Resistant candidiasis.
Mucosal (oropharyngeal, esophageal, and, in women, vaginal) candidiasis is a common infectious complication in HIV-infected patients. There is a wide range of drugs to treat or suppress Candida infections. However, with the increasingly common use of fluconazole as treatment or prophylaxis in patients with relatively advanced HIV disease, mucosal candidiasis that is clinically resistant to fluconazole is increasingly recognized. Susceptibility testing for fluconazole has not been well standardized, and laboratory and clinical correlations often have been difficult to demonstrate. However, the frequency with which Candida strains resistant to fluconazole can be isolated appears to be increasing, particularly in patients with advanced HIV disease. Anecdotal results suggest that patients who fail fluconazole therapy usually do not respond to higher doses of fluconazole, but may occasionally respond to itraconazole or ketoconazole. In vitro susceptibility to these agents does not necessarily ensure clinical efficacy. Amphotericin B is usually effective initially but requires parenteral administration. However, with any therapy, relapses tend to occur and progressively recalcitrant disease often occurs, with increasing morbidity for patients. There is a clear need for studies addressing the incidence of resistance, the risk factors for its development, and more effective therapy.


Liquid chromatographic analysis of maneb and its main degradation product, ethylenethiouera, in fruit juice.
Ethylenethiourea (ETU), a possible human carcinogen and an antithyroid compound, is the main degradation product of the fungicide, maneb, which is widely used in agriculture. In this study, a rapid and accurate method for the determination of maneb and ETU in various fruit juices (tomato, grape and apple) was developed requiring minimal clean-up of sample extract, no derivatization prior to injection and no specialized LC detectors. Samples were cleaned up using silica and octadecylsilica (C18) cartridges before injection into liquid chromatography (LC) with diode-array detection (DAD). Recoveries ranged between 90 and 101% with relative standard deviations from 0.7 to 3.8%. The limits of determination of maneb and ETU were 0.1 and 0.01 mg l(-1), respectively. The proposed method was used to monitor the presence of maneb and ETU in commercial samples taken from different markets of Istanbul, Turkey. Maneb was found in one tomato juice sample at a concentration of 0.45 mg l(-1) but ETU was below the LOQ. Two tomato juices had no detectable maneb residue but contained ETU at levels of 0.08 and 0.11 mg l-(1).


The PNPLA3 rs738409 C > G polymorphism is associated with the risk of progression to cirrhosis in NAFLD patients.
The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C > G single nucleotide polymorphism (SNP) has been associated with steatosis and fibrosis in previous NAFLD populations in which cirrhotic patients were very poorly represented. Since not all NAFLD with fibrosis evolve to cirrhosis, we investigated the specific risk of cirrhosis conferred in NAFLD patients by carrying this SNP. Three groups were studied: patients with NASH-cirrhosis; patients with biopsy-proven non-cirrhotic NAFLD; healthy subjects undergoing medicine check-ups. Epidemiological, anthropometric, and clinical data were collected, and the SNP was analyzed by pyrosequencing. Sixty-one patients with NASH-cirrhosis, 60 with non-cirrhotic NAFLD, and 125 healthy controls were included. Frequency of the PNPLA3 minor (G) allele was increased in patients with NASH-cirrhosis compared with non-cirrhotic NAFLD and controls (allele frequency: 0.598 versus 0.367 versus 0.2, respectively, p < 0.001), and different between the latter two groups (p < 0.001). Three-quarters (74%) of NASH cirrhotics carried at least one G allele, and almost half of them (46%) were GG homozygous. By multivariate analysis in the NAFLD population, each copy of the G allele was associated with an almost doubling of the risk of cirrhosis [OR 1.8 (1.02-3.2)], while being GG homozygous with a tripled risk compared with being CC homozygous [3.01 (1.03-10.8)]. In NAFLD patients, carriage of the PNPLA3G allele, and particularly of the GG genotype, is significantly associated with the risk of cirrhotic evolution. If confirmed in larger series, these results would suggest that most of NASH cases require the contribution of an altered PNPLA3 function to progress until cirrhosis.


Expanding the mutational spectrum associated to neural tube defects: literature revision and description of novel VANGL1 mutations.
Neural Tube Defects (NTD) are a common class of birth defects that occur in approximately 1 in 1000 live births. Both genetic and nongenetic factors are involved in the etiology of NTD. Planar cell polarity (PCP) genes plays a critical role in neural tube closure in model organisms. Studies in humans have identified nonsynonymous mutations in PCP pathway genes, including the VANGL genes, that may play a role as risk factors for NTD. Here, we present the results of VANGL1 and VANGL2 mutational screening in a series of 53 NTD patients and 27 couples with a previous NTD affected pregnancy. We identified three heterozygous missense variants in VANGL1, p.Ala187Val, p.Asp389His, and p.Arg517His, that are absent in controls and predicted to be detrimental on the protein function and, thus, we expanded the mutational spectrum of VANGL1 in NTD cases. We did not identify any new variants having an evident pathogenic effect on protein function in VANGL2. Moreover, we reviewed all the rare nonsynonymous or synonymous variants of VANGL1 and VANGL2 found in patients and controls so far published and re-evaluated them for their pathogenic role by in silico prediction tools. Association tests were performed to demonstrate the enrichment of deleterious variants in reviewed cases versus controls from Exome Variant Server (EVS). We showed a significant (p = 7.0E-5) association between VANGL1 rare genetic variants, especially missense mutations, and NTDs risk.


Identification of a phosphorylation-dependent nuclear localization motif in interferon regulatory factor 2 binding protein 2.
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a muscle-enriched transcription factor required to activate vascular endothelial growth factor-A (VEGFA) expression in muscle. IRF2BP2 is found in the nucleus of cardiac and skeletal muscle cells. During the process of skeletal muscle differentiation, some IRF2BP2 becomes relocated to the cytoplasm, although the functional significance of this relocation and the mechanisms that control nucleocytoplasmic localization of IRF2BP2 are not yet known. Here, by fusing IRF2BP2 to green fluorescent protein and testing a series of deletion and site-directed mutagenesis constructs, we mapped the nuclear localization signal (NLS) to an evolutionarily conserved sequence (354)ARKRKPSP(361) in IRF2BP2. This sequence corresponds to a classical nuclear localization motif bearing positively charged arginine and lysine residues. Substitution of arginine and lysine with negatively charged aspartic acid residues blocked nuclear localization. However, these residues were not sufficient because nuclear targeting of IRF2BP2 also required phosphorylation of serine 360 (S360). Many large-scale phosphopeptide proteomic studies had reported previously that serine 360 of IRF2BP2 is phosphorylated in numerous human cell types. Alanine substitution at this site abolished IRF2BP2 nuclear localization in C(2)C(12) myoblasts and CV1 cells. In contrast, substituting serine 360 with aspartic acid forced nuclear retention and prevented cytoplasmic redistribution in differentiated C(2)C(12) muscle cells. As for the effects of these mutations on VEGFA promoter activity, the S360A mutation interfered with VEGFA activation, as expected. Surprisingly, the S360D mutation also interfered with VEGFA activation, suggesting that this mutation, while enforcing nuclear entry, may disrupt an essential activation function of IRF2BP2. Nuclear localization of IRF2BP2 depends on phosphorylation near a conserved NLS. Changes in phosphorylation status likely control nucleocytoplasmic localization of IRF2BP2 during muscle differentiation.


Leadership in a new health care world.
To understand and cope with the present, it is often very useful to examine the past. In so doing, leaders in nursing can put the events of today into perspective. Further, the rich history of nursing leadership can point us toward the future. The author draws from our history to paint a clear picture of the nurse leader of tomorrow.


Decontamination of the Activation Product Based on a Legal Revision of the Cyclotron Vault Room on the Non-self-shield Compact Medical Cyclotron.
The non-self-shield compact medical cyclotron and the cyclotron vault room were in operation for 27 years. They have now been decommissioned. We efficiently implemented a technique to identify an activation product in the cyclotron vault room. Firstly, the distribution of radioactive concentrations in the concrete of the cyclotron vault room was estimated by calculation from the record of the cyclotron operation. Secondly, the comparison of calculated results with an actual measurement was performed using a NaI scintillation survey meter and a high-purity germanium detector. The calculated values were overestimated as compared to the values measured using the NaI scintillation survey meter and the high-purity germanium detector. However, it could limit the decontamination area. By simulating the activation range, we were able to minimize the concrete core sampling. Finally, the appropriate range of radioactivated area in the cyclotron vault room was decontaminated based on the results of the calculation. After decontamination, the radioactive concentration was below the detection limit value in all areas inside the cyclotron vault room. By these procedures, the decommissioning process of the cyclotron vault room was more efficiently performed.


The effects of Hartcoach, a life style intervention provided by telephone on the reduction of coronary risk factors: a randomised trial.
Cardiovascular disease (CVD) is the leading cause of death worldwide. Secondary prevention is essential, but participation rates for cardiac rehabilitation are low. Furthermore, current programmes do not accomplish that patients with CVD change their lifestyle in a way that their individual risk factors for recurrent events decrease, therefore more effective interventions are needed. In this study, the effectiveness of the Hartcoach-programme, a telephonic secondary prevention program focussing on self management, is studied. A multicenter, randomised parallel-group study is being conducted. Participants are 400 patients with acute myocardial infarction (STEMI, NSTEMI,) and patients with chronic or unstable angina pectoris (IAP). Patients are recruited through the participating hospitals and randomly assigned to the experimental group (Hartcoach-programme plus usual care) or the control group (usual care).The Hartcoach-programme consists of a period of six months during which the coach contacts the patient every four to six weeks by telephone. Coaches train patients to take responsibility for the achievement and maintenance of the defined target levels for their particular individual modifiable risk factors. Target levels and treatment goals are agreed by the nurse and patient together. Data collection is blinded and occurs at baseline and after 26 weeks (post-intervention). Primary outcome is change in cardiovascular risk factors (cholesterol, body mass index, waist circumference, blood pressure, physical activity and diet). Secondary outcomes include chances in glucose, HbA1c, medication adherence, self-management and quality of life. This study evaluates the effects of the Hartcoach-programme on the reduction of individual risk factors of patients with CVDs. Patients who are not invited to follow a hospital based rehabilitation programme or patients who are unable to adhere to such a programme, may be reached by this home based Hartcoach-programme. If positive results are found, the implementation of the Hartcoach-programme will be extended, having implications for the management of many people with CVD. NTR2388.


Nonlinear modeling of auditory-nerve rate responses to wideband stimuli.
The spectral selectivity of auditory nerve fibers was characterized by a method based on responses to random-spectrum-shape stimuli. The method models the average discharge rate of fibers for steady stimuli and is based on responses to approximately 100 noise-like stimuli with pseudorandom spectral levels in 1/8- or 1/16-octave frequency bins. The model assumes that rate is determined by a linear weighting of the spectrum plus a second-order weighting of all pairs of spectrum values within a certain frequency range of best frequency. The method allows prediction of rate responses to stimuli with arbitrary wideband spectral shapes, thus providing a direct test of the degree of linearity of spectral processing Auditory-nerve fibers are shown to rely mainly on linear weighting of the stimulus spectrum; however, significant second-order terms are present and are important in predicting responses to random-spectrum shape stimuli, although not for predicting responses to noise filtered with cat head-related transfer functions. The second-order terms weight the products of levels at identical frequencies positively and the products of different frequencies negatively. As such, they model both curvature in the rate versus level function and suppressive interactions between different frequency components. The first- and second-order characterizations derived in this method provide a measure of higher-order nonlinearities in neurons, albeit without providing information about temporal characteristics.


Induction of interferon-induced transmembrane protein 3 gene expression by lipopolysaccharide in astrocytes.
Astrocytes are important modulators of the immune and inflammatory reactions in the central nervous system. We have recently demonstrated the role of interferon-induced transmembrane protein 3 (IFITM3) in long-lasting neuronal impairments in mice following neonatal immune challenge by injections of the double-stranded RNA analog polyriboinosinic polyribocytidylic acid. Here, we show that IFITM3 is induced after lipopolysaccharide (LPS) treatment in cultured astrocytes. The induction of IFITM3 by LPS was completely suppressed by the addition of anti-interferon-β (IFN-β) antibody. In addition, neutralization of tumor necrosis factor-α (TNF-α) with its antibody partially inhibited the induction of IFITM3, suggesting that LPS induces IFITM3 through autocrine secretion of IFN-β and TNF-α. Furthermore, experiments using pharmacological inhibitors suggest that LPS induces IFITM3 through activation of TANK-binding kinase 1, p38 mitogen-activated protein kinase, and nuclear factor-κB pathways. Together, these findings may provide new insight into the role of IFITM3 in the pathogenesis of neurodevelopmental diseases associated with immune activation.


IL-15 Expression Pattern in Atopic Dermatitis.
An increased expression of interleukin (IL)-15, a cytokine with a key role in stimulating innate and adaptive immune cells, such as dendritic cells (DC), natural killer cells, and T cells, has been observed in infectious and inflammatory diseases, including autoimmune diseases as well as cancer. Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a type 2 immune response. To explore the expression of IL-15 and its pattern in AD skin. Immunofluorescence staining was performed on skin specimens of AD skin, nonlesional AD skin (AD NL), and normal skin (NS) using antibodies directed against IL-15 and CD3, mast cell tryptase, eosinophil cationic protein, CD68, CD11b, CD1a, and vimentin. A significantly higher IL-15 expression in AD and AD NL was observed in both the epidermis (p = 0.0003) and the dermis (p = 0.0154) as compared to NS. Cells expressing IL-15 were mainly keratinocytes, CD1a+ DC, CD11b+ DC, CD68+ macrophages, and vimentin+ fibroblasts. In AD, an increase in the relative numbers of IL-15 expressing CD1a+ DC, macrophages, and fibroblasts was noted. Our results demonstrate an expression of IL-15 in AD similar to that of eosinophilic esophagitis which is also a type 2 disease. IL-15 may serve as a therapeutic target for AD.


Budesonide use and misuse in sports: Elimination profiles of budesonide and metabolites after intranasal, high-dose inhaled and oral administrations.
Budesonide (BUD) is a glucocorticoid (GC) widely used in therapeutics. In sports, the World Anti-doping Agency (WADA) controls the use of GCs, and WADA-accredited laboratories use a reporting level of 30 ng/mL for 6β-hydroxy-budesonide (6βOHBUD) to detect the systemic administration of BUD. In the present work, we examined the urinary excretion profile of 6βOHBUD, BUD, and 16α-hydroxy-prednisolone (16αOHPRED) after intranasal (INT), inhaled (INH) (at high doses) and oral administrations in male and female volunteers. BUD was administered to healthy volunteers using INT route (256 μg/day for three days, n = 4 males and 4 females), INH route (800 μg/day for three days, n = 4 males and 4 females, and 1600 μg/day for three days, n = 4 males) or oral route (3 mg, n = 8 females). Urine samples were collected before and after administration at different time periods, and were analyzed by liquid chromatography-tandem mass spectrometry. 6βOHBUD and BUD concentrations were very low after INT treatment (0.0-7.1 and 0.0-8.1 ng/mL, respectively), and higher after INH treatments (0.0-35.4 and 0.0-48.3 ng/mL, respectively). For 16αOHPRED, elevated concentrations were detected after INT and INH treatments (2.6-66.4 and 3.4-426.5 ng/mL, respectively). Concentrations obtained following oral administration were higher than after therapeutic administrations (2.8-80.6, 1.5-36.1, and 10.4-532.2 ng/mL for 6βOHBUD, BUD, and 16αOHPRED, respectively). After all administrations, concentrations were higher in males than in females. Results demonstrated that 6βOHBUD is the best discriminatory marker and a reporting level of 40 ng/mL was found to be the best criterion to distinguish allowed from forbidden administrations of BUD.


Bacteriology of brain abscess--observations on 50 cases.
The bacteriology of brain abscess is complex--both aerobic and anaerobic organisms are involved, and their incidence varies from centre to centre. In this study of 50 consecutive cases of brain abscess, the value of both modern imaging techniques and the time-honoured Gram's stain was demonstrated. The Gram's stain showed organisms in 41 cases (82%) and culture was positive in 44 cases (88%). Thirty cultures yielded pure aerobic growth: Staphylococcus aureus, beta-haemolytic streptococci and Proteus spp. were predominant. Five cases gave mixed aerobic cultures, and in seven cases anaerobes were isolated. Of these, three showed a mixed aerobic and anaerobic flora. Mycobacterium tuberculosis was cultured from one of the samples, which had shown acid-fast bacilli on direct smear. M. fortuitum was cultured from one sample, although no organisms were seen in the gram-stained preparation.


Satisfaction with dietary life affects oral health-related quality of life and subjective well-being in very elderly people.
Age-related deterioration in physical and oral health reduces healthy life expectancy and is thus an important problem for very elderly people. We investigated the effects of satisfaction with dietary life (SDL) in everyday life on oral health-related quality of life (OHRQoL) and subjective well-being and examined associations between these factors. We evaluated 426 elders aged 85 years or older. All participants completed a questionnaire that inquired about age, gender, drinking status, body mass index, cognitive function, disability, and comorbidities, among other covariates. Oral, physical, and mental health conditions were also examined. Associations of questionnaire results for SDL with items on subjective well-being (Philadelphia Geriatric Center Morale Scale [PGC] and World Health Organization-5 [WHO-5]) and OHRQoL (Geriatric Oral Health Assessment Index [GOHAI]) were confirmed with multiple logistic regression analysis. In a multivariate model adjusted for various confounders, participants with self-reported "enjoyable" SDL had significantly lower risks for having the lowest scores on the GOHAI, PGC, and WHO-5 (odds ratio [OR] = 0.460, 95% confidence interval [CI] = 0.277-0.762; OR = 0.589, 95% CI = 0.348-0.996; and OR = 0.452, 95% CI = 0.263-0.775, respectively). These associations remained after further adjustment for number of teeth.


Herpes simplex virus type II infection of ileum mesothelium: a case report and review of the literature.
Disseminated herpes simplex virus (HSV) infection usually manifests in the immunocompromised. However, anecdotal examples of visceral HSV disease and viremia have complicated type I diabetes. A case of a 53-year-old type I diabetic patient with bowel obstruction one week subsequent to bronchitis is reported. At laparotomy, a perforated segment of ileum was associated with an adhesive peritoneal band. HSV cytopathic atypia and HSV immunohistochemical staining were confined to fibrocytes and mesothelial cells without involvement of the epithelium. Dissemination of symptomatic HSV pneumonia was verified by histology, immunohistochemistry, in situ hybridization, polymerase chain reaction and direct fluorescence antibody. Intravenous acyclovir resolved symptoms. This is a novel documentation of HSV complicating ileal adhesive band disease. Furthermore, this case indicates that the HSV cytopathic effect is not unique to the epithelium. Disseminated infection can manifest in myofibrocytes and mesothelium, distinguishing it from standard epithelial atypia of localized HSV infection.


A review of canakinumab and its therapeutic potential for non-small cell lung cancer.
Inflammation is essential for our innate and adaptive immunity, but chronic inflammation can also be detrimental, playing a role in tumor development and subversion of host immunity. A multitude of proteins and cytokines are involved in chronic inflammation; interleukin-1β, in particular, has been recognized as a critical pro-inflammatory cytokine that can trigger a cascade of inflammatory mediators, promoting angiogenesis, tumor invasiveness, and metastasis. The inhibition of interleukin-1β with the antibody canakinumab was recently highlighted in a large-scale trial studying the effects of the inflammatory modulating antibody in heart disease. In this study, a marked decrease in the incidence of lung cancer (a 67% relative risk reduction) was observed in a high-risk population. Although a number of preclinical studies have demonstrated that canakinumab inhibits interleukin-1β and reduces inflammation, the question remains whether these actions positively affect both cancer incidence and recurrence. This review will summarize the role of inflammation in cancer propagation and development, discuss the biological rationale for targeting interleukin-1β in lung cancer, advocate for further investigation of the anti-inflammatory antibody canakinumab as a new attractive mechanism for future lung cancer therapy, and discuss future and ongoing trials.


Reassess-Realign-Reimagine: A Guide for Mentors Pivoting to Remote Research Mentoring.
Maintaining your research team's productivity during the COVID-19 era can be a challenge. Developing new strategies to mentor your research trainees in remote work environments will not only support research productivity and progress toward degree, but also help to keep your mentees' academic and research careers on track. We describe a three-step process grounded in reflective practice that research mentors and mentees can use together to reassess, realign, and reimagine their mentoring relationships to enhance their effectiveness, both in the current circumstances and for the future. Drawing on evidence-based approaches, a series of questions for mentees around documented mentoring competencies provide structure for remote mentoring plans. Special consideration is given to how these plans must address the psychosocial needs and diverse backgrounds of mentors and mentees in the unique conditions that require remote interactions.


Molecular profiling of pediatric brain tumors: insight into biology and treatment.
Recent history has witnessed unparalleled advances in our understanding of tumor biology, owing in large part to the publication of the human genome project. Paired with improvements in microarray technologies, the combination of genetic and expression profiles provides a unique opportunity to further enhance our understanding of the underlying mechanisms that drive tumor growth. Thus, integrated analysis of identified molecular changes with clinical and histologic data may further delineate a new risk stratification system for pediatric brain tumors, allowing more patient-tailored therapy and molecular-based therapeutic interventions.


Constructing atomic structural models into cryo-EM densities using molecular dynamics - Pros and cons.
Accurate structure determination from electron density maps at 3-5 Å resolution necessitates a balance between extensive global and local sampling of atomistic models, yet with the stereochemical correctness of backbone and sidechain geometries. Molecular Dynamics Flexible Fitting (MDFF), particularly through a resolution-exchange scheme, ReMDFF, provides a robust way of achieving this balance for hybrid structure determination. Employing two high-resolution density maps, namely that of β-galactosidase at 3.2 Å and TRPV1 at 3.4 Å, we showcase the quality of ReMDFF-generated models, comparing them against ones submitted by independent research groups for the 2015-2016 Cryo-EM Model Challenge. This comparison offers a clear evaluation of ReMDFF's strengths and shortcomings, and those of data-guided real-space refinements in general. ReMDFF results scored highly on the various metric for judging the quality-of-fit and quality-of-model. However, some systematic discrepancies are also noted employing a Molprobity analysis, that are reproducible across multiple competition entries. A space of key refinement parameters is explored within ReMDFF to observe their impact within the final model. Choice of force field parameters and initial model seem to have the most significant impact on ReMDFF model-quality. To this end, very recently developed CHARMM36m force field parameters provide now more refined ReMDFF models than the ones originally submitted to the Cryo-EM challenge. Finally, a set of good-practices is prescribed for the community to benefit from the MDFF developments.


Interdisciplinary lymphology: the best place for each discipline in a team.
The term lymphology includes both the physiology and the pathology of the lymphatic system. Many disciplines are involved in the study of the lymphatic system, to correctly diagnose lymphatic diseases and to ultimate provide the best available treatment for the patient. Lymphedema is one of the most common lymphatic diseases, potentially causing significant problems for the patient and for the health system in general. The aim of this article is to discuss the best placement and role for each discipline within an interdisciplinary team in order to provide an effective management of lymphedema and related lymphatic diseases.


High prevalence of occult hepatitis B infection in an African urban population.
Occult hepatitis B infection (OBI), the presence of low hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels in patients without detectable hepatitis B surface antigen (HBsAg), has significant implications for understanding the natural history of hepatitis B infection. We determined the prevalence of OBI in African patients using a sensitive polymerase chain reaction (PCR) assay and describe here the characteristics of OBI in an urban African hospital population. Routine serological testing as well as molecular studies were performed on sera from 314 patients who were part of a previous study from an urban hospital emergency room in Kampala, Uganda, detecting HBV DNA using a nested PCR with amplification of two regions of the HBV genome. HBV viral loads (VL) were determined by real-time PCR (rtPCR) and sequencing performed to determine HBV genotype and S gene mutations. Among 314 subjects tested, 50 (16%) had chronic HBV infection, 94 (30%) had detectable HBV DNA despite testing HBsAg negative (OBI), and 170 (54%) were not infected. VLs of OBI subjects were relatively low although 19 (20%) had VL exceeding 10(4) IU ml(-) . Subjects with chronic HBV infection had a higher median VL compared to OBI patients (P < 0.001). All chronic HBV sequenced (10) and 83/89 OBI sequences were genotype A, the remaining six being genotype D. S-gene mutations were present in some but not all OBI patients (48%). OBI is more prevalent among African patients than previously thought. This may have implications for clinical management and transfusion-related HBV transmission.


Genetics and imaging of pheochromocytomas and paragangliomas: current update.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare, heterogeneous neuroendocrine neoplasms of the autonomous nervous system of chromaffin cell origin that may arise within the adrenal medulla (PCCs) or the sympathetic and parasympathetic paraganglia (PGLs). Currently referred to by the umbrella term pheochromocytomas-paragangliomas (PPGLs), these distinct tumors are characterized by specific histopathology as well as biological and clinical profiles. PPGLs may occur as part of hereditary syndromes (40% of cases) or as sporadic tumors. Currently, there are 12 different hereditary syndromes with characteristic genetic abnormalities, at least 15 well-characterized driver genes and distinct tumor metabolic pathways. Based on the Cancer Genome Atlas (TCGA) taxonomic schemata, PPGLs have been classified into three main clusters of specific genetic mutations and tumor pathways with clinical, biochemical, and prognostic implications. Imaging plays a pivotal role in the initial diagnosis, tumor characterization, evaluation of treatment response, and long-term surveillance. While MDCT and MRI help in the anatomic localization, SPECT, and PET using different radiotracers are crucial in the functional assessment of these tumors. Surgery, chemotherapy, and radiotherapy are currently available treatment options for PPGLs; antiangiogenic drugs are also being used in treating metastatic disease. Evolving knowledge regarding the different genetic abnormalities involved in the pathogenesis of PPGLs has identified potential therapeutic targets that may be utilized in the discovery of novel drugs.


Mutant prevention concentrations of imipenem and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii.
The aim of this study was to determine the usefulness of the MPC of carbapenems against clinical isolates of Pseudomonas spp. and Acinetobacter spp. and to assess its possible relationship with mechanisms of resistance. Detection of the mechanisms of resistance was performed using Antibiotic Susceptibility Testing, Double Disk Synergy, disk antagonism, addition of NaCl to the medium, addition of PBA or EDTA to Carbapenem disks, addition of PBA to Cefoxitin disks, and CCCP test for 10 Pseudomonas spp. and Acinetobacter baumannii strains. The MIC and MPC were determined using the broth macrodilution and plate dilution methods, respectively. Four Acinetobacter baumannii strains produced MBL. Two of them produced Oxacillinase and one produced ESBL. Two Pseudomonas spp. isolates produced both KPC and MBL. The resistant Acinetobacter spp. and Pseudomonas spp. strains had higher MPC values than susceptible ones. However, the Mutant Selection Window was found to be dependent on the degree of resistance but not on a particular mechanism of resistance. The usefulness of the MPC was found to be dependent on its value. Based on our data, we recommend determining the MPC for each isolate before using it during treatment. Furthermore, the use of T>MSW instead of T>MIC is suggested.


The Short- and Long-Term Safety and Efficacy Profile of Subtotal Cholecystectomy: A Single-Centre, Long-Term, Follow-Up Study.
Background Subtotal cholecystectomy (STC) has been reported as an effective method to remove the gallbladder if the hepatocystic triangle anatomy is unfavourable. However, the evidence regarding its long-term outcomes from the United Kingdom (UK) is lacking. This study aimed to assess its short and long-term outcomes with a minimum of one-year follow-up. Methodology We retrospectively analysed all elective and emergency STCs performed in a single UK NHS Trust between 2014 and 2020. Relevant data were collected using electronic patient records and questionnaire-based, long-term, telephonic follow-up (median follow-up of 3.7 years). Outcomes examined were immediate/short-term complications (biliary injury, bile leak, return-to-theatre) and long-term problems (recurrent symptoms, choledocholithiasis, cholangitis/pancreatitis). Results There were a total of 50 STC cases (58% females) out of 4,341 cholecystectomies performed (1.15%), with the median age, body mass index, and length of stay being 69.5 years, 29 kg/m2 and eight days, respectively. Twenty-eight (56%) were emergency. No patient endured bile duct injury. Seven (14%) patients had postoperative bile leak which was significantly more common when Hartmann's pouch was left open (33% vs. 8%; p = 0.03). No bile duct injury was reported. Most were managed conservatively (endoscopic retrograde cholangiopancreatography + stent: four; radiological drainage: one; no intervention: one). Only one patient required laparoscopic lavage and drainage. The true incidence of developing choledocholithiasis over the long term was 4/50 (8%) in our study. The median interval between STC and the diagnosis of postoperative choledocholithiasis was 15.9 months. All four patients had undergone type 1 STC (where the remnant of Hartmann's pouch was closed with sutures); however, subsequent cross-sectional imaging (magnetic resonance cholangiopancreatography or computed tomography) showed that the gallbladder remnant was visible in only two of these four patients. Conclusions STC is a safe option in difficult situations and prevents bile duct injury. Although the risk of bile leak can be reduced by closing Hartmann's pouch remnant, this may slightly increase the risk of subsequent stone formation. Infrequent occurrence of recurrent gallstone-related symptoms or complications favours its use.


Metabolic and Toxic Myelopathies.
Myelopathy may occur as a consequence of various metabolic and toxic conditions. This article provides an update on the clinical presentations, diagnostic evaluations, and management of metabolic and toxic myelopathies. Myelopathy and myeloneuropathy due to vitamin B12 deficiency is increasing in prevalence partly because of an aging population. Early recognition of the clinical symptoms and rapid initiation of treatment is essential. Copper deficiency is now also recognized as causing a similar clinical picture as vitamin B12 deficiency. Conditions leading to copper deficiency include bariatric surgery and excessive zinc intake. Unusual conditions such as lathyrism and konzo are relevant to all neurologists because of emigration from less well-developed countries. Myelopathy can also occur from substance abuse (eg, heroin and nitrous oxide), and early diagnosis could lead to improved patient outcomes. The spinal cord may also be injured in decompression illness that occurs in sport divers and individuals who work in pressurized atmospheres. Knowledge and recognition of the various metabolic and toxic causes of myelopathy is important for the practicing neurologist, as timely diagnosis and rapid initiation of therapy is essential to improve the chances for recovery.


Frequent utilization of the emergency department for acute heart failure syndrome: a population-based study.
Although most research on patients with acute heart failure syndrome (AHFS) has focused on readmissions, this may provide an incomplete picture of health-care utilization. We examined the proportion and characteristics of patients with frequent emergency department (ED) visits for AHFS and associated health-care utilization. A retrospective cohort study of adults with at least 1 ED visit for AHFS between 2010 and 2011 was performed, derived from population-based multipayer data of state ED and inpatient databases for 2 large and diverse states, California and Florida. The analytic sample comprised 113 033 patients with 175 491 ED visits for AHFS. During the 1-year follow-up period, 30.8% of patients had ≥2 (frequent) visits, accounting for 55.4% (95% confidence interval, 55.2-55.5%) of all ED visits for AHFS. In the multivariable model, significant predictors of frequent ED visits were non-Hispanic black race, Hispanic ethnicity, Medicaid insurance, and lower median household income (all P<0.001). At the visit level, patients with frequent ED visits accounted for 55.0% (95% confidence interval, 54.8-5.3%) of all AHFS hospitalizations via ED. Total charges for AHFS were $3.08 billion (95% confidence interval, $3.03-3.14 billion) in Florida alone; patients with frequent ED visits accounted for 53.3% of total charges (95% confidence interval, 53.2-53.3%). In this large cohort study, we found that one third (31%) of ED patients with AHFS had frequent ED visits for this condition and that minority race/ethnicity and lower socioeconomic status were associated with frequent ED visits. Individuals with frequent ED visits accounted for the majority of ED visits, hospitalizations, and hospital charges.


Role of renal dopamine D1 receptors in natriuresis induced by calcium channel blockers.
The direct tubular natriuretic effect of calcium channel blockers (CCBs) may be due to an interaction between CCBs and a renal tubular dopamine receptor. We therefore studied the effects of two chemically unrelated CCBs, diltiazem and isradipine, infused into the right renal artery of 5% saline-loaded anesthetized rats alone or in the presence of a D1 antagonist, SKF-83742. Isradipine (0.03 microgram.kg-1.min-1) or diltiazem (20 but not 10 micrograms.kg-1.min-1) alone produced an increase in urine flow and an approximate doubling of absolute and fractional sodium excretion, which was not seen in the left kidney or in the control animals (analysis of variance, Scheffé's test, P < 0.05). SKF-83742 alone given systemically or into the right renal artery did not affect these parameters but did block the actions of diltiazem or isradipine. There was no change in mean arterial pressure, renal blood flow, or glomerular filtration rate in any of the experiments. In additional studies, we found that a combined infusion of dopamine (0.1 microgram.kg-1.min-1) and diltiazem (10 micrograms.kg-1.min-1) (doses that by themselves did not alter renal function) produced a twofold or greater increase in urine flow and absolute and fractional sodium excretion; glomerular filtration rate was not significantly changed. Intrarenal arterial CCBs, without a change in renal hemodynamics, produce a natriuresis that is blocked by a D1 antagonist. Concomitant administration of diltiazem and dopamine (each in subeffective doses when used alone) produces a synergistic effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Modelling the Maillard reaction during the cooking of a model cheese.
During processing and storage of industrial processed cheese, odorous compounds are formed. Some of them are potentially unwanted for the flavour of the product. To reduce the appearance of these compounds, a methodological approach was employed. It consists of: (i) the identification of the key compounds or precursors responsible for the off-flavour observed, (ii) the monitoring of these markers during the heat treatments applied to the cheese medium, (iii) the establishment of an observable reaction scheme adapted from a literature survey to the compounds identified in the heated cheese medium (iv) the multi-responses stoichiokinetic modelling of these reaction markers. Systematic two-dimensional gas chromatography time-of-flight mass spectrometry was used for the semi-quantitation of trace compounds. Precursors were quantitated by high-performance liquid chromatography. The experimental data obtained were fitted to the model with 14 elementary linked reactions forming a multi-response observable reaction scheme.


[Prevalence of smokers in Moscow Region].
The results of monitoring of bad habits (smoking) among senior schoolchildren in 23 towns of Moscow Region are dynamically described in the paper for 2000-2003. Smoking-related specific features are analyzed with respect to the age and sex differences of teenagers. A database, comprising above 25,000 entries, was created on the prevalence of smokers among city schoolchildren.


Changes in acute viral hepatitis epidemiology in the Turkish adult population: A multicenter study.
The present study aimed to determine the changes in the epidemiology of hepatitis in recent years in an adult Turkish population. Overall, 852 patients with acute viral hepatitis from 17 centers were included in this study. Their sociodemographic characteristics, clinical courses, treatments, and laboratory findings were retrospectively analyzed. The most commonly found microorganisms were the hepatitis B virus (55.2%) and hepatitis A virus (37.6%), and the types of acute viral hepatitis differed significantly according to the age group (p≤0.001). The most frequently reported symptom was fatigue (73.7%), and the most common complications were cholecystitis (0.4%) and fulminant hepatitis (0.4%). The median hospital stay was 9 days (range 1-373). In total, 40.8% patients with acute hepatitis B virus developed immunity. In Turkey, there are significantly large adolescent and adult populations susceptible to acute viral hepatitis. Therefore, larger vaccination programs covering these age groups should be implemented.


Exome array analysis of adverse reactions to fluoropyrimidine-based therapy for gastrointestinal cancer.
Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful.


Xanthoma disseminatum: effective therapy with 2-chlorodeoxyadenosine in a case series.
Xanthoma disseminatum is a rare nonfamilial disease characterized by lipid deposition in skin and internal organs due to histiocytic cell proliferation, classified as a benign non-Langerhans cell histiocytosis. This chronic disease has no known established treatment. We report 8 cases of xanthoma disseminatum with treatment outcomes in long-term follow-up and provide a review of the medical literature. We studied clinical manifestations; disease course; histopathologic and immunopathological findings; and responses to treatment in 8 consecutively seen patients with xanthoma disseminatum, including follow-up. The follow-up period ranged from 3 months to 8 years. Five patients received 2-chlorodeoxyadenosine. Therapy with 2-chlorodeoxyadenosine was effective at inducing remission and long-term control of cutaneous lesions of xanthoma disseminatum in 5 cases. Adverse effects were minimal, and treatment was well tolerated. No improvement was noted in untreated patients. Among 8 cases of xanthoma disseminatum, a positive response to treatment with 2-chlorodeoxyadenosine was seen in 5 cases.


Dimensional changes of the ridge contour after socket preservation and buccal overbuilding: an animal study.
The aim of the study was to volumetrically assess alterations of the ridge contour after socket preservation and buccal overbuilding. In five beagle dogs, four extraction sites were subjected to one of the following treatments: Tx 1: The socket was filled with BioOss Collagen and covered with a free gingival autograft from the palate (SP). Tx 2: The buccal bone plate was forced into a buccal direction using a manual bone spreader and SP was performed. Tx 3: The buccal bone plate was forced into a buccal direction using a manual bone spreader; SP was performed. Tx 4: The socket was filled with BioOss Collagen and a combined free gingival/connective tissue graft was used to cover the socket and for buccal tissue augmentation. Impressions were obtained at baseline, 2 weeks and 4 months post-operatively. Casts were optically scanned and superimposed in one common coordinate system. Using digital image analysis, the volumetric differences per area among the different treatment time points and among the treatment groups were calculated. Four months after tooth extraction, no statistically significant differences with regard to the buccal volume per area could be assessed among the treatment groups. Overbuilding the buccal aspect in combination with socket preservation is not a suitable technique to compensate for the alterations after tooth extraction.


Development of an NIH consortium for preclinicAl AssESsment of CARdioprotective therapies (CAESAR): a paradigm shift in studies of infarct size limitation.
An estimated 935,000 Americans suffer a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For 40 years, the National Heart, Lung, and Blood Institute (NHLBI) has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due largely to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use. Clearly, after 40 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research on cardioprotection, the same standards of scientific rigor that are applied to clinical trials. In compliance with the recommendations of an National Heart, Lung, and Blood Institute (NHLBI)-sponsored workshop held in June 2003 and using the clinical trial networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, a preclinical consortium has been organized that will operate in a manner analogous to a clinical trial network. This infrastructure has been named CAESAR (Consortium for preclinicAl assESsment of cARdioprotective therapies). Under the direction of Roberto Bolli, 4 Institutions (University of Louisville, Johns Hopkins, Emory University, and Medical College of Virginia) will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, dose-response analyses, optimal statistical methods, independent data analysis Cores, an independent statistical Core, verification of tetrazolium data with histology and plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities). Therapies will be tested in 3 species (anesthetized mouse, conscious rabbit, and conscious pig). A major goal is to ensure reproducibility; to this end, each study in each species will be performed in 2 centers using identical protocols. The structure of CAESAR will ensure that the consortium will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. Proposals for studying cardioprotective therapies will be solicited from the entire scientific community. The consortium will be available at no cost to all National Institutes of Health (NIH)-funded investigators. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in the academia and in the biomedical industry), thereby constituting a public resource. Consortium for preclinicAl assESsment of cARdioprotective therapies will be a major paradigm shift in cardioprotection. By screening promising therapies and identifying those that are truly effective in relevant experimental models and, thus, most likely to be effective in patients, CAESAR will dramatically advance our ability to rationally translate basic findings into clinical use. This article will summarize the rationale, structure, and operation of the NHLBI CAESAR Consortium.


Preferential behavior on donating atoms of an ambidentate ligand 2-methylisothiazol-3(2H)-one in its metal complexes.
Five metal complexes of 2-methylisothiazol-3(2H)-one (MIO), [Co(III)(NH3)5(MIO)](3+), [Ru(II)(NH3)5(MIO)](2+), [Ru(III)(NH3)5(MIO)](3+), [Pt(II)Cl3(MIO)](-), and trans-[U(VI)O2(NO3)2(MIO)2], were synthesized, and their structures were determined by single-crystal X-ray crystallography. MIO is an ambidentate ligand and coordinates to metal centers through its oxygen atom in the cobalt(III), ruthenium(III), and uranium(VI) complexes and through its sulfur atom in the ruthenium(II) and platinum(III) complexes. This result suggests that MIO shows preferential behavior on its donating atoms. We also studied the electron-donor abilities of the oxygen and sulfur atoms of MIO. Various physical measurements on the conjugate acid of MIO and the MIO complexes allowed us to determine an acid dissociation constant (pKa) and donor number (DN) for the oxygen atom of MIO and Lever's electrochemical parameter (EL) and a relative covalency parameter (kL) for the sulfur atom.


Nonalcoholic Fatty Liver Disease Predicts Acute Kidney Injury Readmission in Heart Failure Hospitalizations: A Nationwide Analysis.
Nonalcoholic fatty liver disease (NAFLD) has been associated with the progression of chronic kidney disease. However, limited data is available on its impact on acute kidney injury (AKI) in heart failure(HF) patients. All primary adult HF admissions from the national readmission database of 2016-2019 were identified. Admissions from July to December of each year were excluded to allow 6 months of follow-up. Patients were stratified according to the presence of NAFLD. Complex multivariate cox regression was used to adjust for confounders and calculate the adjusted hazard ratio. A total of 420,893 weighted patients admitted with HF were included in our cohort, of whom 780 had a secondary diagnosis of NAFLD. Patients with NAFLD were younger, more likely to be female, and had higher rates of obesity and diabetes mellitus. Both groups had similar rates of chronic kidney disease irrespective of the stage. NAFLD was associated with an increased risk of 6-month readmission with AKI (26.8% vs 16.6%, adjusted hazard ratio:1.44, 95% CI [1.14-1.82], P = 0.003). The mean time to AKI readmission was 150 ± 44 days. NAFLD was associated with a shorter mean time to readmission (145 ± 45 vs 155 ± 42 days, β = -10 days, P = 0.044). Our study from a national database suggests that NAFLD is an independent predictor of 6-months readmission with AKI in patients admitted with HF. Further research is warranted to validate these findings.


Treatment of open tibial-shaft fractures. External fixation and secondary intramedullary nailing.
Between 1979 and 1986, sixteen of 369 open fractures of the tibial shaft were treated by external fixation followed by intramedullary nailing. These fractures comprised one Type-I, two Type-II, and thirteen Type-III injuries. This method of treatment was the original treatment plan in nine patients (56 per cent), for delayed union while the external fixator was still in place in four patients (25 per cent), for loss of reduction in a plaster cast in two patients (13 per cent), and for osteomyelitis and a segmental defect in one patient (6 per cent). The average duration of external fixation was 8.5 weeks; the average time between removal of the external fixator and intramedullary nailing, three weeks; and the average time between injury and nailing, twelve weeks. All sixteen patients were followed until either the fracture had united (eleven patients) or there was an established non-union (five patients). At that time, seventeen additional procedures were performed, including bone-grafting, fibulectomy, and re-nailing. Only five of the sixteen fractures healed without additional surgical procedures or major complications. The five fractures that progressed to a non-union were all Type III, and all were complicated by a deep infection. Over-all, the complications included seven deep infections (an intramedullary infection in four patients, osteomyelitis in two, and a chronic draining sinus associated with a ring sequestrum in one); five minor infections during external fixation, which developed into five of the seven deep infections that occurred after the secondary intramedullary nailing; and eight non-unions, three of which progressed to union after multiple procedures. The over-all incidence of non-union was 50 per cent and that of deep infection, 44 per cent. On the basis of the high incidence of complications in both the present series and the few reports in the literature, we concluded that alternative treatment options should be carefully considered before electing this sequential method of fixation.


New developments in the mental health of refugee children and adolescents.
The increase in refugees globally since 2010 and the arrival of many into Europe since 2015, around 50% of whom are under 18 years, have been the stimulus to greater investigation and publications regarding their mental health. This clinical review summarises selected themes in the field as described in the published literature since 2016. The themes include refugee statistics, premigration and postmigration experiences, psychopathology focusing on parent-child relationships, unaccompanied refugee minors and associations between resettlement, acculturation and mental health. Some important reviews and studies are discussed that address service and treatment provision. While there has been a recent increase in research in this field, more is needed into the course of psychopathology, protective factors and the promotion of integration into resettlement countries, as well as models of service delivery and treatment effectiveness.


Interaction of veterinary antibiotic tetracyclines and copper on their fates in water and water hyacinth (Eichhornia crassipes).
Water hyacinth (Eichhornia crassipes) may provide an alternative solution for the removal of co-contamination between antibiotics and heavy metals from livestock and poultry wastewater. A hydroponic experiment was conducted to investigate interaction of tetracyclines (TCs) and copper (Cu) on growth of E. crassipes, removal of TCs and Cu by plants and their fates in solution. After 20 days, plant growth, concentrations and accumulation of Cu and TCs in plants, removal by plants, and dissipation in solution were significantly influenced by interaction of Cu and TCs. Influence of only Cu or TCs on plant growth was not significant, except for TCs at 15 mg L(-1) which produced a negative effect on plant biomass. The presence of low-Cu and high-TCs acted synergistically to promote the negative effect of TCs on plant biomass, but increasing Cu concentration partially alleviated the adverse effect. Co-contamination of low-concentration Cu and TCs could exert antagonistic effects on the removal and accumulation of Cu and TCs by plants; in contrast, synergistic effects were found for the combination of high-concentration Cu and TCs. The Cu/TCs in solution could effectively be removed using E. crassipes. Plants significantly enhanced dissipation of TCs in solution. Hence, interaction of TCs and Cu should be taken into consideration when judging (1) an ecotoxicological potential of TCs and Cu residues in aquatic environments, and (2) removal efficiency of TCs and Cu in phytoremediation.


Assessment of Clinical and Radiographic Success Rate of Formocresol-based Pulpotomy versus Collagen-based Pulpotomy: An In Vivo Study.
The aim of the study is (a) To use collagen as a pulpotomy material in comparison with the gold standard formocresol-based pulpotomy, (b) to assess the clinical and radiographic success rate of formocresol pulpotomy and collagen-based pulpotomy, and (c) to compare the success rate of formocresol-based pulpotomy and collagen-based pulpotomy over a definitive interval of time. Totally 30 primary first or second molars indicated for pulpotomy after confirming with the operative diagnosis were taken as samples for this study. This split-mouth technique consists of two groups: Group 1-formocresol pulpotomy (n = 15), and group 2-collagen-based pulpotomy (n = 15). Both the procedures were done in the same patient on regular appointments. Pre- and postoperative radiographs were taken. The children were recalled for clinical and radiographic follow-up at 2, 4, and 6 months. The success of the procedure was assessed based on clinical signs (pain, tenderness to percussion, abscess, swelling, fistula, and pathologic mobility) and radiographic findings (radicular radiolucency, internal and external root resorption, periodontal ligament (PDL) space widening, and furcation radiolucency). The Chi-square test was used to compare the differences between the groups. The overall success rate for formocresol pulpotomy (n = 15) was 14, 13, and 10 for the second-, fourth-, and sixth-month review period, respectively. For collagen pulpotomy group (n = 15), the overall success rate was 14, 14, and 14 for the second-, fourth-, and sixth-month review period, respectively. The obtained data from the overall success rate were subjected to statistical analysis, and chi-square test was used. The p-value less than 0.1 was considered a statistically significant result. The chi-square value for the fourth- and sixth-month review was 0.37 and 3.33, respectively. Statistically significant value was obtained from the sixth-month review period (p <0.1), which describes that the overall success rate was better for the collagen pulpotomy group when compared with the formocresol pulpotomy group. Collagen had proven to be a very good alternative for formocresol, its biocompatibility, and regenerative efficiency and is a benchmark for a better clinical success rate in dentistry. However, its implication in pulpotomy should be subjected to further comparative research study on mineral trioxide aggregate (MTA), Biodentine, etc. Keywords: Collagen-based pulpotomy, Formocresol-based pulpotomy.


Bonding personal social capital as an ingredient for positive aging and mental well-being. A study among a sample of Dutch elderly.
The current study aims to add to the limited empirical research of possible benefits of personal social capital for the well-being of elderly. A validated personal social capital scale, measuring both bonding and bridging social capital in a general population, was adjusted to fit the characteristics of the social environment of elderly, to explore the association between social capital and well-being of elderly, as well as the mediating role of loneliness. A sample of 328 Dutch adults, varying in age from 65 to 90 years (Mean = 72.07; SD = 4.90) filled out an online questionnaire including the adapted personal social capital scale for elderly (PSCSE), as well as validated scales measuring social, emotional, and psychological well-being and loneliness. Relevant other (demographic) variables were included for testing construct and criterion validity. CFA analysis revealed the subdimensions bonding and bridging social capital with reliability scores of respectively α = .88 and α = .87, and α = .89 for the total scale. Regression analyses confirmed construct and criterion validity. Subsequently, significant positive associations between bonding social capital and respectively social, emotional and psychological well-being were found. These associations were mediated by loneliness. Bridging social capital was only found to be significantly associated with social well-being, not mediated by loneliness. Our findings have enhanced our understanding of the association between social capital and mental well-being of elderly and indicate that bonding personal social capital in particular may be considered an ingredient for positive aging.


Water and solute absorption from a new hypotonic oral rehydration solution: evaluation in human and animal perfusion models.
Controversy continues regarding the optimal composition of glucose electrolyte oral rehydration solutions for the treatment of acute diarrhoea. Four perfusion models (normal human jejunum, normal rat small intestine, cholera toxin treated secreting rat small intestine and rotavirus infected rat small intestine) have been developed and used to compare the efficacy of a hypotonic oral rehydration solution with standard United Kingdom British National formulary and developing world oral rehydration solutions (WHO). Despite obvious physiological and pathophysiological differences between these models there was general congruence in the water and solute absorption profiles of the different oral rehydration solutions. Hypotonic oral rehydration solution promoted significantly greater water absorption than other oral rehydration solutions in all rat models (p < 0.001) but apparently increased water absorption failed to achieve significance in human jejunum. British National Formulary-oral rehydration solution was unable to reverse net water secretion in both rotavirus and cholera toxin models. Net sodium absorption from hypotonic and WHO-oral rehydration solutions was significantly greater than from the low sodium British National Formulary-oral rehydration solutions (p < 0.001) except in the rotavirus model when absorption was similar to hypotonic-oral rehydration solutions. These findings show that there is agreement in the apparent efficacy of oral rehydration solutions in these animal and human perfusion models, and that improved water absorption with adequate sodium absorption may be achieved by reducing oral rehydration solution osmolality.


CD44‑hyaluronan axis plays a role in the interactions between colon cancer‑derived extracellular vesicles and human monocytes.
During tumor progression, monocytes circulating in the blood or infiltrating tissue may be exposed to tumor-derived extracellular vesicles (TEVs). The first stage of such interactions involves binding of TEVs to the surface of monocytes, followed by their internalization. The present study examines the role of CD44 molecules in the interactions between monocytes and EVs derived from colon cancer cell lines (HCT116 and SW1116). The efficiency of the attachment and engulfment of TEVs by monocytes is linked to the number of TEVs and time of exposure/interaction. The two investigated TEVs, TEVsHCT116 and TEVsSW1116, originating from HCT116 and SW1116 cells, respectively, differ in hyaluronan (HA) cargo, which reflects HA secretion by parental cancer cells. HA-rich TEVsHCT116 are internalized more effectively in comparison with HA-low TEVsSW1116. Blocking of CD44 molecules on monocytes by anti-CD44 monoclonal antibody significantly decreased the engulfment of TEVsHCT116 but not that of TEVsSW1116 after 30 min contact, suggesting the involvement of the HA-CD44 axis. The three subsets of monocytes, classical, intermediate and non-classical, characterized by gradual changes in the expression of CD14 and CD16 markers, also differ in the expression of CD44. The highest expression of CD44 molecules was observed in the intermediate monocyte subset. Blocking of CD44 molecules decreased the internalization of HA-rich TEVs in all three subsets, which is associated with CD44 expression level. It was hypothesized that HA carried by TEVs, potentially as a component of the 'corona' coating, may facilitate the interaction between subsets of monocytes and TEVs, which may influence the fate of TEVs (such as the rate of TEVs adhesion and engulfment) and change monocyte activity.


Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up.
Children and adolescents with differentiated thyroid cancer (DTC) have a good prognosis and prolonged survival even when extensive regional disease or lung metastases are present at the diagnosis; very-long-term follow-up is needed to appreciate what, if any, impact the disease may exert on the ultimate outcome. We retrospectively reviewed the clinical course of 112 patients with DTC who registered at M. D. Anderson Cancer Center between 1944 and 1986, were younger than 20 years old at the time of diagnosis, and were followed for at least 10 years. Surgery alone or combined with radioactive iodine or radiotherapy was used for most cases. At the time of most recent contact, 99 patients remained alive and 13 had died. The 99 patients had 25 +/- 0.9 years of available follow-up (mean +/- SEM) and were 41 +/- 0.9 years of age at time of last contact; one fourth had had recurrent disease at some point since diagnosis. Among the 13 patients who died, one died of complications from coexisting diabetes mellitus, and the cause of death was not clear in one other case. Two patients died of breast cancer 13 and 15 years after thyroid cancer diagnosis. In three cases, cause of death could be considered etiologically related to initial radiotherapy: one patient developed tracheal necrosis 26 years after diagnosis and died of upper airway complications, whereas another two patients developed sarcomas of the cervical region 22 and 29 years after thyroid cancer diagnosis. Lastly, six patients died of thyroid cancer 26 +/- 3.1 years after initial diagnosis (at age 40 +/- 2.1 years). Among these cases, one patient had invasive disease and lung metastases at diagnosis and died of progressive lung metastases after 36 years. The other five patients were initially seen with local/regional disease and developed lung and skeletal metastases after a 2- to 20-year disease-free interval. Our findings support the clinical impression that children and adolescents with DTC live for many years regardless of apparent extent of disease at diagnosis or development of recurrence. Indeed, overall survival was 100% at 10 years even in patients with distant metastases. However, attention to these patients' clinical course beyond the first decade indicates that a small minority (5% to 7%) of patients eventually succumb to progressive disease and that a similar number develop possibly treatment-related lethal complications or second neoplasms. We suggest lifelong surveillance for all such patients.


Taxometric and factor analytic models of anxiety sensitivity: integrating approaches to latent structural research.
This study represents an effort to better understand the latent structure of anxiety sensitivity (AS), as indexed by the 16-item Anxiety Sensitivity Index (ASI; S. Reiss, R. A. Peterson, M. Gursky, & R. J. McNally, 1986), by using taxometric and factor-analytic approaches in an integrative manner. Taxometric analyses indicated that AS has a taxonic latent class structure (i.e., a dichotomous latent class structure) in a large sample of North American adults (N=2,515). As predicted, confirmatory factor analyses indicated that a multidimensional 3-factor model of AS provided a good fit for the AS complement class (normative or low-risk form) but not the AS taxon class (high-risk form). Exploratory factor analytic results suggested that the AS taxon may demonstrate a unique, unidimensional factor solution, though there are alternative indications that it may be characterized by a 2-factor solution. Findings suggest that the latent structural nature of AS can be conceptualized as a taxonic latent class structure composed of 2 types or forms of AS, each of these forms characterized by its own unique latent continuity and dimensional structure.


Clinical Diagnostic Imaging Study of Osteoradionecrosis of the Jaw: A Retrospective Study.
Radiation therapy (RT) plays a significant role in the management of head and neck malignancies. This study aimed to review the clinical symptoms and various imaging findings of osteoradionecrosis (ORN) and provide a clinical perspective on the development of ORN. The retrospective cohort was composed of 57 sites in 54 patients who had a history of RT and suspected ORN and 48 sites in 45 patients who were confirmed to have ORN. Image analyses included computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, bone scintigraphy, and single-photon emission CT (SPECT). The irradiated tissue was damaged by RT, and the extent of damage was correlated with clinical symptoms. The bone marrow showed sclerotic changes and the devitalized bone showed bone resorption after invasive stimulation. Chronic trismus and pathological fracture are considered severe conditions, typically occurring in the last stage of ORN. Furthermore, neurological symptoms were an important sign of tumor recurrence, since diagnostic imaging was difficult. The possible treatment options vary depending on the stage of ORN. We speculate that bone sclerosis reactions and bone resorption are sequential reactions that seem to be protective measures of the bone to radiation injury.


Tomographic imaging of fragmented cortical bone heteroimplant and methylmethacrylate in segmental bone defect of rabbit tibia.
To evaluate the performance of composites consisting of fragmented cortical bone heteroimplant in association with methylmethacrylate preserved in 98% glycerin, in segmental bone defect of rabbit tibia medial metaphysis. In this study were used twelve adult New Zealand rabbits, divided into three groups of four animals each: G30 (30 days), G60 (60 days) and G90 (90 days). The bone defects previously created in the tibia were filled with composites and both were evaluated by cone-beam computed tomography, immediately after surgery and after 30, 60, and 90 days. The composites fulfilled and remained in the sites of bone defects in all cases and were not registered signals of infection, migration or rejection. The implanted composites promoted the bone defects repair without signals of infection and/or rejection. The composites are one more option for bone defects repair.


A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination.
Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.


Vasculopathy associated with the antiphospholipid antibody syndrome.
Antiphospholipid antibodies including the false-positive serologic test for syphilis, the lupus circulating anticoagulant, and the anticardiolipin antibody can be associated with recurrent thrombotic events, recurrent fetal loss, and thrombocytopenia. A range of other possible clinical associations also exists, including neurologic events, skin lesions, and cardiac lesions. The pathology of these lesions and the pathophysiology are discussed. Treatment is controversial but when indicated is directed toward prevention of recurrent episodes using anticoagulants including antiplatelet agents, warfarin, and heparin as well as occasionally prednisone with or without immunosuppressive agents.


Neuromuscular complications of cancer therapy.
The neuromuscular complications of cancer therapy include chemotherapy-induced peripheral neurotoxicity (CIPN), immune-related neuromuscular complications to immune checkpoint inhibitors and radiation-induced neuropathy/plexopathy. With a wider focus on CIPN, we will discuss new pathogenetic insights, recent predictive biomarkers and emerging therapies for neuromuscular complications of cancer therapy. Findings from recent preclinical studies have improved our knowledge on new CIPN pathogenetic pathways, including the activation of senescence-like processes in neurons, axonal degeneration and neuroinflammation. Metabolomics and serum neurofilament light chain levels appear the most promising biomarkers to predict CIPN development and severity. There is some recent evidence of promising pharmacological compounds to prevent or treat CIPN, and new drugs are in early development and testing. A multimodal assessment, with neurophysiological, imaging and patient-reported outcome measures, coupled with the use of reliable blood or genetic biomarkers, may offer pathogenetic grounds for future preventive and symptomatic strategies for the multidisciplinary treatment of neuromuscular complications of cancer therapy.


Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.
We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.


Differential repair enzyme-substrate selection within dynamic DNA energy landscapes.
We demonstrate that reshaping of the dynamic, bulged-loop energy landscape of DNA triplet repeat ensembles by the presence of an abasic site alters repair outcomes by the APE1 enzyme. This phenomenon depends on the structural context of the lesion, despite the abasic site always having the same neighbors in sequence space. We employ this lesion-induced redistribution of DNA states and a kinetic trap to monitor different occupancies of the DNA bulge loop states. We show how such dynamic redistribution and associated differential occupancies of DNA states impact APE1 repair outcomes and APE1 induced interconversions. We correlate the differential biophysical properties of the dynamic, DNA ensemble states, with their ability to be recognized and processed as substrates by the APE1 DNA repair enzyme. Enzymatic digestions and biophysical characterizations reveal that APE1 cuts a fraction (10-12%) of the dynamic, rollameric substrates within the initial kinetic distribution. APE1 interactions also 'induce' rollamer redistribution from a kinetically trapped distribution to an equilibrium distribution, the latter not containing viable APE1 substrates. We distinguish between kinetically controlled ensemble (re)distributions of potential DNA substrates, versus thermodynamically controlled ensemble (re)distribution; features of importance to DNA regulation. We conclude that APE1 activity catalyzes/induces ensembles that represent the thermodynamically optimal loop distribution, yet which also are nonviable substrate states for abasic site cleavage by APE1. We propose that by inducing substrate redistributions in a dynamic energy landscape, the enzyme actually reduces the available substrate competent species for it to process, reflective of a regulatory mechanism for enzymatic self-repression. If this is a general phenomenon, such a consequence would have a profound impact on slowing down and/or misdirecting DNA repair within dynamic energy landscapes, as exemplified here within triplet repeat domains. In short, APE1-instigated redistribution of potential substrates induces a preferred pathway to an equilibrium ensemble of enzymatically incompetent states.


Isolated rat brain capillaries possess intact, structurally complex, interendothelial tight junctions; freeze-fracture verification of tight junction integrity.
Populations of isolated brain capillaries have been proposed as useful models for in vitro studies of the blood-brain barrier. Preliminary investigations of barrier properties using such preparations of brain microvessels have suggested that the tight interendothelial junctions (zonulae occludentes) are intact and retain the impermeability to the protein tracer horseradish peroxidase, exhibited by them in vivo. The endothelial junctions of isolated capillaries are therefore assumed to be functionally "tight' in vitro. In order to determine the precise structural organization of these occluding junctions, including an estimate of their tightness (complexity), and to demonstrate a method for simple but precise assessment of junctional integrity, pellets of isolated rat brain capillaries were freeze-fractured and then replicated with platinum and carbon. The freeze-fracture images of interendothelial zonulae occludentes revealed complex arrays of intramembrane ridges and grooves characteristic of tight junctions. Longitudinal fractures of the cellular lining of capillaries exposed vast expanses of interendothelial plasma membrane interfaces and the junctional complexes situated between the cells. From such arrays, the elaborate and complex architecture of the zonulae occludentes could be readily appreciated. Situated on the PF fracture faces are 6-8 parallel ridges which display a high degree of anastomosing between adjacent strands. The EF fracture face contains grooves complementary to the PF face ridges. The zonulae occludentes of these capillary endothelial cells are similar in complexity to those reported in the literature for reptilian brain capillaries and therefore can be presumed "very tight'. This study demonstrates that freeze-fracture of pellets of brain capillaries alleviates sampling problems inherent in whole tissue preparations and, in addition, demonstrates the usefulness of freeze-fracture as a tool to monitor junction structure during in vitro investigation of the blood-brain barrier.


Skeletal Muscle CLARITY: A Preliminary Study of Imaging The Three-Dimensional Architecture of Blood Vessels and Neurons.
Passive CLARITY is a whole-tissue clearing protocol, based on sodium dodecyl sulfate (SDS) clearing, for imaging intact tissue containing transgenic or immunolabeled fluorescent proteins. In this study, we present an improved passive CLARITY protocol with efficient immunolabeling without the need for electrophoresis or complex instrumentation. In this experimental study, after perfusion of C57BL/6N mice with phosphate-buffered saline (PBS) and then with acrylamide-paraformaldehyde (PFA), the quadriceps femoris muscle was removed. The muscle samples were post-fixed and degassed to initiate polymerization. After removing the excess hydrogel around the muscle, lipids were washed out with the passive CLARITY technique. The transparent whole intact muscles were labeled for vessel and neuron markers, and then imaged by confocal microscopy. Three-dimensional images were reconstructed to present the muscle tissue architecture. We established a simple clearing protocol using wild type mouse muscle and labeling of vasculatures and neurons. Imaging the fluorescent signal was achieved by protein fixation, adjusting the pH of the SDS solution and using an optimum temperature (37˚C) for tissue clearing, all of which contributed to the superiority of our protocol. We conclude that this passive CLARITY protocol can be successfully applied to three-dimensional cellular and whole muscle imaging in mice, and will facilitate structural analyses and connectomics of large assemblies of muscle cells, vessels and neurons in the context of three-dimensional systems.


Phylogeny of the most species-rich freshwater bivalve family (Bivalvia: Unionida: Unionidae): Defining modern subfamilies and tribes.
Freshwater mussels of the order Unionida are key elements of freshwater habitats and are responsible for important ecological functions and services. Unfortunately, these bivalves are among the most threatened freshwater taxa in the world. However, conservation planning and management are hindered by taxonomic problems and a lack of detailed ecological data. This highlights the urgent need for advances in the areas of systematics and evolutionary relationships within the Unionida. This study presents the most comprehensive phylogeny to date of the larger Unionida family, i.e., the Unionidae. The phylogeny is based on a combined dataset of 1032bp (COI+28S) of 70 species in 46 genera, with 7 of this genera being sequenced for the first time. The resulting phylogeny divided the Unionidae into 6 supported subfamilies and 18 tribes, three of which are here named for the first time (i.e., Chamberlainiini nomen novum, Cristariini nomen novum and Lanceolariini nomen novum). Molecular analyses were complemented by investigations of selected morphological, anatomical and behavioral characters used in traditional phylogenetic studies. No single morphological, anatomical or behavioral character was diagnostic at the subfamily level and few were useful at the tribe level. However, within subfamilies, many tribes can be recognized based on a subset of these characters. The geographical distribution of each of the subfamilies and tribes is also presented. The present study provides important advances in the systematics of these extraordinary taxa with implications for future ecological and conservation studies.


A Bispecific Antibody Based on Pertuzumab Fab Has Potent Antitumor Activity.
Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed and activated in metastatic breast cancers. Monoclonal antibodies targeting Her2, such as trastuzumab and pertuzumab, have become important targeted therapies for patients with HER2-positive breast cancer. Both trastuzumab and pertuzumab can reduce Her2 positive tumor burden by inhibiting Her2 signaling and inducing ADCC activities (antibody dependent cell-mediated cytotoxicity). In this study, we have generated a bispecific antibody, Her2(Per)-S-Fab, by linking the pertuzumab Fab to an anti-CD16 single domain antibody. The Her2(Per)-S-Fab can be expressed and purified efficiently from Escherichia coli. In vitro and in vivo experiments showed Her2(Per)-S-Fab had potent cytotoxicity against Her2-positive tumor cells. Thus, Her2(Per)-S-Fab may provide an alternative to treat Her2-positive cancer patients.


[Malignant neuroleptic syndrome in patients with dementia].
The neuroleptic malignant syndrome (NMS) is a side-effect of treatment with neuroleptic drugs. It is infrequent, but underdiagnosed. The diagnosis can be especially difficult to verify, in older patients with dementia because they often have symptoms of NMS, as a consequence of age and dementia. The importance of monitoring serum-creatine-kinase is discussed and proposals for treatment are suggested.


mHealth and patient generated health data: stakeholder perspectives on opportunities and barriers for transforming healthcare.
Wearable devices, mobile health apps, and geolocation technologies place the ability to track, monitor and report data in the individuals' hands - or on their bodies. These innovations create an opportunity for "connected health," where individuals collect data outside of the healthcare encounter and report it to care providers. Collection of such patient-generated health data (PGHD) has the potential to impact the delivery of healthcare through remote monitoring, and by allowing patients and healthcare teams to provide targeted and efficient care that aligns with the health status of individual patients. To understand the value and barriers associated with clinical integration of PGHD we engaged a range of stakeholders, examining their perspectives and experiences of PGHD use. We conducted open-ended interviews with healthcare consumers (patients and care partners), healthcare providers, and healthcare administrators. Open recruitment and purposive sampling were utilized to identify participants that represented the breadth of PGHD use in research and clinical care. Interview guides focused on the value and barriers of PGHD use. Interviews were recorded, transcribed, and analyzed for emergent themes. Themes emerged around the value of PGHD to support care decisions and improve patient-provider communication and engagement, and the promise of applying PGHD to formal care pathways and measurement-based care. Significant barriers included data validity and actionability, and the burden of integrating PGHD into existing care processes. Interviews highlighted areas for future research to better understand how PGHD can advance care transformation. These findings provide rich context for understanding the experiences and needs of the individuals who interface with PGHD. Translating advances in technology and data tracking into successful clinical implementation requires understanding how stakeholders conceptualize and make use of PGHD, the potential value that PGHD can add to care, and the challenges that may limit PGHD's promise. Our results illustrate the value and challenges associated with health-system implementation of PGHD. Efforts to increase the scale and spread of PGHD will benefit from an approach that addresses the value and challenges PGHD brings to clinical care.


Targeting of the hNC16A collagen domain to dendritic cells induces tolerance to human type XVII collagen.
Antibodies, specific to murine DEC205, can be used to target antigens to dendritic cells. The immunodominant domain of human type XVII collagen, hNC16A, was fused to this antibody (DEC-hNC16A) and was administered as expression plasmid by gene gun transfection with the aim of inducing tolerance to human type XVII collagen in a skin transplantation model. Mice transfected with DEC-hNC16A were challenged with skin grafts from transgenic mice engineered to express human type XVII collagen. Graft survival was either prolonged or grafts were accepted infinitely (33% and 16%, respectively) upon treatment with DEC-hNC16A while 100% of grafts were rejected in untreated controls. Graft acceptance was associated with the absence of a CD4+ infiltrate and a dense CD8+ T-cell infiltrate and was not strictly dependent on antibody production. Our results show that DEC-hNC16A targets dendritic cells in vivo leading to prolonged survival of transgenic skin grafts. This indicates that DEC205-targeting may be used for the induction of tolerance to skin antigens, which would increase the chances of successful skin gene therapy of epidermolysis bullosa patients.


The Immunopathology of COVID-19 and the Cannabis Paradigm.
Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.


Spatial integration of compound gratings with various numbers of orientation components.
The human foveal visual system in a detection task was recently modeled as a simple image processor comprising low-pass filtering due to the optical modulation transfer function of the eye, high-pass filtering (lateral inhibition) due to the neural modulation transfer function of visual pathways, addition of internal neural noise, and detection by a local matched filter, the efficiency of which decreases with increasing grating area. The applicability of this model was now tested by studying spatial integration for sums of various numbers of cosine gratings with different orientations. Binocular root-mean-square contrast sensitivity was measured as a function of area for sums of cosine gratings (n = 1 to 16) with the same contrast, phase, and spatial frequency but with an orientation difference of 180/n between the components. In agreement with the model, contrast sensitivity increased in proportion to the square root of grating area at small areas. When grating area exceeded its critical value, the increase saturated, and contrast sensitivity then became independent of area. The critical area and maximum contrast sensitivity of spatial integration first decreased with an increasing number of components, reaching minima at n = 5 to 6, but increased thereafter. A plausible explanation for the variation of critical area and maximum sensitivity could be the variation of the amount of contour and detail per unit area in the sums of cosine gratings. Critical area divided by maximum sensitivity squared refers to the contrast energy threshold at small grating areas. It was independent of the number of components but, because of lateral inhibition, decreased in inverse proportion to spatial frequency squared. Contrast energy threshold as a function of normalized grating area (grating area divided by critical area) also was independent of the number of components and decreased in inverse proportion to spatial frequency squared. Within the framework of the local matched filter model, the dependency of contrast sensitivity on the grating area and number of orientation components resulted from the decrease in the efficiency of contrast energy collection, which was probably due to the increasing amount of contour and detail in the stimulus to be detected.


Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K.
The mechanisms by which the dietary compound tangeretin has anticancer effects may include acting as a prodrug, forming an antiproliferative product in cancer cells. Here we show that tangeretin also inhibits cell cycle progression in hepatocytes and investigate the role of its primary metabolite 4'-hydroxy-5,6,7,8-tetramethoxyflavone (4'-OH-TMF) in this effect. We used epidermal growth factor (EGF)-stimulated rat hepatocytes, with [(3)H]-thymidine incorporation into DNA as an index of progression to S-phase of the cell cycle, and Western blots for phospho-proteins involved in the cell signalling cascade. Incubation of tangeretin with microsomes expressing CYP1A, or with hepatocytes, generated a primary product we identified as 4'-OH-TMF. Low micromolar concentrations of tangeretin or 4'-OH-TMF gave a concentration-dependent inhibition of EGF-stimulated progression to S-phase while having little effect on cell viability. To determine whether time for conversion of tangeretin to an active metabolite would enhance the inhibitory effect we used long pre-incubations; this reduced the inhibitory effect, in parallel with a reduction in the concentration of tangeretin. The EGF-stimulation of hepatocyte cell cycle progression requires signalling through Akt/mTOR/p70S6K kinase cascades. The tangeretin metabolite 4'-OH-TMF selectively inhibited S6K phosphorylation in the absence of significant inhibition of upstream Akt activity, suggesting an effect at the level of mTOR. Tangeretin and 4'-OH-TMF both inhibit cell cycle progression in primary hepatocytes. The inhibition of p70S6K phosphorylation by 4'-OH-TMF raises the possibility that inhibition of the mTOR pathway may contribute to the anticancer influence of a flavonoid-rich diet.


Kidney Health for Everyone Everywhere-From Prevention to Detection and Equitable Access to Care.
The global burden of chronic kidney disease (CKD) is increasing with a projection of becoming the fifth leading cause of years of life lost globally by 2040. CKD is a major cause of catastrophic health expenditure. The costs of dialysis and transplantation consume up to 3% of the entire annual healthcare budget in high-income countries. Crucially, however, both the onset and progression of CKD is potentially preventable. In 2020, the World Kidney Day campaign highlights the importance of preventive interventions-be it primary, i.e. to prevent de novo CKD, or secondary or tertiary, i.e. prevention of worsening early CKD or progression of more advanced CKD to end-stage kidney disease, respectively. Primary prevention should focus on the modification of CKD risk factors and address the structural abnormalities of the kidney and urinary tracts, and exposure to environmental risk factors and nephrotoxins. In persons with pre-existing kidney disease, secondary prevention, including blood pressure optimization, glycemic control and avoiding high-protein high-sodium diet should be the main goal of education and clinical interventions. In patients with moderate to advanced CKD, the management of comorbidities such as uremia and cardiovascular disease along with low-protein diet are among the recommended preventative interventions to avoid or delay dialysis or kidney transplantation. Whereas national policies and strategies for noncommunicable diseases may exist in a country, specific policies directed toward education and awareness about CKD screening, prevention and treatment are often lacking. There is an urgent need to increase awareness for preventive measures throughout populations, professionals and policy makers.


[Effect of polynucleotide adsorption on characteristics of a planar phosphatidylcholine bilayer membrane].
Interaction of DNA with planar bilayer phosphatidylcholine membrane in the presence of CaCl2 increases electric conductance of the membrane several times as a result of the formation of DNA-membrane complex. The same effect was observed in the cases of ribosomal RNA and synthetic homopolymers polyA, polyU and polyA X polyU double helix.