Mini-Cog for the diagnosis of Alzheimer's disease dementia and other dementias within a secondary care setting.
The diagnosis of Alzheimer's disease dementia and other dementias relies on clinical assessment. There is a high prevalence of cognitive disorders, including undiagnosed dementia in secondary care settings. Short cognitive tests can be helpful in identifying those who require further specialist diagnostic assessment; however, there is a lack of consensus around the optimal tools to use in clinical practice. The Mini-Cog is a short cognitive test comprising three-item recall and a clock-drawing test that is used in secondary care settings. The primary objective was to determine the diagnostic accuracy of the Mini-Cog for detecting Alzheimer's disease dementia and other dementias in a secondary care setting. The secondary objectives were to investigate the heterogeneity of test accuracy in the included studies and potential sources of heterogeneity. These potential sources of heterogeneity will include the baseline prevalence of dementia in study samples, thresholds used to determine positive test results, the type of dementia (Alzheimer's disease dementia or all causes of dementia), and aspects of study design related to study quality. We searched the following sources in September 2012, with an update to 12 March 2019: Cochrane Dementia Group Register of Diagnostic Test Accuracy Studies, MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Web of Knowledge), Science Citation Index (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We made no exclusions with regard to language of Mini-Cog administration or language of publication, using translation services where necessary. We included cross-sectional studies and excluded case-control designs, due to the risk of bias. We selected those studies that included the Mini-Cog as an index test to diagnose dementia where dementia diagnosis was confirmed with reference standard clinical assessment using standardised dementia diagnostic criteria. We only included studies in secondary care settings (including inpatient and outpatient hospital participants). We screened all titles and abstracts generated by the electronic database searches. Two review authors independently checked full papers for eligibility and extracted data. We determined quality assessment (risk of bias and applicability) using the QUADAS-2 tool. We extracted data into two-by-two tables to allow calculation of accuracy metrics for individual studies, reporting the sensitivity, specificity, and 95% confidence intervals of these measures, summarising them graphically using forest plots. Three studies with a total of 2560 participants fulfilled the inclusion criteria, set in neuropsychology outpatient referrals, outpatients attending a general medicine clinic, and referrals to a memory clinic. Only n = 1415 (55.3%) of participants were included in the analysis to inform evaluation of Mini-Cog test accuracy, due to the selective use of available data by study authors. There were concerns related to high risk of bias with respect to patient selection, and unclear risk of bias and high concerns related to index test conduct and applicability. In all studies, the Mini-Cog was retrospectively derived from historic data sets. No studies included acute general hospital inpatients. The prevalence of dementia ranged from 32.2% to 87.3%. The sensitivities of the Mini-Cog in the individual studies were reported as 0.67 (95% confidence interval (CI) 0.63 to 0.71), 0.60 (95% CI 0.48 to 0.72), and 0.87 (95% CI 0.83 to 0.90). The specificity of the Mini-Cog for each individual study was 0.87 (95% CI 0.81 to 0.92), 0.65 (95% CI 0.57 to 0.73), and 1.00 (95% CI 0.94 to 1.00). We did not perform meta-analysis due to concerns related to risk of bias and heterogeneity. This review identified only a limited number of diagnostic test accuracy studies using Mini-Cog in secondary care settings. Those identified were at high risk of bias related to patient selection and high concerns related to index test conduct and applicability. The evidence was indirect, as all studies evaluated Mini-Cog differently from the review question, where it was anticipated that studies would conduct Mini-Cog and independently but contemporaneously perform a reference standard assessment to diagnose dementia. The pattern of test accuracy varied across the three studies. Future research should evaluate Mini-Cog as a test in itself, rather than derived from other neuropsychological assessments. There is also a need for evaluation of the feasibility of the Mini-Cog for the diagnosis of dementia to help adequately determine its role in the clinical pathway.


Living with a woman with fibromyalgia from the perspective of the husband.
Fibromyalgia (FM) is a chronic pain syndrome, which affects mostly middle-aged women. The syndrome is poorly understood and treatment is mainly palliative. The diagnosis is established from diagnostic criteria. Living with FM means living a life greatly influenced by the illness in various ways for people affected. Aim of the study. The aim of this study was to describe the experiences of living with a woman with FM from the husbands' perspective. Five men married to women with FM were interviewed using a narrative approach. The interviews were analysed using qualitative thematic content analysis. The analysis resulted in the following seven themes: increasing responsibility and work in the home; being an advocate for and supporting the wife; learning to see the woman's changing needs; changing relationship between spouses; changing relationship with friends and relatives; deepening relationship with the children and lacking information and knowledge about FM. The findings show that the women's illness had a great impact on husbands' lives, and that husbands lacked information about the woman's illness. This study shows that it is not only the women with FM who experience a changed life; the whole family life is influenced and limited by FM. The husband's role in the family changes, first and foremost concerning responsibility and workload within the family. This must be taken into consideration in care planning. This study also highlighted the need of information and knowledge about FM expressed by the participants, information that health care personnel have a great responsibility to give.


In Situ Decellularization of Tissues Applied to the Topographical Analysis of Tumor-Associated Extracellular Matrix.
The extracellular matrix (ECM) is a network woven out of more than 1300 different proteins, of which ≈300 are structural. Their presence, distribution, and abundance change between and within tissues. It is also increasingly clear that the ECM is remodeled in disease-specific patterns. The interactions between organ- or disease-specific ECM and resident cells are a subject of intense research and engineering. Precisely mapping the three-dimensional ECM structure across tissues and diseases is therefore a fundamental task. Here, we discuss in situ decellularization of tissues (ISDoT) as an essential tool to map the ECM supporting primary and metastatic tumors in experimental mice.


Exfoliative cytology of oral mucosa among smokers, opium addicts and non-smokers: a cytomorphometric study.
The present study was conducted to evaluate keratinization as well as nuclear and cytoplasmic changes of oral epithelial cells among smokers, opium addicts and non-smokers through exfoliative cytology technique. Smears of buccal mucosa and mouth floor were collected from 300 males (100 smokers, 100 opium addicts and 100 non-smokers). The nucleus and cytoplasm sizes were determined using image analysis software. Data was analyzed with Mann-Whitney test and Student's t-test on SPSS version 13 statistical software. Statistical significance was defined as P < 0.05. The results revealed statistically significant differences in cellular and nuclear size and the nuclear/cytoplasmic ratio between smokers, opium addicts and non-smokers in different age groups. The mean size of the nucleus compared to that of cytoplasm was significantly higher in smokers and opium addicts compared to non-smokers after correction for age. The results of this study indicate different rates of epithelial cell keratinization in oral cavity among smokers, opium addicts and non-smokers. Also, our results suggest a possible relationship between the number of cigarettes per day, daily opium consumption and an increase in the rate of cellular proliferation of oral mucosal cells. The present study indicated a decrease in cellular diameter as well as an increase in nuclear diameter and nuclear/cytoplasmic ratio in smears taken from both smokers and opium addicts compared to non-smokers.


Whither Magnetic Hyperthermia? A Tentative Roadmap.
The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.


The consequences of diminishing industry support on the independent education landscape: an evidence-based analysis of the perceived and realistic impact on professional development and patient care among oncologists.
In recent years, commercial funding for continuing medical education (CME) has dropped significantly. Yet, little has been written about how this might affect CME in oncology, a field in which new drugs and advances emerge at a rapid pace. This study examines the role oncologists and oncology fellows say that CME plays in their ongoing professional development and their attitudes about the potential and realistic impact upon both the dissemination of medical information and the impact on patient care if commercial support were removed from CME. The study is based upon a national survey of 368 oncology clinicians (283 oncologists and 85 oncology fellows). Respondents indicated that CME is an important part of their ongoing professional development. The majority of oncologists (90%) and oncology fellows (78%) "agreed" or "strongly agreed" that commercial support may be more necessary for oncology than for other specialties due to the rate at which cancer therapies are introduced. Respondents felt loss of commercial support would impact cost, format, and availability of oncology CME programs. Half of oncologists thought eliminating commercial support for CME would have a negative impact on application of new therapies in oncology. Yet, both oncologists and oncology fellows were reluctant to claim the removal of commercial support would negatively affect the practice of evidence-based medicine, patient outcomes, or patient safety. A possible explanation of this apparent contradiction is found in the social sciences literature.


Liver transplantation for acute liver failure due to toxic agent ingestion in children.
ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.


Sarcopenia is a Predictor for Adverse Clinical Outcome in Pediatric Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) has a high impact on nutritional status. Sarcopenia is related to higher risk of surgery and rescue therapy in adults with IBD; however, comparable data in pediatric populations are scarce. We evaluated muscle mass as a predictor of disease outcome in pediatric IBD. All pediatric IBD patients who underwent magnetic resonance enterography (MRE) during 2008 to 2019 were included. Muscle mass was assessed by measuring the area of the psoas muscle at the upper level of L3 on MRE. The psoas area divided by the body surface area (BSA) yielded the psoas index. Clinical and radiological data, including disease location, activity, course, and medications were documented. The control group included non-IBD children who underwent an MR imaging study. We enrolled 101 IBD patients, 69 (68.3%) with Crohn disease (CD) and 32 (31.7%) with ulcerative colitis (UC) (mean age 15.03 ± 3.27 years). The psoas index was significantly lower in the IBD patients compared with the 87 controls (326 vs 528, respectively, P < 0.001). Patients with a psoas index in the lowest quartile had significantly higher risk for biologic therapy (multivariate analysis, hazard ratio [HR] = 12.1, P = 0.046) and disease exacerbation (HR = 9, P = 0.047) independently of body mass index, compared with patients with a psoas index in the uppermost quartile. Sarcopenia correlates with the radiological severity of pediatric IBD and serves as a predictor for adverse clinical disease outcome. Muscle mass measurement in MRE studies may serve as a possible marker for disease outcome in this population.


Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis.
Drosophila Down syndrome cell adhesion molecule (Dscam) can be variably spliced to encode 152,064 distinct single-pass transmembrane proteins. In addition to 19,008 possible ectodomains and two alternative transmembrane segments, it may carry endodomains containing or lacking exons 19 and 23. Here, we determine the role of Dscam endodomain diversity in neural development. Dscam with full-length endodomain is largely restricted to embryogenesis. In contrast, most Dscams lack exons 19 and 23 at postembryonic stages. As implicated from the expression patterns, removal of Dscam exon 19-containing variants disrupts wiring of embryonic neurons while silencing of Dscam transcripts lacking exon 19 or exon 23 effectively blocks postembryonic neuronal morphogenesis. Furthermore, compared with exon 19-containing Dscam, transgenic Dscam without exon 19 is more efficiently targeted to neurites and more potently suppresses axon bifurcation in Dscam mutant neurons. In sum, Dscam with or without exon 19 in its endodomain is used to govern different stage-specific neuronal morphogenetic processes, possibly due to differences in protein targeting.


[Relationship between the cytogenetic effect of different concentrations of thiophosphamide and phosphemide and the duration of their contact with human lymphocytes].
The effect of thiophosphamide at conccentrations of 10, 20 and 30 mcg/ml and phosphamide at concentrations of 35 and 50 mck/ml on human lymphocyte chromosomes at different time of the contact was investigated. The experiments were carried out at GO phase (before adding FGA) at 37 degrees C from 10 to 240 minutes. The fixation was made within 58th hour. A mathematical model, satisfactory describing experimental data on the reaction of mutagen-chromosome interaction during the time of exposition, is suggested. According to this model, the following equation are obtained: rho = (1 - e-(alpha+Kt))2; chi = (see article), where rho is a portion of aberrant cells, chi is the average number of breaks per cell, t is the time of exposition of mutagens with cells, alpha and K are coefficients. Breaks induced by thiophosphamide and phosphamide are distributed among cells according to geometrical parameter under any experimental conditions. The portion of chromatid breaks did not change at any exposition time for both mutagens and remained on the level of 76,53%. The proportion of symmetric and asymmetric exchanges under different experimental conditions did not differe from 1 : 1. The prabability of the formation of complete exchanges in the case of the action of thiophosphamide was higher than in the case of phesphamide.


Comparison of the use of wireless capsule endoscopy with magnetic resonance enterography in children with inflammatory bowel disease.
Magnetic resonance enterography (MRE) and wireless capsule endoscopy (WCE) are equally accepted modalities for noninvasive screening of small bowel involvement (SBI) in children with Crohn's disease (CD) and indeterminate colitis (IC) albeit there is a paucity of data comparing the two and thereby guiding the clinician in selecting the ideal diagnostic approach. Therefore, the goal of this study is to provide additional evidence for capsule endoscopy role in the evaluation of established Crohn's disease exacerbation compared to MRE in relation to Pediatric Crohn's Disease Activity Index (PCDAI), and histological indices. To prospectively compare the findings of MRE and WCE and their agreement with PCDAI or histology in children with CD or IC. Consecutive patients diagnosed with CD and IC were screened for inclusion. After informed consent, patient's demographic and clinical data was abstracted. The current pediatric disease activity index (PCDAI) and endoscopic findings were included. Patients underwent MRE and WCE including preprocedural patency capsule within a maximum of 7 d of each other. Pathological presence of active small bowel disease in ileal and duodenal biopsies were collected if the endoscopy was performed within 2 mo of the WCE study. Patients who failed to pass the PC were excluded from the study. WCE was read by two different experienced gastroenterologists (Attard TM and Colombo JM) blinded to each other's findings and to the findings on MRE (Mardis NJ). Agreement between WCE reviewers, WCE and MRE findings and concordance between positive PCDAI and SBI based on MRE compared with WCE was computed. Forty-five patients were included in the study, 18 withdrew and 27 (20 males and 20 CD), mean age (standard deviation) 13.46 (2.4) years, completed the study protocol. There were no instances of capsule retention. Concordance between gastroenterologist reviewers was excellent for the diagnosis of small intestinal CD with good correlation between the two Lewis scores (r = 0.875, P < 0.001). Concordance between WCE and MRE was poor (69%). In CD patients, when both MRE and WCE were compared using PCDAI > 10 as the standard reference reflecting active small intestinal CD, the sensitivity of MRE and WCE were 100% and 83% respectively and the specificity of MRE and WCE were 57.14% and 78.6%, respectively. If the histology in ileum or/and duodenum was used as the reference for active small bowel involvement, WCE had a higher specificity as compared to MRE (83.3% vs 50%). In patients with Crohn's disease, those with a positive PCDAI (> 10) were more likely to have a positive WCE as compared to those with a negative PCDAI (83% vs 21%; P = 0.018). We suggest that MRE and WCE have a complementary role in the assessment of SBI in CD. WCE detected SBI with a much higher specificity while MRE had a higher sensitivity.


Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD.


Toward Patient-specific Pessary to Manage Pelvic Organ Prolapse: Design and Simulation.
This study proposed a novel design and personalized approach to developing an intra-vaginal device, also known as a pessary, for the treatment of Pelvic Organ Prolapse (POP). Although POP is likely to have a more diverse dynamic than other health conditions in women, it is currently treated as a "one-shape-fits-all" problem in all cases. Pessaries are conservative devices inserted into the vagina to support its internal structure and predominantly come in a ring shape design. Failure rates as high as 50% within the first year of use have been attributed to the poor design of these pessaries; with symptoms such as irritation, bleeding, and lacerations felt by most users. To address this problem, a new base shape design was proposed and its deformation was examined using Finite Element Analysis (FEA). Based on the anatomical measurements of each patient, the base design can be adjusted accordingly. To demonstrate the effectiveness of the proposed design, a comparative study was conducted with the most commonly used support pessary, also known as the ring pessary. In order to model the large deformation of the pessaries, the hyperelastic constitutive law (Yeoh model) was fitted to the available stress-strain data of SIL 30 (a silicone urethane resin supplied by Carbon Inc.). The results showed that re-directing the reaction forces of the pessary towards the lateral walls, supported by the pelvic bones, could decrease the overall displacement of the pessaries, and provide effective symptomatic relief thereby, delaying or preventing surgical procedures.Clinical relevance- There is a clear clinical need to develop a more effective conservative therapy for managing POP. The personalized pessaries proposed in this paper can be an effective method for providing symptomatic relief and avoiding displacement, compared to the currently available devices on the market. Made-to-measure for each patient, the devices are anatomically suited and can be adjusted throughout a patient's treatment plan to allow for higher compliance and overall success rate.


Poxvirus proteomics and virus-host protein interactions.
Studies of the functional proteins encoded by the poxvirus genome provide information about the composition of the virus as well as individual virus-virus protein and virus-host protein interactions, which provides insight into viral pathogenesis and drug discovery. Widely used proteomic techniques to identify and characterize specific protein-protein interactions include yeast two-hybrid studies and coimmunoprecipitations. Recently, various mass spectrometry techniques have been employed to identify viral protein components of larger complexes. These methods, combined with structural studies, can provide new information about the putative functions of viral proteins as well as insights into virus-host interaction dynamics. For viral proteins of unknown function, identification of either viral or host binding partners provides clues about their putative function. In this review, we discuss poxvirus proteomics, including the use of proteomic methodologies to identify viral components and virus-host protein interactions. High-throughput global protein expression studies using protein chip technology as well as new methods for validating putative protein-protein interactions are also discussed.


Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.
Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (beta(1)AR) to transactivate the EGFR. To determine whether beta-adrenergic ligands that do not activate G protein signaling (i.e., beta-blockers) can stabilize the beta(1)AR in a signaling conformation, we screened 20 beta-blockers for their ability to stimulate beta-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce beta(1)AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the beta(1)AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against beta-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires beta(1)AR phosphorylation at consensus G protein-coupled receptor kinase sites and beta-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, beta-arrestin-dependent fashion.


Mechanisms of bacterial resistance to antimicrobial agents, with particular reference to cefotaxime and other beta-lactam compounds.
Many mechanisms exist by which bacteria can become resistant to antimicrobial agents. Although mutational events are important in the development of resistance to some agents, by far the most important factor in resistance is extrachromosomal genetic material in the form of plasmids. Important mechanisms of bacterial resistance to antibiotics are interference with the transport of the antimicrobial agents into the bacterial cell, inactivation of the agent, and alteration of the target site or metabolic pathway by the microorganism. In order to affect bacteria, beta-lactam antibiotics must pass through proteins at the surface of the cell, must evade destruction by beta-lactamases, and must have an affinity for proteins involved in cell wall synthesis. A number of the new beta-lactam antibiotics, because of their great resistance to destruction by beta-lactamases and their high affinity for penicillin-binding proteins, have overcome many of the mechanisms bacteria have used in the past to resist beta-lactam drugs.


The bulge area is the origin of nestin-expressing pluripotent stem cells of the hair follicle.
Nestin-expressing pluripotent stem cells have been found both in the bulge area (BA) as well as the dermal papilla (DP). Nestin-expressing stem cells of both the BA and DP have been previously shown to be able to form neurons and other non-follicle cell types. The nestin-expressing stem cells from the DP have been termed skin precursor or SKP cells. Both nestin-expressing DP and BA cells have been previously shown to effect repair of the injured spinal cord and peripheral nerve, with the BA being the greater and more constant source of the stem cells. The BA contains nestin-expressing stem cells throughout the hair cycle, whereas nestin-expressing dermal papillae stem cells were found in early and mid-anagen only. Our previous studies have shown that the nestin-expressing stem cells in the BA and DP have similar morphological features. The cells from both regions have a small body diameter of approximately 7 µm with long extrusions, as shown by 2-photon imaging. In the present study, using 2-photon imaging of whisker follicles from transgenic mice expressing nestin-driven green fluorescent protein (ND-GFP), we demonstrate that the BA is the source of the nestin-expressing stem cells of the hair follicle. The nestin-expressing stem cells migrate from the BA to the DP as well as into the surrounding skin tissues including the epidermis, and during wound healing, suggesting that the BA may be the source of the stem cells of the skin itself.


Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study.
The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.


Specimen processing techniques for endobronchial ultrasound-guided transbronchial needle aspiration.
Endobronchial ultrasound is used for sampling thoracic pathologic processes. Histologic examination may provide added diagnostic yield to cytologic preparations owing to superior assessment of architecture and immunohistochemistry. It remains unclear whether specific specimen processing technique impacts diagnostic yield. We hypothesized that diagnostic yield using histologic analysis of core needle biopsies is higher than cytologic preparations alone. We evaluated 177 consecutive patients with mediastinal abnormalities. An interventional pulmonologist or thoracic surgeon performed endobronchial ultrasound. We compared diagnostic yields of two specimen processing techniques, fixed slides (cytology) and formalin-fixed core samples (histology). Results were categorized as malignant, benign (infectious, inflammatory), normal nodal tissue, or inadequate sampling (nondiagnostic). Malignancy, a defined benign process, and normal lymph node were considered diagnostic. The diagnostic yield for benign processes was higher by histologic examination (n = 37) than in cytologic preparations (n = 22; p = 0.0064). The diagnostic yield was comparable in malignancy (p = 0.7530). The combination of both techniques provided a higher overall diagnostic rate: 84% (n = 148) by histology, 82% (n = 146) by cytology, and 89% (n = 158) using both. Using two techniques revealed discordance in 23% (n = 40), demonstrating that the use of one technique alone would have resulted in missed diagnoses. Adding histologic analysis of tissue cores obtained by endobronchial ultrasound offers higher diagnostic accuracy than only cytologic preparation of needle aspirates. Histologic and cytologic methods offer comparable diagnostic rates for malignancy. However, diagnostic yield for benign conditions is higher using histologic examination. Together, histology and cytology provide fewer missed diagnoses than either individually. When using endobronchial ultrasound, it is ideal to routinely use both needle aspirate cytology and core biopsy histology.


The effect of maternal antibiotic use in sows on intestinal development in offspring.
The objective of this study is to investigate the effect of a maternal antibiotic administration during the last week of gestation on the early life intestinal development in neonatal piglets. Colonization of the gut with bacteria starts during birth and plays a major role in the intestinal and immunological development of the intestine. We demonstrate that maternal interventions induced changes in the sows (n = 6 to 8 per treatment) fecal microbiota diversity around birth (P < 0.001, day 1). Whole-genome microarray analysis in small intestinal samples of 1-d old piglets (n = 6 to 8 per treatment) showed significantly expressed genes (Padj < 0.05) which were involved in processes of tight junction formation and immunoglobulin production. Furthermore, when performing morphometry analysis, the number of goblet cells in jejunum was significantly (P < 0.001) lower in piglets from amoxicillin administered sows compared with the respective control piglets. Both significantly expressed genes (Padj < 0.05) and significant morphometry data (jejunum P < 0.05 and ileum P < 0.01) indicate that the crypts of piglets from amoxicillin administered sows deepen around weaning (day 26) as an effect of the amoxicillin administration in sows. The latter might imply that the intestinal development of piglets was delayed by maternal antibiotic administration. Taken together, these results show that maternally oral antibiotic administration changes in early life can affect intestinal development of the offspring piglets for a period of at least 5 wk after the maternal antibiotic administration was finished. These results show that modulation of the neonatal intestine is possible by maternal interventions.


[Phenomenology of multiculturalism and intercultural pluralism].
Multiculturalism is defined as the combination, within a given territory, of a social unit and a cultural plurality by way of exchanges and communications among actors who use different categories of expression, analysis and interpretation. A multiculturalist project should not promote a society that is split up into closed groups; on the contrary, it should set forth policies based on communication and cooperation processes among the cultural communities. To understand this concept, we will present the ontological basis of this phenomenonin the search for a communicational solution, with our startpoint being a phenomenological description of the way in which multiculturalism manifests to us in life; to later deepen into the meaning of the phenomenon,and finally offer a pluralist solution to the problems and challenges cultural differences bring about.


Improvements in physical wellbeing over the first two years on antiretroviral therapy in western Kenya.
Improvements in physical wellbeing during the first six months on antiretroviral therapy (ART) are well known, but little is known regarding long-term follow-up. We conducted a prospective cohort study among 222 HIV-positive adult tea plantation workers in western Kenya to assess wellbeing over their first two years on ART. Study subjects completed a standardized questionnaire during repeat ART clinic visits. A 30-day recall period was used to elicit the number of days when subjects experienced poor health and the number of days that pain made it difficult to complete usual activities at home and work. A seven-day recall period was used to assess the severity of bodily pain, nausea, fatigue, and rash. Prevalence of most symptoms declined over time. A median of seven days poor health during the first month on ART declined to three days in the 24th month (p=0.043). For pain making usual activities difficult, a median of seven days during the first month on ART fell to zero by 12 months (p< or =0.0001) but increased to three days by two years. Any bodily pain (range 59-83%) and fatigue (range 51-84%) over the past seven days were common through two years. However, pain and fatigue often over the past seven days declined over two years (from 24-10% (p=0.067) and 41-15% (p=0.002)). Skin rash was rare at all times, though higher at two years (8.6%) than any other time. Initial improvements in physical wellbeing were sustained over two years, however, increased pain and skin rash at year two may indicate problems as treatment programs mature. These improvements in physical wellbeing will be important in sustaining the long-term success of HIV treatment programs.


Functional roles of alternative splicing factors in human disease.
Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell-type or tissue-specific manner, and at different developmental stages. AS is regulated by RNA-binding proteins, including cell- or tissue-specific splicing factors. In the past few years, technological advances have defined genome-wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact.


Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype.
To determine the proportion and physiological characteristics of nonobese patients with obstructive sleep apnea (OSA) and their response to prescribed therapy. Data from 163 consecutive in-laboratory diagnostic sleep studies for participants referred to an academic teaching-hospital sleep clinic for suspected OSA were assessed. Sleep and anthropometric parameters at baseline and follow-up (up to 22 mo) were examined and compared between obese and nonobese patients with a diagnosis of OSA (apnea-hypopnea index > 5 events/h sleep). A key nonanatomical contributor to OSA pathogenesis, the respiratory arousal threshold, was compared between groups. Twenty-five percent of the participants with a diagnosis of OSA had a body mass index (BMI) within the normal range (BMI < 25 kg/m2) and 54% had a BMI < 30 kg/m2 (nonobese). Of the patients prescribed continuous positive airway pressure (CPAP), more nonobese patients reported not using their CPAP machine at all at follow-up (36% vs. 13%, p = 0.03). Objective CPAP compliance was also lower in the nonobese patients with OSA (5.1 ± 0.4 vs. 6.4 ± 0.4 h/night, p < 0.03). A higher proportion of the nonobese patients had a low respiratory arousal threshold compared to obese OSA patients (86% vs. 60%, p < 0.001). A substantial proportion of patients with OSA are not obese. These patients are challenging to treat with existing therapies as they are less adherent and compliant with CPAP therapy. Nonanatomical contributors to OSA, such a low threshold for arousal, are likely to be particularly important in OSA pathogenesis in nonobese patients with OSA. These findings have important implications for the pathogenesis of OSA in nonobese patients and potential therapeutic targets for this group of patients.


Psychosocial correlates of smokeless tobacco use among Indiana adolescents.
Adolescent tobacco use is influenced by intrapersonal (e.g., impulse control) and external factors, such as behaviors of friends and peers. The relationships of these factors to smokeless tobacco (ST) use are not yet fully understood. This is especially true as it pertains to the simultaneous examination of psychological and normative perceptions. Using constructs of the Biopsychosocial Model, this study investigates factors associated with lifetime ST use among middle and high school students. Data were analyzed from 938 Indiana middle and high school students. Binary sequential logistic regression was performed to examine the relationship of personal characteristics and psychosocial measures to adolescent lifetime ST use. Approximately 9 % reported having ever used ST, among which 78.6 % were male. Females and younger students were less likely to have used ST in their lifetime, whereas participants with a sibling smoker and those who compared their life to the lives of others were more likely to report lifetime ST usage. In the presence of psychological and normative variables, sex, age, and comparing one's life to others remained significant. Additionally, participants who perceived higher friend approval of substance use were significantly more likely to report lifetime ST use. Understanding the normative perceptions of adolescents may lend insight into the drivers of ST use adolescent subgroups and, which may enable community and school officials to tailor interventions to prevent ST initiation and promote cessation.


Effects of a cholecystokinin receptor antagonist on rat exocrine pancreatic response to raw soya flour.
1 Raw soya flour (RSF) in the diet induces pancreatic hypertrophy and hyperplasia in the rat, changes ascribed to production of a high circulating level of cholecystokinin (CCK) due to inhibition of trypsin in the duodenum. Prolonged ingestion results in pancreatic adenomas and carcinomas. 2 L-364, 718, a potent, highly specific CCK antagonist was used to investigate the short-term role of CCK. 3 In rats fed 50% RSF and L-364, 718 5 mg kg-1 p.o. twice daily for 4 d, there was inhibition of pancreatic hypertrophy and hyperplasia, which is further evidence that peripherally-acting CCK plays a major role in the generation of RSF-mediated changes in the pancreas.


Effect of root surface treatment with propolis and fluoride in delayed tooth replantation in rats.
Replantation is an acceptable option for treatment of an avulsed permanent tooth. Nevertheless, an extended extraoral period damages the periodontal ligament and results in external root resorption. The purpose of this study was to assess by histologic and histometric analysis, the influence of propolis 15% (natural resinous substance collected by Apis mellifera bees from various plants) and the fluoride solution used as root surface treatment on the healing process after delayed tooth replantation. Thirty Wistar (Rattus norvegicus albinus) rats were submitted to extraction of their upper right incisor. The teeth were maintained in a dry environment for 60 min. After this, the pulp was extirpated and the papilla, enamel organ and periodontal ligament were removed with scalpel. The teeth were divided into three experimental groups: Group I - teeth immersed in 20 ml of physiologic saline; Group II - teeth immersed in 20 ml of 2% acidulated phosphate sodium fluoride; Group III - teeth immersed in 20 ml of 15% propolis. After 10 min of immersion in the solutions, the root canals were dried and filled with calcium hydroxide paste and the teeth were replanted. The animals were euthanized 60 days after replantation. The results showed that similar external root resorption was seen in the propolis and fluoride groups. Teeth treated with physiologic saline tended to have more inflammatory root resorption compared with those treated with fluoride or propolis. However, the comparative analysis did not reveal statistically significant differences (P > 0.05) between the treatment modalities when used for delayed tooth replantation.


Components of Isolated Skeletal Muscle Differentiated Through Antibody Validation.
Isolation of skeletal muscles allows for the exploration of many complex diseases. Fibroblasts and myoblast play important roles in skeletal muscle morphology and function. However, skeletal muscles are complex and made up of many cellular populations and validation of these populations is highly important. Therefore, in this article, we discuss a comprehensive method to isolate mice skeletal muscle, create satellite cells for tissue culture, and use immunofluorescence to validate our approach.


Dasatinib-associated reversible demyelinating peripheral polyneuropathy in a case of chronic myeloid leukemia.
Tyrosine kinase inhibitors (TKIs) are essential for the treatment of chronic myeloid leukemia (CML). Adverse effects of dasatinib have been reported; however, few reports have highlighted the association between dasatinib and demyelinating peripheral neuropathy (DPN). We report a patient with CML who developed acute onset of DPN associated with dasatinib therapy. A 46-year-old Japanese woman was treated with dasatinib for 7 months after the diagnosis of CML and she achieved a major molecular response (MMR). However, dysphagia, hoarseness, and muscle weakness progressively developed over 2 weeks. Nerve conduction studies revealed extensive demyelinating changes. Dasatinib was discontinued and the patient received intravenous immunoglobulin (IVIg), resulting in resolution of the symptoms. However, 1 month after the re-initiation of dasatinib therapy, muscle weakness developed again, indicating possible involvement of dasatinib in the development of DPN. She was then treated with IVIg, followed by prednisolone and nilotinib instead of dasatinib. These treatments eventually led to improvements of the symptoms and helped her achieve an MMR. This case suggests that dasatinib may carry risks of DPN possibly through immune-mediated disorders. It is clinically important to realize that dasatinib can cause extensive DPN, and a quick discontinuation and a switch to another TKI may be indicated.


Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.
Acute renal failure (ARF) occurs with significant frequency after myeloablative and nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Myeloablative (conventional) HCT is the standard of care for cure of various malignant disorders. The newer modality of nonmyeloablative ("mini-allo") HCT is reserved for patients with advanced age and comorbidities who are ineligible for myeloablative HCT. The present study compares the incidence of ARF between patients undergoing concurrent myeloablative and nonmyeloablative HCT in the same period at the same institution. This retrospective cohort study from 1997 to 2003 compares 140 myeloablative and 129 nonmyeloablative patients from the Fred Hutchinson Cancer Research Center. Severity of ARF was classified into 4 grades based on the increase in serum creatinine levels in the first 100 days after HCT. Mortality was studied at 100 days and 1 year. Nonmyeloablative patients were significantly older and had greater pretransplantation comorbidity at baseline. Despite this, patients undergoing myeloablative HCT had a greater incidence of severe ARF (grades 2 and 3, 73% versus 47%; P < 0.001). The incidence of dialysis also was 4-fold greater (12% versus 3%; P < 0.001) in the myeloablative than nonmyeloablative group. On multivariate analysis after controlling for baseline characteristics, myeloablative HCT was associated with a 4.8-fold greater incidence of ARF compared with nonmyeloablative HCT. Nonrelapse mortality also was greater in the myeloablative group at 100 days and 1 year. The incidence and severity of ARF, as well as nonrelapse mortality, occurring after nonmyeloablative HCT is significantly lower compared with myeloablative HCT.


A conserved region between the TPR and activation domains of p67phox participates in activation of the phagocyte NADPH oxidase.
The phagocyte NADPH oxidase, dormant in resting cells, is activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants. The membrane-integrated protein gp91(phox) serves as the catalytic core, because it contains a complete electron-transporting apparatus from NADPH to molecular oxygen for superoxide production. Activation of gp91(phox) requires the cytosolic proteins p67(phox), p47(phox), and Rac (a small GTPase). p67(phox), comprising 526 amino acids, moves upon cell stimulation to the membrane together with p47(phox) and there interacts with Rac; these processes are prerequisite for gp91(phox) activation. Here we show that a region of p67(phox) (amino acids 190-200) C-terminal to the Rac-binding domain is evolutionarily well conserved and participates in oxidase activation at a later stage in conjunction with an activation domain. Alanine substitution for Tyr-198, Leu-199, or Val-204 abrogates the ability of p67(phox) to support superoxide production by gp91(phox)-based oxidase as well as its related oxidases Nox1 and Nox3; the activation also involves other invariant residues such as Leu-193, Asp-197, and Gly-200. Intriguingly, replacement of Gln-192 by alanine or that of Tyr-198 by phenylalanine or tryptophan rather enhances superoxide production by gp91(phox)-based oxidase, suggesting a tuning role for these residues. Furthermore, the Y198A/V204A or L199A/V204A substitution leads to not only a complete loss of the activity of the reconstituted oxidase system but also a significant decrease in p67(phox) interaction with the gp91(phox) NADPH-binding domain, although these mutations affect neither the protein integrity nor the Rac binding activity. Thus the extended activation domain of p67(phox) (amino acids 190-210) containing the D(Y/F)LGK motif plays an essential role in oxidase activation probably by interacting with gp91(phox).


Preparation of Direct Healthcare Professional Communication: An Exploratory Study on the Experiences and Perceptions of European Pharmaceutical Companies and the EMA.
Despite the regulatory requirement for cooperation between marketing authorization holders (MAHs) and European Medicines Agency (EMA) in the direct healthcare professional communication (DHPC) preparation, no literature has explored DHPCs from an industry-regulator perspective. This constitutes a significant knowledge gap as any possibility of improving current DHPC effectiveness depends on decisions in the cooperative preparation phase. Thus, this EU-centered study explores differences in perceptions and experiences of DHPCs of European MAHs and EMA. European MAHs (n = 6) and EMA representatives (n = 2) were interviewed. The verbatim transcripts were coded into themes using NVivo software. Interview analysis was performed following a phenomenological approach of meaning condensation. The DHPC process was perceived as burdensome by the industry. One company stated the process was time-consuming either due to EMA's internal lengthy approval process or the translation activities with local company affiliates and national competent authorities. Three companies stated that DHPCs were not effective. One company stated that DHPCs are sent out due to legal obligations and not because of their use as a risk minimization measure (RMM). Newly emerged safety concerns were found difficult to phrase. Optimization proposals included improved timelines, scrutinization of healthcare professionals and better communication tools in clinical practice. DHPCs were not perceived as optimal, although the most effective intervention as it targets healthcare professionals directly. Continuous evaluation by EMA of DHPCs and evaluation on how to reach healthcare professionals are necessary. It is believed that industry perceptions from this study can support EMA with improved regulatory decision making to benefit public health.


The role of small airways in obstructive airway diseases.
This review article is a summary of a seminar organised by the European Respiratory Society on "The role of small airways in obstructive airway diseases" which was held in October 2010 in Amsterdam, the Netherlands. The aims of the seminar were to identify important questions related to small airways involvement in asthma and chronic obstructive pulmonary disease (COPD), and to discuss future approaches based on current and evolving knowledge. Data obtained by pathological and physiological measurements in small airways and their relevance to clinical manifestations and therapeutics in asthma and COPD were reviewed. It was concluded that our knowledge on the roles of small airways in asthma and COPD is limited. Studies of large numbers of well-characterised subjects using multiple methods (genetic characterisation, cell biology and physiology, imaging) and integration of the data using mathematical models are suggested to be of interest. The availability of these techniques coupled with our ability to better target inhaled molecules to small airways provide a unique opportunity for a reappraisal of the relevance of small airways in chronic airway diseases.


Survivin isoforms and clinicopathological characteristics in colorectal adenocarcinomas using real-time qPCR.
To investigate three isoforms of survivin in colorectal adenocarcinomas. We used the LightCycler Technology (Roche), along with a common forward primer and reverse primers specific for the splice variants and two common hybridization probes labeled with fluorescein and LightCycler-Red fluorophore (LC-Red 640). Real time quantitative polymerase chain reaction (PCR) was performed on cDNAs from 52 tumor specimens from colorectal cancer patients and 10 unrelated normal colorectal tissues. In the patients group, carcinoembryonic antigen (CEA) and CA19-9 tumor markers were also measured immunochemically. Wild type survivin mRNA isoform was expressed in 48% of the 52 tumor samples, survivin-2b in 38% and survivin-ΔΕx3 in 29%, while no expression was found in normal tissues. The mRNA expression of wild type survivin presented a significant correlation with the expression of the ratio of survivin-2b, survivin-ΔΕx3, survivin-2b/wild type survivin and survivin-ΔΕx3/wild type survivin (P < 0.001). The mRNA expression of wild-survivin and survivin-ΔΕx3 was related with tumor size and invasion (P = 0.006 and P < 0.005, respectively). A significant difference was found between survivin-2b and morphologic cancer type. Also, the ratio of survivin-ΔEx3/wild-survivin was significantly associated with prognosis. No association was observed between the three isoforms and grade, metastasis, Dukes stage and gender. The three isoforms were not correlated with CEA and CA19-9. Survivin isoforms may play a role in cell apoptosis and their quantification could provide information about clinical management of patients suffering from colorectal cancer.


Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.


Costs and cost-effectiveness of the meeting centres support programme for people living with dementia and carers in Italy, Poland and the UK: The MEETINGDEM study.
We examined the costs and cost-effectiveness of the Meeting Centre Support Programme (MCSP) implemented and piloted in the UK, Poland and Italy, replicating the Dutch Meeting Centre model. Dutch Meeting Centres combine day services for people with dementia with carer support. Data were collected over 2015-2016 from MCSP and usual care (UC) participants (people with dementia-carer dyads) at baseline and 6 months. We examined participants' health and social care (HSC), and societal costs, including Meeting Centre (MC) attendances. Costs and outcomes in MCSP and UC groups were compared. Primary outcomes: Persons with dementia: quality-adjusted life years (EQ-5D-5L-derived); QOL-AD. DQoL was examined as a secondary outcome. Carers: Short Sense of Competence Questionnaire (SSCQ). Incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves were obtained by bootstrapping outcome and cost regression estimates. Eighty-three MCSP and 69 UC dyads were analysed. The 6-month cost of providing MCSP was €4,703; participants with dementia attended MC a mean of 45 times and carers 15 times. Including intervention costs, adjusted 6-month HSC costs were €5,941higher in MCSP than in UC. From the HSC perspective: in terms of QALY, the probability of cost-effectiveness was zero over willingness-to-pay (WTP) ranging from €0 to €350,000. On QOL-AD, the probability of cost-effectiveness of MCSP was 50% at WTP of €5,000 for a one-point increase. A one-point gain in the DQoL positive affect subscale had a probability of cost-effectiveness of 99% at WTP over €8,000. On SSCQ, no significant difference was found between MCSP and UC. Evidence for cost-effectiveness of MCSP was mixed but suggests that it may be cost-effective in relation to gains in dementia-specific quality of life measures. MCs offer effective tailored post-diagnostic support services to both people with dementia and carers in a context where few evidence-based alternatives to formal home-based social services may be available.


The classification of the human gastroenteropancreatic endocrine cells.
A description of the gastroenteropancreatic cells as identified by immunocytochemical techniques is presented. A functional classification of these cells is proposed where function is defined as the production of a chemical messenger be it a polypeptide or a biogenic amine. The discovery of the polypeptide-containing neurons has created a new area for investigation. This will be outlined briefly although the majority of the peptidergic-type synaptic profiles have as yet to be linked with the production of a particular polypeptide.


Comparative bioavailability of two oral formulations of clozapine in steady state administered in schizophrenic volunteers under individualized dose regime.
In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.


Psychological resilience and depressive symptoms in older adults diagnosed with post-polio syndrome.
Depression is a serious comorbidity in people with disabilities; however, few studies have focused on depressive symptoms in older adults with post-polio syndrome (PPS). This study used a resilience conceptual framework that focused on patient psychosocial strengths to investigate the relationship between psychological resilience factors (e.g., acceptance, self-efficacy, personal resources, interpersonal relationships, self-rated health, spiritual growth, stress management) and depressive symptoms in a large sample (N = 630) of people older than 65 years who were diagnosed with PPS. Forty percent of the sample scored > or = 10 on the Center for Epidemiologic Studies Short Depression Scale (CES-D10), which is a higher percentage than what has been previously cited in other studies; however, 53% of the sample had good or excellent self-rated health, suggesting psychological resilience. Depression scores were regressed on seven selected resilience factors after controlling for functional limitations. Four of the seven variables accounted for 30% of the variance in depressive symptoms, with spiritual growth representing the main predictor (beta = -.26). The implications for rehabilitation nurses in developing a patient-strengths perspective in the assessment and counseling of older adults with PPS are discussed.


Detection of intramyocardially injected DiR-labeled mesenchymal stem cells by optical and optoacoustic tomography.
The distribution of intramyocardially injected rabbit MSCs, labeled with the near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo-cyanine-iodide (DiR) using hybrid Fluorescence Molecular Tomography-X-ray Computed Tomography (FMT-XCT) and Multispectral Optoacoustic Tomography (MSOT) imaging technologies, was investigated. Viability and induction of apoptosis of DiR labeled MSCs were assessed by XTT- and Caspase-3/-7-testing in vitro. 2 × 106, 2 × 105 and 2 × 104 MSCs labeled with 5 and 10 μg DiR/ml were injected into fresh frozen rabbit hearts. FMT-XCT, MSOT and fluorescence cryosection imaging were performed. Concentrations up to 10 μg DiR/ml did not cause apoptosis in vitro (p > 0.05). FMT and MSOT imaging of labeled MSCs led to a strong signal. The imaging modalities highlighted a difference in cell distribution and concentration correlated to the number of injected cells. Ex-vivo cryosectioning confirmed the molecular fluorescence signal. FMT and MSOT are sensitive imaging techniques offering high-anatomic resolution in terms of detection and distribution of intramyocardially injected stem cells in a rabbit model.


General cognitive performance declines with female age and is negatively related to fledging success in a wild bird.
Identifying the causes and fitness consequences of intraspecific variation in cognitive performance is fundamental to understand how cognition evolves. Selection may act on different cognitive traits separately or jointly as part of the general cognitive performance (GCP) of the individual. To date, few studies have examined simultaneously whether individual cognitive performance covaries across different cognitive tasks, the relative importance of individual and social attributes in determining cognitive variation, and its fitness consequences in the wild. Here, we tested 38 wild southern pied babblers (Turdoides bicolor) on a cognitive test battery targeting associative learning, reversal learning and inhibitory control. We found that a single factor explained 59.5% of the variation in individual cognitive performance across tasks, suggestive of a general cognitive factor. GCP varied by age and sex; declining with age in females but not males. Older females also tended to produce a higher average number of fledglings per year compared to younger females. Analysing over 10 years of breeding data, we found that individuals with lower general cognitive performance produced more fledglings per year. Collectively, our findings support the existence of a trade-off between cognitive performance and reproductive success in a wild bird.


Altered patterns of T cell cytokine production induced by relapsed pre-B ALL cells.
Relapse of pediatric acute lymphoblastic leukemia (ALL) remains a significant clinical problem. The graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation indicates that immune mechanisms may play a role in the control of ALL blasts. In this study, we analyzed primary diagnostic and relapsed pre-B ALL samples for the surface expression of several molecules implicated in immune responses and for the induction of allogeneic T cell responses. There were no significant differences in the expression of CD11a, CD40, CD80 and CD86 or MHC classes I and II molecules between the diagnostic and relapsed samples. We found no significant differences in the overall ability of diagnostic and relapsed pre-B ALL samples to induce T cell proliferation and cytokine production. However, in the case of T cell responses induced by diagnostic ALL samples, there was excellent correlation between proliferation and production of all cytokines analyzed. In the case of relapsed samples, the only correlation obtained was with IL-5. This observation indicates that the nature of the immune response generated by relapsed ALL cells in an allogeneic setting differs from that obtained with diagnostic samples, suggests a biasing towards a Th2 response may contribute to the evasion of effective immune responses by relapsed ALL.


New Insights into Nutrition and Gut-Liver Axis: A Focus on Non-Alcoholic Fatty Liver Disease.
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease and represents a public health issue in Western industrialized countries [...].


Eubacterium minutum is an earlier synonym of Eubacterium tardum and has priority.
The recently proposed species Eubacterium minutum and Eubacterium tardum appeared to be similar from their published descriptions. The aim of this study was to perform phenotypic and genetic analyses of strains of both species to clarify their taxonomic position. The type strains of E. minutum and E. tardum exhibited identical biochemical and protein profiles and their 16S rRNA gene sequences displayed 99.9% similarity. The G + C content of the DNA of both strains was estimated at 45 mol%. It is concluded that E. minutum and E. tardum are synonyms; E. minutum has priority. An emended description of E. minutum is given.


[Antibodies to brain galactocerebrosides in the serum and cerebrospinal fluid of patients with disseminated sclerosis].
The titers of antibodies (AB) to myelin's glycolipids galactocerebrosides (GC) as well as some other immunological indices were measured in 63 patients with multiple sclerosis (MS), in 14 patients with other similar neurological diseases and in 9 individuals with cerebellospinal ataxias. The correlation between the frequency of revelation of high serum AB titers and MS stage was observed. Thus the highest frequency was observed at primary progredient current of MS and at decline of its aggravation while the latter was found in steady remission. The correlation between level of AB to blood serum GC and blood immune complexes concentrations (complement and antistreptolysin O) was established too. Meanwhile these were not bound in patients with cerebellospinal ataxias and with other neurologic diseases or the titers of AB to GC were quite low in such cases. The titers of AB to GC in liquor were rather high in 2 patients with MS and in 1 patient with viral encephalitis while there were no AB to GC in other cases. That may be caused by determination of immunoglobulins of M class in reactions of complement binding. The determination of AB to GC in blood serum may be quite usefull in differential diagnosis of MS and other similar clinical conditions.


The role of CCN2 in cartilage and bone development.
CCN2, a classical member of the CCN family of matricellular proteins, is a key molecule that conducts cartilage development in a harmonized manner through novel molecular actions. During vertebrate development, all cartilage is primarily formed by a process of mesenchymal condensation, while CCN2 is induced to promote this process. Afterwards, cartilage develops into several subtypes with different fates and missions, in which CCN2 plays its proper roles according to the corresponding microenvironments. The history of CCN2 in cartilage and bone began with its re-discovery in the growth cartilage in long bones, which determines the skeletal size through the process of endochondral ossification. CCN2 promotes physiological developmental processes not only in the growth cartilage but also in the other types of cartilages, i.e., Meckel's cartilage representing temporary cartilage without autocalcification, articular cartilage representing hyaline cartilage with physical stiffness, and auricular cartilage representing elastic cartilage. Together with its significant role in intramembranous ossification, CCN2 is regarded as a conductor of skeletogenesis. During cartilage development, the CCN2 gene is dynamically regulated to yield stage-specific production of CCN2 proteins at both transcriptional and post-transcriptional levels. New functional aspects of known biomolecules have been uncovered during the course of investigating these regulatory systems in chondrocytes. Since CCN2 promotes integrated regeneration as well as generation (=development) of these tissues, its utility in regenerative therapy targeting chondrocytes and osteoblasts is indicated, as has already been supported by experimental evidence obtained in vivo.


Demand analysis of tobacco consumption in Malaysia.
We estimated the price and income elasticity of cigarette demand and the impact of cigarette taxes on cigarette demand and cigarette tax revenue in Malaysia. The data on cigarette consumption, cigarette prices, and public policies between 1990 and 2004 were subjected to a time-series regression analysis applying the error-correction model. The preferred cigarette demand model specification resulted in long-run and short-run price elasticities estimates of -0.57 and -0.08, respectively. Income was positively related to cigarette consumption: A 1% increase in real income increased cigarette consumption by 1.46%. The model predicted that an increase in cigarette excise tax from Malaysian ringgit (RM) 1.60 to RM2.00 per pack would reduce cigarette consumption in Malaysia by 3.37%, or by 806,468,873 cigarettes. This reduction would translate to almost 165 fewer tobacco-related lung cancer deaths per year and a 20.8% increase in the government excise tax revenue. We conclude that taxation is an effective method of reducing cigarette consumption and tobacco-related deaths while increasing revenue for the government of Malaysia.


Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study.
COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV1) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity.


First successful autologous chondrocyte implantation in Pakistan.
Osteochondritis dissecans entails a hyaline cartilage defect of the articular surface causing pain and functional restriction in young adults, sometimes resulting in early degenerative arthritis. Conventional treatment methods such as abrasion chondroplasty and mosaicplasty have limitations in terms of quality of the resultant cartilage and donor site morbidity. A more recent technique, autologous chondrocyte implantation (ACI) results in hyaline cartilage formation and gives good long-term outcome, but requires a high-level cell culture facility and two surgical procedures. The patient was a young female with knee pain, intermittent locking and feeling of "joint mouse". MRI scan and arthroscopy showed a 2 x 2 cm full thickness osteochondral defect in the medial femoral condyle. A free fragment of articular cartilage was found, which was extracted arthroscopically, and chondrocytes were cultured from it in the Juma laboratory. Subsequently, patient underwent surgery whereby the chondrocytes were injected under a periosteal patch sewn over the defect. Over six months, patient's symptoms completely resolved and she returned to full function. A repeat arthroscopy after one year revealed complete filling of the previous defect with normal appearing cartilage indicating success of the procedure. This technology can be utilized for treating patients with a variety of conditions affecting hyaline cartilage of joints.


Smart surgical glasses for orofacial cleft surgery training in high- and low-income countries: A proof of concept.
The coronavirus 2019 pandemic urged us to find alternatives for education through remote proctoring and international surgical collaborations among high-, middle-, and low-income countries. Smart surgical glasses are promising for remote surgical education and international surgical collaborations. This study aimed to assess the usability of smart surgical glasses during cleft surgery and explore their potential in remote surgical education and collaboration. Six plastic surgical cases were randomly selected and recorded using the RODS&CONES glasses in 4K (3840 × 2160p). A 23-point questionnaire was sent to one plastic surgeon, one plastic surgery resident, and eight doctors who were not trained to critically appraise the video and audio quality of the smart surgical glasses and their applicability for remote surgical education. The participants indicated that the smart glasses had several significant advantages over conventional on-site education, such as facilitating a better view of the surgical field and providing possibilities for remote interaction. The audio quality was considered excellent. The main limitations were image stabilization issues and loss of video connection due to weak wireless fidelity. All participants appreciated the use of smart glasses for remote education and considered them a promising tool for enhancing the quality of surgical education. The glasses can enable remote assistance and education of local surgical residents and may facilitate sustainable surgical collaborations among high-, middle-, and low-income countries.


Cysteine proteinase procoagulant from amnion-chorion.
Various coagulation abnormalities are associated with pregnancy. Several investigators have suggested that there may be a unique procoagulant associated with amniotic tissue and fluid. We identified a cysteine proteinase from malignant tissue, cancer procoagulant, and had reason to believe a similar proteinase may be present in amniotic tissue. Amniotic fluid and extracts of amnion-chorion were purified by immunoaffinity chromatography with an antibody that was developed to cancer procoagulant antigen. The purified amnion-chorion procoagulant initiated clotting in normal and factor VII-deficient citrated human plasma and directly activated pure human factor X in a two-stage clotting assay. It was inhibited by 1 mmol/L of iodoacetamide and 0.1 mmol/L of HgCl2, and the procoagulant activity was activated by 10 mmol/L of KCN; these are classic properties of cysteine proteinases. The pure amnion-chorion procoagulant had the same mol wt and immunologic determinants as cancer procoagulant from rabbit V2 carcinoma, as determined by crossed immunodiffusion, suggesting that the same or very similar proteins were associated with both tissues. Thus, this procoagulant may be derived from both undifferentiated and dedifferentiated cells.


Association between body height and chronic low back pain: a follow-up in the Nord-Trøndelag Health Study.
To study potential associations between body height and subsequent occurrence of chronic low back pain (LBP). Prospective cohort study. The North-Trøndelag Health Study (HUNT). Data were obtained from a whole Norwegian county in the HUNT2 (1995-1997) and HUNT3 (2006-2008) surveys. Altogether, 3883 women and 2662 men with LBP, and 10,059 women and 8725 men without LBP, aged 30-69 years, were included at baseline and reported after 11 years whether they suffered from LBP. Chronic LBP, defined as pain persisting for 3 months during the previous year. Associations between body height and risk and recurrence of LBP were evaluated by generalised linear modelling. Potential confounders, such as BMI, age, education, employment, physical activity, smoking, blood pressure and lipid levels were adjusted for. In women with no LBP at baseline and body height ≥ 170 cm, a higher risk of LBP was demonstrated after adjustment for other risk factors (relative risk 1.19, 95% CI 1.03 to 1.37; compared with height <160 cm). No relationship was established among men or among women with LBP at baseline. In women without LBP, a body height ≥ 170 cm may predispose to chronic LBP 11 years later. This may reflect mechanical issues or indicate a hormonal influence.


Effects of housing and chronic cannulation on plasma ACTH and corticosterone in the rat.
Effects of housing and cannulation on plasma ACTH and corticosterone levels were evaluated to validate a method for obtaining repeated blood samples for ACTH from conscious rats. Resting morning, evening, or noise-stimulated (4 min of metal rattling) levels of plasma ACTH or corticosterone obtained by decapitation were similar in rats housed alone or in pairs. Individually housed, cannulated rats had slightly elevated morning levels of plasma ACTH and corticosterone, but the evening and noise-stimulated increases in hormone levels were similar to those in unoperated, decapitated rats. A hemorrhage stimulus administered on separate days to cannulated rats evoked highly replicable elevations in plasma ACTH and corticosterone. These results demonstrate that 1) ACTH and corticosterone secretion are similar in rats housed alone versus in pairs, and 2) long-term cannulation permits multiple intra-animal comparisons of basal and acutely stimulated plasma ACTH and corticosterone levels that are useful reflections of those measured in decapitated rats.


The Impact of a National Faculty Development Program Embedded Within an Academic Professional Organization.
A sizeable literature describes the effectiveness of institution-based faculty development programs in nurturing faculty educators as scholars, but national programs are less common and seldom evaluated. To fill this role, the Educational Scholars Program (ESP) was created within the Academic Pediatric Association (APA) in 2006. It is a national, three-year, cohort-based certification program focused on fostering educational scholarship. This article describes the development and outcomes of an innovative program embedded within the framework of a national professional organization, and offers a model for potential adaptation by similar organizations to enhance their support of educators.After 10 years, 171 scholars have enrolled in the ESP, and 50 faculty have participated. Scholars are assigned a faculty advisor and participate in three full-day sessions at a national meeting; online, interactive learning modules; and a mentored, scholarly project. The program receives support from the APA in four organizational frames: structural, human resource, political, and symbolic. The self-perceived scholarly proficiency of the scholars in Cohort 1 increased significantly over time, and their productivity and collaborations increased during and after the program. Scholars wrote enthusiastically about their experience in yearly and postprogram evaluations. In interviews, eight past APA presidents explained that the ESP strengthened the APA's mission, created new leaders, and provided a new model for other APA programs. Outcomes of the ESP suggest that a longitudinal faculty development program embedded within a national professional organization can create a social enterprise not only within the organization but also within the broader national community of educator-scholars.


[Recognition of commensal microflora by pattern recognition receptors in human physiology and pathology].
Contemporary data on the interaction of commensal microflora and Toll-like pattern recognition receptors are presented. These receptors recognize normal intestine microflora in physiological conditions, and this interaction is necessary for the maintenance of homeostasis and damage reparation of the intestine, for the induction of heat shock cytoprotective proteins. As a side effect in disruption of immunologic tolerance and misbalance of protective immunological mechanisms, multiorgan pathologic changes of organs and tissues may develop, including chronic inflammation processes of various localization.


Optimal sampling design for spatial capture-recapture.
Spatial capture-recapture (SCR) has emerged as the industry standard for estimating population density by leveraging information from spatial locations of repeat encounters of individuals. The precision of density estimates depends fundamentally on the number and spatial configuration of traps. Despite this knowledge, existing sampling design recommendations are heuristic and their performance remains untested for most practical applications. To address this issue, we propose a genetic algorithm that minimizes any sensible, criteria-based objective function to produce near-optimal sampling designs. To motivate the idea of optimality, we compare the performance of designs optimized using three model-based criteria related to the probability of capture. We use simulation to show that these designs outperform those based on existing recommendations in terms of bias, precision, and accuracy in the estimation of population size. Our approach, available as a function in the R package oSCR, allows conservation practitioners and researchers to generate customized and improved sampling designs for wildlife monitoring.


Post-ruminal choline supply during negative nutrient balance alters components of hepatic mTOR signaling and plasma amino acids in lactating Holstein cows.
Choline requirements for dairy cattle are unknown. However, enhanced post-ruminal supply of choline may increase flux through the methionine cycle to spare Met for other functions such as protein synthesis and phosphatidylcholine (PC) synthesis during periods of negative nutrient balance (NNB). The objective was to investigate the effects of post-ruminal choline supply during a feed restriction-induced NNB on hepatic abundance and phosphorylation of mTOR (mechanistic target of rapamycin)-related signaling proteins, hepatic lipidome and plasma amino acids (AA). Ten primiparous rumen-cannulated Holstein cows (158 ± 24 DIM) were used in a replicated 5 × 5 Latin square design with 4 d of treatment and 10 d of recovery (14 d/period). Treatments were unrestricted intake with abomasal infusion of water, restricted intake (R; 60% of net energy for lactation requirements to induce NNB) with abomasal infusion of water (R0) or restriction plus abomasal infusion of 6.25, 12.5, or 25 g/d choline ion. Liver tissue was collected via biopsy on d 5 after infusions ended and used for Western blot analysis to measure proteins involved in mTOR signaling and untargeted lipidomics. Blood was collected on d 1-5 for plasma AA analysis. Statistical contrasts for protein and AA data were A0 vs. R0 (CONT1), R0 vs. the average of choline dose (CONT2) and tests of linear and quadratic effects of choline dose. Analysis of lipidomic data was performed with the web-based metabolomic processing tool MetaboAnalyst 5.0. Ratios of p-RPS6KB1:tRPS6KB1, p-EEF2:tEEF2, and p-EIF2:tEIF2 were greater with R (CONT1). Among those, supply of choline led to decreases in p-EEF2:tEEF2 (CONT2), p-EIF2:tEIF2 and tended to decrease p-EIF4BP1:tEIF4BP1. However, the effect was quadratic only for p-EEF2:tEEF2 and p-EIF2A:tEIF2A, reaching a nadir at 6.25 to 12.5 g/d choline ion. The ratio of p-RPS6KB1:tRPS6KB1 was not affected by supply of choline and was close to 2-fold greater at 25 g/d choline vs. A0. Plasma Met concentration decreased with R (CONT1), but increased linearly with choline. Restriction also increased plasma 3-methyl-histidine (CONT1). The partial least squares discriminant analysis model of liver lipids distinguished treatments, with 13.4% of lipids being modified by treatment. One-way ANOVA identified 109 lipids with a false discovery rate ≤0.05. The largest group identified was PC species; all 35 detected decreased with R vs. A0, but there were few differences among choline treatments. Overall, data suggested that dephosphorylation of EEF2 and EIF2A due to enhanced choline supply potentially helped maintain or increase protein synthesis during NNB. While activation of mTOR was not altered by choline, this idea is partly supported by the increased circulating Met. However, enhanced post-ruminal choline had limited effects on the species of lipid produced during a period of NNB.


Water-soluble Pd nanoparticles synthesized from ω-carboxyl-S-alkanethiosulfate ligand precursors as unimolecular micelle catalysts.
This report describes a two-phase synthesis of water-soluble carboxylate-functionalized alkanethiolate-capped Pd nanoparticles from ω-carboxyl-S-alkanethiosulfate sodium salts. The two-phase methodology using the thiosulfate ligand passivation protocol allowed a highly specific control over the surface ligand coverage of these nanoparticles, which are lost in a one-phase aqueous system because of the base-catalyzed hydrolysis of thiosulfate to thiolate. Systematic synthetic variations investigated in this study included the concentration of ω-carboxyl-S-alkanethiosulfate ligand precursors and reducing agent, NaBH4, and the overall ligand chain length. The resulting water-soluble Pd nanoparticles were isolated and characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), (1)H NMR, UV-vis, and FT-IR spectroscopy. Among different variations, a decrease in the molar equivalent of NaBH4 resulted in a reduction in the surface ligand density while maintaining a similar particle core size. Additionally, reducing the chain length of the thiosulfate ligand precursor also led to the formation of stable nanoparticles with a lower surface coverage. Since the metal core size of these Pd nanoparticle variations remained quite consistent, direct correlation studies between ligand properties and catalytic activities against hydrogenation/isomerization of allyl alcohol could be performed. Briefly, Pd nanoparticles dissolved in water favored the hydrogenation of allyl alcohol to 1-propanol whereas Pd nanoparticles heterogeneously dispersed in chloroform exhibited a rather high selectivity towards the isomerization product (propanal). The results suggested that the surrounding ligand environments, such as the ligand structure, conformation, and surface coverage, were crucial in determining the overall activity and selectivity of the Pd nanoparticle catalysts.


The early outcome of primary anterior sagittal approach for low anorectal malformations in female patients.
To document our experience of the primary anterior sagittal anorectoplasty (ASARP) in female patients with lower and wide fistula in term of the early post operative outcome. A retrospective descriptive study was conducted in one surgical unit of the National Institute of Child Health Karachi, from January 2010 to April 2018. The study included female patients with diagnosis of imperforate anus with wide Vestibular or Perineal fistula with minimal or no straining during defecation and no excoriation of perineum. All patients underwent primaryASARP. Data regarding the age of the patients, site of fistula, the difficulties in dissection, post operative complications, stoma and re-do ASARP needed, were documented. Wound assessment was done during hospital stay, at two weeks and then at three months after surgery. Outcome was documented in terms of complications of surgery and cosmetic appearance of perineum. Data was analyzed on SPSS version 20. A total of 70 patients underwent primary surgery, 48(68.57%) females had perineal fistula while 22(31.42%) had vestibular fistula. Age ranges between three months to 276 months with median of 6±39.73 months. No major injury to the rectal or vaginal wall occurred during surgical procedure. In early post-operative period, 12(17.14%) patients had wound infection with or without various extent of disruption. A total of seven (10.11%) patients underwent stoma formation, six (8.57%) patients because of wound disruption with in a week of primary surgery and in one patient due to severe anal stenosis and retraction of anal segment within three month follow up. Median hospital stay was 5±1.52 days. In 38(54.28%) paients complete wound healing occurred with no per or post operative complications. In 25(35.71%) patients, minor complications were noted and treated accordingly and results were labelled satisfactory with acceptable perineal appearance. The single stage procedure can be a good choice for both vestibular and perineal fisula. In majority of cases wound heals completely with minimal or no scaring and give good cosmetic results.


Physical activity characterization: does one site fit all?
It is evident that a growing number of studies advocate a wrist-worn accelerometer for the assessment of patterns of physical activity a priori, yet the veracity of this site rather than any other body-mounted location for its accuracy in classifying activity is hitherto unexplored. The objective of this review was to identify the relative accuracy with which physical activities can be classified according to accelerometer site and analytical technique. A search of electronic databases was conducted using Web of Science, PubMed and Google Scholar. This review included studies written in the English language, published between database inception and December 2017, which characterized physical activities using a single accelerometer and reported the accuracy of the technique. A total of 118 articles were initially retrieved. After duplicates were removed and the remaining articles screened, 32 full-text articles were reviewed, resulting in the inclusion of 19 articles that met the eligibility criteria. There is no 'one site fits all' approach to the selection of accelerometer site location or analytical technique. Research design and focus should always inform the most suitable location of attachment, and should be driven by the type of activity being characterized.


Adverse childhood experiences and the risk of depressive disorders in adulthood.
Research examining the association between childhood abuse and depressive disorders has frequently assessed abuse categorically, thus not permitting discernment of the cumulative impact of multiple types of abuse. As previous research has documented that adverse childhood experiences (ACEs) are highly interrelated, we examined the association between the number of such experiences (ACE score) and the risk of depressive disorders. Retrospective cohort study of 9460 adult health maintenance organization members in a primary care clinic in San Diego, CA who completed a survey addressing a variety of health-related concerns, which included standardized assessments of lifetime and recent depressive disorders, childhood abuse and household dysfunction. Lifetime prevalence of depressive disorders was 23%. Childhood emotional abuse increased risk for lifetime depressive disorders, with adjusted odds ratios (ORs) of 2.7 [95% confidence interval (CI), 2.3-3.2] in women and 2.5 (95% CI, 1.9-3.2) in men. We found a strong, dose-response relationship between the ACE score and the probability of lifetime and recent depressive disorders (P<0.0001). This relationship was attenuated slightly when a history of growing up with a mentally ill household member was included in the model, but remained significant (P<0.001). The number of ACEs has a graded relationship to both lifetime and recent depressive disorders. These results suggest that exposure to ACEs is associated with increased risk of depressive disorders up to decades after their occurrence. Early recognition of childhood abuse and appropriate intervention may thus play an important role in the prevention of depressive disorders throughout the life span.


Sequence of HA gene of avian influenza A/Chicken/Guangdong/SS/1994 (H9N2) virus.
The RNA of the hemagglutinin (HA) gene of A/Chicken/Guangdong/SS/1994 (H9N2) was reverse transcription-polymerase chain reaction amplified, and the cDNA was cloned into a plasmid vector. The complete coding sequence of the HA gene was sequenced and included 1683 nucleotides, which encoded for a protein of 560 amino acids. The potential glycosylation sites related to HA protein function were highly conserved. The amino acid sequence of the HA proteolytic cleavage was G-S-S-R/G. This cleavage site sequence is compatible with a low-pathogenic avian influenza virus. Sequence comparison of this HA gene with other H9 influenza virus sequences in the GenBank database showed a 82%-97% nucleotide and amino acid sequence similarity.


Cationic and PEGylated Amphiphilic Cyclodextrins: Co-Formulation Opportunities for Neuronal Sirna Delivery.
Optimising non-viral vectors for neuronal siRNA delivery presents a significant challenge. Here, we investigate a co-formulation, consisting of two amphiphilic cyclodextrins (CDs), one cationic and the other PEGylated, which were blended together for siRNA delivery to a neuronal cell culture model. Co-formulated CD-siRNA complexes were characterised in terms of size, charge and morphology. Stability in salt and serum was also examined. Uptake was determined by flow cytometry and toxicity was measured by MTT assay. Knockdown of a luciferase reporter gene was used as a measure of gene silencing efficiency. Incorporation of a PEGylated CD in the formulation had significant effects on the physical and biological properties of CD.siRNA complexes. Co-formulated complexes exhibited a lower surface charge and greater stability in a high salt environment. However, the inclusion of the PEGylated CD also dramatically reduced gene silencing efficiency due to its effects on neuronal uptake. The co-formulation strategy for cationic and PEGylated CDs improved the stability of the CD.siRNA delivery systems, although knockdown efficiency was impaired. Future work will focus on the addition of targeting ligands to the co-formulated complexes to restore transfection capabilities.