The N-terminal dimerization is required for TDP-43 splicing activity.
TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.


Modulation of extracellular matrix gene expression in bovine high-density chondrocyte cultures by ascorbic acid and enzymatic resuspension.
To define the influence of time in culture on gene expression for extracellular matrix proteins we have examined the progression of changes in gene expression for chondrocyte extracellular matrix proteins from the time the chondrocytes are initially isolated from their native cartilaginous matrix through 13 days of high-density culture. We have also determined the effect of matrix depletion and shape change by enzymatically resuspending cells after 6 days in culture and sampling the replated cells at intervals up to 13 days. Northern blots of chondrocyte RNA were hybridized with probes for collagen alpha 1(II), alpha 1(I), aggrecan, link protein, and decorin mRNA. The steady-state level of alpha 1(II) collagen mRNA dropped to 45% of the initial value within 24 h, with a further decrease to 21% by Day 3. A similar decline occurred, but less rapidly in ascorbate supplemented cultures with values of 78%, at 24 h and 62% at Day 3. Very low levels of alpha 1(I) collagen mRNA were detectible in cells maintained for 2 weeks without ascorbate supplementation. Type I collagen alpha 1(I) mRNA was not detected in freshly isolated chondrocytes or at the earliest times in culture but was increasingly abundant from Days 5-13 in the presence of ascorbate. Ascorbic acid supplementation altered the pattern of aggrecan expression over time. Without ascorbate there was an increase in steady-state aggrecan mRNA with time in culture, but in the presence of ascorbate, aggrecan mRNA levels peaked at early culture times and progressively diminished. Decorin steady-state mRNA levels in cultures not supplemented with ascorbic acid steadily increased over time in culture following a lag of several days. In cultures treated with ascorbate, however, there was a progressive increase in decorin steady-state mRNA levels from the first day in culture. Resuspending chondrocytes by digestion of the cell layer with pronase and collagenase at Day 6, which resulted in a transient shape change as well as matrix depletion, resulted in a greater than 2-fold increase in alpha 1(II) mRNA at Day 7 in ascorbate supplemented cultures. Only with ascorbate was there a small increase in decorin mRNA at Day 7, after resuspension. Aggrecan mRNA, however, showed a 3-fold increase without ascorbate and a 10-fold increase with ascorbate within 24 h of resuspension. Similarly, link protein steady-state mRNA showed an 8-fold increase without ascorbate and a 9-fold increase with ascorbate within 24 h after resuspension.


[Non-ischemic priapism (post-traumatic arteriovenous fistula of the right cavernous body) in the background of Landusy-Dejerine myopathy].
Landouzy-Dejerine myopathy (Facial-shoulder-shoulder myodystrophy) is a disease which causes weakness of the muscles of the shoulder girdle, back and hip muscles, which predisposes patients to an increased risk of injury and disability. The article presents a clinical observation of non-ischemic priapism, which developed as a result of perineal trauma with the formation of a fistula of the right cavernous body in a patient against the background of facial shoulder-shoulder myodystrophy. Methods for the differential diagnosis of this condition are also discussed.


Factors associated with parents' and adolescents' perceptions of oral health and need for dental treatment.
The aim of this study was to characterize the association between clinical and psychosocial factors as they related to perceptions by parents and adolescents to the adolescent's oral health status and treatment need. Additionally, the degree to which adolescent's and parent's perceptions of oral health and treatment need were related was examined. Data from the Pennsylvania oral health needs assessment for 530 parent-adolescent pairs were used to address the objectives of this study. Comparisons between clinical oral health measures, psychosocial factors, and the parent- and adolescent-reported perceptions of the adolescent's oral health status were made using descriptive and inferential statistics, including exploratory factor analysis and path analysis. Parents and adolescents exhibited only modest concordance on ratings of the adolescent's oral health status and need for dental treatment. Furthermore, parents tended to rate their adolescent's oral health status as better than did the adolescent. The results of the path analysis showed that adolescents based their ratings of oral health status more on oral symptoms, while parents rated their adolescent's oral health more on esthetic or psychosocial factors. Adolescents and parents based their perceptions of oral health status and treatment need on different underlying factors. Additionally, adolescents' perceptions of their oral health status and treatment needs did not appear to be communicated to their parents.


Tobacco use related attitudes and behaviors in Indian Adolescents: association with school-based prevention education.
Background: Adolescent tobacco use in India has increased substantially within the past few decades. Schools can serve as an important avenue for prevention education, but little is known about the current practices of Indian schools in relation to tobacco use prevention education. Methods: To assess the extent and influence tobacco use prevention education in Indian schools,we analyzed the Global Youth Tobacco Survey data for India, which was a population-based study of a national random sample of 10112 students from 180 private and public schools.Variables such as student demographic profile, tobacco use behavior, perceptions about tobacco use, and exposure to school-based tobacco use prevention education were considered for analyses. Results: Prevalence of any form of tobacco use (14%) and current smoking (8%) was found to differ by gender. A quarter of the students believed that boys who smoke are more attractive or have more friends compared to non-smokers, and almost half of the students reported that smoking and health were never discussed as a part of a lesson in school. The association between school-based prevention education and tobacco use behavior was assessed (after adjustment forage, gender, and parental smoking). Students who were educated in school about tobacco use and its effects were significantly more likely to have negative attitude toward tobacco use and less likely to report use of tobacco. Conclusion: School-based tobacco use prevention education has beneficial influence on adolescents in India. Given the early age of initiation of tobacco use, school curricula in India should emphasize on tobacco use prevention education.


Development of Host-Orthogonal Genetic Systems for Synthetic Biology.
The construction of a host-orthogonal genetic system can not only minimize the impact of host-specific nuances on fine-tuning of gene expression, but also expand cellular functions such as in vivo continuous evolution of genes based on an error-prone DNA polymerase. It represents an emerging powerful approach for making biology easier to engineer. In this review, the recent advances are described on the design of genetic systems that can be stably inherited in the host cells and are responsible for important biological processes including DNA replication, RNA transcription, protein translation, and gene regulation. Their applications in synthetic biology are summarized and the future challenges and opportunities are discussed in developing such systems.


Ileal Peyer's patches in experimental infections of calves with rotaviruses and enterotoxigenic Escherichia coli: a light and electron microscopic and enzyme histochemical study.
The effect of rotaviruses and enterotoxigenic Escherichia coli administered in various sequences to cesarean-derived, colostrum-deprived calves was studied using light and electron microscopy. The structure of the lymphoid tissue in the ileum, the number of mitoses in the crypts, number of intraepithelial lymphocytes, and enzyme histochemistry (alkaline phosphatase, acid phosphatase, succinic dehydrogenase, beta-galactosidase, and leucinaminopeptidase) of the ileal dome epithelium were evaluated. The area of lymphoid follicles in Peyer's patches of the ileum was investigated morphometrically. Monoinfections with either rotavirus or enterotoxigenic E. coli induced a significant increase in lymphoid follicle area, but did not affect dome epithelial cells. Dual infections did not consistently affect the follicle area, but the number of intraepithelial lymphocytes and the mitotic indices exceeded those of comparable monoinfections. Changes in activity of enzymes in the ileal dome epithelial area were minor.


Hyaluronan binding motifs of USP17 and SDS3 exhibit anti-tumor activity.
We previously reported that the USP17 deubiquitinating enzyme having hyaluronan binding motifs (HABMs) interacts with human SDS3 (suppressor of defective silencing 3) and specifically deubiquitinates Lys-63 branched polyubiquitination of SDS3 resulting in negative regulation of histone deacetylase (HDAC) activity in cancer cells. Furthermore, USP17 and SDS3 mutually interact with each other to block cell proliferation in HeLa cells but the mechanism for this inhibition in cell proliferation is not known. We wished to investigate whether the HABMs of USP17 were responsible for tumor suppression activity. Similarly to USP17, we have identified that SDS3 also has three consecutive HABMs and shows direct binding with hyaluronan (HA) using cetylpyridinium chloride (CPC) assay. Additionally, HA oligosaccharides (6-18 sugar units) competitively block binding of endogenous HA polymer to HA binding proteins. Thus, administration of HA oligosaccharides antagonizes the interaction between HA and USP17 or SDS3. Interestingly, HABMs deleted USP17 showed lesser interaction with SDS3 but retain its deubiquitinating activity towards SDS3. The deletion of HABMs of USP17 could not alter its functional regulation on SDS3-associated HDAC activity. Furthermore, to explore whether HABMs in USP17 and SDS3 are responsible for the inhibition of cell proliferation, we investigated the effect of USP17 and SDS3-lacking HABMs on cell proliferation by soft agar, apoptosis, cell migration and cell proliferation assays. Our results have demonstrated that these HABMs in USP17 and its substrate SDS3 are mainly involved in the inhibition of anchorage-independent tumor growth.


Accuracy of self-reported height and weight in women: an integrative review of the literature.
Height and weight are two of the most commonly used anthropometric measurements in clinical practice and research. Self-reported height and weight measurement is a simple, efficient, inexpensive, and non-invasive method of collecting data from large numbers of people. This integrative review of the published research examined the accuracy of self-reported height and weight measurements in women. Twenty-six studies examined the accuracy of self-reported height in 39,244 women. Twenty-one of the studies found that women overestimate height. Thirty-four studies reviewed the accuracy of self-reported weight in 57,172 women, and all 34 studies reported that women underestimated weight. Although mean variations between self-reported and measured values were small, a significant percentage of women in study groups had very large errors. Inaccurate measurements of both height and weight can cause significant inaccuracies in calculation of body mass index, which is used as a guide for identifying persons at risk for disease. These findings indicate that direct measurement of height and weight should be performed whenever possible for optimal measurements in clinical practice and clinically oriented research.


Eliminating disparities in pain management.
Not all patients are treated equally for their pain with some therefore being undertreated. Discrepancies still exist in the way physicians treat special populations of patients such as racial minorities, women, and substance abusers. All healthcare providers need to be aware of the not so readily apparent disparities resulting from stereotyping, bias, ageism, and socioeconomic considerations. Physicians can best provide appropriate and equal care by following pain management guidelines; however, they may receive contradictory information and be apprehensive about prescribing opioids, especially to substance abusers. In this "refreshed" article, the authors describe patient encounters with patients of color and offer some goals for removing inequality and inequity from clinical settings.


[Clinical evaluation of gallium-67 scintigraphy in comparison with autopsy findings in the elderly, with particular reference to histological findings and classification of pulmonary cancer].
A correlative study of autopsy findings and retrospective review of gallium scintigrams were performed in 106 elderly patients. Of the cases studied, 57% demonstrated positive gallium study in the present series. Histological correlation was undertaken in cases of lung cancer. Among them, squamous cell carcinoma showed the highest incidence of positive results (83%), whereas adenocarcinoma was the lowest (35%). There is no apparent correlation between subtypes of histological classification of adenocarcinoma and abnormal accumulation of gallium. However, abnormal accumulation of the nuclide seems to be rather related with interstitial reactions, namely fibrotic changes, lymphocyte infiltration and vascularization.


Genome sequencing on both strands: the Janus strategy.
The design of large scale DNA sequencing projects such as genome analysis demands a new approach to sequencing strategy, since neither a purely random nor a purely directed method is satisfactory. We have developed a strategy that combines these two methods in a way that preserves the advantages of both while avoiding their particular limitations. Computer simulations showed that a specific balance of random and directed sequencing was required for the most efficient strategy, termed the Janus strategy, which has been used in the Escherichia coli genome sequencing project. This approach depended on obtaining sequence easily from either strand of a cloned insert, and was facilitated by inversion of the insert in the engineered M13 vector Janus, by site-specific recombination. The inversion was accomplished simply by growth on the appropriate host strain, when the DNA strand incorporated into the new single stranded phage was complementary to that in the original phage, and was sequenced by the same simple protocol as the first strand.


Neural plasticity following lesions of the primate occipital lobe: The marmoset as an animal model for studies of blindsight.
For nearly a century it has been observed that some residual visually guided behavior can persist after damage to the primary visual cortex (V1) in primates. The age at which damage to V1 occurs leads to different outcomes, with V1 lesions in infancy allowing better preservation of visual faculties in comparison with those incurred in adulthood. While adult V1 lesions may still allow retention of some limited visual abilities, these are subconscious-a characteristic that has led to this form of residual vision being referred to as blindsight. The neural basis of blindsight has been of great interest to the neuroscience community, with particular focus on understanding the contributions of the different subcortical pathways and cortical areas that may underlie this phenomenon. More recently, research has started to address which forms of neural plasticity occur following V1 lesions at different ages, including work using marmoset monkeys. The relatively rapid postnatal development of this species, allied to the lissencephalic brains and well-characterized visual cortex provide significant technical advantages, which allow controlled experiments exploring visual function in the absence of V1. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 314-327, 2017.


[Pollution Level, Distribution Characteristic, and Ecological Risk Assessment of Environmentally Persistent Pharmaceutical Pollutants in Surface Water of Jiangsu Province].
Because Jiangsu is an important economic province of China, it is necessary to examine the pollution characteristics and assess the ecological risk of environmentally persistent pharmaceutical pollutants (EPPPs) in this region. In this study, surface water samples were obtained from grade 1-4 rivers and lakes (with an area of 50 km2 or more) in Jiangsu Province, and then analyzed to determine the pollution level of EPPPs. In total, 35 EPPPs were detected in the surface water of Jiangsu Province, with total concentrations in the samples ranging from 66.74 to 2189.83 ng·L-1. The 17 EPPPs with a detection rate of more than 25% are discussed in this study. The total concentrations of 35 EPPPs were 72.48-1142.79 ng·L-1, and the mean concentration was 345.20 ng·L-1. The total concentration of EPPPs was higher in the north and south than in the central part of Jiangsu. Yangzhou city had the highest concentration of EPPPs in the whole province, and the main sources of this pollution were domestic sewage, shipping sewage discharge, and drug use in fishery breeding. The total concentration of EPPPs decreased on both sides of the region, with the Beijing-Hangzhou Canal and waste from the Yellow River forming the middle line. An ecological risk assessment of 17 EPPPs showed that single target drugs posed a low risk to water ecology in Jiangsu Province. The combined risk quotient of 17 EPPPs in water of Jiangsu Province was 0.03-0.52, indicating that EPPPs posed a low to moderate risk.


Physical compatibility of various drugs with neonatal total parenteral nutrient solution during simulated Y-site administration.
The physical compatibility of various drugs with neonatal total parenteral nutrient (TPN) solution during simulated Y-site administration was evaluated. Study drugs were selected based on the lack of compatibility data with them and neonatal TPN solution and the frequency of use in a local neonatal unit. These drugs included amiodarone, caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, midazolam, pentobarbital, phenobarbital, and rifampin. Equal volumes of neonatal TPN solution or sterile water for injection were combined with study drugs or sterile water for injection at concentrations used clinically in neonates. Each test was performed in triplicate. The samples were examined via turbidimetric analysis and visually against light and dark backgrounds immediately after mixing and at 0.25, 0.5, 1, 2, and 3 hours after mixing. Analysis of variance was used to determine statistically significant differences between the test and control solutions. Many of the drugs studied exhibited no visual or turbidimetric evidence of incompatibility when combined with neonatal TPN solution for up to three hours in a simulated Y-site injection. Pentobarbital, phenobarbital, and rifampin formed visible precipitation immediately after mixing with the neonatal TPN solution. Caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, and midazolam exhibited no visual or turbidimetric evidence of incompatibility when combined with a neonatal TPN solution for up to three hours in a simulated Y-site injection. Amiodarone, pentobarbital, phenobarbital, and rifampin were not compatible with the neonatal TPN solution and should not be coadministered via Y-site injection.


Dorsal column mapping in resection of intramedullary spinal cord tumors: a prospective comparison of two methods and neurological follow-up.
In surgery for intramedullary spinal cord tumors (imSCT), distortion of the anatomy challenges the visual identification of dorsal columns (DC) for midline myelotomy. Dorsal column mapping (DCM) and spinal cord stimulation (SCS) can identify DC neurophysiologically. We compare application and feasibility of both methods. Patients with surgically treated imSCT were prospectively included between 04/2017 and 06/2019. The anatomical midline (AM) was marked. SSEPs at the DC after stimulation of tibial/median nerve with an 8-channel DCM electrode and cortical SSEP phase reversal at C3/C4 after SCS using a bipolar concentric probe were recorded. Procedural and technical aspects were compared. Standardized neurological examinations were performed preoperatively, 1 week postoperatively and after more than 12 months. The DCM electrode detected the midline in 9/13 patients with handling limitations in the remaining patients. SCS was applicable in all patients with determination of the midline in 9/13. If both recordings could be acquired (6/13), concordance was 100%. If baseline SSEPs were poor, both methods were limited. SCS was less time-consuming (p = 0.001), cheaper, and easier to handle. In 92% of cases, the AM and neurophysiologic midlines were concordant. After myelotomy, 3 patients experienced > 50% reduction in amplitude of SSEPs. Despite early postoperative worsening of DC function, long-term follow-up showed significant recovery and improvement in quality of life. DCM and SCS may help confirm and correct the AM for myelotomy in imSCT, leading to a favorable long-term neurological outcome in this cohort. SCS evolved to be superior concerning applicability, cost-effectiveness, and time expenditure.


Phytochemical Composition and Antibacterial Activity of Barleria albostellata C.B. Clarke Leaf and Stem Extracts.
Barleria albostellata (Acanthaceae) is a shrub located in South Africa and is relatively understudied. However, plants within this genus are well known for their medicinal and ethnopharmacological properties. This study aimed to characterise the phytochemical compounds and antibacterial efficacies of B. albostellata. Phytochemical analysis, fluorescence microscopy and gas chromatography-mass spectrometry (GC-MS) analysis were performed to determine the composition of compounds that may be of medicinal importance. Crude leaf and stem extracts (hexane, chloroform and methanol) were subjected to an antibacterial analysis against several pathogenic microorganisms. The qualitative phytochemical screening of leaf and stem extracts revealed the presence various compounds. Fluorescence microscopy qualitatively assessed the leaf and stem powdered material, which displayed various colours under bright and UV light. GC-MS chromatograms represents 10-108 peaks of various compounds detected in the leaf and stem crude extracts. Major pharmacologically active compounds found in the extracts were alpha-amyrin, flavone, phenol, phytol, phytol acetate, squalene and stigmasterol. Crude extracts positively inhibited Gram-positive and Gram-negative bacteria. Significance was established at p < 0.05 for all concentrations and treatments. These results indicate that the leaves and stems of B. albostellata are rich in bioactive compounds, which could be a potential source of antibacterial agents for treating various diseases linked to the pathogenic bacteria studied. Future discoveries from this plant could advance the use of indigenous traditional medicine and provide novel drug leads.


Certain mutations observed in the 5' sequences of the G gamma- and A gamma-globin genes of beta S chromosomes are specific for chromosomes with major haplotypes.
In this paper we describe the distribution of some specific sequence differences in the 5' flanking regions of the A gamma- and G gamma-globin genes from 100 Black adult and 57 newborn SS patients from the southeastern United States, from 76 individuals with AS, S-beta-thal, SC, AC, or A-beta-thal, and from 31 normal individuals. Haplotypes for all adult individuals have been previously determined using various restriction endonucleases. The DNA samples were amplified, dot blotted, and hybridized with 32P-labeled specific oligonucleotide probes. All 134 chromosomes with haplotype 19 were positive for the G----T substitution at position -657 (A gamma), while 132 were also positive for the C----G mutation at -369 (G gamma). The three specific changes for the chromosome with haplotype 20 were found on all 54 chromosomes with this haplotype. The C----T mutation at -158 5' to G gamma was present on all 41 chromosomes with haplotype 3, and on two chromosomes with a related atypical haplotype. Normal and beta-thal chromosomes with each of these substitutions had the same 5' subhaplotype as beta S haplotypes 19 or 20, respectively. The close relationship between the occurrence of specific mutations and the haplotype of beta S chromosomes makes the determination of these haplotypes with specific oligonucleotide probes attractive with respect to time and expense.


Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke.
Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF-1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome. Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0-2) or unfavorable (mRS=3-6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted. Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (±1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37-0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56-4.84; p<0.001). Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke.


Phenotypic and genetic alterations in pre-cancerous cells in the colon.
Cell dysplasia in polyps and in ulcerative colitis are thought to be the pre-cancerous lesion leading to invasive colon cancer. Many polyps and dysplastic lesions in ulcerative colitis have phenotypic changes (blood group antigen, cytokeratins, CEA, TAG-72.3 antigen expression) and genetic changes (c-K-ras mutation, enhanced c-myc expression and pp60c-src activity) which are characteristic of invasive cancers. Thus, these early pre-cancerous lesions may be a late stage in the genetic evolution of colon cancer.


Rapid Clozapine Titration in Patients with Treatment Refractory Schizophrenia.
The aim of this study is to evaluate the safety and effectiveness of rapid clozapine titration in patients with schizophrenia in hospital settings. We conducted a retrospective two-center cohort study to compare the safety and effectiveness of clozapine with different titration rates in treatment-refractory patients with schizophrenia. In the first center, clozapine was started at 25-50 mg followed by 50-100 mg as needed every 6 h on day 1, followed by increases of 50-100 mg/day. In the second center, titration was slower; clozapine initiated with 12.5-50 mg on day 1 followed by increases of 25-50 mg/day. The number of days between starting of clozapine until discharge was shorter in the rapid titration group (22.4 ± 8.72 vs 27.0 ± 10.5, p = 0.1). Number of days of total hospital stay were significantly shorter in the rapid titration group (29.6 ± 10.6 vs 41.2 ± 14.8, p = 0.002). Hypotension was more common in the rapid titration group and one patient had suspected myocarditis. Rapid clozapine titration appeared safe and effective. The length of stay following initiation of clozapine was shorter in the rapid-titration group, although this was not statistically significant. However starting clozapine earlier together with rapid titration has significantly shortened the length of hospital stay in patients with treatment refractory schizophrenia.


Treatment of anorexia nervosa with long-term risperidone in an outpatient setting: case study.
There are currently few studies focusing on the efficacy of long-term atypical antipsychotics to treat anorexia nervosa in the pediatric population. This case report follows the treatment of a 17 year-old female with anorexia nervosa over her four-year undergraduate career. After two years of multidisciplinary treatment, low-dose risperidone was initiated due to persistence of her disease. She expressed decreased rigidity around meal times, her weight improved and she had resumption of menses. She was compliant with treatment through graduation and maintained her weight gain. Atypical antipsychotics are a treatment option in the management of anorexia nervosa. Risperidone has not been studied as frequently as olanzapine for eating disorders. Risperidone was chosen for its more favorable side effect profile and decreased cost to the patient. Previous studies on anorexia nervosa treatment have occurred during inpatient treatment and have limited follow-up due to patients' refusal to initiate or maintain medication compliance. This case presents 17 months of outpatient data. The efficacy of risperidone therapy was evaluated with frequent weight checks, subjective decrease in rigidity, serial complete metabolic panels, and restoration of menses. In this case report, an adolescent female treated with low-dose risperidone had decreased rigid thinking, weight gain and resolution of secondary amenorrhea without medication side effects. Therefore, the atypical antipsychotic risperidone may be an effective long-term outpatient treatment option for patients with anorexia nervosa.


Late onset clozapine-induced sierositis: the case of ms C.
Polisierositis is a rare but not negligible adverse event of a therapy with clozapine, that occurs usually during the titration phase of clozapine or just after the reachment of the plateau, and politherapy increases the incidence rate. Ms. C. is a 42 years old smoker woman who suffers from a schizophrenia associated to a borderline personality disorder. In 2007 a therapy with clozapine was introduced with good tolerance and efficacy on her symptoms for a long period. In August 2015, after a period characterized by many psychiatric ward admissions an augmentation with valproic acid and sertraline was done, with partial symptoms improvement. In June 2016, she developed pleuritis and pericarditis and underwent pleural and pericardial drainage. After clozapine interruption (andzuclopentixol titration) the symptoms progressively decreased and in August 2016 she had a complete remission. Even if uncommon, sierositis should be taken into consideration also in long term clozapine treatment, especially when associated with other drugs, as valproate or sertraline, although the role of the latter is less clear. Moreover, patients life habits (smoke), allergic or rheumatological disorders or temporary intake of other drugs (like antifungins) should be recorded carefully for their possible effects on cytochrome P450 substrates.


Ocular changes in TgF344-AD rat model of Alzheimer's disease.
Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed. Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response and luminance threshold recording from the superior colliculus. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques. As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature. In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was observed further in human AD retina. Along with Ab deposition, the inflammatory response was manifested by microglial recruitment and complement activation. Further studies are needed to elucidate the significance and mechanisms of these pathological changes [corrected].


Crestal bone remodeling in loaded and unloaded implants and the microgap: a histologic study.
The aim of this study was to histologically evaluate the crestal bone response to loaded and unloaded implants in beagle dogs. Sand-blasted and acid-etched implants (Bone System, Milano, Italy) were placed in the mandible of six beagle dogs. The two premolars and the first molars had been extracted 3 months previously. Each dog received 12 implants in the mandible, and a total of 72 implants were used in this study. Three months after implantation, second-stage surgeries were performed for placement of abutments or healing screws. Three dogs were killed after 6 months, and three dogs were killed after 12 months. All 72 implants were retrieved. No statistically significant differences were found in the amount of bone loss between test and control implants, both at 6 and 12 months. Statistically significant differences were found, in both groups, between the bone loss observed at 6 months and that found at 12 months. Loading does not seem to be a relevant factor in the peri-implant bone resorption observed during the first year of function. Our results support previous findings that bone crest level changes could depend on the location of the microgap.


Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma.
For the current issue of the Journal, we asked Drs Jimmy Chong and Bhupendrasinh Chauhan to comment on and put into context the Cochrane Review on the efficacy and safety of adding antileukotriene agents (LTRAs) to low-dose inhaled corticosteroids (ICS) in children with persistent asthma (1). In the treatment of children with mild persistent asthma, low-dose ICS are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an LTRA to existing ICS as one of three therapeutic options to intensify therapy (step 3). Trials were identified from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographical databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, AMED and CINAHL, and a manual search of respiratory journals and meeting abstracts, as well as the web-site www.clinicaltrials.gov. The search was conducted until January 2013. Randomized controlled trials (RCTs) that involved children and adolescents one to 18 years of age, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS, and in whom LTRAs were added to ICS and compared with the same, an increased or a tapering dose of ICS for at least four weeks were considered for inclusion. Sandard methods outlined by The Cochrane Collaboration were used. Five paediatric (parallel group or cross-over) trials met the inclusion criteria. Two (40%) trials were considered to be at a low risk for bias. Four published trials, representing 559 children (≥6 years of age) and adolescents with mild-to-moderate asthma, contributed data to the review. No trial enrolled preschool-age children. All trials used montelukast as the LTRA, administered for between four and 16 weeks. Three trials evaluated the combination of LTRAs and ICS compared with the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (n=268 participants; RR 0.80 [95% CI 0.34 to 1.91]). There was also no statistically significant difference in percent change in forced expiratory volume in 1 s (FEV1) in this trial, with a mean difference (MD) of 1.3 (95% CI -0.09 to 2.69); however, a significant group difference was observed in the morning and evening peak expiratory flow rates: n=218 participants; MD 9.70 L/min (95% CI 1.27 L/min to 18.13 L/min) and MD 10.70 L/min (95% CI 2.41 L/min to 18.99 L/min), respectively. One trial compared the combination of LTRAs and ICS with a higher dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over a 16-week period (n=182 participants; RR 0.82 [95% CI 0.54 to 1.25]), nor was there any significant difference in exacerbations requiring hospitalization. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding LTRAs as a means to taper the dose of ICS. The addition of LTRAs to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared with the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although LTRAs have been licensed for use in children for >10 years, the paucity of paediatric trials, the absence of data regarding preschool-age children and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of LTRAs as add-on therapy to ICS as a step 3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS. The full text of the Cochrane Review is available in The Cochrane Library (1).


Exploring the usefulness of comprehensive care plans for children with medical complexity (CMC): a qualitative study.
The Medical Home model recommends that Children with Special Health Care Needs (CSHCN) receive a medical care plan, outlining the child's major medical issues and care needs to assist with care coordination. While care plans are a primary component of effective care coordination, the creation and maintenance of care plans is time, labor, and cost intensive, and the desired content of the care plan has not been studied. The purpose of this qualitative study was to understand the usefulness and desired content of comprehensive care plans by exploring the perceptions of parents and health care providers (HCPs) of children with medical complexity (CMC). This qualitative study utilized in-depth semi-structured interviews and focus groups. HCPs (n = 15) and parents (n = 15) of CMC who had all used a comprehensive care plan were recruited from a tertiary pediatric academic health sciences center. Themes were identified through grounded theory analysis of interview and focus group data. A multi-dimensional model of perceived care plan usefulness emerged. The model highlights three integral aspects of the care plan: care plan characteristics, activating factors and perceived outcomes of using a care plan. Care plans were perceived as a useful tool that centralized and focused the care of the child. Care plans were reported to flatten the hierarchical relationship between HCPs and parents, resulting in enhanced reciprocal information exchange and strengthened relationships. Participants expressed that a standardized template that is family-centered and includes content relevant to both the medical and social needs of the child is beneficial when integrated into overall care planning and delivery for CMC. Care plans are perceived to be a useful tool to both health care providers and parents of CMC. These findings inform the utility and development of a comprehensive care plan template as well as a model of how and when to best utilize care plans within family-centered models of care.


Trends in mortality differentials and life expectancy for male social security-covered workers, by socioeconomic status.
This article presents an analysis of trends in mortality differentials and life expectancy by average relative earnings for male Social Security-covered workers aged 60 or older. Because average relative earnings are measured at the peak of the earnings distribution (ages 45-55), it is assumed that they act as a rough proxy for socioeconomic status. The historical literature reviewed in this analysis generally indicates that mortality differentials by socioeconomic status have not been constant over time. For this study, time trends are examined by observing how mortality differentials by average relative earnings have been changing over 29 years of successive birth cohorts that encompass roughly the first third of the 20th century. Deaths for these birth cohorts are observed at ages 60-89 from 1972 through 2001, encompassing roughly the last third of the 20th century. The large size and long span of death observations allow for disaggregation by age and year-of-birth groups in the estimation of mortality differentials by socioeconomic status. This study finds a difference in both the level and the rate of change in mortality improvement over time by socioeconomic status for male Social Security-covered workers. Average relative earnings (measured as the relative average positive earnings of an individual between ages 45 and 55) are used as a proxy for adult socioeconomic status. In general, for birth cohorts spanning the years 1912-1941 (or deaths spanning the years 1972-2001 at ages 60-89), the top half of the average relative earnings distribution has experienced faster mortality improvement than has the bottom half. Specifically, male Social Security-covered workers born in 1941 who had average relative earnings in the top half of the earnings distribution and who lived to age 60 would be expected to live 5.8 more years than their counterparts in the bottom half. In contrast, among male Social Security-covered workers born in 1912 who survived to age 60, those in the top half of the earnings distribution would be expected to live only 1.2 years more than those in the bottom half. The life expectancy estimates in this article represent one possible outcome under one set of assumptions. These projections should not be regarded as an accurate depiction of the future. Specifically, this study adopts a simple projection method in which differentials are assumed to follow the pattern observed over the last 30 years of the 20th century for the first 30 years of the 21st century. This assumption lacks theoretical underpinnings because the causes of the widening differentials observed over the past 30 years have not been determined. On the one hand, if the trend of widening mortality differentials by year of birth observed over the past 30 years does not continue, the projection method used in this analysis could lead to an overestimation of future differences in life expectancy between socioeconomic groups. On the other hand, if mortality differentials do not narrow by age as observed in the past, the projection method used could lead to an underestimation of the differences in life expectancy between socioeconomic groups aged 60 or older.


Intraurethral pressure recording. A comparison betwen tip-transducer catheters and open-end catheters with constant flow.
This paper presents the results of a comparative study of intraurethral pressure recording with two different catheter systems: (1) Open-end water-filled catheters with constant flow connected to conventional pressure transducers, and (2) Micro-transducers mounted in the tip of a dacron catheter. When open-end catheters were used, the best reproducibility of the urethra pressure profile was obtained, if the catheter dimensions 6-8 F were used and if the flow in the catheters was kept to approximately 1-2 ml/min. In addition, the withdrawal rate of the open-end catheters should not exceed 3-4 mm/sec. The best reproducibility of the intraurethral pressure was obtained with the micro-transducer. It was free from measuring artefacts and seemed from this investigation superior to the open-end catheter systems, both for clinical practice and for research.


Extreme obesity and risk of placental abruption.
Data on extreme obesity and placental abruption are scarce. This study aimed to determine the association between pre-pregnancy weight and placental abruption and whether pregnancy weight gain impacts this risk. We used the Missouri maternally linked cohort files (years 1989-1997). Analyses were restricted to singleton live births (n = 461 729). Maternal body mass index (BMI) was classified as normal (18.5-24.9) (referent group), obese [Class 1 (30.0-34.9), Class 2 (35.0-39.9) and extreme or Class 3 (> or =40)]. Pregnancy weight gain categories included: < or =0.22 kg/week (low), 0.23-0.68 kg/week (moderate) and > or =0.69 kg/week (high). Adjusted odds ratios generated from generalized estimating equations for logistic regression models were used to approximate relative risks. RESULTS; Obese women were less likely to have placental abruption than normal weight women (adjusted odds ratio = 0.8, 95% confidence interval 0.7-0.9). The risk was similar regardless of severity of obesity. However, analyses stratified by weight gain during pregnancy indicated that reduced risk was limited to obese women with low or moderate weight gain during pregnancy, although the analyses by subclass of obesity were only statistically significant for women with moderate weight gain. Among women with moderate weight gain, the risk of placental abruption decreased with increasing BMI in a dose-dependent pattern (P < 0.01). Obesity is associated with reduced risk for placental abruption when the weight gain during pregnancy is moderate. These findings underscore the need for further research on the role of nutritional status during pregnancy as a protective factor against placental abruption so that preventive strategies may be appropriately developed.


A radiopharmacological study without human radiation exposure.
The development, study and control of new drugs today is hardly conceivable without nuclear medicine studies. Nuclear physicians on ethical commissions bear great responsibility in the planning and execution of such studies. In order to protect subjects and patients those nuclear techniques are therefore to be welcome which do not include exposure to radiation. Nuclear techniques used in in-vitro diagnostics (RIA) and the determination of naturally occurring nuclides incorporated in the human body belong to this category. With the aid of a clinico-pharmacological study of a new combination of diuretics it is shown that both methods supply valuable pharmacodynamic evidence.


Delayed Recognition of Thoracic and Lumbar Vertebral Compression Fractures in Minor Accident Cases.
Osteoporotic vertebral compression fractures (VCFs) in the elderly are commonly diagnosed after a minor fall or trauma; however, the majority of these patients have either been previously evaluated for osteoporosis or are already under some form of medical treatment for osteoporosis at the time of the fall. Although accidents are a known cause of VCFs, these fractures are too often undiagnosed. In reviewing a group of patients seen after minor falls or automobile accidents who were complaining of general spine pain, we found a smaller subgroup with previously undiagnosed VCFs. These fractures were also the initial signs of a previously unrecognized osteoporotic process. Initial diagnosis, treatment, and therapy were usually focused on other spinal segments (i.e. mainly the lumbar spine) until both the VCF and the osteoporosis were identified. The purpose of this report is to raise awareness and discuss the steps for improved diagnosis of osteoporotic VCFs. A retrospective analysis was conducted on a large group of patients from one pain/accident clinic in a 24 month period. These patients were diagnosed with VCFs subsequent to the initial evaluation due to either persistent pain after conservative therapy or complaints of pain beyond the original injured area (i.e. typically the lumbar spine). At this point, a more detailed history was taken, including any past treatment for osteoporosis, or previous falls or injury to exclude the possibility of pre-existing fractures. A more focused examination of the painful area was completed, consisting of percussion at the fracture site identified on magnetic resonance imaging (MRI) or computed tomography (CT) scan. If possible, a bone scan was ordered to separate acute and subacute traumatic fractures from old/chronic fractures. Additionally, we surveyed two other similar pain/accident clinics who saw a comparable number and population of patients diagnosed with VCFs within a 24 month period to make a comparison of the number of VCFs they identified. Ten out of approximately 2700 patients seen over a 24 month period sustained acute thoracic or lumbar VCFs during a minor accident and were not previously diagnosed with osteoporosis. Since approximately 30% of the 2,700 patients had new accidents, 10 out of 800 new patients (1.25%) were found to have VCFs without a known history of osteoporosis. Two other surveyed pain/accident, clinics saw a similar number and population of patients in the same time period; however, each only diagnosed two or three VCFs while examining a similar number of patients in the clinic. In these two other clinics, a much lower percentage (0.3%) of patients were diagnosed with new VCFs. Awareness of the possibility of osteoporotic VCFs is the first step in detecting them. This study reveals the presence of a small but real risk of overlooking osteoporotic VCFs in minor trauma cases. When necessary, repeat or obtain better quality imaging in spinal segments affected by persistent pain. The thoracolumbar junction (i.e. T12 & L1 vertebrae) is especially at risk for sustaining VCFs. The delayed recognition of these VCFs and the patient's underlying osteoporosis after minor accident cases could present a major problem, as the critical time for patients to receive the proper medical or surgical treatments responsible for correcting and preventing further spinal deformity and pain has been reduced.


Genetics of resistance to Salmonella typhimurium in newly hatched chicks.
1. A survey of inbred and partially inbred lines of chickens showed pronounced differences in mortality following challenge of the newly hatched chicks with Salmonella typhimurium. Lines W, 6(1) and N were highly resistant to challenge, whereas lines C and 15I were highly susceptible. 2. This difference in susceptibility was observed with a range of 5 strains of S. typhimurium of different degrees of virulence and also following both oral and intramuscular challenge. 3. The inheritance of resistance was studied in detail by examining a series of crosses between the susceptible line C and resistant line W. The pattern of mortality in crosses and back-crosses between these lines indicated resistance is dominant and was consistent with the inheritance of a dominant autosomal resistance gene. 4. There was no evidence of maternal effects in these crosses, and no evidence of association with the major histocompatability complex.


Health status of older immigrants to Canada.
Using the 2000/2001 Canadian Community Health Survey (CCHS), this paper examines the health status of the older (aged immigrant population relative to that of non-immigrants in order to identify areas where their health statuses diverge. First, we compare the health status of older immigrants (foreign-born) aged 55 and over in Canada to the Canadian-born in terms of age and gender using multiple measures of health status including self-assessed health. Second, we identify the factors associated with health status using the determinants of health framework. In both cases, the key questions are whether differences in health status exist and whether they are explained primarily by socio-economic, socio-demographic, or lifestyle factors that may point to problems with the Canadian health care system. Findings indicate that there is a relative comparability in the health status of older immigrants, even after controlling for age.


Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth.
Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)-induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors.


Racial disparities in trauma exposure, psychiatric symptoms, and service use among female patients in Veterans Affairs primary care clinics.
We sought to compare female African-American (n = 84) and Caucasian (n = 99) veterans from primary care clinics at 4 Veterans Affairs Medical Centers (VAMCs) on rates of trauma, posttraumatic stress disorder, other psychiatric diagnoses, functional status, and use of VA services and disability benefits. Analyses were based on a cross-sectional, epidemiologic design incorporating self-report measures, structured interviews, and chart reviews. With the exception of higher rates of child sexual abuse among Caucasian women and higher rates of physical assault among African-American women, there were no other statistically significant racial differences across analyses. However, some clinically meaningful trends emerged, and the implications of these findings are discussed within the context of our other results. Among female veterans seen in VA primary care clinics, African-Americans and Caucasians do not differ dramatically with regard to the manifestation or severity of psychopathology, or in their use of relevant VA health care services and disability benefits. These data are important because women represent the fastest growing segment of the VA population after aging veterans. Further research is needed to replicate and extend these findings to ensure that female veterans' needs are adequately identified and met by VAMC providers.


[CD99 regulates redifferentiation of classical Hodgkin's lymphoma cell line L428 towards B cells].
To explore the effect of CD99 overexpression on the morphology and differentiation-related phenotypes of classical Hodgkin's lymphoma cell line L428 and investigate the role of CD99 gene in Hodgkin/Reed-Sternberg (HRS) cell generation and transformation. The effect of CD99 overexpression on the cell morphology was detected by HE staining and phalloidin staining. Differentiation-related protein expressions were detected by immunocytochemistry and flow cytometry after stable transfection of CD99 gene in L428 cells. CD99 overexpression caused a decrease of the cell size and reorganization of the actin cytoskeleton in L428 cells. Upregulation of CD99 led to the loss of classical Hodgkin's lymphoma diagnosis marker CD30 and CD15 and the restoration of the B-cell makers of PAX5, CD19, CD79α, BCL-6, and CD10. CD99 overexpression leads to redifferentiation of L428 cells towards B cells, suggesting that the loss of B-cell phenotype in classical Hodgkin's lymphoma is very likely a result of down-regulated CD99 expression.


Mechanisms of action of anti-seizure drugs and the anticonvulsant screening program of the National Institute of Neurological Disorders and Stroke.
To determine the efficacy of the Anticonvulsant Screening Program (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) in identifying new anti-seizure drugs with new mechanisms of action (MOA). The ASP does not itself identify the nature of the MOA, but on further basic investigation, many of these drugs prove eventually to have a wide variety of new and novel MOA. Data were tabulated from multiple sources, including the ASP and the literature. Since it was established in 1975, the ASP has contributed to the identification of at least 9 new anti-seizure drugs. The effectiveness of the program was evaluated by ascertaining the number of MOA of the anti-seizure drugs discovered by the ASP screening techniques. Considering the MOA of drugs marketed after 1975 - and the MOA of investigational compounds not yet marketed - the ASP has contributed to the identification of anti-seizure drugs that possess 16 distinctly different MOA. The ever-evolving screening approach of the ASP has many characteristics of a final common pathway for anti-seizure drug discovery.


MANAGEMENT OF ENDOCRINE DISEASE: Polycystic ovary syndrome and nonalcoholic fatty liver disease.
Polycystic ovary syndrome (PCOS) is a frequent endocrine disease in women, with a number of metabolic and reproductive consequences. Obesity, insulin resistance (IR) and type 2 diabetes are prominent metabolic characteristics of PCOS and common factors affecting liver function and generating nonalcoholic fatty liver disease (NAFLD). Multiple genes involved in the synthesis of androgens, cytokines and IR, as well as acquired factors, such as endocrine disruptors, could associate the etiopathogenesis of PCOS and NAFLD. Besides the high prevalence of PCOS in general population, NAFLD was shown to be a frequent condition in transition periods, such as adolescence and menopause. Although liver biopsy is considered to be the gold standard for diagnosing liver damage, its routine use in such a prevalent condition as PCOS can be related to a higher rate of complications. Therefore, it is necessary to be able to diagnose NAFLD using simple and reliable surrogate markers. Recently, fatty liver index and NAFLD fatty liver score analyzed in large cohorts of PCOS women have been shown as accurate markers of liver damage in this metabolically vulnerable population. Lifestyle changes are still the mainstay of the management of NAFLD in PCOS, although prospective randomized controlled clinical studies remain a priority in the field. With regard to medications, metformin may be the drug of choice for treating PCOS patients with NAFLD when pharmacologic therapy is considered. Liraglutide use in obese PCOS has shown favorable effects on the predictors of liver fibrosis. In this review, we aim to summarize the influence of the common risk factors and to discuss the diagnostic approaches and management options for NAFLD in patients with PCOS.


Revisiting the 1990 special issue on minority children: an editorial perspective 15 years later.
The 2006 Special Issue on Race, Ethnicity, and Culture in Child Development occurs 15 years after the 1990 Special Issue on Minority Children and marks roughly 50 years since the historic 1954 Brown v. Board of Education Supreme Court decision. This issue provides an assessment of how researchers have represented development of America's diverse youth. This commentary provides a perspective of the progress and needs inferred from the 1990 special issue. A consistent theme is the necessity to link research and developmental theorizing with the intentions of the Brown v. Board of Education decision, as the relevant integration is often left to legal scholars, Whiteness studies theorists, and a few child-development-focused researchers (e.g., Cross, 1991; Spencer, 2005).


Image analysis by electron microscopy of two-dimensional crystals developed on a mercury surface of chaperonin from Thermus thermophilus.
Two-dimensional crystals of functional chaperonin molecules, which are protein complexes of cpn60 and cpn10, isolated from Thermus thermophilus were prepared on a mercury surface under oxygen atmosphere and were observed by electron microscope after transferring them to carbon coated specimen grids. The crystals showed the hexagonal lattice with unit cell dimensions of a = b = 12.4 nm and gamma = 120 degrees. The averaged image at a 3 nm resolution of the chaperonin has a doughnut-like shape which has seven peripheral masses and a central cavity. Preincubation of the chaperonin with MgATP changed the mobility in non-denaturating PAGE but did not cause distinguishable change of shape. The location of cpn10 in the chaperonin molecule is discussed.


Role of the receptor-mediated apoptosis in Helicobacter pylori in gastric epithelial cells.
Two major pathways leading to apoptosis have been described. It has been shown that Helicobacter pylori-mediated apoptosis is mainly effected through the mitochondrial pathway (type II). The role of the type I pathway, including the death receptors, has been discussed controversially. Therefore, we investigated the role of Fas ligand (FasL) and TRAIL in H. pylori-mediated apoptosis by overexpressing antiapoptotic proteins in the human gastric epithelial cell line AGS. AGS cells overexpressing the antiapoptotic proteins dnFADD, CrmA and Bcl-2 were generated. Apoptosis induced by Fas and H. pylori was monitored by histone ELISA. To investigate the role of TRAIL-mediated apoptosis, AGS cells were transduced with antisense constructs against the proapoptotic TRAIL receptors DR4 and DR5. Protein expression of Fas, TRAIL, DR4, and DR5 was analyzed by Western blot. Fas and H. pylori-mediated apoptosis was significantly inhibited in all generated cell lines, mainly in cells overexpressing CrmA and Bcl-2 with equal effectiveness. In the presence of H. pylori, TRAIL ligand and DR5 receptor were continuously expressed whereas DR4 expression was increasing time dependently. TRAILDR5 antisense significantly reduced H. pylori-mediated apoptosis. H. pylori-mediated apoptosis is characterized by activation of either type I or type II pathway. Caspase-8 plays an important role since it triggers the Type II pathway. Fas and TRAIL play an important role in the H. pylori-mediated apoptosis.


Vaccination of chickens with strain CVL30, a genetically defined Salmonella enteritidis aroA live oral vaccine candidate.
Newly hatched chicks were vaccinated orally with a genetically defined Salmonella enteritidis aroA candidate, strain CVL30. In chickens immunized with 10(5) or 10(9) CFU and challenged by the intravenous route with 10(8) CFU of S. enteritidis 109 Nalr at 8 weeks old, there were similar reductions in colonization of the spleens, livers, and ceca of vaccinees compared with unvaccinated controls. Two groups of newly hatched female chicks were vaccinated orally with 10(9) CFU of strain CVL30, and one group was revaccinated intramuscularly with 10(9) CFU at 16 weeks old. When challenged intravenously with S. enteritidis 109 Nalr at 23 weeks old, there was a reduction in the colonization of spleens, livers, ovaries, and ceca compared with unvaccinated controls. Inclusion of the intramuscular booster gave increased protection to the ovary, although the vaccine strain was isolated on one occasion from a batch of eggs laid at 20 weeks old. In chickens immunized with 10(9) CFU of strain CVL30 and challenged orally with 10(9) CFU of S. enteritidis 109 Nalr, there was a reduction in intestinal shedding of the challenge strain from vaccines compared with unvaccinated controls. Circulating immunoglobulin G antibodies to lipopolysaccharide (LPS) were detected in unvaccinated controls within 7 to 10 days of oral challenge. In contrast, circulating immunoglobulin G antibodies to LPS in vaccinees were not altered by the oral challenge, which suggested that vaccination reduced or prevented invasion by the challenge strain from the gut or multiplication of the challenge strain in the tissues. Newly hatched chicks were vaccinated orally with ca. 10(9) CFU of strain CVL30, and 1 day later, the vaccines and unvaccinated controls were challenged orally with 10(5) or 10(9) CFU of S. enteritidis 109 Nalr. Colonization of the ceca and invasion from the gut by the S. enteritidis challenge strain was reduced in the vaccines up to 5 days postchallenge compared with controls. In a second trial, vaccinees and controls were challenged orally with 10(7) or 10(9) CFU of S. typhimurium 2391 Nalr. In contrast to the challenge with S. enteritidis, colonization of the ceca and invasion by the S. typhimurium strain were not greatly reduced.


Insights into substrate transport and water permeation in the mycobacterial transporter MmpL3.
Mycobacteria, such as Mycobacterium tuberculosis, are characterized by a uniquely thick and waxy cell envelope that consists of two membranes, with a variety of mycolates comprising their outer membrane (OM). The protein Mycobacterial membrane protein Large 3 (MmpL3) is responsible for the transport of a primary OM component, trehalose monomycolate (TMM), from the inner (cytoplasmic) membrane (IM) to the periplasmic space, a process driven by the proton gradient. Although multiple structures of MmpL3 with bound substrates have been solved, the exact pathway(s) for TMM or proton transport remains elusive. Here, employing molecular dynamics simulations we investigate putative pathways for either transport species. We hypothesized that MmpL3 will cycle through similar conformational states as the related transporter AcrB, which we used as targets for modeling the conformation of MmpL3. A continuous water pathway through the transmembrane region was found in one of these states, illustrating a putative pathway for protons. Additional equilibrium simulations revealed that TMM can diffuse from the membrane into a binding pocket in MmpL3 spontaneously. We also found that acetylation of TMM, which is required for transport, makes it more stable within MmpL3's periplasmic cavity compared with the unacetylated form.


Demystifying artificial intelligence and deep learning in dentistry.
Artificial intelligence (AI) is a general term used to describe the development of computer systems which can perform tasks that normally require human cognition. Machine learning (ML) is one subfield of AI, where computers learn rules from data, capturing its intrinsic statistical patterns and structures. Neural networks (NNs) have been increasingly employed for ML complex data. The application of multilayered NN is referred to as "deep learning", which has been recently investigated in dentistry. Convolutional neural networks (CNNs) are mainly used for processing large and complex imagery data, as they are able to extract image features like edges, corners, shapes, and macroscopic patterns using layers of filters. CNN algorithms allow to perform tasks like image classification, object detection and segmentation. The literature involving AI in dentistry has increased rapidly, so a methodological guidance for designing, conducting and reporting studies must be rigorously followed, including the improvement of datasets. The limited interaction between the dental field and the technical disciplines, however, remains a hurdle for applicable dental AI. Similarly, dental users must understand why and how AI applications work and decide to appraise their decisions critically. Generalizable and robust AI applications will eventually prove helpful for clinicians and patients alike.


A kala-azar control programme for remote tribal communities.
Indigenous people have been trained to provide a culturally appropriate kala-azar control programme for the tribal population of Sahibganj, Bihar, India. Cultural resistance to modern medicine has been overcome and the influence of village witch-doctors has been countered.


Collagenous spherulosis in epithelial-myoepithelial carcinoma of the parotid gland. Histological and immunohistological study of a case.
Previously unreported histological and immunohistochemical features of collagenous spherulosis in an epithelial-myoepithelial carcinoma found in an 80-year-old woman are described. The multinodular tumor located in the right parotid gland was completely removed surgically. No local recurrence of the tumor appeared during the 22-month period of periodic checkups. This is believed to be the first report on collagenous spherulosis in an epithelial-myoepithelial carcinoma of the salivary gland. Different immunohistochemical characteristics of epithelial and myoepithelial neoplastic cells were found very useful for their analysis namely in parts of the tumor where one cell type greatly predominated (e.g. clear cell-type predominance). The double staining of histological sections can in this sense be recommended for the differentiation from other clear cell tumors of salivary glands allowing the correct categorization of the neoplasm.


Both Ca2+ -dependent and -independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine.
In chronic liver injury, hepatic stellate cells (HSCs) have been implicated as regulators of sinusoidal vascular tone. We studied the relative role of Ca(2+)-dependent and Ca(2+)-independent contraction pathways in rat HSCs and correlated these findings to in situ perfused cirrhotic rat livers. Contraction of primary rat HSCs was studied by a stress-relaxed collagen lattice model. Dose-response curves to the Ca(2+) ionophore A-23187 and to the calmodulin/myosin light chain kinase inhibitor W-7 served to study Ca(2+)-dependent pathways. Y-27632, staurosporin, and calyculin (inhibitors of Rho kinase, protein kinase C, and myosin light chain phosphatase, respectively) were used to investigate Ca(2+)-independent pathways. The actomyosin interaction, the common end target, was inhibited by 2,3-butanedione monoxime. Additionally, the effects of W-7, Y-27632, and staurosporin on intrahepatic vascular resistance were evaluated by in situ perfusion of normal and thioacetamide-treated cirrhotic rat livers stimulated with methoxamine (n = 25 each). In vitro, HSC contraction was shown to be actomyosin based with a regulating role for both Ca(2+)-dependent and -independent pathways. Although the former seem important, an important auxiliary role for the latter was illustrated through their involvement in the phenomenon of "Ca(2+) sensitization." In vivo, preincubation of cirrhotic livers with Y-27632 (10(-4) M) and staurosporin (25 nM), more than with W-7 (10(-4) M), significantly reduced the hyperresponsiveness to methoxamine (10(-4) M) by -66.8 +/- 1.3%, -52.4 +/- 2.7%, and -28.7 +/- 2.8%, respectively, whereas in normal livers this was significantly less: -43.1 +/- 4.2%, -40.2 +/- 4.2%, and -3.8 +/- 6.3%, respectively. Taken together, these results suggest that HSC contraction is based on both Ca(2+)-dependent and -independent pathways, which were shown to be upregulated in the perfused cirrhotic liver, with a predominance of Ca(2+)-independent pathways.


In situ studies of metal-semiconductor interactions with synchrotron radiation.
The capabilities and performance of a UHV system for in situ studies of metal-semiconductor interactions are described. The UHV system consists of interconnected deposition and analysis chambers, each of which is capable of maintaining a base pressure of approximately 1 x 10(-10) torr. The deposited materials and their reaction products can be studied in situ with RHEED, XAFS, AES, XPS, UPS and ARUPS. Results from a study of the reaction of 0.7- and 1.7-monolayer-thick films of cobalt with strained silicon-germanium alloys are presented. The signal-to-noise ratio obtained in these experiments indicates that the apparatus is capable of supporting in situ EXAFS studies of approximately 0.1-monolayer-thick films.


Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100.
Processing of the nf kappa b2 gene product p100 to generate p52 is an important step in NF-kappa B regulation. This step is regulated by a nonclassical NF-kappa B signaling pathway involving the NF-kappa B-inducing kinase (NIK). NIK induces p100 processing by triggering phosphorylation of specific C-terminal serines of p100. However, the downstream molecular events leading to p100 processing remain unclear. Here we show that NIK induced the physical recruitment of beta-transducin repeat-containing protein (beta-TrCP), a component of the SCF ubiquitin ligase complex, to p100. This event required the phosphorylation sites as well as the death domain of p100. Using the RNA interference technique, we demonstrated that beta-TrCP is essential for NIK-induced p100 ubiquitination and processing. Interestingly the constitutive processing of p100 mutants was independent of beta-TrCP. These results suggest that beta-TrCP is an essential component of NIK-induced p100 processing.


MiR-487a resensitizes mitoxantrone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by targeting breast cancer resistance protein (BCRP/ABCG2).
Breast cancer resistance protein (BCRP/ABCG2) specifically transports various chemotherapeutic agents and is involved in the development of multidrug resistance (MDR) in cancer cells. MicroRNAs (miRNAs) can play an important role in modulating the sensitivity of cancer cells to chemotherapeutic agents. Therefore, after confirming that BCRP was increased in the mitoxantrone (MX)-resistant MCF-7 breast cancer cell line MCF-7/MX compared with its parental sensitive MCF-7 cell line, we aimed to explore the miRNAs that regulate BCRP expression and sensitize breast cancer cells to chemotherapeutic agents. In the present study, bioinformatic analysis indicated that miR-487a was one of the miRNAs that could bind to the 3' untranslated region (3'UTR) of BCRP. Quantitative RT-PCR (qRT-PCR) analysis demonstrated that the expression of miR-487a was reduced in MCF-7/MX cells, and a luciferase reporter assay demonstrated that miR-487a directly bound to the 3'UTR of BCRP. Moreover, ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of MX in resistant MCF-7/MX breast cancer cells. Meanwhile, inhibition of miR-487a increased BCRP expression at the mRNA and protein levels and induced MX resistance in sensitive MCF-7 breast cancer cells. Furthermore, the reduced expression of BCRP and increased antitumor effects of MX were also detected in MCF-7/MX xenograft tumors treated with the miR-487a agmir. Thus, our results suggested that miR-487a can directly regulate BCRP expression and reverse chemotherapeutic drug resistance in a subset of breast cancers.


Individual, social and community-level predictors of wellbeing in a US sample of transgender and gender non-conforming individuals.
In the last decade, increased attention has been paid to the physical and mental health needs of transgender and gender non-conforming individuals. However, despite this surge of research, scant literature addresses factors associated with wellbeing among members of this population. Using data from the US Social Justice Sexuality Survey, this study examines predictors of wellbeing in a sample of transgender and gender non-conforming individuals. Results indicate that higher levels of wellbeing are predicted by education, older age and a greater sense of connectedness to the lesbian, gay, bisexual and transgender community. Additionally, although health insurance did not have a significant impact on wellbeing, increased general health was associated with greater wellbeing, as was perceived comfort of the healthcare provider regarding the respondent's sexual identity. These findings can inform multi-level intervention with transgender and gender non-conforming persons to promote their wellbeing, as well as guide policies and practices around healthcare provider training. Future research should further examine the interconnected predictors of wellbeing among members of this population.


Palaeoclimatic insights into future climate challenges.
Palaeoclimatic data document a sensitive climate system subject to large and perhaps difficult-to-predict abrupt changes. These data suggest that neither the sensitivity nor the variability of the climate are fully captured in some climate-change projections, such as the Intergovernmental Panel on Climate Change (IPCC) Summary for Policymakers. Because larger, faster and less-expected climate changes can cause more problems for economies and ecosystems, the palaeoclimatic data suggest the hypothesis that the future may be more challenging than anticipated in ongoing policy making. Large changes have occurred repeatedly with little net forcing. Increasing carbon dioxide concentration appears to have globalized deglacial warming, with climate sensitivity near the upper end of values from general circulation models (GCMs) used to project human-enhanced greenhouse warming; data from the warm Cretaceous period suggest a similarly high climate sensitivity to CO(2). Abrupt climate changes of the most recent glacial-interglacial cycle occurred during warm as well as cold times, linked especially to changing North Atlantic freshwater fluxes. GCMs typically project greenhouse-gas-induced North Atlantic freshening and circulation changes with notable but not extreme consequences; however, such models often underestimate the magnitude, speed or extent of past changes. Targeted research to assess model uncertainties would help to test these hypotheses.


Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?
Extended adjuvant (5-10 years) therapy targeted to the estrogen receptor (ER) has significantly decreased mortality from breast cancer (BC). Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops. Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a 'super SERD' which destroys ER but improves women's health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The 'one in three' rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.


Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin.
We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF.


A ratiometric near-infrared fluorescent probe for hydrazine and its in vivo applications.
Based on modulation of the conjugated polymethine π-electron system of a cyanine dye derivative, a ratiometric near-infared fluorescent probe (Cy7A) for hydrazine (N2H4) has been designed and synthesized. Cy7A can be selectively hydrazinolysized with great changes in its fluorescent excitation/emission profiles, which makes it possible to detect N2H4 in water samples and living cells and, for the first time, visualize N2H4 in living mice.


An evaluation of theophylline for idiopathic apnea of infancy.
19 infants admitted with a diagnosis of infantile apnea who were found to have periodic breathing were given oral theophylline to determine its effect. They were studied at a mean age of 7.1 weeks (1-16.4 week). Each infant was studied during two naps, immediately before and 7 days following the institution of theophylline therapy, which averaged 2.8 h in duration during which electro-oculograms, end-tidal CO2, heart rate, impedance respirations, and transcutaneous pO2 (tcpO2) were continuously monitored. Theophylline therapy (mean dose 2.3 mg/kg q. 6 h) was associated with a significant reduction of apnea attack rates in both REM and non-REM sleep. Periodic breathing and the number of minutes per hour of sleep during which the TC pO2 was between 40-50 mm Hg in non-REM sleep also decreased. There was no significant reduction in the number of obstructive apneas, the number of bradycardias with apnea, nor the largest single fall in tcpO2. Theophylline can significantly reduce central apnea and periodicity in the age group studied, but the long-term effects of such therapy require further assessment.


Cadmium Sulfide Quantum Dots, Mitochondrial Function and Environmental Stress: A Mechanistic Reconstruction through In Vivo Cellular Approaches in Saccharomyces cerevisiae.
Research on the effects of engineered nanomaterials (ENMs) on mitochondria, which represent one of the main actors in cell function, highlighted effects on ROS production, gametogenesis and organellar genome replication. Specifically, the mitochondrial effects of cadmium sulfide quantum dots (CdS QDs) exposure can be observed through the variation in enzymatic kinetics at the level of the respiratory chain and also by analyzing modifications of reagent and products in term of the bonds created and disrupted during the reactions through Fourier-transform infrared spectroscopy (FTIR). This study investigated both in intact cells and in isolated mitochondria to observe the response to CdS QDs treatment at the level of electron transport chain in the wild-type yeast Saccharomyces cerevisiae and in the deletion mutant Δtom5, whose function is implicated in nucleo-mitochondrial protein trafficking. The changes observed in wild type and Δtom5 strains in terms of an increase or decrease in enzymatic activity (ranging between 1 and 2 folds) also differed according to the genetic background of the strains and the respiratory chain functionality during the CdS QDs treatment performed. Results were confirmed by FTIR, where a clear difference between the QD effects in the wild type and in the mutant strain, Δtom5, was observed. The utilization of these genetic and biochemical approaches is instrumental to clarify the mitochondrial mechanisms implicated in response to these types of ENMs and to the stress response that follows the exposure.


Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach.
Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli.


Resveratrol augments paclitaxel sensitivity by modulating miR-671-5p/STOML2/PINK1/Parkin-mediated autophagy signaling in A549 cell.
Paclitaxel (PTX) resistance has become a notable clinical concern of Non-small cell lung cancer (NSCLC). Our study aim is to investigate the effects of Resveratrol (RES) on NSCLC cells that have developed resistance to PTX. The NSCLC cell line A549 was employed in this investigation to establish a PTX-resistant NSCLC cell line, denoted as A549/PTX, and established tumor transplantaton model. The presence of miR-671-5p, Stomatin-like protein 2 (STOML2), and mitophagy biomarkers was evaluated using quantitative teal-time PCR (qRT-PCR) and western blot, The assessment of cell proliferation and apoptosis was conducted through the utilisation of colony formation and flow cytometry assays. The investigation of mitochondrial autolysosomes was conducted using transmission electron microscopy (TEM). Our results showed that the application of RES therapy resulted in a substantial improvement in the sansitivity of A549/PTX cells. RES exhibited an augmentation of apoptosis and a suppression of mitophagy in A549/PTX cells. RES induced an upregulation in the expression of miR-671-5p. This, in turn, leaded to the inhibition of STOML2, a protein that directly interacts with PINK1. In summary, our research indicates that RES improved the susceptibility of A549/PTX cells to PTX through miR-671-5p-mediated STOML2 inhibition.


The dorsal filament of the weakly electric Apteronotidae (Gymnotiformes; Teleostei) is specialized for electroreception.
The Apteronotidae, a family of weakly electric fish from South America (Gymnotiformes), possess a structure called the dorsal filament with an unknown function and evolutionary origin. This study compared the gross anatomy of the dorsal filament of 13 species of apteronotids and used light microscopy to examine the filaments of Adontosternarchus balaenops, Apteronotus albifrons, and Apteronotus leptorhynchus. The dorsal filament is an unscaled, thin, tapering structure attached to a mid-dorsal groove on the posterior half of the fish's back. The interior of the filament is a gelatinous mucopolysaccharide matrix (connective tissue) containing blood vessels and a bilateral nerve in which nearly all the afferents are large (8-10 mu m) and heavily myelinated. The location of the anterior origin of the filament varies from 0.48 to 0.66 of the body length, posterior to the snout, in 13 species. The filament is covered with hundreds of large-type tuberous electroreceptors and some ampullary receptors, at approximately the same density and ratio as those on the nearby back. The morphology of the large-type tuberous receptors and their afferents suggests that they are phase-coding T-units. A double layer of epithelial cells separates the ventral side of the filament from the groove in the trunk of the fish, except at the anterior origin where the interior of the filament is continuous with the body. This specialized double epithelium could provide a high resistance barrier to electrical current. This study was unable to distinguish between two hypotheses: that the dorsal filament is a modified adipose fin (as suggested previously), retained only in this family of Gymnotiformes; or that it is a uniquely derived character of the Apteronotidae.


Human granulocytic ehrlichiosis as a common cause of tick-associated fever in Southeast Sweden: report from a prospective clinical study.
Between May and December 1998, tick-associated febrile illness was prospectively studied in Southeast Sweden in order to assess the occurrence of human granulocytic ehrlichiosis (HGE). Inclusion criteria were fever (> or = 38.0 degrees C), with or without headache, myalgia or arthralgia in patients with an observed tick bite or tick exposure within 1 month prior to onset of symptoms. Patients with clinical signs of Lyme borreliosis were included. Of the 27 patients included, we identified 4 cases of HGE. Three of the patients had coinfection with Lyme borreliosis, which presented as erythema migrans. All 27 patients presented with a 2-5 d history of fever. None of the clinical signs or laboratory parameters monitored was helpful in predicting ehrlichiosis in this group with tick-associated fever conditions. Within the HGE-negative group (n = 23), 12 patients had clinical or laboratory signs of Lyme borreliosis. For 11 patients, the aetiology of the fever remained unclear. Our results suggest that HGE is common in tick-infested areas of Southeast Sweden, and may occur as a coinfection of Lyme borreliosis. Granulocytic ehrlichiosis should be suspected in patients who present with tick-associated fever, with or without erythema migrans. Ehrlichia serology and PCR should be employed to confirm the diagnosis.


Designing and testing regenerative pulp treatment strategies: modeling the transdentinal transport mechanisms.
The need for simulation models to thoroughly test the inflammatory effects of dental materials and dentinogenic effects of specific signaling molecules has been well recognized in current dental research. The development of a model that simulates the transdentinal flow and the mass transfer mechanisms is of prime importance in terms of achieving the objectives of developing more effective treatment modalities in restorative dentistry. The present protocol study is part of an ongoing investigation on the development of a methodology that can calculate the transport rate of selected molecules inside a typical dentinal tubule. The transport rate of biological molecules has been investigated using a validated CFD code. In that framework we propose a simple algorithm that, given the type of molecules of the therapeutic agent and the maximum acceptable time for the drug concentration to attain a required value at the pulpal side of the tubules, can estimate the initial concentration to be imposed.


Self-Efficacy, Depression, and Self-Care Activities in Adult Jordanians with Type 2 Diabetes: The Role of Illness Perception.
Diabetes mellitus is reaching epidemic levels worldwide. In a developing country like Jordan, type 2 diabetes mellitus (T2DM) has reached a prevalence rate of 17.1%. This cross-sectional study examined the relationship between self-care activities and: illness perception, depression, social support, religiosity and spiritual coping, and self-efficacy among patients with T2DM. A random sample of 220 patients with T2DM, who attended Jordan University Hospital in Jordan were enrolled. The data were collected through a structured interview and the medical files. The instruments consisted of a sociodemographic and clinical standardised questionnaires: Brief Illness Perception Questionnaire, Patients' Health Questionnaire-9; ENRICH Social Support Instrument; Religious and Spiritual Coping Subscale; Diabetes Management Self-Efficacy Scale; and Summary of Diabetes Self-Care Activities. Bivariate analysis investigated the relationship between variables. Structure Equation Modelling (SEM) was performed to test the proposed conceptual model. The study found that approximately 70% of the respondents suffered some form of depressive symptoms. The SEM showed a direct relationship between self-efficacy and self-care activities (β = 0.40; p < 0.001). Depression was indirectly related to self-care activities through self-efficacy (β = -0.20; p = 0.003); nevertheless, it was directly related to perception of: treatment control, consequences, and emotional representations. Overall, the sequence between illness perception and self-efficacy was mediated by depression. Strategies to promote self-efficacy and illness perception are vital in customising a diabetes health plan to meet Arabic cultural expectations.


Cross-tissue patterns of DNA hypomethylation reveal genetically distinct histories of cell development.
Establishment of DNA methylation (DNAme) patterns is essential for balanced multi-lineage cellular differentiation, but exactly how these patterns drive cellular phenotypes is unclear. While > 80% of CpG sites are stably methylated, tens of thousands of discrete CpG loci form hypomethylated regions (HMRs). Because they lack DNAme, HMRs are considered transcriptionally permissive, but not all HMRs actively regulate genes. Unlike promoter HMRs, a subset of non-coding HMRs is cell type-specific and enriched for tissue-specific gene regulatory functions. Our data further argues not only that HMR establishment is an important step in enforcing cell identity, but also that cross-cell type and spatial HMR patterns are functionally informative of gene regulation. To understand the significance of non-coding HMRs, we systematically dissected HMR patterns across diverse human cell types and developmental timepoints, including embryonic, fetal, and adult tissues. Unsupervised clustering of 126,104 distinct HMRs revealed that levels of HMR specificity reflects a developmental hierarchy supported by enrichment of stage-specific transcription factors and gene ontologies. Using a pseudo-time course of development from embryonic stem cells to adult stem and mature hematopoietic cells, we find that most HMRs observed in differentiated cells (~ 60%) are established at early developmental stages and accumulate as development progresses. HMRs that arise during differentiation frequently (~ 35%) establish near existing HMRs (≤ 6 kb away), leading to the formation of HMR clusters associated with stronger enhancer activity. Using SNP-based partitioned heritability from GWAS summary statistics across diverse traits and clinical lab values, we discovered that genetic contribution to trait heritability is enriched within HMRs. Moreover, the contribution of heritability to cell-relevant traits increases with both increasing HMR specificity and HMR clustering, supporting the role of distinct HMR subsets in regulating normal cell function. Our results demonstrate that the entire HMR repertoire within a cell-type, rather than just the cell type-specific HMRs, stores information that is key to understanding and predicting cellular phenotypes. Ultimately, these data provide novel insights into how DNA hypo-methylation provides genetically distinct historical records of a cell's journey through development, highlighting HMRs as functionally distinct from other epigenomic annotations.