Prognostic impact of micromegakaryocytes in primary myelodysplastic syndromes.
Micromegakaryocytes (microMKs) are considered a myelodysplastic feature of myeloid neoplasms in adults, with an adverse prognosis connotation. However, this notion in MDS has not been well proved. In our cohort of 287 MDS, patients with microMKs showed lower overall survival (OS) (HR, 2.12; 95% CI, 1.47-3.06; p = 0.000036) and higher risk of acute myeloid leukemia (AML) evolution (HR, 4.8; 95% CI, 2.9-11.01; p = 0.00021). Results were validated with an independent cohort. In multivariate analysis, the presence of microMKs maintained its independent association with OS (HR, 1.54, 95% CI, 1.13-2.1, p = 0.0059) and AML transformation (HR, 2.28, 95% CI, 1.2-4.4, p = 0.014). Moreover, by adding 1 point to the IPSS-R score in patients with microMKs, we improved the IPSS-R accuracy. Interestingly, adding that 1-point, 29% of intermediate IPSS-R risk group patients were upgraded to the high-risk group. In summary, we confirmed that the presence of microMKs implies worse outcomes in MDS and suggested a modification improving IPSS-R.


Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha.
For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.


Pembrolizumab induced pericardial tamponade: A case report.
The occurrence of a large pericardial effusion is not a commonly noted adverse event associated with pembrolizumab and our report demonstrates that a rapid development can be diagnosed with close monitoring and triage to acute medical settings. Pembrolizumab is an immune checkpoint inhibitor used in various types of cancers. Pericardial tamponade is a rare side effect reported in only very few case reports. Early recognition and therapeutic intervention is vital in all cases. We report a case of a 54-year-old male with Stage 3 lung adenocarcinoma who developed cardiac tamponade secondary to pembrolizumab and subsequently required pericardial window.


Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous CYBB regulation and expression.
X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene, resulting in the inability of phagocytic cells to eliminate infections. To design a lentiviral vector (LV) capable of recapitulating the endogenous regulation and expression of CYBB, a bioinformatics-guided approach was used to elucidate the cognate enhancer elements regulating the native CYBB gene. Using this approach, we analyzed a 600-kilobase topologically associated domain of the CYBB gene and identified endogenous enhancer elements to supplement the CYBB promoter to develop MyeloVec, a physiologically regulated LV for the treatment of X-CGD. When compared with an LV currently in clinical trials for X-CGD, MyeloVec showed improved expression, superior gene transfer to hematopoietic stem and progenitor cells (HSPCs), corrected an X-CGD mouse model leading to complete protection against Burkholderia cepacia infection, and restored healthy donor levels of antimicrobial oxidase activity in neutrophils derived from HSPCs from patients with X-CGD. Our findings validate the bioinformatics-guided design approach and have yielded a novel LV with clinical promise for the treatment of X-CGD.


Lack of association between CXCL9 and CXCL10 gene polymorphisms and the outcome of rheumatoid arthritis treatment with methotrexate.
Methotrexate (MTX) in low doses is used in the therapy of rheumatoid arthritis (RA). The aim of many studies is to identify factors predicting the outcome of treatment with methotrexate in rheumatoid arthritis. The action of MTX in RA is associated with the inhibition of inflammatory mediators synthesis. CXCL9 and CXCL10 chemokines play the important role in inflammatory response in RA patients. The aim of this study was to examine the association between CXCL9/10 gene polymorphisms and response to therapy of RA patients with MTX. The study included 422 patients diagnosed with rheumatoid arthritis, treated with MTX in doses 20 mg weekly. Good responders were defined as patients who were receiving MTX and had a DAS28 of ≤ 2.5 at 6 months of therapy. Poor-responders were defined as patients who were receiving MTX and had a DAS28 of > 2.5. There were not statistically significant associations between studied polymorphisms and the outcome of rheumatoid arthritis treatment with methotrexate. The results of this study suggest lack of associations between the polymorphisms in CXCL9 and CXCL10 genes and the response to MTX in RA patients.


Increased synthesis of specific proteins during glutamate-induced neuronal death in cerebellar culture.
We have previously shown that glutamate-induced neurotoxicity is mediated by a sodium-chloride component and a calcium component in our cerebellar granule cell culture. In order to further characterize these two different components, the time course of neuronal death induced by glutamate (100 microM) in basal solution and in low sodium-chloride solution was studied by morphological and biochemical criteria. As shown by phase-contrast microscopy, cerebellar granule cells exhibited clear neuronal degeneration within 4 h after exposure to this excitotoxin. These morphological changes correlated [35S]methionine incorporation into proteins which rapidly declined during the first hour of treatment. Qualitative change in [35S]methionine incorporation into proteins was further investigated by two-dimensional gel electrophoresis performed after glutamate exposure in basal solution and in low sodium-chloride solution. Most of the proteins showed a decreased labelling after glutamate exposure as expected, but some polypeptides showed an increased labelling or appeared to be newly synthesized. Furthermore, a different pattern of protein synthesis was observed when glutamate exposure was performed in basal solution or in low sodium-chloride solution. The identification of these polypeptides and their implication in the neuronal death are discussed.


Priority ethical issues in oncology nursing: current approaches and future directions.
To describe ethical issues determined to be highly important to oncology nurses and to discuss strategies by which the Oncology Nursing Society (ONS) can address these priority concerns. Survey on oncology nurses regarding ethical issues; nursing literature. Nine priority ethical issues of oncology nurses are identified. Past, current, and future ONS activities that address these priority issues are discussed. ONS must support activities to increase the knowledge, confidence, and involvement of oncology nurses in discussions and decision making related to the ethical issues. The top three priority ethical issues for oncology nurses are assisted suicide, end-of-life decisions, and pain management. Efforts should be made to increase ethics expertise among the ONS membership.


RAE1 mediated ZEB1 expression promotes epithelial-mesenchymal transition in breast cancer.
Breast cancer metastasis accounts for most of the deaths from breast cancer. Since epithelial-mesenchymal transition (EMT) plays an important role in promoting metastasis of cancer, many mechanisms regarding EMT have been studied. We previously showed that Ribonucleic acid export 1 (RAE1) is dysregulated in breast cancer and its overexpression leads to aggressive breast cancer phenotypes by inducing EMT. Here, we evaluated the functional capacity of RAE1 in breast cancer metastasis by using a three-dimensional (3D) culture system and xenograft models. Furthermore, to investigate the mechanisms of RAE1-driven EMT, in vitro studies were carried out. The induction of EMT with RAE1-overexpression was confirmed under the 3D culture system and in vivo system. Importantly, RAE1 mediates upregulation of an EMT marker ZEB1, by binding to the promoter region of ZEB1. Knockdown of ZEB1 in RAE1-overexpressing cells suppressed invasive and migratory behaviors, accompanied by an increase in epithelial and a decrease in mesenchymal markers. Taken together, these data demonstrate that RAE1 contributes to breast cancer metastasis by regulating a key EMT-inducing factor ZEB1 expression, suggesting its potential as a therapeutic target.


MED12-related Hardikar syndrome: Two additional cases and novel phenotypic features.
Hardikar syndrome (HS) is a MED12-related ultra-rare multiple congenital malformation syndrome known to affect the gastrointestinal, cardiac, and genitourinary systems among other features including cleft lip/palate and pigmentary retinopathy. Only 10 patients affected with HS have been previously described in literature, of which seven were molecularly confirmed. We report a 20-year-old and a 13-month-old patient with HS diagnosed by exome sequencing bringing the total number of clinically diagnosed cases to 12 and MED12 associated to 9. We describe previously unreported molecular and clinical findings associated with HS and review all reported cases to permit prompt diagnosis, appropriate management, and genetic counseling of HS patients.


Scimitar sign with normal pulmonary venous drainage and systemic arterial supply. Scimitar syndrome or bronchopulmonary sequestration?
The classic definition of the scimitar syndrome is a triad of hypoplasia of the right lung with anomalous venous drainage and a systemic arterial supply of a variable degree. We report a case in which a scimitar-shaped anomalous vein was observed on the plain chest radiograph, but subsequently a pulmonary angiogram showed that it drained normally into the left atrium.


Clinicopathological Profile of Cervical Tubercular Lymphadenitis with Special Reference to Fine Needle Aspiration Cytology.
Tuberculosis (TB) is a major killer with a majority of 80-100 per lakh and 2-3% of patients attending our hospital are suffering from tuberculosis. Glandular TB appears to be high in our society. Fifty cases of cervical lymph nodes were collected in ENT department and studied. The diagnosis of TB cervical lymph nodes by disease process is only on 'Histopathological ground'.The aim of the present study is to establish the claim of TB cervical lymph node as a disease process.


Limited differentiation to neurons and astroglia from neural stem cells in the cortex and striatum after ischemia/hypoxia in the neonatal rat brain.
We examined whether progenitor neural stem cells can differentiate successfully into mature neurons and astrocytes in a rat model of neonatal hypoxic-ischemic encephalopathy. Seven-day-old Wistar rats were subjected to hypoxic-ischemic stress. At days 5 to 7 after hypoxic-ischemic stress, 5-bromodeoxyuridine (an early marker of cell proliferation) was injected, and the brains were retrieved at 14, 28, and 42 days after hypoxic-ischemic stress. Immunohistochemical and immunofluorescent studies were carried out for 5-bromodeoxyuridine, neuronal nuclear antigen (a marker protein of matured neuron), and glial fibrillary acidic protein (a protein marker of mature astrocytes). Only 1% of neuronal nuclear antigen-positive and 4.6% of glial fibrillary acidic protein-positive cells could be detected among the 5-bromodeoxyuridine-immunopositive cells in the peri-infarcted area of the cortex and the striatum, respectively, at 14 days after hypoxic-ischemic stress. There were no such double-staining cells at 28 and 42 days after hypoxic-ischemic stress. The intrinsic ability for neurologic self-repair was limited at the maturation step after hypoxic-ischemic stress in the neonatal rat brain.


The effect of fecal turbidity on norovirus detection by reverse transcriptase polymerase chain reaction.
A 10-min fecal preparation results in greater specimen turbidity than a 45-min protocol, but reverse transcriptase polymerase chain reaction (RT-PCR) norovirus test sensitivity is essentially the same. Feces processed so that particle size does not exceed approximately 560 nm do not display greater norovirus RT-PCR inhibitory effects than those that have undergone greater purification.


One-pot synthesis of N-confused porphyrin-dipyrrin conjugates and their optical properties.
A conjugated N-confused porphyrin-dipyrrin system NCP-IN-X (X = H, Br, Cl, OMe, COOEt) has been reported via N-Confused tetraphenylporphyrin (NCTPP) as a π-enlarged pyrrole and substituted trimethylindole subunits in 75-82% yields by one pot. All the NCP-INs show red-shifted absorption and emission in the NIR range compared with NCTPP in a series nonpolar and polar solvents. Interesting, relative higher emission in DMF can be observed. The structures of dipyrrin-NCP conjugates are characterized by 1H-NMR and high resolution mass spectrum (HR-MS). Four frontier molecular orbital and simulated stick absorption spectra are calculated by DFT and TD-DFT calculation which is in good agreement with the experiments.


Subclinical left ventricular dysfunction in asymptomatic chronic mitral regurgitation patients with normal ejection fraction: a combined tissue Doppler and velocity vector imaging-based study.
The optimal timing of the surgery in asymptomatic severe mitral regurgitation (MR) remains a challenge. The aim of the study is to evaluate the subclinical changes in LV longitudinal functions by using a novel strain imaging technique; velocity vector imaging (VVI); in patients with chronic MR. We studied 54 patients with asymptomatic, nonischemic, chronic MR (56.8 ± 9 years and 56% male) and 30 healthy controls (55 ± 6.5 years and 55% male) with normal ejection fraction. Patients with MR were analyzed in tertiles according to their regurgitant volumes (RV) and regurgitant fractions (RF): mild MR (RV < 30 mL, RF < 30% n = 7), moderate MR (RV: 30-59 mL, RF = 30-50%; n = 29), and severe MR (RV > 60 mL, RF ≥ 50%; n = 18). Conventional echocardiography and VVI-based strain imaging were performed to analyze LV functions. LV longitudinal peak systolic strain and strain rate (SRs) were significantly impaired in moderate and severe MR patients. Changes in LV longitudinal deformation were more significant in patients with severe MR. All deformation parameters showed a marked negative correlation with RV (LV Strain r =-0.583, P = 0.0001; LV SR r =-0.408, P = 0.002, respectively). LV long-axis functions are important markers of LV contractility in MR patients. Novel echocardiographic techniques may provide additional data on subclinical changes in the LV and give way to the optimal timing for the surgery in severe MR patients.


Degradable PEGylated Protein Conjugates Utilizing RAFT Polymerization.
Poly(ethylene glycol) (PEG)-protein therapeutics exhibit enhanced pharmacokinetics, but have drawbacks including decreased protein activities and polymer accumulation in the body. Therefore a major aim for second-generation polymer therapeutics is to introduce degradability into the backbone. Herein we describe the synthesis of poly(poly(ethylene glycol methyl ether methacrylate)) (pPEGMA) degradable polymers with protein-reactive end-groups via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the subsequent covalent attachment to lysozyme through a reducible disulfide linkage. RAFT copolymerization of cyclic ketene acetal (CKA) monomer 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) with PEGMA yielded two polymers with number-average molecular weight (Mn ) (GPC) of 10.9 and 20.9 kDa and molecular weight dispersities (Ð) of 1.34 and 1.71, respectively. Hydrolytic degradation of the polymers was analyzed by 1H-NMR and GPC under basic and acidic conditions. The reversible covalent attachment of these polymers to lysozyme, as well as the hydrolytic and reductive cleavage of the polymer from the protein, was analyzed by gel electrophoresis and mass spectrometry. Following reductive cleavage of the polymer, an increase in activity was observed for both conjugates, with the released protein having full activity. This represents a method to prepare PEGylated proteins, where the polymer is readily cleaved from the protein and the main chain of the polymer is degradable.


Myoglobin modified electrodes as anchors for d metal cationic complexes.
The capability of adsorption of different electroactive cationic Re(V)-amine complexes onto myoglobin-containing electrodes has been investigated. The goal of this work was the development of an Au/thiol/myo electrode and, after incubation of such ensemble in the presence of three different Re(V)-amine complexes, the evaluation of the extent of surface coverage by the complexes (as a way to evaluate the interaction complex-protein) using electrochemical techniques. Our results showed that a protein-containing electrode could therefore be used for the detection of the interaction of small electroactive cationic complexes and the biomolecule. The extent of the coverage of the myoglobin electrode by the complex depends on the number of free tails from the ligands and the total charge of the complex.


The activation of glucose dehydrogenase by p-chloromercuribenzoate.
p-Chloromercuribenzoate alters various reactions of rat liver glucose (hexose phosphate) dehydrogenase differently. The reagent has little effect on the glucose: NAD or the glucose: NADP oxidoreductases, doubles the rates of oxidations of galactose-6-phosphate and glucose-6-phosphate by NADP and greatly stimulates the oxidations of glucose-6-phosphate and galactose-6-phosphate by NAD. The reagent appears to react with a sulfhydryl group of the enzyme since activation is reversed and prevented by mercaptoethanol. The direct reaction of the reagent with the enzyme is indicated by its lower thermal stability in the presence of the p-chloromercuribenzoate. The size of the enzyme appears to be the same when determined by sucrose gradient centrifugation in the presence or absence of p-chloromercuribenzoate. In microsomes, the oxidation of NADH or NADPH hampers measurements of glucose dehydrogenase. Since p-chloromercuribenzoate inhibits microsomal oxidation of reduced nicontinamide nucleotides, it is possible to assay for glucose dehydrogenase accurately in the presence of the mercurial in microsomes and microsomal extracts and thus measure the effectiveness of a detergent in extracting the enzyme from microsomes.


Case report of a patient with Erdheim-Chester disease presenting with neuro-endocrine symptoms and negative for BRAF mutation.
Erdheim-Chester disease (ECD) is a rare progressive disease affecting multiple systems. It has recently been recognized as a neoplastic disease following the discovery of activating mutations in the MAPK pathway. There are several striking signs of ECD, such as the long bone involvement, as well as the hairy kidney appearance on computed tomography scan. It is rare for ECD to manifest neurological symptoms. Central nervous system involvement is a strong prognostic factor and independent predictor of death. ECD is characterized by the overproduction and accumulation of foamy histiocytes and Touton's giant cells in various tissues and organs. ECD is a multisystem disorder in which any organ may be affected. This case report describes a 57-year-old woman with headaches and ataxia as the first clinical manifestation, without characteristic bone pain, but with delayed enuresis. In addition to the renal involvement, this patient had rarer splenic involvement. The imaging presentation of this patient was similar to that of a "multiple meningiomas". A combination of clinical, imaging and pathology for the diagnosis of ECD. Patients were given INF-α therapy. Fortunately, the patient responded well to INF-α treatment. ECD patient with neuro-endocrine symptoms.


Patients' experience in the early recovery phase after removal of intraoral squamous cell carcinoma with carbon dioxide laser.
Laser excision of oral cancer is well established. The aim of this cross-sectional survey was to ask patients about their main symptoms and the severity of them during the first postoperative weeks. We devised a short questionnaire in collaboration with patients, and did a cross-sectional survey of 50 consecutive patients who had laser excision of T1 and T2 oral cancers over a two-year period. The response rate was 76% (38/50). Twenty patients reported that eating was "quite a bit" or "very much of a problem" and 13 reported similar for pain. The main problems were eating (n=27), pain (n=16), numbness (n=14), speech (n=13), and swallowing (n=12). It took 11 patients more than 4 weeks to recover, and 11 of the 20 who were employed needed to take time off work (modal duration 3 or 4 weeks). Thirteen patients sought advice postoperatively from the clinic, ward or secretary's office, general practitioner, or accident and emergency department (or other out-of-hours service). The survey shows that morbidity associated with laser excision is relatively high, and more studies are required to provide a better evidence base that will inform improvements in postoperative recovery and care.


Empirical bayes approach for dynamic bayesian borrowing for clinical trials in rare diseases.
Application of Bayesian methods is one the tools that can be used to face the multiple challenges that are met when clinical trials must be conducted in rare diseases. We propose in this work to use a dynamic Bayesian borrowing approach, based on a mixture prior, to complement the control arm of a comparative trial and estimate the mixture parameter by an Empirical Bayes approach. The method is compared, using simulations, with an approach based on a pre-specified (non-adaptive) informative prior. The simulation study shows that the proposed method exhibits similar power as the non-adaptive prior and drastically reduce type I error in case of severe discrepancy between the informative prior and the study control arm data. In case of limited discrepancy between the informative prior and the study control arm data, then our proposed adaptive prior does not reduce the inflation of the type I error.


Prevalence of drug use among pregnant women in a rural area.
To determine the prevalence of alcohol and illegal drug use among pregnant women in a rural midwestern area. Descriptive, prospective study. Private tertiary medical center in a rural midwestern area. A nonprobability convenience sample of 202 women enrolling for prenatal care. Hypothesized that the prevalence of alcohol and illegal drug use by pregnant women in a rural midwestern area may be similar to the prevalence in urban areas. The prevalence for perinatal drug use among the sample was 3.9%, with a 95% exact binomial confidence interval of 1.7% to 7.7%. The 3.9% prevalence level is significantly lower than the 11% prevalence levels projected by urban studies (p = .0006). Additional studies need to be conducted on rural populations, however, with periodic testing performed throughout pregnancy. Further studies should examine, through self-reporting, prevalence rates of tobacco and alcohol use during pregnancy.


Use of bacterially-expressed antigen for detection of antibodies to the EBV-specific deoxyribonuclease in sera from patients with nasopharyngeal carcinoma.
A cDNA clone, BG9, corresponding to the open reading frame BGLF5 of Epstein-Barr virus (EBV) DNase was inserted into an E. coli expression vector, pET3a, to generate a recombinant plasmid, pDNase 5. High level of expression of a DNase activity was detected in the E. coli transformed with pDNase 5 following induction with IPTG. The enzyme activity was purified using DEAE-cellulose, phosphocellulose and DNA-cellulose column chromatography. The purified protein appeared to be nearly homogeneous in SDS-PAGE using Coomassie blue staining. The requirement for divalent cations and optimum pH as well as inhibitory concentrations of ionic strength and polyamines for the purified enzyme activity were determined and seemed to be very similar to those of the enzyme activity purified from an EBV producing lymphoblastoid cell line. Using the purified enzyme as an antigen and anti-IgA as the secondary antibody, 82% (64/78) and 91% (71/78) of sera from patients with nasopharyngeal carcinoma (NPC) were shown to be positive by dot immunobinding assay and ELISA, respectively. The results suggest that purified E. coli expressed EBV DNase may be useful for preparing specific test for large scale screening of patients with NPC.


Ab Initio Structure and Dynamics of CO2 at Supercritical Conditions.
Green technologies rely on green solvents and fluids. Among them, supercritical CO2 already finds many important applications. The molecular-level understanding of the dynamics and structure of this supercritical fluid is a prerequisite for rational design of future green technologies. Unfortunately, the commonly employed Kohn-Sham density functional theory (DFT) is too computationally demanding to produce meaningfully converged dynamics within a reasonable time and with a reasonable computational effort. Thanks to subsystem DFT, we analyze finite-size effects by considering simulation cells of varying sizes (up to 256 independent molecules in the cell) and finite-time effects by running 100 ps trajectories. We find that the simulations are in reasonable and semiquantitative agreement with the available neutron diffraction experiments and that, as opposed to the gas phase, the CO2 molecules in the fluid are bent with an average OCO angle of 175.8°. Our simulations also confirm that the dimer T-shape is the most prevalent configuration. Our results further strengthen the experiment-simulation agreement for this fluid when comparing radial distribution functions and diffusion coefficient, confirming subsystem DFT as a viable tool for modeling structure and dynamics of condensed-phase systems.


Radiofrequency catheter ablation for ventricular tachycardia.
The management of ventricular tachycardia (VT) has evolved considerably in recent times. The majority of patients with VT have structural heart disease and often implantable defibrillators. Implantable defibrillators can terminate ventricular arrhythmias and prevent sudden death but do not prevent these arrhythmias from occurring. Ventricular tachycardia may also occur in patients without structural heart disease and although these patients generally have a benign prognosis, the symptoms can be significant. Radiofrequency catheter ablation has a definite role as an alternative to anti-arrhythmic therapy in both groups of patients. This review outlines the indications, techniques and outcomes of catheter ablation in the management of patients with ventricular tachycardia.


The effect of 1alpha-hydroxyvitamin D3 on calcium and mineral content of bone in renal osteodystrophy.
Ten patients with renal osteodystrophy were treated with 1alpha-hydroxyvitamin D3 for 18 months. The effect of treatment was measured by a number of different methods and bone mass assessed by mineral and neutron activation analysis. In the majority of patients, raised serum levels of parathyroid hormone and alkaline phosphatase, histological features and radiological changes returned to normal. These effects were inconsistent in patients with a raised serum calcium level before starting treatment. In general, in patients without evidence of severe hyperparathyroidism there was a reduction in the rate of fall or an increase in the mineral and calcium content of the bone.


[Light- and electron microscopical investigation on the pathogenesis of Kaposi's sarcoma (author's transl)].
In Kaposi's sarcoma (K.S.) the regular metabolism between endothelial cell, extracellular matrix and fibrocyte is disturbed. Thereby the composition of the extracellular matrix change and via a feed-back to the CNS and hormonal system in return changes of endothelial cells and fibrocytes appear. Processing of misinformation sum up in transformation of fibrocytes to tumor cells and destruction of endothelial cells. Initial a widening of the interendothelial borders of the capillary bed seem to be of great importance for the pathogenesis of K.S., because for long time spaces lymphedemas preceed the tumor. With this immunoreactions occur which probably are accompanied by autoimmuno-processes


Statistical analysis of metabolomics data.
Statistical matters form an integral part of a metabolomics experiment. In this chapter we describe several important aspects in the analysis of metabolomics data such as the removal of unwanted variation and the identification of differentially abundant metabolites, along with a number of other essential statistical considerations.


Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia.
Cardiovascular diseases are the principal cause of death in women in developed countries and are importantly promoted by hypertension. The salt sensitivity of blood pressure (BP) is considered as an important cardiovascular risk factor at any BP level. Preeclampsia is a hypertensive disorder of pregnancy that arises as a risk factor for cardiovascular diseases. This study measured the salt sensitivity of BP in women with a severe preeclampsia compared with women with no pregnancy hypertensive complications. Forty premenopausal women were recruited 10 years after delivery in a case-control study. Salt sensitivity was defined as an increase of >4 mm Hg in 24-hour ambulatory BP on a high-sodium diet. The ambulatory BP response to salt was significantly increased in women with a history of preeclampsia compared with that of controls. The mean (95% confidence interval) daytime systolic/diastolic BP increased significantly from 115 (109-118)/79 (76-82) mm Hg on low-salt diet to 123 (116-130)/80 (76-84) on a high-salt diet in women with preeclampsia, but not in the control group (from 111 [104-119]/77 [72-82] to 111 [106-116]/75 [72-79], respectively, P<0.05). The sodium sensitivity index (SSI=Δmean arterial pressure/Δurinary Na excretion×1000) was 51.2 (19.1-66.2) in women with preeclampsia and 6.6 (5.8-18.1) mm Hg/mol per day in controls (P=0.015). The nocturnal dip was blunted on a high-salt diet in women with preeclampsia. Our study shows that women who have developed preeclampsia are salt sensitive before their menopause, a finding that may contribute to their increased cardiovascular risk. Women with a history of severe preeclampsia should be targeted at an early stage for preventive measures of cardiovascular diseases.


Identification of driver genes regulating immune cell infiltration in cervical cancer by multiple omics integration.
Cervical cancer (CC) is one of the most common cancers in women. However, copy number alteration (CNA)-driven dysregulated genes and their functions in CC are still rarely investigated. In the present study, we conducted integrative analysis of CNA and gene expression data from The Cancer Genome Atlas (TCGA) cervical cancer to identify dysregulated genes triggered by CNAs. The integration of copy number status and RNA expression revealed 763 amplified and 1,391 deleted genes significantly dysregulated by the CNAs (P-value < 1e-8). Among these CNA genes, five driver genes, including PI3KCA, PI3KCB, DVL3, WWTR1, and ERBB2, exhibited a strong association with immune cell infiltration, suggesting that the pathways that they participate in may be involved in regulating immune cell infiltration. Moreover, we also observed that the genes of immunotherapeutic targets were abundantly expressed in the wild-type samples, suggesting that immunotherapy based on these immunotherapeutic targets may be applied to wild-type samples. In addition, the two CNA driver genes, DVL3 and ERBB2, might be sensitive and resistant biomarkers for examining the tumor's response to chemoradiotherapy, respectively. Particularly, the expression of ERBB2 was also observed to be higher in responders of chemotherapy than non-responders. Furthermore, a subset of CNA genes was identified to predict the prognosis of cervical cancer. In summary, our systematic data analysis of these CNA genes not only improved our understanding of the veiled mechanism behind immune cell infiltration, but also provided the potential clinical application of these CNA genes in cervical cancer.


The role of psychological influences in rheumatoid arthritis.
Patients with rheumatoid arthritis were tested on a number of psychological variables, including locus of control, cognitive style, general psychopathology and problem solving. Demographic data were also noted, including social supports and life events. Those people whose serum was positive for rheumatoid factor showed a negative style of thinking, particularly in relation to their illness, and they were more likely to believe in powerful external forces. There were no differences between these patients and those who did not have rheumatoid factor on the general measure of psychopathology, except that the positive group experience more phobias. This latter result is in contradiction to previous findings, and a number of possible reasons are discussed.


Monosymptomatic hypochondriacal syndromes in dermatology.
Monosymptomatic hypochondriasis (MH) is a term applied to the manifestation of a single prominent belief that one is diseased in some particular way despite evidence to the contrary. Although MH may assume a variety of clinical forms, three consistently described syndromes are found in the literature: (1) delusions of parasitosis (the belief that one is infested with vermin), (2) delusions of dysmorphosis (the belief that one is physically misshapen and unattractive), and (3) delusions of bromosis (the belief that one emits an offensive body odor). These syndromes may be the clinical expression of a number of underlying pathologic conditions, including psychiatric disorders, structural brain disease, metabolic and endocrine disease, and toxic states. Treatment of MH is based on the biopsychosocial evaluation of the patient and on addressing the multiple etiologic factors often found in these patients.


Peter H. Kelly, Paul W. Seviour and Susan D. Iversen (1975) "Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum" [Brain Res. 94 (3) 507-522].
Eight μg of 6-hydroxydopamine (6-OHDA) injected bilaterally into the nucleus accumbens septi (NAS) or the caudate nucleus of the rat resulted in 79% and 50% depletion of endogenous dopamine (DA) at these respective sites. Fourteen days after the injection a low dose of amphetamine failed to induce the characteristic locomotor response in the NAS-lesioned rats but did so in the caudate-lesioned animals. By contrast the caudate lesion, but not the NAS lesion, abolished intense forms of stereotyped behaviour induced by higher doses of amphetamine. Both lesioned groups exhibited supersensitivity to the dopamine agonist, apomorphine; the NAS group showed enhanced locomotor activity and the caudate group enhanced stereotyped behaviour. The block of amphetamine locomotion and the enhanced response to apomorphine were maximal around 14 days after the operation and gradually attenuated up to 90 days. There is evidence that remaining DA levels in the NAS are greater at 90 than at 14 days postoperatively. Thus recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS. The author reviews the impact of a paper published 40 years ago which was among the first to localise the different behavioural actions of amphetamine in rats to specific brain regions, using local 6-hydroxydopamine-induced lesions of dopaminergic pathways This article is part of a Special Issue entitled SI:50th Anniversary Issue.


Influence of saccharides and sodium chloride on growth and differentiation of Trypanosoma cruzi.
The influence of saccharides, especially glucose and fructose, on the metacyclogenesis and growth of Trypanosoma cruzi has been investigated. In the absence of glucose and fructose in the media, both the percentage of metacyclic forms and the growth increased significantly. Furthermore, the addition of NaCl to the medium without monosaccharides strongly increased the formation of metacyclic forms. Presence of NaCl and absence of monosaccharides showed a synergic effect on differentiation of T. cruzi.


All-cause mortality in patients with diabetes under glucagon-like peptide-1 agonists: A population-based, open cohort study.
The glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting. We conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015. Patients with T2DM exposed to GLP1a (n=8345) were compared to age, gender, body mass index, duration of T2DM and smoking status-matched patients with T2DM unexposed to GLP1a (n=16,541). Patients with diabetes receiving GLP1a were significantly less likely to die from any cause compared to matched control patients with diabetes (adjusted incidence rate ratio [aIRR]: 0.64, 95% CI: 0.56-0.74, P-value<0.0001). Similar findings were observed in low-risk patients (aIRR: 0.64, 95% CI: 0.53-0.76, P -value=0.0001). No significant difference in the risk of incident CVD was detected in the low-risk patients (aIRR: 0.93, 95% CI: 0.83-1.12). Subgroup analyses suggested that effect is persistent in the elderly or across glycated haemoglobin categories. GLP1a treatment in a real-world setting may confer additional mortality benefit in patients with T2DM irrespective of their baseline CVD risk, age or baseline glycated haemoglobin and was sustained over the observation period.


A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer.
Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene-expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.


Overdiagnosis and Risks of Breast Cancer Screening.
Since its widespread introduction 30 years ago, screening mammography has contributed to substantial reduction in breast cancer-associated mortality, ranging from 15% to 50% in observational trials. It is currently the best examination available for the early diagnosis of breast cancer, when survival and treatment options are most favorable. However, like all medical tests and procedures, screening mammography has associated risks, including overdiagnosis and overtreatment, false-positive examinations, false-positive biopsies, and radiation exposure. Women should be aware of the benefits and risks of screening mammography in order to make the most appropriate care decisions for themselves.


Acromegaly with cardiomyopathy, cardiac thrombus and hemorrhagic cerebral infarct: a case report of therapeutic dilemma with review of literature.
Cardiomyopathy with congestive heart failure (CHF) is a rare complication of growth hormone (GH)-secreting pituitary adenoma occurring in 3% of cases. We report a case of acromegaly complicated not only by CHF but also by the presence of intracardiac thrombus and cardioembolic stroke with hemorrhagic formation. A 46-year-old Filipino female presented with amenorrhea, progressive coarsening of facial features, deepening of voice and enlargement of digits. She experienced easy fatigability, orthopnea and bipedal edema. The cardiac apex beat was sustained and displaced. Growth hormone was nonsuppressible. Cranial magnetic resonance imaging showed pituitary macroadenoma with hemorrhage. Incidentally, there was a left frontal lobe cortical infarct with hemorrhagic component. The echocardiogram demonstrated cardiomyopathic changes with a left ventricular thrombus. The primary treatment for GH-producing adenoma is surgery; however, this patient has high surgical risk from her severe cardiomyopathy. Radiotherapy poses a greater risk because of increased cerebrovascular mortality. Somatostatin receptor ligands are significantly associated with improvement of cardiovascular and hemodynamic parameters. Dopamine agonists must be considered regardless of prolactin level and immunostaining. The risks and benefits of any treatment must be emphasized in the presence of conflicting clinical features such as in the case reported.


An antenatal prediction model for adverse birth outcomes in an urban population: The contribution of medical and non-medical risks.
in the Netherlands the perinatal mortality rate is high compared to other European countries. Around eighty percent of perinatal mortality cases is preceded by being small for gestational age (SGA), preterm birth and/or having a low Apgar-score at 5 minutes after birth. Current risk detection in pregnancy focusses primarily on medical risks. However, non-medical risk factors may be relevant too. Both non-medical and medical risk factors are incorporated in the Rotterdam Reproductive Risk Reduction (R4U) scorecard. We investigated the associations between R4U risk factors and preterm birth, SGA and a low Apgar score. a prospective cohort study under routine practice conditions. six midwifery practices and two hospitals in Rotterdam, the Netherlands. 836 pregnant women. the R4U scorecard was filled out at the booking visit. after birth, the follow-up data on pregnancy outcomes were collected. Multivariate logistic regression was used to fit models for the prediction of any adverse outcome (preterm birth, SGA and/or a low Apgar score), stratified for ethnicity and socio-economic status (SES). factors predicting any adverse outcome for Western women were smoking during the first trimester and over-the-counter medication. For non-Western women risk factors were teenage pregnancy, advanced maternal age and an obstetric history of SGA. Risk factors for high SES women were low family income, no daily intake of vegetables and a history of preterm birth. For low SES women risk factors appeared to be low family income, non-Western ethnicity, smoking during the first trimester and a history of SGA. the presence of both medical and non-medical risk factors early in pregnancy predict the occurrence of adverse outcomes at birth. Furthermore the risk profiles for adverse outcomes differed according to SES and ethnicity. to optimise effective risk selection, both medical and non-medical risk factors should be taken into account in midwifery and obstetric care at the booking visit.


[The complex clinical picture of lumbar discopathy in a prospective survey].
The primary symptom of discopathy lumbalis is low back pain. Nowadays, low back pain is the most often cause of medical examinations worldwide. It affects almost 80 per cent of the population. It is the most frequent disease in rheumatological consulting rooms, and the fifth most frequent in family practice. The target of my examination was to compare the acute and chronic clinical features of lumbalis discopathy, to define its risk factors and to present the major guidelines used in diagnosing the disease. The author surveyed fifty patients using a questionnaire. The questionnaire comprised each patient's occupation, the formation of the disease, the therapy adopted, the diagnosis, and the risk factors. Nineteen patients had acute symptoms and twelve of them had to be operated on with discus hernia. Eight out of the twelve operated patients underwent a computed tomography and/or magnetic resonance examination. 47 per cent of the patients with acute symptoms only had the x-ray exams. In 32 per cent of the patients, the complaints evolved into a chronic disease. 84 per cent of the operated patients still need a regular conservative treatment. In the process of diagnosing, symptoms are authoritative. Two-directional x-ray exams are always needed, a computer tomography or magnetic resonance examination is may be also considered reasoned in clinically stagnating cases before operations. Such examinations are superfluous in cases when complaints ease after a few days. Risk factors such as the anatomical variations and abnormal growth of the spine, lack of exercise, jobs involving sitting or standing positions as well as bending and lifting play an important role in the process which may turn the disease into a chronic one.


Conjugation of benzo[a]pyrene metabolites by freshwater green alga Selenastrum capricornutum.
Benzo[a]pyrene (BaP) undergoes metabolic transformation in mammals via oxidative, hydrolytic, and conjugative processes; however, little is known concerning BaP conjugation in freshwater algae. It has been shown in this laboratory that BaP is metabolized by Selenastrum capricornutum via a dioxygenase pathway. This study describes the conjugation of BaP metabolites by a green alga, Selenastrum capricornutum. Cultures were exposed to 1160 micrograms/l [14C]BaP for 4 days at 23 degrees C under gold fluorescent lights on a diurnal cycle of 16 h light, 8 h dark. Of the total metabolites in the algal culture, 89% were present in media. BaP and non-conjugated metabolites were separated from conjugated metabolites by chromatography on neutral alumina columns using solvents of increasing polarity. Seventy-one percent of the BaP metabolites were conjugates of which 12.2%, 12.0% and 12.4% were sulfate ester and alpha- and beta-glucose conjugates, respectively. Conjugates that coeluted with sulfate esters were hydrolyzed with arylsulfatase, alpha- or beta-glucosidase; high performance liquid chromatography (HPLC) analysis indicated that the major product of each enzymatic hydrolysis was the 4,5-dihydrodiol (87.2, 69 and 53%, respectively). Eighty-six percent of the conjugates were acid labile following incubation for 2 h in 4 N HCl at 37 degrees C. To our knowledge this is the first demonstration of the metabolism of a polynuclear aromatic hydrocarbon by a freshwater green alga through a dioxygenase pathway and subsequent conjugation and excretion.


A sectoral analysis of the role of Foreign Direct Investment in pollution and energy transition in OECD countries.
The sustainable development agenda has been driving the global debate on environmental policy for several years now. Developed countries have stricter environmental controls and are under pressure from international agencies to cut pollution. However, many of these countries have been accused of using Foreign Direct Investment to shift their environmental burden to countries with lower environmental restrictions, rather than reducing their overall environmental impact. Should developed countries continue to transfer their emissions? What role does the energy structure of recipient countries play in this investment? A Panel Autoregressive Distributed Lag Model was carried out for a set of 15 OECD countries, from 2005 to 2018. The main findings upheld the Pollution Halo hypothesis. However, they also confirmed the Pollution Haven hypothesis, which was unexpected for developed countries, with their higher environmental standards. It seems that Foreign Direct Investment may increase pollution by increasing overall energy consumption, rather than by transferring polluting industries. Foreign Direct Investment inflows seem to be more environmentally friendly than inward stock, particularly in the electricity and services sectors. Energy transition could be achieved without the polluting effect of Foreign Direct Investment. Investment in the electricity sector may be a way of decoupling economic growth from pollution.


Domain-specific regulation of foxP2 CNS expression by lef1.
FOXP2 is a forkhead transcription factor critical for normal development of language in humans, but little is known of its broader function and regulation during central nervous system (CNS) development. We report here that lef1, a member of the Lef/Tcf family of transcription factors activated by Wnt signaling, regulates foxP2 during embryogenesis, and we isolate novel foxP2 enhancers which are lef1-dependent. Loss, knock down, or inhibition of lef1 led to loss of foxP2 expression. We isolated DNA fragments from the foxP2 genomic region that function as enhancers to drive GFP expression in the CNS during development, including in the telencephalon, diencephalon, eye, tectum, and hindbrain. Three of these enhancers, foxP2-enhancerA.1, foxP2-enhancerB, and foxP2-enhancerD, contain putative Lef1 binding sites, and are regulated by lef1. However, two other genomic fragments containing Lef1 sites failed to function in vivo as enhancers. Chromatin immunoprecipitation confirmed that Lef1 binds to sites in foxP2-enhancerA.1 and foxP2-enhancerB. This work shows that lef1 is necessary for expression of foxP2 in the tectum, mid-hindbrain boundary, and hindbrain during CNS development, and is the first insight into the upstream regulation of foxP2 during development. We also demonstrate that in silico prediction of potential lef1 binding sites poorly predicts their ability to function in vivo as enhancers. The foxP2 enhancers we identified will allow dissection of foxP2's role during CNS development.


Yokukansankachimpihange, a traditional Japanese (Kampo) medicine, enhances the adaptation to circadian rhythm disruption by increasing endogenous melatonin levels.
The traditional Japanese (Kampo) medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) have similar formulas and the same indications. In animals or cultured cells, the neuropharmacological actions of YKS are sometimes more beneficial than those of YKSCH. Since both drugs are used to treat sleep disorders in Japan, we examined the ameliorative effects of YKS and YKSCH on circadian rhythm disturbance and compared their efficacy using a mouse model of circadian rhythm disruption. Ramelteon was used as the positive control. Ramelteon treatment significantly reversed decreased running wheel activity during the advanced dark phase, indicating facilitation of circadian adaptation. YKS treatment also reversed the activity in the early period of drug treatment; however, it was not statistically significant. YKSCH treatment significantly reversed the decreased activity during the advanced dark phase. Plasma melatonin (MT) levels were significantly increased in the YKSCH but not in the YKS group. The ameliorative effect of YKSCH on rhythm disruption was significantly inhibited by coadministration of the MT2 receptor antagonist. Therefore, the therapeutic effect of YKSCH on circadian rhythm disruption would be attributable, to elevated endogenous MT levels. Taken together, YKS and YKSCH have different pharmacological properties and may be more precisely prescribed depending on patients' psychological symptoms.


The Inhibitory Effects of Anti-ERC/Mesothelin Antibody 22A31 on Colorectal Adenocarcinoma Cells, within a Mouse Xenograft Model.
The expression of Renal Carcinoma (ERC)/mesothelin is enhanced in a variety of cancers. ERC/mesothelin contributes to cancer progression by modulating cell signals that regulate proliferation and apoptosis. Based on such biological insights, ERC/mesothelin has become a molecular target for the treatment of mesothelioma, pancreatic cancer, and ovarian cancer. Recent studies revealed about 50-60% of colorectal adenocarcinomas also express ERC/mesothelin. Therefore, colorectal cancer can also be a potential target of the treatment using an anti-ERC/mesothelin antibody. We previously demonstrated an anti-tumor effect of anti-ERC antibody 22A31 against mesothelioma. In this study, we investigated the effect of 22A31 on a colorectal adenocarcinoma cell line, HCT116. The cells were xenografted into BALB/c nu/nu mice. All mice were randomly allocated to either an antibody treatment group with 22A31 or isotype-matched control IgG1κ. We compared the volume of subsequent tumors, and tumors were pathologically assessed by immunohistochemistry. Tumors treated with 22A31 were significantly smaller than those treated with IgG1κ and contained significantly fewer mitotic cells with Ki67 staining. We demonstrated that 22A31 exhibited a growth inhibitory property on HCT116. Our results implied that ERC/mesothelin-targeted therapy might be a promising treatment for colorectal cancer.


Multiomic analysis identifies natural intrapatient temporal variability and changes in response to systemic corticosteroid therapy in chronic rhinosinusitis.
The pathophysiology and temporal dynamics of affected tissues in chronic rhinosinusitis (CRS) remain poorly understood. Here, we present a multiomics-based time-series assessment of nasal polyp biopsies from three patients with CRS, assessing natural variability over time and local response to systemic corticosteroid therapy. Polyp tissue biopsies were collected at three time points over two consecutive weeks. Patients were prescribed prednisone (30 mg daily) for 1 week between Collections 2 and 3. Polyp transcriptome, proteome, and microbiota were assessed via RNAseq, SWATH mass spectrometry, and 16S ribosomal RNA and ITS2 amplicon sequencing. Baseline interpatient variability, natural intrapatient variability over time, and local response to systemic corticosteroids, were investigated. Overall, the highly abundant transcripts and proteins were associated with pathways involved in inflammation, FAS, cadherin, integrin, Wnt, apoptosis, and cytoskeletal signaling, as well as coagulation and B- and T-cell activation. Transcripts and proteins that naturally varied over time included those involved with inflammation- and epithelial-mesenchymal transition-related pathways, and a number of common candidate target biomarkers of CRS. Ten transcripts responded significantly to corticosteroid therapy, including downregulation of TNF, CCL20, and GSDMA, and upregulation of OVGP1, and PCDHGB1. Members of the bacterial genus Streptococcus positively correlated with immunoglobulin proteins IGKC and IGHG1. Understanding natural dynamics of CRS-associated tissues is essential to provide baseline context for all studies on putative biomarkers, mechanisms, and subtypes of CRS. These data further our understanding of the natural dynamics within nasal polypoid tissue, as well as local changes in response to systemic corticosteroid therapy.


Low left atrial appendage emptying velocity is a predictor of atrial fibrillation recurrence after catheter ablation.
Recurrence of atrial fibrillation (AF) after catheter ablation (CA) remains common and studies have shown about 5%-9% annual recurrence rate after CA. We sought to assess the echocardiogram derived left atrial appendage (LAA) emptying velocity as a predictor of AF recurrence after CA. To determine if LAA emptying is a marker of recurrence of AF post-CA METHODS: A total of 303 consecutive patients who underwent CA for AF between 2014 and 2020 were included. Baseline clinical characteristics and echocardiographic data of the patients were obtained by chart review. LAA emptying velocities were obtained from transesophageal echocardiogram (TEE). LA voltage was obtained during the mapping for CA. Chi-square test and nominal logistic regression were used for statistical analysis. An receiver operator characteristic curve was used to determine LAA velocity cut-off. Mean patient age was 61.7 ± 10.5; 32% were female. Mean LAA emptying velocity was 47.5 ± 20.2. A total of 103 (40%) patients had recurrence after CA. In the multivariable model, after adjusting for potential confounders, LAA emptying velocity of ≥52.3 was associated with decreased AF recurrence postablation (odds ratio [OR]: 0.55; 95% confidence interval [CI]: 0.31-0.97; p = .03*). There were 190 (73%) patients in normal sinus rhythm during TEE and CA, and sensitivity analysis of these patients showed that LAA velocity ≥52.3 remained associated with decreased AF recurrence (OR: 0.35; 95% CI: 0.15-0.82; p = .01*). LAA emptying velocity measured during preprocedural TEE can serve as a predictor of AF recurrence in patients undergoing CA.


Standards of reporting: the use of CONSORT PRO and CERT in individuals living with osteoporosis.
The Consolidated Standards of Reporting Trials for Patient-Reported Outcomes (CONSORT PRO) and the Consensus on Exercise Reporting Template (CERT) have been developed to improve the quality and transparency of reporting standards in scientific research. The purpose of this study was to provide evidence for the adoption of CONSORT PRO and CERT by researchers examining the link between exercise and quality of life in individuals living with osteoporosis. A systematic search was conducted to identify randomized control trials published in English evaluating exercise interventions on quality of life in individuals living with osteoporosis. Reporting standards were assessed using CONSORT PRO and CERT. A total of 127 studies were identified with 23 meeting inclusion criteria. "Good" evidence for eight (42.1%) CONSORT PRO and two (12.5%) CERT items was found. Adherence to CONSORT PRO was not related to the year of publication, journal impact factor, or study quality. Adherence to CONSORT PRO and CERT reporting standards is inadequate in the literature examining exercise interventions on quality of life in individuals living with osteoporosis. Sufficient reporting is paramount to knowledge translation, interpretation by interventionists, and clinician confidence in understanding if (and how) exercise is associated with quality of life outcomes in this cohort. Concerns associated with failure to include this information are highlighted.


Failed Emergency Department disposition to the ward of patients with thoracic injury.
To characterise patients who were admitted to the ward following Emergency Department (ED) management for thoracic injury yet went on to require Intensive Care Unit (ICU) admission. To identify risk factors for failed ward management. All patients admitted to the ward following chest trauma from 2002 to 2006 were identified from the Alfred Hospital trauma database. Patients who went on to require ICU admission were compared to those admitted to and discharged from the ward without requiring ICU. Possible predictors of ICU admission were analysed. There were 764 patients during the study period who were admitted to the ward following chest trauma. Of these, 70 patients went on to require Intensive Care admission. Patients requiring ICU admission spent a significantly longer time in hospital and required significantly more rehabilitation. Multivariate analysis using stepwise logistic regression confirmed intercostal catheter (ICC) insertion and higher injury severity scores as significant independent variables associated with ICU admission. Associated abdominal injury, along with multiple rib fractures and flail were also predictive of failed ward management. This study demonstrated that intercostal catheter insertion (tube thoracostomy) was an independent risk factor for deterioration following admission along with multiple rib fractures and certain associated injuries. This should be considered when admitting patients to the ward.


The relationship of endometrial pathologies with endometrial thickness and inflammatory markers in breast cancers using tamoxifen.
Some proliferative and neoplastic changes can be seen in the endometrium of breast cancers using tamoxifen adjuvant therapy (TMX-BC). Identifying risk groups is crucial, but methods and frequency of endometrial follow-up are still controversial. This study aimed to investigate the clinical, ultrasonographic, and inflammatory factors to differentiate pathological endometrium in TMX-BC. This study retrospectively analyzed endometrial biopsy results of TMX-BC (n 361). Normal endometrium (Group I, n 237) and pathological endometrium (Group II, n 124) were compared for clinical, ultrasonographic, and inflammatory features. Neutrophil and platelet to lymphocyte ratio (NLR; PLR), mean platelet volume (MPV), platelet distribution width (PDW), red blood cell distribution width (RDW), and lymphocyte-monocyte ratio (LMR) were the inflammatory markers. The majority of TMX-BC with endometrial biopsy were asymptomatic (72.6%) and had normal endometrium (65.7%). Pathologic endometrium included endometrial polyp (31.9%), endometrial hyperplasia (1.7%), and endometrial cancer (0.8%). The duration of tamoxifen, cancer stage, vaginal bleeding, and menopause was similar in Group I and Group II (p > 0.05). Group II had increased endometrial thickness (11.22 ± 5.44 mm) compared to Group I (8.51 ± 3.43 mm). Group II had higher RDW and PDW than Group I (p < 0.05). Endometrial thickness ≥ 10 mm had significant diagnostic potential in postmenopausal women (AUC 0.676, p 0.000, CI 0.5-0.7), but not in premenopause. PDW and RDW may be promising markers for pathological endometrium differentiation, but these preliminary findings should be validated by clinical studies. Measurement of endometrial thickness in asymptomatic patients may predict high-risk women with pathological endometrium in postmenopausal women. Further studies are needed in premenopausal women and those using tamoxifen for more than 5 years.


A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma.
Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 34 patients (29%) as determined by IG-NGS clonality assessment and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ∼60% of patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based Ig/TCR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation.


Balance measured by the sway balance smart-device application does not discriminate between older persons with and without a fall history.
Clinical functional assessments of balance often lack specificity and sensitivity in discriminating and predicting falls among community-dwelling older adults. We determined the feasibility of using a smart-device application measuring balance to discriminate fall status among older adults. We also evaluated differences between smart-device balance measurements when secured with or without a harness. A cross-sectional study design to determine the ability of the Sway Balance smart-device application (SWAY) to discriminate older adults based on fall history. The Berg Balance Scale (BBS) and Activities-Specific Balance Confidence Scale (ABC) were used as comparative, clinically based assessments. Community-dwelling older adults with (n = 25) and without (n = 32) a history of fall(s) participated. Multivariate analysis of variance was used to determine differences among assessments based on fall history. Logistic regression models determined the ability of each assessment to discriminate fall history. Older adults with and without a history of falls were not significantly different on SWAY (P = 0.92) but were different on BBS (P = 0.01), and ABC (P < 0.001). Similarly, SWAY did not discriminate fall history (P = 0.92), while BBS and ABC both discriminated fall history (P < 0.01). Paired t tests between SWAY scores with and without a harness indicated no differences (P ≥ 0.05). Among the older adults studied, the BBS and ABC measures discriminated groups defined by fall history, while the SWAY smart-device balance application did not. Modifications to the application may improve the discriminating ability of the measure in the recognition of fall status in older adults.


Morphological response and tumor shrinkage as predictive factors in metastatic colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.
Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases. We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders." Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6 months, p = 0.47; 26.6 vs. 24.6 months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6 months, p < 0.01; 30.7 vs. 17.8 months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS. MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered.


Capability of processed EEG parameters to monitor conscious sedation in endoscopy is similar to general anaesthesia.
Reliable and safe sedation is a prerequisite for endoscopic interventions. The current standard is rather safe, yet, an objective device to measure sedation depth is missing. To date, anaesthesia monitors based on processed electroencephalogram (EEG) have not been utilised in conscious sedation. To investigate EEG parameters to differentiate consciousness in endoscopic propofol sedation. In total, 171 patients aged 21-83 years (ASA I-III) undergoing gastrointestinal and bronchial endoscopy were enrolled. Standard monitoring and a frontotemporal two-channel EEG were recorded. The state of consciousness was identified by repeated requests to squeeze the investigator's hand. In total, 1132 state-of-consciousness (SOC) transitions were recorded in procedures ranging from 5 to 69 min. Thirty-four EEG parameters from the frequency domain, time-frequency domain and complexity measures were calculated. Area under the curve ranged from 0.51 to 0.82 with complexity and optimised frequency domain parameters yielding the best results. Prediction of the SOC with processed EEG parameters is feasible, and the results for sedation in endoscopic procedures are similar to those reported from general anaesthesia. These results are insufficient for a clinical application, but prediction capability may be increased with optimisation and modelling.


A comparison of the efficacy and safety of combined aclidinium bromide and formoterol fumarate in the treatment of chronic obstructive pulmonary disease: A protocol for systematic review and meta-analysis.
To systematically evaluate the efficacy and safety of combined aclidinium bromide and formoterol fumarate for chronic obstructive pulmonary disease (COPD). Electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, WanFang, and China National Knowledge Infrastructure (CNKI) database were searched for studies on the use of combined aclidinium bromide and formoterol fumarate in the treatment of COPD. Two independent researchers performed literature screening, data extraction, and assessment of quality of studies. The strength of the association of the efficacy and safety of combined aclidinium bromide and formoterol fumarate in the treatment of COPD was evaluated according to the odds ratio (OR), mean differences (MDs), and 95% confidence interval (CI). Statistical analysis was carried out via using RevMan 5.3 software. The results of the present study will be published in a peer-reviewed journal. The conclusion of the present study will provide evidence to judge whether combined aclidinium bromide and formoterol fumarate is an effective and safety intervention in the treatment of COPD. INPLASY202070063.


Comparison of Efficacy and Safety Between Roux-en-Y Gastric Bypass (RYGB) vs One Anastomosis Gastric Bypass (OAGB) vs Single Anastomosis Duodeno-ileal Bypass with Sleeve Gastrectomy (SADI-S): a Systematic Review of Bariatric and Metabolic Surgery.
In recent years, combined restrictive and hypo-absorptive procedures have gained widespread acceptance. The rationale of this systematic review is to compare the safety and efficacy between Roux-en-Y gastric bypass (RYGB), one anastomosis gastric bypass (OAGB) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). Eighteen eligible studies were finalized for this review. Weight loss outcomes were greater with SADI-S (5 years) and OAGB (10 years). SADI-S offered better resolution of diabetes whereas hypertension and dyslipidaemia resolution were better with OAGB. Although early complications and mortality were higher with SADI-S, late complications were more frequent with RYGB. Both SADI-S and OAGB are as effective as RYGB for weight loss, but OAGB offers lesser complications. However, more data is imperative to determine the next gold standard procedure.


Morphological alterations in amygdalo-hippocampal substructures in narcolepsy patients with cataplexy.
Although the role of hypocretin-mediated amygdalo-hippocampal dysfunction is hypothesized to be linked with narcolepsy, there have been no human MRI studies investigating the relationship between their regional volume and key symptoms of narcolepsy. To investigate the morphological changes of amygdalo-hippocampus and its relationship with clinical features in patients with narcolepsy, point-wise morphometry that allowed for measuring the regional volumes of amygdalo-hippocampus on T1-weighted MRI was applied. Participants were 33 drug-naïve patients and 35 age-/gender-matched controls (mean ± SD: 27 ± 6 years). We compared hippocampal and amygdalar subfields volumes between patients and controls and correlated between volume and clinical and neuropsychological features in patients. Bilateral hippocampal atrophy (183 vertices) was identified mainly located within the CA1 subfield (FDR < 0.05). Significant amygdalar volume reduction was found in the areas of the centromedial (102 vertices) and laterobasal nuclear groups (LB, 35 vertices). There was no volume increase in patients relative to controls (FDR >0.2). After controlling depressive mood, sleep quality, age, and gender, hippocampal CA1 atrophy and amygdalar centromedial atrophy were associated with longer duration of daytime sleepiness and shorter mean REM sleep latency (|r| >0.44, p < 0.01). The amygdalar centromedial atrophy was associated with longer duration of cataplexy (|r| >0.47, p < 0.005). Subfields atrophy of amygdalo-hippocampus in untreated patients with narcolepsy that was found relative to controls suggests that CA1 of the hippocampus and centromedial area of amygdala are closely related to the severity of narcolepsy and play a crucial role in the circuitry of cataplexy.


Impact of donor and prolonged cold ischemia time of neonatal pig pancreas on neonatal pig islet transplant outcome.
Genetically modified pigs (GMP) have been developed to alleviate the shortage of donors in human islet transplantation and rejection. In this study, we characterized and compared the islets from GalTKO, GalTKO/hCD46, GalTKO/hCD46/hCD39, and wild-type (WT) neonatal pigs. Islets were isolated from GMP and WT pig pancreases that have been packaged with ice pack for at least 24 hours. The difference in gene expression and function of islets were evaluated by microarray analysis and transplantation of islets under the kidney capsule of streptozotocin-induced diabetic immune-deficient mice, respectively. Blood glucose levels of these mice were monitored weekly post-transplantation for >100 days, and islet grafts were collected and evaluated for the presence of endocrine cells. The genes involved in extracellular components, cell adhesion, glucose metabolism, and inflammatory response are differentially expressed between GMP and WT pig islets. Variation in the ability of pig islets in correcting the diabetic state of the mouse recipients appears to be dependent on the pig donor. In addition, prolonged cold ischemia time had a negative effect on the transplant outcome. All normoglycemic mice were able to respond well to glucose challenge despite the initial differences in the ability of islet transplants to reverse their diabetic state. Islet xenografts of normoglycemic mice contained abundant insulin- and glucagon-positive cells. The effect of GMP and WT neonatal pig islet transplants on hyperglycemia in mice appears to be dependent on the pig donor, and prolonged cold ischemia time negatively affects the neonatal pig islet transplant outcome.


Glucocorticoid and calcitonin receptor expression in central giant cell lesions: implications for therapy.
Central giant cell lesion is an uncommon benign jaw lesion, with uncertain aetiology, and variable clinical behaviour. Studies of molecular markers may help to understand the nature and behaviour of this lesion, and eventually may represent a target for pharmacological approaches to treatment. The aim of this study was to analyse the expression of glucocorticoid and calcitonin receptors in central giant cell lesions before and after treatment with intralesional steroid. Paraffin-embedded blocks from patients who underwent treatment with intralesional triamcinolone hexacetonide injections were stained immunohistochemically. Biological material from patients who underwent a surgical procedure after treatment were tested immunohistochemically. 18 cases (9 aggressive and 9 non-aggressive) were included. The difference in calcitonin receptor expression was not statistically significant between the aggressive and non-aggressive lesions and between the patients with a good response and those with a moderate/negative response to treatment. Glucocorticoid receptor expression in the multinucleated giant cells was higher in patients with a good response. It can be postulated that immunohistochemical staining for glucocorticoid receptors may provide a tool for selecting the therapeutic strategy. An H-score greater than 48 for glucocorticoid receptors in multinucleated giant cells predicted a good response in this study.


A highly antigenic proteoglycan-like component of cholinergic synaptic vesicles.
A monoclonal antibody, tor70, recognizes an antigenic determinant on the inside surface of synaptic vesicles, purified from the electric organ of Narcine brasiliensis. The antigenic determinant appears to be unique to vesicles since it co-purifies with vesicle content and is blocked by an antiserum specific for synaptic vesicle antigens. Immunoblotting of vesicle proteins after sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows that the antigen has a low heterogeneous electrophoretic mobility and corresponds to a major protein component of pure synaptic vesicles. Synaptic vesicles contain a proteoglycan-like material since proteolytic digestion yields a ruthenium red-binding material that migrates during electrophoresis with a mammalian heparin standard. The only major vesicle component with which the proteoglycan-like material co-elutes during chromatography on Sepharose 6B is the material recognized by tor70. The antigen adsorbs specifically to beads coated with the lectin wheat germ agglutinin. Isolation of the tor70 antigen by velocity sedimentation in sodium dodecyl sulfate-sucrose gradients shows it to contain glucosamine (0.75 nmol/microgram of protein) and uronic acid but no galactosamine. Earlier work has shown that specific antiserum to pure synaptic vesicles could be used to identify nerve terminals, quantitate vesicle components, purify membranes, and monitor exocytosis. We now know that one of the components recognized by the antiserum is a molecule with properties of a proteoglycan, attached to the inside surface of vesicle membranes.


How effective are current therapies for acromegaly?
Currently available therapies for acromegaly are transsphenoidal surgery (TSS), radiotherapy (RT) and medical therapy with the dopamine agonists and somatostatin analogues. The goals of these therapies for acromegaly are to normalize excessive hormone secretion, thus normalizing serum levels of growth hormone (GH) and of insulin-like growth factors (IGF-I), to reduce the clinical signs and symptoms of acromegaly and to reduce tumor size in order to relieve any symptoms due to tumor mass effect. These goals should be accomplished while preserving pituitary function and with as few side effects as possible.TSS, the initial choice of therapy in most patients, is the most effective therapy at reducing the signs and symptoms of mass effect such as visual or neurological compromise. TSS is potentially curative, but the outcome is highly dependent on the tumor size, the degree of tumor invasion and the expertise of the surgeon. TSS can achieve biochemical control with normalization of IGF-I in 80-90% of patients with microadenomas and in 50-60% of those with macroadenomas. RT may be used as adjunctive therapy after unsuccessful surgery. RT can lower GH levels and normalize IGF-I levels, but there is a long lag time before this effect is achieved. Biochemical control is not achieved for 6-10 years after conventional fractionated RT; the time to clinical effect after gamma knife RT seems to be shorter. The most common complication after all forms of RT for acromegaly is the development of new hypopituitarism. Medical therapy has assumed the major role as adjunctive therapy of acromegaly. The dopamine agonists used for the therapy of acromegaly include bromocriptine, quinagolide and cabergoline. Cabergoline seems to be the most efficacious of the dopamine agonists for the treatment of acromegaly, with normalization of IGF-I being achieved in up to 35% of patients treated. Dopamine agonists are generally not effective at reducing the size of pure GH-secreting pituitary tumors. Somatostatin analogues are the most effective medical therapy currently available for acromegaly. The clinically available long-acting somatostatin analogues are long-acting octreotide and slow-release lanreotide. Overall, IGF-I levels normalize in about 66% of patients treated with long-acting octreotide and in 48% of patients treated with lanreotide. About 30% of GH-secreting tumors treated with somatostatin analogues as adjunctive therapy will have some shrinkage, and the amount of shrinkage usually ranges between 20 and 50% of tumor size. Signs and symptoms of the disease improve in about two-thirds of patients treated with long-acting somatostatin analogues. Gastrointestinal side effects are common when initiating somatostatin analogue therapy, but these effects do not typically limit continued use. Multi-modality therapy for acromegaly is often needed to achieve disease control. However, even combinations of currently available therapies cannot achieve all the goals of therapy in many patients with acromegaly.


Climate-driven variation in mosquito density predicts the spatiotemporal dynamics of dengue.
Dengue is a climate-sensitive mosquito-borne disease with increasing geographic extent and human incidence. Although the climate-epidemic association and outbreak risks have been assessed using both statistical and mathematical models, local mosquito population dynamics have not been incorporated in a unified predictive framework. Here, we use mosquito surveillance data from 2005 to 2015 in China to integrate a generalized additive model of mosquito dynamics with a susceptible-infected-recovered (SIR) compartmental model of viral transmission to establish a predictive model linking climate and seasonal dengue risk. The findings illustrate that spatiotemporal dynamics of dengue are predictable from the local vector dynamics, which in turn, can be predicted by climate conditions. On the basis of the similar epidemiology and transmission cycles, we believe that this integrated approach and the finer mosquito surveillance data provide a framework that can be extended to predict outbreak risk of other mosquito-borne diseases as well as project dengue risk maps for future climate scenarios.


ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis.
Acetaminophen (AAP) overdose is the most frequent cause of drug-induced liver failure. c-Jun N-terminal kinase (JNK) is thought to play a central role in AAP-induced hepatocellular necrosis. The apoptosis repressor with caspase recruitment domain (ARC) is a death repressor that inhibits death receptor and mitochondrial apoptotic signaling. Here, we investigated ARC's therapeutic effect and molecular mechanisms on AAP-induced hepatocellular necrosis. We tested the in vivo and in vitro effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on murine AAP hepatotoxicity. Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by AAP overdose in C57BL/6 mice. AAP triggered caspase-independent necrosis, as evidenced by liver histology, elevated serum transaminases, and secreted HMGB1 that was inhibited by ARC. ARC-mediated hepatoprotection was not caused by an alteration of AAP metabolism, but resulted in reduced oxidative stress. AAP overdose led to induction of RIP-dependent signaling with subsequent JNK activation. Ectopic ARC inhibited JNK activation by specific interactions between ARC and JNK1 and JNK2. Importantly, survival of mice was even preserved when ARC therapy was initiated in a delayed manner after AAP administration. This work identifies for the first time ARC-JNK-binding with subsequent inhibition of JNK signaling as a specific mechanism of ARC to interfere with AAP-dependent necrosis. Our data suggests that AAP-mediated induction of RIP signaling serves as a critical switch for hepatocellular necrosis. The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans.


Long-term crestal bone changes in implants placed in augmented sinuses with minimal or moderate remaining alveolar bone: A 10-year retrospective case-series study.
To evaluate long-term clinical and radiographic outcomes of dental implants placed after lateral window sinus augmentation utilizing the sagittal sandwich technique. Patients treated with sinus augmentation were included in this retrospective case-series study. The surgical procedure was performed with particulate autogenous bone- and anorganic bovine bone-derived mineral (3:7 ratio). Implants were grouped based on baseline residual alveolar ridge height: group S (residual alveolar ridge height of 0.1-3.5 mm), group M (height of 3.5-7mm), and group C (native bone). Radiographs were taken at baseline (abutment installation) and annually throughout the 10-year follow-up. A total of 86 patients (92 sinus lifts) and 209 implants were included. Ten sinus membrane perforations were recorded (11% incidence), and graft infections occurred in 3 cases (3.2% incidence). During the 10-year follow-up, 3 implants (1.4%) failed. No significant differences in the mean implant marginal bone loss (MBL) between the three groups were found after 1-, 2-, and 5-year follow-up (p > .05). At 10 years, group C exhibited more MBL than group M with a mean difference of -0.53 mm (p = .01). After 10 years, MK III implants displayed significantly more bone loss in native bone than those in augmented bone with a mean difference of 0.48 mm (p = .02). Five patients and 7 implants developed peri-implantitis with no significant differences between the groups (p = .570). Implant placement after two-stage sinus grafting utilizing the sagittal sandwich technique is a relatively safe and predictable procedure with minimal complications and MBL after 10-year follow-up.


Pain Incidence, Treatment, and Associated Symptoms in Hospitalized Persons with Dementia.
Moderate to severe pain has been frequently reported in hospitalized older adults. Pain in hospitalized persons with dementia within the context of other common symptoms, functional decline, delirium, and behavioral and psychological symptoms of dementia (BPSD), has received little attention. Describe the incidence of pain, the pharmacologic management of pain, and the association of pain with physical function, delirium, and BPSD in hospitalized persons with dementia. Descriptive, cross-sectional study. Six medical units in three hospitals. Baseline data from 299 hospitalized persons with dementia enrolled in the Family-centered Function-focused Care (Fam-FFC) cluster randomized trial. Descriptive analyses of pain used the Pain Assessment in Advanced Dementia (PAINAD) scale and the use of medication for pain management. Linear regression analyses tested relationships between pain and:1) physical function (Barthel Index), 2) delirium severity (Confusion Assessment Method Severity Short Form) and 3) BPSD severity (Neuropsychiatric Inventory- Questionnaire). The majority of the sample was female (61.9%), non-Hispanic (98%), and Black (53.2%), with a mean age of 81.58 (SD=8.54).Of the 299 patients, 166 (56%) received pain medication. Of the 108 individuals who demonstrated pain, 40% (n=43) did not receive pain medication. When controlling for age, gender, cognition, and comorbidities, pain was significantly associated with function, delirium severity, and BPSD severity. Results suggest that pain may be undertreated in hospitalized persons with dementia, and should be considered upon admission to optimize function, decrease delirium, and prevent or decrease BPSD.


Optical coherence refraction tomography.
Optical coherence tomography (OCT) is a cross-sectional, micron-scale imaging modality with widespread clinical application. Typical OCT systems sacrifice lateral resolution to achieve long depths of focus for bulk tissue imaging, and hence tend to have better axial than lateral resolution. Such anisotropic resolution can obscure fine ultrastructural features. Furthermore, conventional OCT suffers from refraction-induced image distortions. Here, we introduce optical coherence refraction tomography (OCRT), which extends the superior axial resolution to the lateral dimension, synthesising undistorted cross-sectional image reconstructions from multiple conventional images acquired with angular diversity. In correcting refraction-induced distortions to register the OCT images, OCRT also achieves spatially resolved refractive index imaging. We demonstrate >3-fold improvement in lateral resolution as well as speckle reduction in imaging tissue ultrastructure, consistent with histology. With further optimisation in optical designs to incorporate angular diversity into clinical instruments, OCRT could be widely applied as an enhancement over conventional OCT.


Feedback of individual genetic and genomics research results: A qualitative study involving grassroots communities in Uganda.
Genetics and genomics research (GGR) is associated with several challenges including, but not limited to, methods and implications of sharing research findings with participants and their family members, issues of confidentiality, and ownership of data obtained from samples. Additionally, GGR holds significant potential risk for social and psychological harms. Considerable research has been conducted globally, and has advanced the debate on return of genetic and genomics testing results. However, such investigations are limited in the African setting, including Uganda where research ethics guidance on return of results is deficient or suboptimal at best. The objective of this study was to assess perceptions of grassroots communities on if and how feedback of individual genetics and genomics testing results should occur in Uganda with a view to improving ethics guidance. This was a cross-sectional study that employed a qualitative exploratory approach. Five deliberative focus group discussions (FGDs) were conducted with 42 participants from grassroots communities representing three major ethnic groupings. These were rural settings and the majority of participants were subsistence farmers with limited or no exposure to GGR. Data were analysed through thematic analysis, with both deductive and inductive approaches applied to interrogate predetermined themes and to identify any emerging themes. NVivo software (QSR international 2020) was used to support data analysis and illustrative quotes were extracted. All the respondents were willing to participate in GGR and receive feedback of results conditional upon a health benefit. The main motivation was diagnostic and therapeutic benefits as well as facilitating future health planning. Thematic analysis identified four themes and several sub-themes including 1) the need-to-know health status 2) paternity information as a benefit and risk; 3) ethical considerations for feedback of findings and 4) extending feedback of genetics findings to family and community. Participation in hypothetical GGR as well as feedback of results is acceptable to individuals in grassroots communities. However, the strong therapeutic and/or diagnostic misconception linked to GGR is concerning given that hopes for therapeutic and/or diagnostic benefit are unfounded. Viewing GGR as an opportunity to confirm or dispute paternity was another interesting perception. These findings carry profound implications for consent processes, genetic counselling and research ethics guidance. Privacy and confidentiality, benefits, risks as well as implications for sharing need to be considered for such feedback of results to be conducted appropriately.


Effects of nasal obstruction on facial development.
The relationship between nasal obstruction and facial growth is controversial. Much of the controversy relates to the lack of sophistication in quantifying nasal versus oral respiration and the lack of longitudinal data. Nevertheless, a number of studies in laboratory animals, nonhuman primates, and humans have shown a relationship between nasal airway obstruction and aberrant facial growth. In monkeys, occlusion of the nares with silicon plugs triggered deviant muscle function and altered morphogenesis. In general, the nasally obstructed animals had longer faces and unusual dental malocclusions. In human studies allergic, mouth-breathing children have longer, narrower faces and retrognathic jaws, compared with control subjects. Medical intervention has not been shown to influence the pattern of facial growth in children with allergies. Surgical therapy to relieve nasal airway obstruction in children (whether adenoidectomy or turbinectomy) has not been shown to predictably affect ultimate facial form. Therefore, although an increasing body of literature demonstrates a relationship between nasal airway obstruction and facial growth, the clinician should be cautious in prescribing aggressive therapy or in promising dramatic results.


Mixed Monte Carlo/Molecular Dynamics simulations of the prion protein.
In this paper we present the results of mixed Monte Carlo/Molecular Dynamics (MC/MD) simulations of the D178N mutant of the human prion protein. We have used the MC moves for polypeptide sampling known as Concerted Rotations with Angles (CRA) to selectively sample the region of the prion protein comprising the β-sheet and one of the α-helices. The results indicate that the MC/MD simulations sample the phase space substantially faster than regular Molecular Dynamics simulations starting with the same initial conditions. This work further indicates the MC/MD technique as a potentially powerful simulation tool, allowing the selective sampling of a region of a physical system that is deemed important.


Intramedullary subependymoma of the cervical spinal cord.
The authors report a rare case of intramedullary subependymoma of the spinal cord. The case is discussed and a review of the literature is presented.


Habitat-, age-, and sex-related alterations in oxidative stress biomarkers in the blood of mute swans (Cygnus olor) inhabiting pomeranian coastal areas (Northern Poland).
The mute swan (Cygnus olor) can be considered a representative species of birds associated with the aquatic environment and responding very clearly to changes in the environment. Assuming that the condition of the mute swan population well reflects the state of the environment, this species was used in our research as a bioindicative species. Thus, the aim of our study was to elucidate the association between metal contents in soil samples collected from a habitat of mute swans and element contents in their feathers as well as the levels of biomarkers of lipid peroxidation, oxidatively modified proteins, and total antioxidant capacity in the blood of mute swans living in three agglomerations in coastal areas in the southern part of the Baltic Sea (Pomeranian region, northern Poland). We compared the effects of inhabitation, age, and sex on the ecophysiological accumulation of metals in three wintering populations of the mute swan from coastal areas of northern Poland, i.e., Słupsk, Gdynia, and Sopot. In Słupsk, the anthropogenic pressure was related predominantly to the level of Al and, to a lesser extent, to the content of Rh and Ru. We found maximum levels of lipid peroxidation biomarkers in the blood of the mute swans from Gdynia (38.20 ± 6.35 nmol MDA·mL-1). At the same time, maximum levels of aldehydic and ketonic derivatives of oxidatively modified proteins were noted in the blood of swans from Sopot compared to the values obtained in mute swans from Słupsk and Gdynia. This trend suggesting high levels of oxidative stress biomarkers was also confirmed by a decrease in the total antioxidant capacity in these groups.