNT and the corneal sensation threshold (p = 0.04; r = 0.69). RNFL thickness was significantly reduced in the temporal quadrants, but no correlation was found with CNT and CNL changes (p > 0.05). CNL and CNT changes are evident even in the early stages of DM, and RNFL reduction was recorded in the temporal quadrants. These findings indicate that, in the eye with diabetes, neuropathy may represent an early marker of the disease.


Distinction of thioredoxin transnitrosylation and denitrosylation target proteins by the ICAT quantitative approach.
S-Nitrosylation is a reversible PTM for regulating protein function. Thioredoxin-1 (Trx1) catalyzes either transnitrosylation or denitrosylation of specific proteins, depending on the redox status of the cysteines within its conserved oxidoreductase CXXC motif. With a disulfide bond formed between the two catalytic cysteines, Trx1 is not only inactive as a denitrosylase, but it may also be nitrosylated at Cys73 and serve as a transnitrosylating agent. Identification of Trx1-mediated transnitrosylation or denitrosylation targets will contribute to a better understanding of Trx1's function. Previous experimental approaches based on the attenuation of CXXC oxidoreductase activity cannot readily distinguish Trx1 transnitrosylation targets from denitrosylation targets. In this study, we used the ICAT method in conjunction with the biotin switch technique to differentiate Trx1 transnitrosylation targets from denitrosylation target proteins from neuroblastoma cells. We demonstrate that the ICAT approach is effective for quantitative identification of putative Trx1 transnitrosylation and denitrosylation target peptides. From these analyses, we confirmed reports that peroxiredoxin 1 is a Trx1 transnitrosylation, but not a denitrosylation target, and we found several other proteins, including cyclophilin A to be modulated in this manner. Unexpectedly, we found that many nitrosylation sites are reversibly regulated by Trx1, suggesting a more prominent role for Trx1 in regulating S-nitrosylation.


Propensity to work among chronically unemployed adult drug users.
Analyses were conducted to compare rates of employment before, during, and after employment at the therapeutic workplace, which is a novel employment-based treatment for drug misuse. Participants in two clinical trials attended the therapeutic workplace at higher rates than they worked before intake and six months after discharge. These data suggest that unemployed chronic drug misusers will attend work at higher rates at the therapeutic workplace than in the community when paid modest wages, and that the failure of chronic drug misusers to obtain employment in the community may not result from lack of interest in work.


Is resting-state functional connectivity revealed by functional near-infrared spectroscopy test-retest reliable?
Recently, resting-state functional near-infrared spectroscopy (rs-fNIRS) research has experienced tremendous progress. Resting-state functional connectivity (RSFC) has been adopted as a pivotal biomarker in rs-fNIRS studies. However, it is yet to be clear if the RSFC derived from rs-fNIRS is reliable. This concern impedes extensive utilization of rs-fNIRS. We systematically address the issue of reliability. Sixteen subjects participate in two rs-fNIRS sessions held one week apart. RSFC in sensorimotor system is calculated using the seed-correlation approach. Then, test-retest reliability is evaluated at three different scales (map-, cluster-, and channelwise) for individual- and group-level RSFC derived from different types of fNIRS signals [oxygenated (HbO), deoxygenated (HbR), and total hemoglobin (HbT)]. The results show that, for HbO signals, individual-level RSFC generally has good-to-excellent map-/clusterwise reliability, while group-level RSFC has excellent reliability. For HbT signals, the results are similar. For HbR signals, the clusterwise reliability is comparable to that for HbO while the mapwise reliability is slightly lower (fair to good). Focusing on RSFC at a single channel, we report poor channelwise reliability for all three types of signals. We hereby propose that fNIRS-derived RSFC is a reliable biomarker if interpreted in map- and clusterwise manners. However, channelwise interpretation of individual RSFC should proceed with caution.


Toward Nurses' Transformative Agency in Transitional Care for Older Adults: A Change-Laboratory Intervention.
Mobilization of nurses' agency across healthcare sectors is needed to counter challenges associated with older adults' transitions between hospital and primary care. Based on Cultural Historical Activity theory and the Change Laboratory method, we developed a learning intervention with 16 nurses. The aim was to foster the nurses' transformative agency to improve care. Video-recording of nine learning sessions were transcribed and analyzed. Results demonstrated that shared transformative agency exhibited as an emergent phenomenon crossing sectoral boundaries as a prerequisite for change in transitional care. The nurses progressed from acting as individuals criticizing the current conditions to collectively forming a vision around a transitional care model. This was nurtured through the nurses' negotiations which included a recognition of sharing similar challenges deriving from the healthcare organization and related financial restrictions, and conflicting healthcare and nursing ideals across healthcare sectors. The evolution of transformative agency was grounded in a professional nursing identity.


Transgenic maize plants expressing a fungal phytase gene.
Maize seeds are the major ingredient of commercial pig and poultry feed. Phosphorus in maize seeds exists predominantly in the form of phytate. Phytate phosphorus is not available to monogastric animals and phosphate supplementation is required for optimal animal growth. Undigested phytate in animal manure is considered a major source of phosphorus pollution to the environment from agricultural production. Microbial phytase produced by fermentation as a feed additive is widely used to manage the nutritional and environmental problems caused by phytate, but the approach is associated with production costs for the enzyme and requirement of special cares in feed processing and diet formulation. An alternative approach would be to produce plant seeds that contain high phytase activities. We have over-expressed Aspergillus niger phyA2 gene in maize seeds using a construct driven by the maize embryo-specific globulin-1 promoter. Low-copy-number transgenic lines with simple integration patterns were identified. Western-blot analysis showed that the maize-expressed phytase protein was smaller than that expressed in yeast, apparently due to different glycosylation. Phytase activity in transgenic maize seeds reached approximately 2,200 units per kg seed, about a 50-fold increase compared to non-transgenic maize seeds. The phytase expression was stable across four generations. The transgenic seeds germinated normally. Our results show that the phytase expression lines can be used for development of new maize hybrids to improve phosphorus availability and reduce the impact of animal production on the environment.


The tumor suppressors p33ING1 and p33ING2 interact with alien in vivo and enhance alien-mediated gene silencing.
The tumor suppressor p33ING1 is involved in DNA repair and cell cycle regulation. Furthermore, p33ING1 is a transcriptional silencer that recognizes the histone mark for trimethylated lysine 4 at histone H3. Interestingly, expression of p33ING1 and p33ING2 is able to induce premature senescence in primary human fibroblasts. The corepressor Alien is involved in gene silencing mediated by selected members of nuclear hormone receptors. In addition, Alien acts as a corepressor for E2F1, a member of the E2F cell cycle regulatory family. Furthermore, recent findings suggest that Alien is complexed with transcription factors participating in DNA repair and chromatin. Here, using a proteomic approach by surface-enhanced laser desorption ionization and mass spectrometry (SELDI-MS) combined with immunological techniques, we show that Alien interacts in vivo with the tumor suppressor p33ING1 as well as with the related tumor suppressor candidate p33ING2. The interaction of Alien with p33ING1 and p33ING2 was confirmed in vitro with GST-pull-down, suggesting a direct binding of Alien to these factors. The binding domain was mapped to a central region of Alien. Functionally, the expression of p33ING1 or p33ING2 enhances the Alien-mediated silencing, suggesting that the interaction plays a role in transcriptional regulation. Thus, the findings suggest that the identified interaction between Alien and the tumor suppressors p33ING1 and p33ING2 reveals a novel cellular protein network.


Axial Neck-Shoulder Pain After Posterior Correction and Fusion for Adolescent Idiopathic Scoliosis With Structural Thoracic Curve: Does Cranial Fusion Level Affect Neck Symptoms?
A retrospective cohort study using prospectively collected data. To investigate the incidence and impact of fusion to the upper thoracic spine on neck-shoulder symptoms after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Axial neck-shoulder pain is established as a sequela of posterior cervical spine surgery and is mainly caused by the dissection of extensor muscles in the cervical and upper thoracic spine. Sixty-three female patients with AIS who underwent PSF using segmental pedicle screw constructs for structural main thoracic curve with a minimum 2-year follow-up were included. Axial neck-shoulder pain was assessed using the visual analog scale and cervical spine function domain score of the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire. The patients were divided into 2 groups, a higher group (underwent fusion up to T3 or above, n=27) and a lower group (underwent fusion up to T4 or below, n=36), and radiologic and clinical outcomes were compared. The incidence of axial neck-shoulder pain (visual analog scale ≥30) preoperatively and at the 2-year follow-up was 29 and 40%, respectively. The pain and mental health domains of the Scoliosis Research Society-22 and cervical spine function domain of the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire were correlated with the severity of axial neck pain. In the comparison of clinical outcomes between the 2 groups, the pain domain score of the Scoliosis Research Society-22 in the lower group was significantly better than that in the higher group at the 2-year follow-up ( P <0.05). Other parameters showed no significant differences preoperatively or at the 2-year follow-up. Female patients with AIS had a relatively high incidence of axial neck-shoulder pain after PSF, which affected their health-related quality of life. Both groups showed similar clinical outcomes, and the cranial fusion level did not affect axial neck-shoulder pain and cervical spine function. Level 3.


Accuracy of high-resolution ultrasound in the detection of meniscal tears and determination of the visible area of menisci.
Imaging is of great importance in diagnosing meniscal tears. The aim of this study was to assess the accuracy of high-resolution ultrasound in the diagnosis of meniscal tears, with arthroscopic examination as the standard reference, after resolution was confirmed with a target-mounted reference phantom. An additional goal was to elucidate the area of the meniscus that could be visualized with the same ultrasound machine after placement of markers into the menisci of cadaveric knees. Seventy patients were included for the assessment of the accuracy of a high-resolution ultrasound machine with a 14.0 to 6.0-MHz linear transducer. The preoperative ultrasound diagnosis, in terms of the presence and type of tear, was compared with that in the surgical reports. In the cadaveric studies, nine needles were placed in the peripheral zone of the menisci at regular intervals and the number of needles that could be observed with the system was recorded. The overall sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound examination for meniscal tears were 88%, 85%, 85%, and 88%, respectively. These statistical parameters did not differ significantly between the medial and lateral menisci. The sensitivity for diagnosing horizontal, vertical, radial, flap, bucket-handle, and complex tears and for detecting discoid lateral menisci was 83%, 64%, 0%, 64%, 54%, 90%, and 80%, respectively. Ten percent of the lateral menisci could not be evaluated because of poor images. The cadaveric studies revealed that the ultrasound visualized the entire meniscus except for the anterior horn. The findings of this study suggest that ultrasound examination may be suitable for screening for meniscal tears. The fact that almost 10% of the lateral menisci could not be evaluated because of poor images appears to be a weakness of ultrasound.


Effects of lifestyle modification and lipid intake variations on patients with peripheral vascular disease.
The aim of the present study was to evaluate the effects of diets enriched in monounsaturated fatty acids (MUFA) (olive oil) or MUFA plus n-3 polyunsaturated fatty acids (PUFA) (olive oil plus fish oil), associated with an intervention program that focused on lifestyle habits, physical performance, plasma lipids, and lipoprotein composition in patients with peripheral vascular disease (PVD). A 15-month longitudinal nutritional and lifestyle intervention study was carried out with 24 free-living male patients aged 58.0 +/- 2.2 years diagnosed with PVD (Fontaine grade II). The patients were clinically evaluated and counseled to change their dietary and lifestyle habits for six months, after this period they consumed an olive oil-based diet for three months: after a three-month wash-out period, their diet was supplemented with a combination of fish oil and olive oil for the final three months. Lifestyle interventions resulted in a significant decrease in cigarette smoking and an increase in physical activity. Claudicometry was lower at the end of the study than at the beginning. Intake of the fish oil supplement led to significant changes in lipid lipoprotein composition, decreasing low-density lipoprotein (LDL) cholesterol. The lifestyle intervention program, together with a high intake of olive plus fish oil, seems to produce important beneficial effects in nutritional management, physical performance, and clinical parameters of PVD patients.


Increased excision of O6-methylguanine from rat liver DNA after chronic administration of dimethylnitrosamine.
Male BDIV rats were given dimethylnitrosamine (2 mg/kg daily) by stomach tube on weekdays for a total of 9 weeks, the final dose being of 14C-labeled material. Control rats received only the labeled dimethylnitrosamine. Liver DNA was isolated at various times later (from 2 to 12 hr), and normal and alkylated purines were determined after hydrolysis in mild acid by chromatography on Sephadex G-10. The levels (measured as dpm/micronmol of parent base) of 7-methylguanine in the DNA of the pretreated rats were the same as or slightly higher than those of the control animals, and the persistence of this product was similar in both groups. This was also true for 3-methyladenine. In contrast, the initial amount of O6-methylguanine in the liver DNA of the pretreated rats was one-third of the amount found in the control rats, and the rate of loss of this product from DNA was higher in the pretreated animals. These differences were reflected in the alkylation product ratios: the 3-methyladenine:7-methylguanine ratios were closely similar in the two groups of animals at all times, whereas the O6-methylguanine:7-methylguanine ratio was initially 3 times higher in the control animals and fell more slowly. DNA synthesis (as measured by the incorporation of [3H]thymidine) was higher in the liver, kidney, and lung of rats receiving dimethylnitrosamine pretreatment. These findings are discussed with respect to the hepatocarcinogenicity of chronically administered dimethylnitrosamine.


mRNA structure determines specificity of a polyQ-driven phase separation.
RNA promotes liquid-liquid phase separation (LLPS) to build membraneless compartments in cells. How distinct molecular compositions are established and maintained in these liquid compartments is unknown. Here, we report that secondary structure allows messenger RNAs (mRNAs) to self-associate and determines whether an mRNA is recruited to or excluded from liquid compartments. The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence. These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity. Thus, the shape of RNA can promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell.


Additional transduction events after subretinal readministration of recombinant adeno-associated virus.
Subretinal delivery of recombinant adeno-associated virus (rAAV) results in a systemic humoral response in the adult immunocompetent mouse. We characterized this response and determined whether it is possible to readminister rAAV to the subretinal space despite the presence of antibodies to the vector. A systemic humoral response to rAAV capsid proteins was induced by either unilateral subretinal injection or by intradermal administration of 1 x 10(9) infectious units of rAAV carrying the cDNA encoding green fluorescent protein (GFP), rAAV-GFP. Experiments were performed in cohorts of adult C57BL/6 mice. Assessment of systemic humoral response to viral capsid protein was performed through enzyme-linked immunoabsorbent assay (ELISA) and infection inhibition studies of serum samples 3 weeks after virus delivery. The rAAV-GFP virus was readministered by subretinal injection. GFP expression after subretinal administration was evaluated ophthalmoscopically throughout the course of the experiment and histologically at the termination of the experiment. We observed significant systemic humoral responses to viral capsid protein after subretinal delivery of rAAV. Intradermal injection resulted in a larger humoral response (with a higher percentage of neutralizing antibodies) than subretinal injection. Additional transduction events were observed after readministration of rAAV despite the presence of strong humoral response to the vector.


Combined exposure to alcohol and cannabis during development: Mechanisms and outcomes.
Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions.


[Endovascular treatment of diseases of the descending thoracic aorta].
Endovascular repair as treatment of aortic diseases seems promising. We report the first Danish results of endografting of the descending thoracic aorta. Nineteen patients (median age 68 years, range 22-78 years) underwent endovascular treatment of diseases in the descending thoracic aorta: atherosclerotic aneurysm (n = 7), ruptured aneurysm (n = 3), Type B dissection (n = 3), traumatic rupture (n = 3), pseudoaneurysm (n = 2) and a defective aortic prosthesis (n = 1). The patients were followed with chest CT scans and clinically. In all cases the endograft was successfully deployed in the intended positions. Median total hospital stay was 5 days, range 2-21 days. Eight patients had post-implantation syndrome. No deaths occurred within the first post-operative month. During the follow-up period (median 12 months, range 1-56 months) five deaths were observed. One of the patients died from aortobronchial fistula related to the endograft. One patient had an endoleak, and two had expanded aneurysm. None of these patients was treated. In selected patients, endoluminal grafting of the descending thoracic aortic is a safe and successful alternative to open graft repair in treating aneurysm, ruptured aneurysm, traumatic rupture and dissection. However, long-term evaluation is still required.


Bone-immune cell crosstalk: bone diseases.
Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.


Targeting cognitive deficits in schizophrenia: a review of the development of a new class of medicines from the perspective of community mental health researchers.
Schizophrenia is a chronic disorder associated with positive and negative symptoms and wide-ranging deficits in neurocognitive function. Neurocognitive deficits are considered to be the core pathophysiological symptoms of the illness. Neurocognitive deficits are also closely associated with functional outcome. At present, cognitive deficits remain one of the most important unmet therapeutic needs in schizophrenia. Neuroscientific discoveries over the past decades have enriched our understanding of the neurobiological mechanism underlying cognitive deficits in schizophrenia. This research has identified new molecular mechanisms and processes as promising pharmacological targets. However, in spite of extensive efforts to develop a new class of cognitive-enhancing medicines for the treatment of schizophrenia over the past 5 years, no novel pharmacological agents have received the regulatory approvals required by the Food and Drug Administration. The efficacy and safety outcomes from selective Phase II clinical trials are reviewed. The evolving concept of neurocognition and the current guidelines for the design and methodology of clinical trials of cognitive-enhancing drugs for the treatment of individuals with schizophrenia are critically examined. The future directions in the development of cognitive-enhancing medicines for the treatment of schizophrenia from the perspective of clinicians and researchers from community mental health settings are discussed.


Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: enzyme dose and interval.
Degenerative joint changes have been reported in human mucopolysaccharidosis VI (MPS VI) and are a prominent feature of feline MPS VI. Joint disease has proven refractory to intravenous enzyme replacement therapy (ERT) in the MPS VI cat because enzyme is unable to reach cells in cartilage. In this study, enzyme was infused directly into the intraarticular space to determine whether joint tissues are able to respond to replacement enzyme. Clearance of glycosaminoglycans from chondrocytes was observed at a dose of 10 microg recombinant human N-acetylgalactosamine-4-sulfatase (rh4S), but greater clearance was observed with higher doses. The chondrocytes at the articular surface were cleared preferentially. Lysosomal vacuolation in cruciate ligament and synovial cells also decreased upon addition of rh4S. One month after injection of rh4S, a slight reaccumulation of storage was observed at the surface of the joint, but extensive reaccumulation was observed 2 mo after injection. These results indicate that by bypassing the synovium using intraarticular ERT, significant reduction in storage material in joint tissues can be achieved. Localized ERT in the joint space provides a mechanism for delivering enzyme directly to the articular cartilage and a potential therapy for joint pathology in MPS VI.