Predicting asthma using imbalanced data modeling techniques: Evidence from 2019 Michigan BRFSS data.
Studies in the past have examined asthma prevalence and the associated risk factors in the United States using data from national surveys. However, the findings of these studies may not be relevant to specific states because of the different environmental and socioeconomic factors that vary across regions. The 2019 Behavioral Risk Factor Surveillance System (BRFSS) showed that Michigan had higher asthma prevalence rates than the national average. In this regard, we employ various modern machine learning techniques to predict asthma and identify risk factors associated with asthma among Michigan adults using the 2019 BRFSS data. After data cleaning, a sample of 10,337 individuals was selected for analysis, out of which 1,118 individuals (10.8%) reported having asthma during the survey period. Typical machine learning techniques often perform poorly due to imbalanced data issues. To address this challenge, we employed two synthetic data generation techniques, namely the Random Over-Sampling Examples (ROSE) and Synthetic Minority Over-Sampling Technique (SMOTE) and compared their performances. The overall performance of machine learning algorithms was improved using both methods, with ROSE performing better than SMOTE. Among the ROSE-adjusted models, we found that logistic regression, partial least squares, gradient boosting, LASSO, and elastic net had comparable performance, with sensitivity at around 50% and area under the curve (AUC) at around 63%. Due to ease of interpretability, logistic regression is chosen for further exploration of risk factors. Presence of chronic obstructive pulmonary disease, lower income, female sex, financial barrier to see a doctor due to cost, taken flu shot/spray in the past 12 months, 18-24 age group, Black, non-Hispanic group, and presence of diabetes are identified as asthma risk factors. This study demonstrates the potentiality of machine learning coupled with imbalanced data modeling approaches for predicting asthma from a large survey dataset. We conclude that the findings could guide early screening of at-risk asthma patients and designing appropriate interventions to improve care practices.


Amniotic membrane transplantation for conjunctival tumor.
To evaluate the possibility of amniotic membrane transplantation (AMT) for the treatment of conjunctival tumor. Preserved AMT was performed in 26 patients (26 eyes) with conjunctival tumor, including 9 eyes (34.62%) with malignant tumor (conjunctival malignant melanoma, corneal and conjunctival squamous cell carcinoma, conjunctival lymphoma), 17 eyes (65.38%) with benign tumor (conjunctival papilloma, conjunctival dermoid tumor, conjunctival nevus, hemangioma etc.). All the patients are followed up for 1-53 months. No acute rejection was observed after preserved AMT. Ideal healing was found in conjunctiva wound. Preserved AMT is a very effective method to repair wound after giant conjunctival tumor operation. Complete removal of tumor and perfect fixation are the key of ocular surface reconstruction.


One-step method for generating PEG-like plasma polymer gradients: chemical characterization and analysis of protein interactions.
In this work we report a one-step method for the fabrication of poly(ethylene glycol) PEG-like chemical gradients, which were deposited via continuous wave radio frequency glow discharge plasma polymerization of diethylene glycol dimethyl ether (DG). A knife edge top electrode was used to produce the gradient coatings at plasma load powers of 5 and 30 W. The chemistry across the gradients was analyzed using a number of complementary techniques including spatially resolved synchrotron source grazing incidence FTIR microspectroscopy, X-ray photoelectron spectroscopy (XPS) and synchrotron source near edge X-ray absorption fine structure (NEXAFS) spectroscopy. Gradients deposited at lower load power retained a higher degree of monomer like functionality as did the central region directly underneath the knife edge electrode of each gradient film. Surface derivatization experiments were employed to investigate the concentration of residual ether units in the films. In addition, surface derivatization was used to investigate the reactivity of the gradient films toward primary amine groups in a graft copolymer of poly (L-lysine) and poly(ethylene glycol) (PLL-g-PEG copolymer) which was correlated to residual aldehyde, ketone and carboxylic acid functionalities within the films. The protein adsorption characteristics of the gradients were analyzed using three proteins of varying size and charge. Protein adsorption varied and was dependent on the chemistry and the physical properties (such as size and charge) of the proteins. A correlation between the concentration of ether functionality and the protein fouling characteristics along the gradient films was observed. The gradient coating technique developed in this work allows for the efficient and high-throughput study of biomaterial gradient coating interactions.


Neurobiological Mechanisms of Nicotine Reward and Aversion.
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and β2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including β3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and β4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.


McDonough feline sarcoma virus: characterization of the molecularly cloned provirus and its feline oncogene (v-fms).
The genetic structure of the McDonough strain of feline sarcoma virus (SM-FeSV) was deduced by analysis of molecularly cloned, transforming proviral DNA. The 8.2-kilobase pair SM-FeSV provirus is longer than those of other feline sarcoma viruses and contains a transforming gene (v-fms) flanked by sequences derived from feline leukemia virus. The order of genes with respect to viral RNA is 5'-gag-fms-env-3', in which the entire feline leukemia virus env gene and an almost complete gag sequence are represented. Transfection of NIH/3T3 cells with cloned SM-FeSV proviral DNA induced foci of morphologically transformed cells which expressed SM-FeSV gene products and contained rescuable sarcoma viral genomes. Cells transformed by viral infection or after transfection with cloned proviral DNA expressed the polyprotein (P170gag-fms) characteristic of the SM-FeSV strain. Two proteolytic cleavage products (P120fms and pp55gag) were also found in immunoprecipitates from metabolically labeled, transformed cells. An additional polypeptide, detected at comparatively low levels in SM-FeSV transformants, was indistinguishable in size and antigenicity from the envelope precursor (gPr85env) of feline leukemia virus. The complexity of the v-fms gene (3.1 +/- 0.3 kilobase pairs) is approximately twofold greater than the viral oncogene sequences (v-fes) of Snyder-Theilen and Gardner-Arnstein FeSV. By heteroduplex, restriction enzyme, and nucleic acid hybridization analyses, v-fms and v-fes sequences showed no detectable homology to one another. Radiolabeled DNA fragments representing portions of the two viral oncogenes hybridized to different EcoRI and HindIII fragments of normal cat cellular DNA. Cellular sequences related to v-fms (designated c-fms) were much more complex than c-fes and were distributed segmentally over more than 40 kilobase pairs in cat DNA. Comparative structural studies of the molecularly cloned proviruses of Synder-Theilen, Gardner-Arnstein, and SM-FeSV showed that a region of the feline-leukemia virus genome derived from the pol-env junction is represented adjacent to v-onc sequences in each FeSV strain and may have provided sequences preferred for recombination with cellular genes.


Dermal Exposure to Vesicating Nettle Agent Phosgene Oxime: Clinically Relevant Biomarkers and Skin Injury Progression in Murine Models.
Phosgene oxime (CX), categorized as a vesicating chemical threat agent, causes effects that resemble an urticant or nettle agent. CX is an emerging potential threat agent that can be deployed alone or with other chemical threat agents to enhance their toxic effects. Studies on CX-induced skin toxicity, injury progression, and related biomarkers are largely unknown. To study the physiological changes, skin clinical lesions and their progression, skin exposure of SKH-1 and C57BL/6 mice was carried out with vapor from 10 µl CX for 0.5 min or 1.0 min durations using a designed exposure system for consistent CX vapor exposure. 1 min exposure caused sharp (SKH-1) or sustained (C57BL/6) decrease in respiratory and heart rate leading to mortality in both mouse strains. Both exposures caused immediate blanching, erythema with erythematous ring (wheel) and edema, and an increase in skin bi-fold thickness. Necrosis was also observed in the 0.5 min CX exposure group. Both mouse strains showed comparative skin clinical lesions upon CX exposure; however, skin bifold thickness and erythema remained elevated up to 14 days post exposure in SKH-1 mice but not in C57BL/6 mice. Our data suggest that CX causes immediate changes in the physiological parameters and gross skin lesions resembling urticaria, which could involve mast cell activation and intense systemic toxicity. This novel study recorded and compared the progression of skin injury to establish clinical biomarkers of CX dermal exposure in both the sexes of two murine strains relevant for skin and systemic injury studies and therapeutic target identification. Significance Statement Phosgene oxime (CX), categorized as a vesicating agent, is considered as a potent chemical weapon and is of high military and terrorist threat interest since it produces rapid onset of severe injury as an urticant. However, biomarkers of clinical relevance related to its toxicity and injury progression are not studied. Data from this study provides useful clinical markers of CX skin toxicity in mouse models using a reliable CX exposure system for future mechanistic and efficacy studies.


Thermal conduction tensor imaging and energy flow analysis of brain: a feasibility study using MRI.
The imaging of the distribution of thermal conductivity tensor at various points in a tissue is an essential need when accurate knowledge of heat energy flow in tissue is required for diagnostic and therapeutic management in oncology, neurology, and interventional radiology. Conventionally, tissue thermal conductivity is assumed as scalar, which induces errors in obtaining proper heat flow distribution. Using statistical thermodynamics principles, we present a method for constructing thermal conductivity tensor image of a tissue or an organ, using an MRI scanner. We elucidate the necessary tensorial cross-property relationship between different transport processes and confirm the same by experimental data. Using the proposed method, we perform a preliminary study of the procedure of thermal conductivity tensor imaging of the human brain as a case study. The methodology is quantitatively elucidated by measurement of tissue anisotropy distribution, tensor eigenvalues, and path tracking, along with three illustrative examples showing that transport properties estimated by the proposed thermal conductivity approach closely corroborates, with over 90% accuracy, to the experimentally measured values of the transport parameters which have been independently experimentally measured directly. By combining diffusion and perfusion tensor imaging approaches using mobility-encoding and spin-labelling methodologies respectively, we delineate the possible applications of this novel imaging modality to clinical problems of energy flow mapping involving biological heat transfer equations, such as planning of hyperthermic treatment to brain tumors, and electrode localization for deep brain stimulation in Parkinson's disease.


Photoperiod influences growth rate and plasma insulin-like growth factor-I levels in juvenile rainbow trout, Oncorhynchus mykiss.
The effect of different photoperiod regimes and the subsequent influence of melatonin on growth and insulin-like growth factor-I (IGF-I) were assessed in juvenile rainbow trout. In Experiment 1, triplicate groups of all female underyearling rainbow trout were exposed to one of three photoperiods; simulated natural photoperiod (SNP), constant short-days (LD 8:16), or constant long-days (LD 18:6) from June to December 2000 under ambient water temperatures. Fish exposed to LD 18:6 grew to a significantly heavier mean weight than the other treatments. Regression analysis showed a strong correlation between circulating plasma IGF-I, growth rate and temperature. Furthermore, it was apparent that fish exposed to LD 18:6 expressed significantly higher circulating levels of IGF-I. In a second experiment, duplicate groups of all female yearling trout were exposed to one of three photoperiods; SNP, LD 8:16, or constant light (LL), with sub groups receiving either a slow-release melatonin implant (18 mg), sham implant or left intact (control). LL increased growth rate in controls, reaching a significantly greater weight than SNP or LD 8:16 photoperiods but did not affect circulating IGF-I levels. Melatonin implants reduced growth rate in all photoperiod treatments below that of their respective controls but again did not affect circulating IGF-I levels. No differences in growth rate were found in implanted fish between photoperiods suggesting that a diel cycle of melatonin is necessary for the perception of daylength. These results would indicate that extended photoperiods (LD 18:6) may cause direct photostimulation of growth through up-regulation of IGF-I production. In contrast, in the absence of a changing diel melatonin signal, growth appeared to be maintained by a possible underlying endogenous rhythm, which was phase advanced under LL, as such plasma IGF-I levels simply reflected growth rate rather than photostimulation of the somatotropic axis. Overall, these findings indicate that measuring plasma IGF-I may be a useful tool for studying environmental influences on growth in rainbow trout.


Renal cell carcinoma in young adults: a study of 130 cases and a review of previous series.
To characterize a large series of renal cell carcinomas (RCCs) in young patients and to compare the data obtained to previously published data. A total of 130 RCCs diagnosed in patients <40 years of age were collected from 9 different hospitals in Spain. Cases were re-evaluated following the diagnostic criteria of the 2004 WHO classification of renal tumors. Histologically, tumors were classified as clear cell (50.7%), papillary (8.5%), chromophobe (14.6%), unclassified (16.9%) and clear cell papillary (9.3%) RCCs. Organ-confined disease (OCD) was detected in 83.6% of the cases. Tumor size and Fuhrman's grade were statistically correlated (Spearman's rho = 0.391). CD10 (p = 0.000), CK7 (p = 0.000), CD15 (p = 0.016), CD117 (p = 0.000), 34betaE12 cytokeratin (p = 0.034) and e-cadherin (p = 0.000) immunostaining significantly differentiated the five histological categories. OCD was more common in young RCC patients. The clear cell phenotype accounted for only 50% of RCCs in this age group, with an increasing number of chromophobe and unclassified RCCs. Clear cell RCCs with a papillary growth pattern accounted for a significant proportion of the cases.


Efficient and accurate density-based prediction of macromolecular polarizabilities.
Accurately and efficiently predicting macromolecules' polarizabilities is an open problem. In this work, we employ a few simple density-based quantities from the information-theoretic approach (ITA) to predict polarizability of proteins. We first build quantitative structure/property relationships between molecular polarizabilities and ITA quantities. We then verify the broad applicability of ITA quantities for polarizability prediction for inorganic, organic, and biological systems with both localized and delocalized electronic structure. As a proof-of-concept application, we predict the molecular polarizabilities of complex proteins. Based on the linear regression equations for 20 natural amino acid residues, 400 dipeptides, and 8000 tripeptides, one then predicts the molecular polarizability of a larger peptide or even a protein once the molecular wavefunction is obtained. Because it is extremely costly to determine the wavefunction for a macromolecule like a protein, we propose to combine the ITA with the linear-scaling generalized energy-based fragmentation (GEBF) method to predict the macromolecular polarizability. In GEBF, the total molecular polarizability is obtained as a linear combination of the corresponding quantities from a series of small subsystems. We can predict them based on the subsystem wavefunction and linear regression equations rather than compute them from the nearly-intractable coupled-perturbed Hartree-Fock or Kohn-Sham equations for the whole macromolecule. Computational results showcase that the GEBF-ITA protocol should be an inexpensive yet accurate theoretical tool for predicting macromolecular polarizabilities.


The persistence of irregular treatment of hypertension in the former Soviet Union.
Hypertension is one of the leading causes of avoidable mortality in the former Soviet Union (fSU). In previous work, the authors described patterns of irregular hypertension treatment in eight countries of the fSU in 2001. This paper presents new data on changes in the use of hypertension treatment in the same countries. Using household survey data from 18 420 (2001) and 17 914 (2010) respondents from Armenia, Azerbaijan (2010 only), Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia and Ukraine, the authors describe changes in rates of irregular treatment use (less than daily) between 2001 and 2010. Multivariate logistic regression was also used to analyse the characteristics associated with irregular treatment. Irregular treatment was extremely high at 74% in 2001 and only fell to 68% in 2010 (all countries combined). Irregular treatment remained particularly high in 2010 in Armenia (79%), Kazakhstan (73%) and Moldova (73%). Recurring characteristics associated with irregular treatment included gender (men), younger age, higher fitness levels, and consuming alcohol and tobacco. Irregular hypertension treatment continues to be a major problem in the countries of the fSU and requires an urgent response.


Trigeminal neuralgia--case and treatment analysis at the Department of Oral Surgery of the University Hospital Dubrava.
The aim of the study was to explore certain risk factors for trigeminal neuralgia (TN), assess the prevalence of misdiagnoses of TN made by primary care dentists, compare the treatment practice for TN at the Department of Oral Surgery with the guidelines, and the importance of interdisciplinary approach in TN treatment. The study included 237 patient records (70 men and 167 women, aged 5-91 years) referred to the Department under the diagnosis of TN. From their medical records, demographic data, referral diagnose, clinical diagnose, additional diagnostic procedures and treatment were analysed. Neuralgia of the trigeminal nerve affects predominantly elderly female population, while the impact of the season on the incidence of the disease has not been determined. The most common therapy used at the Department were blockades, carbamazepine or their combination. 63.3% patients were referred for further diagnostic tests following the first examination. The number of misdiagnosed cases referred by primary care dentists (33.6%) points that better training in diagnosing TN is needed for the dental practitioners. The treatment methods at the Department need to be harmonized with the latest guidelines on neuralgia treatment. Due to the complexity of etiological factors, an interdisciplinary approach is necessary.


Acute changes in hamstrings musculo-articular dissipative properties induced by cyclic and static stretching.
This study was designed to measure changes in musculo-articular dissipative properties related to viscosity that were induced by passive cyclic and static stretching. Musculo-articular dissipative properties were assessed by calculating a dissipation coefficient using potential elastic energies stored and restituted during cyclic stretching. Eight subjects performed five passive knee extensions/flexions cycles on a Biodex dynamometer at 5 degrees . s (-1) to 80 % of their maximal range of motion before and after a static stretching protocol. Electromyographic activity from the hamstring muscles was monitored and remained constant during cyclic stretching and after static stretching (p > 0.05). The dissipation coefficient decreased during cyclic stretching (- 28.8 +/- 6.0 %, p < 0.001), while it was slightly increased after static stretching (+ 3.8 +/- 5.0 %, p = 0.037). The findings showed that energy stored and energy restituted decreased during cyclic stretching and after static stretching (p < 0.05). During unloading, passive torque remained constant during cyclic stretching, but was decreased after static stretching. The findings indicate that musculo-articular dissipative properties were primarily affected by a single cycle of motion, and were not influenced by static stretching procedures. The decrease in dissipation coefficient following cyclic motion indicates that the musculo-articular system displays thixotropic behavior.


Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts.
Non-syndromic pediatric cataracts are defined as opacification of the crystalline lens that occurs during the first years of life without affecting other organs. Given that this disease is one of the most frequent causes of reversible blindness in childhood, the main objective of this study was to propose new responsible gene candidates that would allow a more targeted genetic approach and expand our genetic knowledge about the disease. We present a whole exome sequencing (WES) study of 20 Spanish families with non-syndromic pediatric cataracts and a previous negative result on an ophthalmology next-generation sequencing panel. After ophthalmological evaluation and collection of peripheral blood samples from these families, WES was performed. We were able to reach a genetic diagnosis in 10% of the families analyzed and found genes that could cause pediatric cataracts in 35% of the cohort. Of the variants found, 18.2% were classified as pathogenic, 9% as likely pathogenic, and 72.8% as variants of uncertain significance. However, we did not find conclusive results in 55% of the families studied, which suggests further studies are needed. The results of this WES study allow us to propose LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, and CHMP4A as potential candidates to further investigate for their role in pediatric cataracts, and AQP5 and locus 2q37 as causal genes.


Consent problems and the Southeast Asian refugee.
More than 24,000 refugees of Southeast Asian descent live in Wisconsin. These people, of a different cultural background with different methods of treating the sick, on occasion seek medical aid. It is incumbent on the treating physicians to understand the cultural differences and the avenues open to them to render treatment to these people. This paper reviews these concerns.


The antileukemic effects of saffron (Crocus sativus L.) and its related molecular targets: A mini review.
Saffron (Crocus sativus L.), and its main constituents, crocin, and crocetin have shown promising effects as an antileukemic agent in animal models and cell culture systems. Saffron retards the growth of cancer cells via inhibiting nucleic acid synthesis and enhancing antioxidative system. It can induce apoptosis and chemosensitivity via inhibiting multidrug resistance proteins. Saffron also induces differentiation pathways via inhibiting promyelocytic leukemia/retinoic acid receptor-α, histone deacetylase1, and tyrosyl DNA phosphodiesterase-1 as well. The present review highlights the most recent findings on the antileukemic effects of saffron and its underlying molecular targets. The emerging evidence suggests that saffron has a selective toxicity effect against leukemic cells while is safe for the normal cells.


The promise and practice of cardiovascular risk reduction: a disease management perspective. Clinical Quality Improvement Network (CQIN) Investigators.
Interpretive analysis of epidemiological, clinical trials and practice pattern data for cardiovascular risk reduction in the contemporary setting of unprecedented demographic changes. Literature review and audit results of the Clinical Quality Improvement Network (CQIN). Coronary artery disease (CAD) is the largest single cause of death in Canada. CAD is age-related and the population is rapidly ageing, a combination that threatens an epidemic of future CAD events. Epidemiological data demonstrate a direct relation of CAD risk and serum cholesterol levels and no threshold cholesterol level below which there is no CAD risk. The epidemiological data also suggest CAD risk can be reduced by lowering serum cholesterol and this hypothesis has now been incontrovertibly confirmed by repeated randomized clinical trials. Most recently, reduction of all-cause mortality with cholesterol-lowering therapy in high risk subjects has also been confirmed. Despite the overwhelming trials and epidemiological evidence, CQIN effectiveness analyses reveal far from optimal risk assessment and management practices among high risk patients. Serum cholesterol is directly related to CAD risk. Reduction of cholesterol reduces CAD, and all-cause, mortality in high risk patients. There is a large window of opportunity to improve lipid-lowering practices, and patient outcomes, for the most deadly diseases in our society.


Advanced consumable-free morphological analysis of intact red blood cells by a compact scanning flow cytometer.
Whereas modern automated blood cell analyzers measure the volume of individual red blood cells (RBCs), leading to four RBC indices (mean corpuscular volume, MCV; mean corpuscular hemoglobin, MCH; mean corpuscular hemoglobin concentration, MCHC; red cell distribution width, and RDW), the RBC shape has not been assessed by clinical screening tools. We applied the scanning flow cytometer (SFC) for complete characterization of intact RBC morphology in terms of diameter, maximal and minimal thicknesses, volume, surface area, sphericity index, spontaneous curvature, hemoglobin concentration, and content. The above-mentioned individual RBC characteristics were measured without fluorescent markers and other chemicals by a SFC equipped only with 660 nm laser for RBC illumination and single detector for measurement of angle-resolved light scattering. The distributions over all RBC characteristics were constructed and processed statistically to form the novel 31 RBC indices for 22 donor samples. Our results confirm the possibility of precise, label-free, enhanced morphological analysis of individual intact RBCs with compact single-detector flow cytometer. Detailed characterization of RBCs with high statistics and precision can be used to increase the value of screening examinations and to reveal pathologies accompanied by abnormality of RBC shape. © 2017 International Society for Advancement of Cytometry.


A dynamic model for stem cell homeostasis and patterning in Arabidopsis meristems.
Plants maintain stem cells in their meristems as a source for new undifferentiated cells throughout their life. Meristems are small groups of cells that provide the microenvironment that allows stem cells to prosper. Homeostasis of a stem cell domain within a growing meristem is achieved by signalling between stem cells and surrounding cells. We have here simulated the origin and maintenance of a defined stem cell domain at the tip of Arabidopsis shoot meristems, based on the assumption that meristems are self-organizing systems. The model comprises two coupled feedback regulated genetic systems that control stem cell behaviour. Using a minimal set of spatial parameters, the mathematical model allows to predict the generation, shape and size of the stem cell domain, and the underlying organizing centre. We use the model to explore the parameter space that allows stem cell maintenance, and to simulate the consequences of mutations, gene misexpression and cell ablations.


Overexpression of Dmp1 fails to rescue the bone and dentin defects in Fam20C knockout mice.
FAM20C is a kinase phosphorylating the small-integrin-binding ligand, N-linked glycoproteins (SIBLINGs), a group of extracellular matrix proteins that are essential for bone and dentin formation. Previously, we showed that Sox2-Cre;Fam20Cfl/fl mice had bone and dentin defects, along with hypophosphatemia and significant downregulation of dentin matrix protein 1 (DMP1). While the assumed phosphorylation failure of the SIBLINGs is likely associated with the defects in the Fam20C-deficient mice, it remains unclear if the downregulation of Dmp1 contributes to these phenotypes. In this study, we crossed 3.6 kb Col1-Dmp1 transgenic mice with 3.6 kb Col1-Cre;Fam20Cfl/fl mice to overexpress Dmp1 in the mineralized tissues of Fam20C conditional knockout (cKO) mice. X-ray, micro-computed tomography, serum biochemistry and histology analyses showed that expressing the Dmp1 transgene failed to rescue the bone and dentin defects, as well as the serum levels of FGF23 and phosphate in the Fam20C-cKO mice. These results indicated that the downregulation of Dmp1 may not directly associate with, or significantly contribute to the bone and dentin defects in the Fam20C-cKO mice.


From street canyon microclimate to indoor environmental quality in naturally ventilated urban buildings: Issues and possibilities for improvement.
Many buildings in urban areas are more or less naturally ventilated. A good understanding of the current status and issues of indoor environmental quality (IEQ) in naturally ventilated urban buildings and the association with urban microclimate is fundamental for improving their IEQ. This paper reviews past studies on (a) the microclimate in urban street canyons, (b) the potential influence of such microclimate on IEQ of nearby naturally ventilated buildings, and (c) the real-life IEQ status in these buildings. The review focuses mainly on studies conducted by on-site measurements. The microclimate in urban street canyons is characterized by low wind speed, high surface temperature difference, high pollutant concentration, and high noise level. Insufficient ventilation rates and excessive penetration of outdoor pollutants are two key risks involved in naturally ventilated urban buildings. Existing knowledge suggests that reasonable urban planning and careful building envelope design are the primary methods to ensure acceptable IEQ and maximize the utilization of natural ventilation. However, quantitative studies of both microclimate in street canyons and IEQ in buildings are still highly insufficient in many aspects, which make cross comparison and influencing factors analysis currently impossible. Based on the limitations of previous studies and the current issues of naturally ventilated urban buildings, suggestions are made for future studies to better understand and improve IEQ in naturally ventilated urban buildings.


Hot spot microvessel density and the mitotic activity index are strong additional prognostic indicators in invasive breast cancer.
Recent studies have drawn attention to intratumoral microvessel density (MVD) as a prognostic factor in invasive breast cancer. Various methods have been applied to assess MVD and the prognostic value of MVD in different studies varies considerably. Counting of microvessels in the most highly vascularized area (hot spot) of a tumour is the method most widely used. In this study we compared three counting methods. To assess MVD in 112 cases of invasive breast cancer with long-term follow-up we performed microvessel counting in the hot spot of the tumour in four and 10 fields of vision (HS-MVD4 and HS-MVD10) and microvessel counting in 10 fields of vision distributed systematically over the whole tumour area (global MVD). The HS-MVD4, HS-MVD10 and global MVD showed good correlations with each other. HS-MVD4 provided the highest number of microvessels (median value 71) followed by HS-MVD10 and global MVD, with median values of 58 and 39, respectively. HS-MVD4 showed the best prognostic value for overall survival (P = 0.0001) whereas HS-MVD10 showed less (P = 0.01) and the global MVD showed no (P = 0.75) prognostic value. In univariate analysis, the HS-MVD4 was the second strongest prognostic factor after tumour size. In multivariate survival analysis, the HS-MVD4, mitotic activity index (MAI), lymph node status and tumour size were found to be independent prognostic factors. When combining MVD4 and MAI in lymph node negative patients, none of the patients with low MVD (< 71/mm2) and a low MAI (< 10 per 10 HPF) died, in contrast to patients with a high MVD or high MAI who have a 10-year survival of 57%. These data suggest that the hot spot MVD in four fields of vision is a major independent prognostic factor for overall survival in invasive breast cancer. For the first time, it is shown that hot spot MVD provides additional prognostic information to well established factors like lymph node status and the MAI, and may therefore be useful for designing treatment strategies in invasive breast cancer.


Current concepts in mandibular reconstruction by microsurgical free flaps.
Restoration of form and function after composite oro mandibular resections, especially those of the symphysis, is one of the greatest challenges facing the reconstructive surgeon. Loss of the anterior mandibular arch results in serious impairment of oral competence, speech, deglutition, and mastication producing th~ striking cosmetic disfigurement characterized by the "Andy Gump" caricature of the 1930s (Fig. l)Y The pathomechanics of this deformity are due to anterior and medial deviation of the lateral mandibular segments by the residual mylohyoid muscles and superior displacement by the medial pterygoid, masseter, and temporalis muscles. In comparison, these deforming forces are relatively absent following lateral mandibulectomy. Prevention of the "Andy Gump" deformity and its sequelae is paramount and often mandates composite replacement of bone, skin and mucosa. Additionally, through-and-through lateral or posterior defects requiring trilaminar replacement of skin, bone and mucosa or long bone gaps crossing the midline with massive soft tissue losses pose formidable reconstructive challenges.


Liquid-crystal cell with a wide viewing angle and a high cell contrast.
A liquid-crystal cell operating in the normally white mode is introduced that displays a wide viewing angle together with a high cell contrast. A wide viewing angle is achieved by reducing the twist angle in the cell to below 90 degrees and by reducing the Dnd parameter, while a high cell contrast is obtained by incorporating an in-plane, low-valued compensating retardation film with values lying in the range of 10-50 nm. The optimization of the cell parameters together with the polarizer arrangement permit cell transmittances approaching 100% to be obtained when the cell is in the inactivated phase and with Dnd values down toward the theoretical limit of 0.27 mum. Further improvements in the optical angular properties can be obtained by the placing together of two such cells so that the angular bisector of the surface alignment directors of the two cells lies antiparallel. Such optical shutters find applications in fast, automatically darkening welding filters where a fast response time from the light to the dark protective state is required, together with both a large viewing cone in the low transmittance state and a clear field of view in the light phase.


Nickel carcinogenesis of the respiratory tract.
The role of some nickel compounds and other chemical carcinogens in the causation of cancer of the nose and paranasal sinuses must be recognized. Preventive health measures taken by the nickel industry to eliminate the hazard of nickel carcinogenesis have included improved worker hygiene, reduction of refinery dusts and aerosols, and a strict monitoring of employees by regular examination and plasma nickel testing. The treatment of carcinoma limited to the naso-antral wall or ethmoid labyrinth by an en bloc resection is described, as well as the management of cribriform plate CSF leaks sometimes associated with the ethmoid resection. A subcutaneous cheek flap from the lateral rhinotomy is reflected inward against the cribriform plate to control cerebrospinal fluid rhinorrhea.


Modification of adenovirus capsid with a designed protein ligand yields a gene vector targeted to a major molecular marker of cancer.
The future of genetic interventions in humans critically depends on the selectivity and efficiency of gene transfer to target tissues. The viral gene vectors explored to date cannot selectively transduce the desired targets. While substantial progress has been made in developing targeting strategies for adenovirus (Ad) vectors, future advances in this direction are severely limited by the shortage of naturally existing molecules available for use as targeting ligands. This shortage is due to fundamental and irresolvable differences at the level of both posttranslational modifications and intracellular trafficking between the Ad structural proteins and those natural proteins that are involved in interactions with the cell surface and could otherwise be considered as potential targeting ligands. We hypothesized that this problem could be resolved by altering the natural tropism of Ad vector through incorporation into its capsid of a rationally designed protein ligand, an affibody, whose structural, functional, and biosynthetic properties make it compatible with the Ad assembly process. We tested this hypothesis by redesigning the receptor-binding Ad protein, the fiber, using affibodies specific for human epidermal growth factor receptor type 2 (Her2), a major molecular marker of human tumors. The biosynthesis and folding of these fiber chimeras were fully compatible with Ad virion formation, and the resultant viral vectors were capable of selective delivery of a dual-function transgene to Her2-expressing cancer cells. By establishing the feasibility of this affibody-based approach to Ad vector targeting, the present study lays the foundation for further development of Ad vector technology toward its clinical use.


Ionic liquid nanostructure enables alcohol self assembly.
Weakly structured solutions are formed from mixtures of one or more amphiphiles and a polar solvent (usually water), and often contain additional organic components. They contain solvophobic aggregates or association structures with incomplete segregation of components, which leads to a poorly defined interfacial region and significant contact between the solvent and aggregated hydrocarbon groups. The length scales, polydispersity, complexity and ill-defined structures in weakly structured solutions makes them difficult to probe experimentally, and obscures understanding of their formation and stability. In this work we probe the nanostructure of homogenous binary mixtures of the ionic liquid (IL) propylammonium nitrate (PAN) and octanol as a function of composition using neutron diffraction and atomistic empirical potential structure refinement (EPSR) fits. These experiments reveal why octanol forms weakly structured aggregates in PAN but not in water, the mechanism by which PAN stabilises the octanol assemblies, and how the aggregate morphologies evolve with octanol concentration. This new understanding provides insight into the general stabilisation mechanisms and structural features of weakly structured mixtures, and reveals new pathways for identifying molecular or ionic liquids that are likely to facilitate aggregation of non-traditional amphiphiles.


Comparative pharmacology of the nitrobenzylthioguanosine-sensitive and -resistant nucleoside transport mechanisms of Ehrlich ascites tumor cells.
A variety of nucleoside transport inhibitors and substrates were compared for their capacities to inhibit the zero-trans influx of [3H]uridine in Ehrlich ascites tumor cells. ATP-depleted cells accumulated [3H]uridine primarily by facilitated diffusion (Vmax = 16 pmol/sec/microliter cell water) via both nitrobenzylthioguanosine (NBTGR)-sensitive (IC50 = 0.53 nM, 100 microM [3H]uridine) and NBTGR-resistant (IC50 = 71 microM, 100 microM [3H]uridine) mechanisms with uridine Km estimates of 99 and 284 microM, respectively. Dilazep also distinguished between the transporter subtypes with IC50 values of 1.4 nM and 1.8 microM, respectively, for inhibiting 100 microM [3H]uridine influx. Incubation of cells with 50 nM NBTGR allowed the selective study of inhibitor effects on NBTGR-resistant [3H]uridine influx. Dipyridamole, cyclopentyladenosine, 2-phenylaminoadenosine, etoposide, teniposide, diazepam, chlordiazepoxide, triazolam and the lidoflazine derivative 2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4- fluorophenyl)pentyl]-1-piperazineacetamide (R75231), were significantly less potent as inhibitors of NBTGR-resistant influx, when compared with their capacities to inhibit the total mediated influx of [3H]uridine. In contrast, 2-fluoroadenosine, 2-chloroadenosine, 5'-N-ethylcarboxamidoadenosine and soluflazine were relatively more effective as inhibitors of the NBTGR-resistant component. Mioflazine, a compound related to both soluflazine and R75231, did not distinguish between transporter subtypes. The NBTGR-resistant transporter also had a distinctive substrate specificity; guanosine, 2'-deoxyguanosine, cytidine and 2'-deoxycytidine were significantly less effective as inhibitors of NBTGR-resistant [3H]uridine influx.(ABSTRACT TRUNCATED AT 250 WORDS)


The Impact of Model-Based Clutter Suppression on Cluttered, Aberrated Wavefronts.
Recent studies reveal that both phase aberration and reverberation play a major role in degrading ultrasound image quality. We previously developed an algorithm for suppressing clutter, but we have not yet tested it in the context of aberrated wavefronts. In this paper, we evaluate our previously reported algorithm, called aperture domain model image reconstruction (ADMIRE), in the presence of phase aberration and in the presence of multipath scattering and phase aberration. We use simulations to investigate phase aberration corruption and correction in the presence of reverberation. As part of this paper, we observed that ADMIRE leads to suppressed levels of aberration. In order to accurately characterize aberrated signals of interest, we introduced an adaptive component to ADMIRE to account for aberration, referred to as adaptive ADMIRE. We then use ADMIRE, adaptive ADMIRE, and conventional filtering methods to characterize aberration profiles on in vivo liver data. These in vivo results suggest that adaptive ADMIRE could be used to better characterize a wider range of aberrated wavefronts. The aberration profiles' full-width at half-maximum of ADMIRE, adaptive ADMIRE, and postfiltered data with 0.4- mm-1 spatial cutoff frequency are 4.0 ± 0.28 mm, 2.8 ± 1.3 mm, and 2.8 ± 0.57 mm, respectively, while the average root-mean square values in the same order are 16 ± 5.4 ns, 20 ± 6.3 ns, and 19 ± 3.9 ns, respectively. Finally, because ADMIRE suppresses aberration, we perform a limited evaluation of image quality using simulations and in vivo data to determine how ADMIRE and adaptive ADMIRE perform with and without aberration correction.


Persistent asthma due to isocyanates. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI).
Thirty-five subjects with occupational asthma due to toluene diisocyanate (TDI) exposure were examined. All the subjects were studied with inhalation challenges with TDI and with methacholine. TDI asthma was documented by a positive inhalation challenge to low levels of TDI. Airway responsiveness to methacholine was in the range of asthmatic patients at the time of diagnosis. After an average follow-up interval of 10 months, all the subjects were re-examined. Of the 35 subjects examined, 30 subjects (85.7%) left the workplace, and 5 remained in the same job. Twenty-seven subjects (77.1%) continued to have asthmatic attacks requiring medication for relief of symptoms. At follow-up examination, TDI asthma was documented by a positive inhalation challenge to TDI in 27 subjects. Of these 27 TDI reactors, 22 subjects were removed from occupational exposure to TDI. The TDI reactors had persistent respiratory symptoms and airway hyperresponsiveness to methacholine. At follow-up visit, 8 subjects (22.9%) lost sensitization to TDI; 5 subjects (62.5%) in this group had also normal airway responsiveness to methacholine after removal from exposure. Only 1 subject among the TDI nonreactors complained of mild respiratory symptoms. At diagnosis, there were no significant differences between subjects who recovered and those who did not with regard to age, smoking habits, atopy, duration of exposure to isocyanates, duration of symptoms, baseline FEV1 (% pred), and baseline airway responsiveness to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)


Differential expression of ryanodine receptor in the developing rat cochlea.
Ryanodine receptors (RyRs) are one of the intracellular calcium channels involved in regulation of intracellular free calcium concentration ([Ca(2+)]i). The immunolocalization of RyRs was investigated in the developing rat cochlea at different postnatal days (PND). The change of [Ca(2+)]i in isolated outer hair cells (OHCs) was determined. Morphological results showed low expression of RyRs in the Kolliker's organ from the PND 5 group. RyR expression in inner hair cells (IHCs) increased as the rats aged, and was mature after PND 14. RyRs in OHCs were expressed near the synaptic area of afferent and efferent nerves. RyRs in supporting cells were expressed widely and strongly. The application of ACh, ryanodine + ACh, and thapsigargin + ACh could induce a significant increase in [Ca(2+)]i in OHCs in the presence of extracellular calcium. This increase of [Ca(2+)]i induced by ACh was caused by not only the calcium influx through surface calcium channels, but also the calciuminduced calcium release (CICR) from intracellular RyR-sensitive calcium stores. Morphological and Ca imaging results suggested that RyRs expression is related to cochlear maturity, and may play an important role in its function.


Simultaneous Septal Perforation and Deviation Repair with a Chondromucosal Transposition Flap.
Nasal septal perforations can cause issues of epistaxis, whistling, crusting, saddle deformity, and obstruction, which motivate patients to seek surgical repair. Numerous methods of septal perforation repair have been described, with surgical success rates ranging from 52% to 100%, but few studies address situations with concomitant septal deviation. In treating patients with septal perforation and deviation, both issues should be addressed for optimal outcomes. While routine septoplasty involves the removal of septal cartilage, septal perforation repair involves the addition of interposition grafts. The composite chondromucosal septal rotation flap harmoniously combines these seemingly conflicting goals as an effective and efficient technique for septal perforation repair. We present 3 patients successfully treated for their septal perforation and septal deviation concurrently with this technique.


Costs of treating bleeding and perforated peptic ulcers in The Netherlands.
Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs includes perforations and bleeds. Several preventive strategies are being tested for cost-effectiveness, but little is known about the costs of the complications they are trying to prevent. We estimated the direct costs of hospital treatment of bleeding and perforated ulcers in a university hospital, from data in discharge letters and the hospital management information system. Eligible patients had been treated in the VU University Medical Center between January 1997 and August 2000 for an ulcer bleed or perforation (International Classification of Diseases code 531-4). Resource use comprised hospitalization days and diagnostic and therapeutic interventions. Insurance claim prices determined the costs from the payers' perspective. In a secondary analysis we excluded resource use that was clearly related to the treatment of comorbid illness. Fifty-three patients with a bleeding (n = 35) or perforated ulcer (n = 15) or both (n = 3) were studied, including 14 with comorbidity; 22 complications occurred in the stomach, 29 in the duodenum, one in both stomach and duodenum, and one after partial gastrectomy. A simultaneous bleed and perforation was most expensive (26,000 euro), followed by perforation (19,000 euro) and bleeding (12,000 euro). A bleed in the duodenum was more expensive than in the stomach (13,000 euro vs 10,000 euro), while the opposite was seen for perforations (13,000 euro vs 21,000 euro). Comorbidity increased costs substantially: even after correction for procedures unrelated to the ulcer complication, comorbidity more than doubled the costs of treatment. Treatment of complicated ulcers is expensive, especially in patients with comorbid conditions.


Microanatomy of the central myelin-peripheral myelin transition zone of the trigeminal nerve.
The aim of this study was to evaluate the microanatomy of the central myelin-peripheral myelin transitional zone (TZ) in trigeminal nerves from cadavers. One hundred trigeminal nerves from 50 cadaver heads were examined. The cisternal portion of the nerve (from the pons to Meckel's cave) was measured. Horizontal sections were stained and photographed. The photomicrographs were used to measure the extent of central myelin on the medial and lateral aspects of the nerve and to classify TZ shapes. The cisternal portions of the specimens ranged from 8 to 15 mm long (mean, 12.3 mm; median, 11.9 mm). The data from the photomicrographs revealed that the extent of central myelin (distance from pons to TZ) on the medial aspect of the nerve (range, 0.1-2.5 mm; mean, 1.13 mm; median, 1 mm) was shorter than that on the lateral aspect (range, 0.17-6.75 mm; mean, 2.47 mm; median, 2.12 mm). The data definitively prove that the root entry zone (REZ, nerve-pons junction) and TZ of the trigeminal nerve are distinct sites and that these terms should never be used interchangeably. The measurements showed that the central myelin occupies only the initial one-fourth of the trigeminal nerve length. If trigeminal neuralgia is caused exclusively by vascular compression of the central myelin, the problem vessel would always have to be located in this region. However, it is well known that pain from trigeminal neuralgia can resolve after vascular decompression at more distal sites. This suggests that the effects of surgical decompression are caused by another mechanism.


Optimization of Xylooligosaccharides Production by Native and Recombinant Xylanase Hydrolysis of Chicken Feed Substrates.
Poultry production faces several challenges, with feed efficiency being the main factor that can be influenced through the use of different nutritional strategies. Xylooligosaccharides (XOS) are functional feed additives that are attracting growing commercial interest due to their excellent ability to modulate the composition of the gut microbiota. The aim of the study was to apply crude and purified fungal xylanases, from Trichoderma harzianum, as well as a recombinant glycoside hydrolase family 10 xylanase, derived from Geobacillus stearothermophilus T6, as additives to locally produced chicken feeds. A Box-Behnken Design (BBD) was used to optimize the reducing sugar yield. Response surface methodology (RSM) revealed that reducing sugars were higher (8.05 mg/mL, 2.81 mg/mL and 2.98 mg/mL) for the starter feed treated with each of the three enzymes compared to the treatment with grower feed (3.11 mg/mL, 2.41 mg/mL and 2.62 mg/mL). The hydrolysis products were analysed by thin-layer chromatography (TLC), and high-performance liquid chromatography (HPLC) analysis and showed that the enzymes hydrolysed the chicken feeds, producing a range of monosaccharides (arabinose, mannose, glucose, and galactose) and XOS, with xylobiose being the predominant XOS. These results show promising data for future applications as additives to poultry feeds.


Sub-second adsorption for the pico-molar monitoring of diltiazem in pharmaceutical preparations by fast Fourier transformation with the use of continuous cyclic voltammetry at an Au microelectrode in a flowing system.
Diltiazem was determined at the sub-nanomolar level for the first time by a new technique, involving fast Fourier continuous cyclic voltammetry in a flow-injection system. The best performance was achieved with the basic parameters being set at pH value of 2.0, scan rate value of 35 V/s, accumulation potential of 300 mV and accumulation time of 0.8 s. This paper additionally introduces a special computer based numerical method for the calculation of the analyte signal and the noise reduction. Concerning the electrode response calculations were carried out according to the partial and total charge exchanges on the electrode surface after subtraction of background current from that of noise. Furthermore, to obtain a sensitive determination, the currents integration range included all potential scan ranges, even oxidation and reduction of the Au surface electrode, during the measurements. In general, the potential waveform includes the potential steps for cleaning, accumulation and the step of the potential ramp of the analyte. This potential waveform was applied to an Au disk microelectrode in a continuous way. Finally, the method was found to be linear for the concentration range of 1-41450 pg/ml (r = 0.9986), while showing a limit of detection and quantitation of 0.29 and 1 pg/ml, respectively.


Extraction of electrical characteristics from pixels of multifrequency EIT images.
Computer modelling has shown that electrical characteristics of individual pixels may be extracted from within multiple-frequency electrical impedance tomography (MFEIT) images formed using a reference data set obtained from a purely resistive, homogeneous medium. In some applications it is desirable to extract the electrical characteristics of individual pixels from images where a purely resistive, homogeneous reference data set is not available. One such application of the technique of MFEIT is to allow the acquisition of in vivo images using reference data sets obtained from a non-homogeneous medium with a reactive component. However, the reactive component of the reference data set introduces difficulties with the extraction of the true electrical characteristics from the image pixels. This study was a preliminary investigation of a technique to extract electrical parameters from multifrequency images when the reference data set has a reactive component. Unlike the situation in which a homogeneous, resistive data set is available, it is not possible to obtain the impedance and phase information directly from the image pixel values of the MFEIT images data set, as the phase of the reactive reference is not known. The method reported here to extract the electrical characteristics (the Cole-Cole plot) initially assumes that this phase angle is zero. With this assumption, an impedance spectrum can be directly extracted from the image set. To obtain the true Cole-Cole plot a correction must be applied to account for the inherent rotation of the extracted impedance spectrum about the origin, which is a result of the assumption. This work shows that the angle of rotation associated with the reactive component of the reference data set may be determined using a priori knowledge of the distribution of frequencies of the Cole-Cole plot. Using this angle of rotation, the true Cole-Cole plot can be obtained from the impedance spectrum extracted from the MFEIT image data set. The method was investigated using simulated data, both with and without noise, and also for image data obtained in vitro. The in vitro studies involved 32 logarithmically spaced frequencies from 4 kHz up to 1 MHz and demonstrated that differences between the true characteristics and those of the impedance spectrum were reduced significantly after application of the correction technique. The differences between the extracted parameters and the true values prior to correction were in the range from 16% to 70%. Following application of the correction technique the differences were reduced to less than 5%. The parameters obtained from the Cole-Cole plot may be useful as a characterization of the nature and health of the imaged tissues.


Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease.
Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).


OBP-functionalized/hybrid superparamagnetic nanoparticles for Candida albicans treatment.
Infections caused by the opportunistic yeast Candida albicans are one of the major life threats for hospitalized and immunocompromised patients, as a result of antibiotic and long-term antifungal treatment abuse. Odorant binding proteins can be considered interesting candidates to develop systems able to reduce the proliferation and virulence of this yeast, because of their intrinsic antimicrobial properties and complexation capabilities toward farnesol, the major quorum sensing molecule of Candida albicans. In the present study, a hybrid system characterized by a superparamagnetic iron oxide core functionalized with bovine odorant binding protein (bOBP) was successfully developed. The nanoparticles were designed to be suitable for magnetic protein delivery to inflamed areas of the body. The inorganic superparamagnetic core was characterized by an average diameter of 6.5 ± 1.1 nm and a spherical shape. Nanoparticles were functionalized by using 11-phosphonoundecanoic acid as spacer and linked to bOBP via amide bonds, resulting in a concentration level of 26.0 ± 1.2 mg bOBP/g SPIONs. Finally, both the biocompatibility of the developed hybrid system and the fungistatic activity against Candida albicans by submicromolar OBP levels were demonstrated by in vitro experiments.


Chronic intracranial EEG monitoring for localizing the epileptogenic zone: an electroclinical correlation.
To evaluate the diagnostic yield and identify predictive factors of the surgical outcome in patients with intractable partial epilepsy undergoing chronic intracranial EEG monitoring (CIEM). The clinical, magnetic resonance imaging (MRI) and electrophysiologic data of 108 patients that underwent CIEM were retrospectively reviewed. The discharge pattern and spatial extent of the initial ictal discharge were determined by blinded visual inspection and computerized analysis. The main predictive indicator for epilepsy surgery outcome in patients that underwent CIEM was the presurgical MRI findings. Most patients with hippocampal atrophy or complete lesionectomy were rendered seizure free after epilepsy surgery (83 and 80%, respectively), whereas only a small minority of patients with partial lesionectomy or no detected MRI lesion had seizure-free operative outcomes (21 and 22%, respectively). Multifocal independent initiation of the initial ictal discharge was associated with a poor surgical outcome. In contrast, the pattern and local spatial extent of the initial ictal discharge observed with CIEM failed to predict the surgical outcome. The main predictor of the surgical outcome in patients that underwent CIEM was the MRI findings, whereas CIEM had only limited use in localizing the epileptogenic zone in the absence of an MRI lesion. The reported findings indicate a low specificity of CIEM in defining the site of seizure onset, which in turn significantly impairs the reliability of CIEM in delineating the epileptogenic zone for epilepsy surgery. Further studies are required to define the indications and patient subpopulations who can benefit from CIEM before epilepsy surgery.


Differential expression of the FMRF gene in adult and hatchling stellate ganglia of the squid Loligo pealei.
The giant fiber system of the squid Loligo pealei mediates the escape response and is an important neurobiological model. Here, we identified an abundant transcript in the stellate ganglion (SG) that encodes a FMRFamide precursor, and characterized FMRFamide and FI/LRF-amide peptides. To determine whether FMRFamide plays a role in the adult and hatchling giant fiber system, we studied the expression of the Fmrf gene and FMRFamide peptides. In stage 29 embryos and stage 30 hatchlings, Ffmr transcripts and FMRFamide peptide were low to undetectable in the SG, in contrast to groups of neurons intensely expressing the Fmrf gene in several brain lobes, including those that innervate the SG. In the adult SG the Fmrf gene was highly expressed, but the FMRFamide peptide was in low abundance. Intense staining for FMRFamide in the adult SG was confined to microneurons and fibers in the neuropil and to small fibers surrounding giant axons in stellar nerves. This shows that the Fmrf gene in the SG is strongly regulated post-hatching, and suggests that the FMRFamide precursor is incompletely processed in the adult SG. The data suggest that the SG only employs the Fmrf gene post-hatching and restricts the biosynthesis of FMRFamide, demonstrating that this peptide is not a major transmitter of the giant fiber system. This contrasts with brain lobes that engage FMRFamide embryonically as a regulatory peptide in multiple neuronal systems, including the afferent fibers that innervate the SG. The biological significance of these mechanisms may be to generate diversity within Fmrf-expressing systems in cephalopods.


Cost of illness of patient-reported adverse drug events: a population-based cross-sectional survey.
To estimate the cost of illness (COI) of individuals with self-reported adverse drug events (ADEs) from a societal perspective and to compare these estimates with the COI for individuals without ADE. Furthermore, to estimate the direct costs resulting from two ADE categories, adverse drug reactions (ADRs) and subtherapeutic effects of medication therapy (STE). Cross-sectional study. The adult Swedish general population. The survey was distributed to a random sample of 14 000 Swedish residents aged 18 years and older, of which 7099 responded, 1377 reported at least one ADE and 943 reported an ADR or STE. Societal COI, including direct and indirect costs, for individuals with at least one self-reported ADE, and the direct costs for prescription drugs and healthcare use resulting from self-reported ADRs and STEs were estimated during 30 days using a bottom-up approach. The economic burden for individuals with ADEs were (95% CI) 442.7 to 599.8 international dollars (Int$), of which direct costs were Int$ 279.6 to 420.0 (67.1%) and indirect costs were Int$ 143.0 to 199.8 (32.9%). The average COI was higher among those reporting ADEs compared with other respondents (COI: Int$ 442.7 to 599.8 versus Int$ 185.8 to 231.2). The COI of respondents reporting at least one ADR or STE was Int$ 468.9 to 652.9. Direct costs resulting from ADRs or STEs were Int$ 15.0 to 48.4. The reported resource use occurred both in hospitals and outside in primary care. Self-reported ADRs and STEs cause resource use both in hospitals and in primary care. Moreover, ADEs seem to be associated with high overall COI from a societal perspective when comparing respondents with and without ADEs. There is a need to further examine this relationship and to study the indirect costs resulting from ADEs.


The terminal structures of linear plasmids from Rhodococcus opacus.
The telomers of several linear plasmids of Rhodococcus opacus (formerly Nocardia opaca) were studied. The plasmids pHG201, pHG204 and pHG205 carry proteins bound to their ends, as shown by gel retardation experiments. A sequence hybridizing with the terminal sequence of pHG207, a recombinant linear plasmid consisting of the left part of pHG204 and the right part of pHG205, which was analysed in a previous study by the authors, could be detected in all linear plasmids of the wild-type R. opacus strains MR11 and MR22. However, only pHG204 and pHG206 carry terminal inverted repeats (TIRs) like pHG207. Cloning and sequencing of the terminal fragment of pHG204 revealed a nearly perfect TIR of 1016 bp. In contrast, the termini of pHG201 and pHG205 share little homology. Sequence analysis of the two end fragments of pHG201 revealed a similarity of only 65% within the terminal 34/32 bp and a perfect TIR of only 3 bp. The results support the assumption that long TIRs are not absolutely necessary for replication and maintenance of linear plasmids.


Brain structural correlates of trajectories to cognitive impairment in men with and without HIV disease.
There are distinct trajectories to cognitive impairment among participants in the Multicenter AIDS Cohort Study (MACS). Here we analyzed the relationship between regional brain volumes and the individual trajectories to impairment in a subsample (n = 302) of the cohort. 302 (167 HIV-infected; mean age = 55.7 yrs.; mean education: 16.2 yrs.) of the men enrolled in the MACS MRI study contributed data to this analysis. We used voxel-based morphometry (VBM) to segment the brain images to analyze gray and white matter volume at the voxel-level. A Mixed Membership Trajectory Model had previously identified three distinct profiles, and each study participant had a membership weight for each of these three trajectories. We estimated VBM model parameters for 100 imputations, manually performed the post-hoc contrasts, and pooled the results. We examined the associations between brain volume at the voxel level and the MMTM membership weights for two profiles: one considered "unhealthy" and the other considered "Premature aging." The unhealthy profile was linked to the volume of the posterior cingulate gyrus/precuneus, the inferior frontal cortex, and the insula, whereas the premature aging profile was independently associated with the integrity of a portion of the precuneus. Trajectories to cognitive impairment are the result, in part, of atrophy in cortical regions linked to normal and pathological aging. These data suggest the possibility of predicting cognitive morbidity based on patterns of CNS atrophy.


Demented versus non-demented very old inpatients: the same comorbidities but poorer functional and nutritional status.
demented patients have been reported to be healthier than other old people of the same age. to assess comorbid conditions, functional and nutritional status in medically ill hospitalised patients with normal cognition or affected by dementia of various causes and severities, or mild cognitive impairment (MCI). a prospective study was carried out, between January and December 2004, in the Rehabilitation and Geriatric Hospital (HOGER). activities of daily living (ADL), instrumental activities of daily living (IADL) and mini nutritional assessment (MNA) scores were assessed as a function of the status of the patient two weeks before admission to hospital. On admission, cognitive status was assessed by a systematic battery of neuropsychological tests, comorbid conditions were assessed with the Charlson comorbidity index (CCI), and body mass index (BMI) and functional independence measure (FIM) were determined. BMI and FIM were also determined on discharge. we studied 349 patients (mean age 85.2 +/- 6.7; 76% women): 161 (46.1%) cognitively normal, 37 (10.6%) with MCI and 151 (43.3%) demented (61 Alzheimer's disease (AD), 62 mixed dementia (MD) and 17 vascular dementia (VaD)). ADL, IADL, FIM and MNA scores on admission decreased with cognitive status, regardless of the type of dementia. Functionality at discharge remained significantly lower in demented patients than in other patients. CCI was high and similar in all three groups (mean 4.6 +/- 2.7). Patients with VaD had poorer health than other demented patients, with a higher average comorbidity score, more frequent hypertension, stroke and hyperlipidaemia. Comorbidity did not increase with severity levels of dementia. in this cohort of very old inpatients, demented patients, non-demented patients and patients with MCI had similar levels of comorbidity, but demented patients had a poorer functional and nutritional status.


11 TOPS photonic convolutional accelerator for optical neural networks.
Convolutional neural networks, inspired by biological visual cortex systems, are a powerful category of artificial neural networks that can extract the hierarchical features of raw data to provide greatly reduced parametric complexity and to enhance the accuracy of prediction. They are of great interest for machine learning tasks such as computer vision, speech recognition, playing board games and medical diagnosis1-7. Optical neural networks offer the promise of dramatically accelerating computing speed using the broad optical bandwidths available. Here we demonstrate a universal optical vector convolutional accelerator operating at more than ten TOPS (trillions (1012) of operations per second, or tera-ops per second), generating convolutions of images with 250,000 pixels-sufficiently large for facial image recognition. We use the same hardware to sequentially form an optical convolutional neural network with ten output neurons, achieving successful recognition of handwritten digit images at 88 per cent accuracy. Our results are based on simultaneously interleaving temporal, wavelength and spatial dimensions enabled by an integrated microcomb source. This approach is scalable and trainable to much more complex networks for demanding applications such as autonomous vehicles and real-time video recognition.


Phonological parafoveal pre-processing in children reading English sentences.
Although previous research has shown that, in English, both adult and teenage readers parafoveally pre-process phonological information during silent reading, to date, no research has been conducted to investigate such processing in children. Here we used the boundary paradigm during silent sentence reading, to ascertain whether typically developing English children, like adults, parafoveally process words phonologically. Participants' eye movements (adults: n = 48; children: n = 48) were recorded as they read sentences which contained, in preview, correctly spelled words (e.g., cheese), pseudohomophones (e.g., cheeze), or spelling controls (e.g., cheene). The orthographic similarity of the target words available in preview was also manipulated to be similar (e.g., cheese/cheeze/cheene) or dissimilar (e.g., queen/kween/treen). The results indicate that orthographic similarity facilitated both adults' and children's pre-processing. Moreover, children parafoveally pre-processed words phonologically very early in processing. The children demonstrated a pseudohomophone advantage from preview that was broadly similar to the effect displayed by the adults, although the orthographic similarity of the pseudohomophone previews was more important for the children than the adults. Overall, these results provide strong evidence for phonological recoding during silent English sentence reading in 8-9-year-old children.


Intracellular alkalinization stimulates bile flow and vesicular-mediated exocytosis in IPRL.
Intracellular pH recovery from an acute alkaline load in rat hepatocytes is mediated by a Cl(-)-HCO3- exchanger, which is electroneutral, Na+ independent, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) sensitive. Stimulation of this Cl(-)-HCO3- exchanger requires intact microtubules, suggesting that vesicular transport may be required to activate this exchanger. To determine if intracellular alkalinization stimulates biliary HCO3- excretion and bile flow in the intact liver by vesicle-mediated exocytosis, isolated perfused rat livers (IPRL) were alkalinized by two protocols. Isohydric changes in CO2 and HCO3- concentrations induced transient increases in bile flow by 36% (P < 0.01), which were abolished by DIDS (0.01 mM), inhibited by pretreatment with colchicine (P = 0.01), but not affected by membrane depolarization with the K(+)-channel blocker BaCl2 (1 mM). Similarly, perfusion with 20 mM NH4Cl produced a 42% increase in bile flow (P < 0.01) and a 26% increase in biliary HCO3- excretion. Both the increases in bile flow and HCO3- excretion were almost completely blocked by DIDS and inhibited by pretreatment with colchicine (P < 0.01). Biliary excretion of horseradish peroxidase was also increased during intracellular alkalinization with either protocol (P < 0.01). These findings suggest that intracellular alkalinization stimulates bile flow and biliary HCO3- excretion. Microtubule-dependent vesicular-mediated exocytosis is involved in this response.


Eradicating Helicobacter pylori and symptoms of non-ulcer dyspepsia.
To examine the effect of eradication of Helicobacter pylori on symptoms of non-ulcer dyspepsia. Four week prospective study. One hospital outpatient and endoscopy department. 90 adults with persistent symptoms typical of non-ulcer dyspepsia but no clinical or endoscopic evidence of other peptic, biliary, pancreatic, or malignant disease; all had histological and microbiological evidence of infection with H pylori. 83 patients completed the treatment regimen. Colloidal bismuth subcitrate 120 mg four times a day for four weeks (27 patients); metronidazole 400 mg and amoxycillin 500 mg each three times a day for one week (27); and bismuth subcitrate 120 mg four times a day for four weeks, metronidazole 400 mg three times a day for one week, plus amoxycillin 500 mg three times a day for the first week (29). Change in symptom scores determined with questionnaire; histological evidence of gastritis and microbiological evidence of presence of H pylori in biopsy specimens. Overall, H pylori was eradicated in 41 (49%) patients. Although gastritis scores improved significantly in only patients in whom H pylori had been eradicated (from 1.56 to 0.61, p less than 0.01 v from 1.83 to 1.07, p = 0.52) mean symptom scores after treatment were similar in patients in whom H pylori had or had not been eradicated (3.0 v 2.3, NS). Similarly the mean symptom score improved whether or not gastritis improved (2.8 v 3.1 respectively, p = 0.72). The observations were similar for treatment groups analysed individually. Antral infection with the organism does not seem to have an important aetiological role in non-ulcer dyspepsia short term.


Chemical studies on tobacco smoke LXVIII. Analysis of volatile and tobacco-specific nitrosamines in tobacco products.
The yields of volatile N-nitrosamines in cigarette smoke are primarily dependent upon the nitrate content of the tobacco and, to some extent, on the protein content. Cellulose acetate tips, such as those found on most commercial filter cigarettes, selectively remove at least 70% of the volatile N-nitrosamines, independently of the pH of the weakly acidic or weakly alkaline smoke. So far, three tobacco-specific N-nitrosamines have been detected in tobacco and tobacco smoke. During tobacco processing and smoking, N'-nitrosonornicotine is formed by nitrosation of nicotine and, to a minor degree, by nitrosation of nornicotine, whereas 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone originates from oxidative nitrosation of nicotine. N'-Nitrosoanatabine is formed by nitrosation of the second most abundant tobacco alkaloid, anatabine. The tobacco-specific N-nitrosamines in the smoke arise partly from the tobacco by transfer and partly by nitrosation of the alkaloids during smoking (pyrosynthesis). Preliminary results indicate that cellulose acetate filter tips may selectively remove considerable amounts of the nonvolatile nitrosamines from the smoke.


An efficient method for retro-Claisen-type C-C bond cleavage of diketones with tropylium catalyst.
The retro-Claisen reaction is frequently used in organic synthesis to access ester derivatives from 1,3-dicarbonyl precursors. The C-C bond cleavage in this reaction is usually promoted by a number of transition-metal Lewis acid catalysts or organic Brønsted acids/bases. Herein we report a new convenient and efficient method utilizing the tropylium ion as a mild and environmentally friendly organocatalyst to mediate retro-Claisen-type reactions. Using this method, a range of synthetically valuable substances can be accessed via solvolysis of 1,3-dicarbonyl compounds.


Female-specific specialization of a posterior end region of the midgut symbiotic organ in Plautia splendens and allied stinkbugs.
Many stinkbugs (Insecta: Hemiptera: Heteroptera) are associated with bacterial symbionts in a posterior region of the midgut. In these stinkbugs, adult females excrete symbiont-containing materials from the anus for transmission of the beneficial symbionts to their offspring. For ensuring the vertical symbiont transmission, a variety of female-specific elaborate traits at the cellular, morphological, developmental, and behavioral levels have been reported from diverse stinkbugs of the families Plataspidae, Urostylididae, Parastrachiidae, etc. Meanwhile, such elaborate female-specific traits for vertical symbiont transmission have been poorly characterized for the largest and economically important stinkbug family Pentatomidae. Here, we investigated the midgut symbiotic system of a pentatomid stinkbug, Plautia splendens. A specific gammaproteobacterial symbiont was consistently present extracellularly in the cavity of numerous crypts arranged in four rows on the midgut fourth section. The symbiont was smeared on the egg surface upon oviposition by adult females, orally acquired by newborn nymphs, and thereby transmitted vertically to the next generation and important for growth and survival of the host insects. We found that, specifically in adult females, several rows of crypts at the posterior end region of the symbiotic midgut were morphologically differentiated and conspicuously enlarged, often discharging the symbiotic bacteria from the crypt cavity to the main tract of the symbiotic midgut. The female-specific enlarged end crypts were also found in other pentatomid stinkbugs Plautia stali and Carbula crassiventris. These results suggest that the enlarged end crypts represent a female-specific specialized morphological trait for vertical symbiont transmission commonly found among stinkbugs of the family Pentatomidae.


Relation Between Respiratory Muscle Strength and Skeletal Muscle Mass and Hand Grip Strength in the Healthy Elderly.
To evaluate sarcopenic indices in relation to respiratory muscle strength (RMS) in elderly people. This study included 65 volunteers over the age of 60 (30 men and 35 women). The skeletal muscle mass index (SMI) was measured using bioimpedance analysis. Limb muscle function was assessed by handgrip strength (HGS), the Short Physical Performance Battery (SPPB), and gait speed. RMS was addressed by maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) using a spirometer. The relationships between RMS and other sarcopenic indices were investigated using the Pearson correlation coefficients and multiple regression analysis adjusted for age, HGS, and SPPB. Both MIP and MEP were positively correlated with SMI (r=0.451 and r=0.388, respectively, p<0.05 in both). HGS showed a significant correlation with both MIP and MEP (r=0.560, p<0.01 and r=0.393, p<0.05, respectively). There was no significant correlation between gait speed and either MIP or MEP. The SPPB was positively correlated with MEP (r=0.436, p<0.05). In the multiple regression analysis, MIP was significantly associated with HGS and SMI (p<0.001 and p<0.05, respectively), while MEP was related only with HGS (p<0.05). This study suggests that respiratory muscles, especially inspiratory muscles, are significantly related to limb muscle strength and skeletal muscle mass. The clinical significance of MIP and MEP should be further investigated with prospective studies.


Interventions for the treatment of oral cavity and oropharyngeal cancers: surgical treatment.
Surgery is a common treatment option in oral cavity cancer (and less frequently in oropharyngeal cancer) to remove the primary tumour and sometimes neck lymph nodes. People with early-stage disease may undergo surgery alone or surgery plus radiotherapy, chemotherapy, immunotherapy/biotherapy, or a combination of these. Timing and extent of surgery varies. This is the third update of a review originally published in 2007. To evaluate the relative benefits and harms of different surgical treatment modalities for oral cavity and oropharyngeal cancers. We used standard, extensive Cochrane search methods. The latest search date was 9 February 2022. Randomised controlled trials (RCTs) that compared two or more surgical treatment modalities, or surgery versus other treatment modalities, for primary tumours of the oral cavity or oropharynx. Our primary outcomes were overall survival, disease-free survival, locoregional recurrence, and recurrence; and our secondary outcomes were adverse effects of treatment, quality of life, direct and indirect costs to patients and health services, and participant satisfaction. We used standard Cochrane methods. We reported survival data as hazard ratios (HRs). For overall survival, we reported the HR of mortality, and for disease-free survival, we reported the combined HR of new disease, progression, and mortality; therefore, HRs below 1 indicated improvement in these outcomes. We used GRADE to assess certainty of evidence for each outcome. We identified four new trials, bringing the total number of included trials to 15 (2820 participants randomised, 2583 participants analysed). For objective outcomes, we assessed four trials at high risk of bias, three at low risk, and eight at unclear risk. The trials evaluated nine comparisons; none compared different surgical approaches for excision of the primary tumour. Five trials evaluated elective neck dissection (ND) versus therapeutic (delayed) ND in people with oral cavity cancer and clinically negative neck nodes. Elective ND compared with therapeutic ND probably improves overall survival (HR 0.64, 95% confidence interval (CI) 0.50 to 0.83; I2 = 0%; 4 trials, 883 participants; moderate certainty) and disease-free survival (HR 0.56, 95% CI 0.45 to 0.70; I2 = 12%; 5 trials, 954 participants; moderate certainty), and probably reduces locoregional recurrence (HR 0.58, 95% CI 0.43 to 0.78; I2 = 0%; 4 trials, 458 participants; moderate certainty) and recurrence (RR 0.58, 95% CI 0.48 to 0.70; I2 = 0%; 3 trials, 633 participants; moderate certainty). Elective ND is probably associated with more adverse events (risk ratio (RR) 1.31, 95% CI 1.11 to 1.54; I2 = 0%; 2 trials, 746 participants; moderate certainty). Two trials evaluated elective radical ND versus elective selective ND in people with oral cavity cancer, but we were unable to pool the data as the trials used different surgical procedures. Neither study found evidence of a difference in overall survival (pooled measure not estimable; very low certainty). We are unsure if there is a difference in effect on disease-free survival (HR 0.57, 95% CI 0.29 to 1.11; 1 trial, 104 participants; very low certainty) or recurrence (RR 1.21, 95% CI 0.63 to 2.33; 1 trial, 143 participants; very low certainty). There may be no difference between the interventions in terms of adverse events (1 trial, 148 participants; low certainty). Two trials evaluated superselective ND versus selective ND, but we were unable to use the data. One trial evaluated supraomohyoid ND versus modified radical ND in 332 participants. We were unable to use any of the primary outcome data. The evidence on adverse events was very uncertain, with more complications, pain, and poorer shoulder function in the modified radical ND group. One trial evaluated sentinel node biopsy versus elective ND in 279 participants. There may be little or no difference between the interventions in overall survival (HR 1.00, 95% CI 0.90 to 1.11; low certainty), disease-free survival (HR 0.98, 95% CI 0.90 to 1.07; low certainty), or locoregional recurrence (HR 1.04, 95% CI 0.91 to 1.19; low certainty). The trial provided no usable data for recurrence, and reported no adverse events (very low certainty). One trial evaluated positron emission tomography-computed tomography (PET-CT) following chemoradiotherapy (with ND only if no or incomplete response) versus planned ND (before or after chemoradiotherapy) in 564 participants. There is probably no difference between the interventions in overall survival (HR 0.92, 95% CI 0.65 to 1.31; moderate certainty) or locoregional recurrence (HR 1.00, 95% CI 0.94 to 1.06; moderate certainty). One trial evaluated surgery plus radiotherapy versus radiotherapy alone and provided very low-certainty evidence of better overall survival in the surgery plus radiotherapy group (HR 0.24, 95% CI 0.10 to 0.59; 35 participants). The data were unreliable because the trial stopped early and had multiple protocol violations. In terms of adverse events, subcutaneous fibrosis was more frequent in the surgery plus radiotherapy group, but there were no differences in other adverse events (very low certainty). One trial evaluated surgery versus radiotherapy alone for oropharyngeal cancer in 68 participants. There may be little or no difference between the interventions for overall survival (HR 0.83, 95% CI 0.09 to 7.46; low certainty) or disease-free survival (HR 1.07, 95% CI 0.27 to 4.22; low certainty). For adverse events, there were too many outcomes to draw reliable conclusions. One trial evaluated surgery plus adjuvant radiotherapy versus chemotherapy. We were unable to use the data for any of the outcomes reported (very low certainty). We found moderate-certainty evidence based on five trials that elective neck dissection of clinically negative neck nodes at the time of removal of the primary oral cavity tumour is superior to therapeutic neck dissection, with increased survival and disease-free survival, and reduced locoregional recurrence. There was moderate-certainty evidence from one trial of no difference between positron emission tomography (PET-CT) following chemoradiotherapy versus planned neck dissection in terms of overall survival or locoregional recurrence. The evidence for each of the other seven comparisons came from only one or two studies and was assessed as low or very low-certainty.


Association of dietary fiber and risk of hip fracture in men from the Framingham Osteoporosis Study and the Concord Health and Ageing in Men Project.
Data in the Offspring Framingham Osteoporosis Study (FOS) suggested that higher intake of dietary fiber was modestly protective against loss of bone mineral density at the femoral neck in men but not in women. To examine the relationship of fiber intake with risk of hip fractures in men. We included 367 men from the FOS Original cohort, 1730 men from the FOS Offspring cohort, and 782 men from the Concord Health and Ageing in Men Project (CHAMP) in the analysis. Incident fractures were defined as medically confirmed first occurrence of osteoporotic fractures at the proximal femur. Fiber intake was estimated via a validated food frequency questionnaire (FFQ) or diet history. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate the pooled relative risk in meta-analysis. Seventy-two incident hip fractures were identified, of which 24 occurred in the FOS Original cohort [mean (SD): age 75.3 (5.1) years; follow-up time: 8.5 (6.2) years; dietary fiber: 19 (8) (g/d)], 19 in the FOS Offspring cohort [58.8 (9.8) years; 11.0 (5.9) years; 19 (8) (g/d)], and 29 in CHAMP [81.4 (4.5) years; 5.2 (1.5) years; 28 (10) (g/d)]. We did not find significant associations within each cohort between fiber intake and risk of hip fractures. The pooled HR (95% CI) was 0.80 (0.39, 1.66) comparing energy-adjusted dietary fiber at tertile 3 vs. tertile 1 (I2 = 0, p = 0.56). These data suggested that dietary fiber was not associated with risk of incident hip fractures in men.


Incidence of deep vein thrombosis and justification of chemoprophylaxis in Indian patients: a prospective study.
Venous thromboembolism (VTE) is considered a major health problem in western countries necessitating thromboprophylaxis. Only a few studies are available regarding incidence in Indian patients resulting in uncertainty regarding thromboprophylaxis for our patients. In our prospective study over a period of 3 years we studied 150 patients (average age 55 years) to determine the incidence of Deep Vein Thrombosis (DVT). These patients were admitted in ICU who remained bedridden for many days and were observed for atleast four weeks. No mechanical or chemical form of deep venous thrombosis prophylaxis was used. All the patients underwent duplex ultrasonography between 7th and 14th postoperative day. None of the patients developed pulmonary embolism (PE). DVT developed in only 10 patients (6.6%). In India there is much lower incidence of DVT as compared to western countries.


Surgical outcomes after resection of both hepatic and pulmonary metastases from colorectal cancer.
The efficacy and the indications of resection of synchronous or metachronous hepatic and pulmonary metastases from colorectal cancer (CRC) are controversial. This study retrospectively reviewed the cases of CRC patients who underwent both liver and lung resection to define the appropriate indications for surgical resection in patients with hepatic and pulmonary metastases. A total of 39 patients with both hepatic and pulmonary metastases from CRC underwent both liver and lung resection from January 1987 to December 2009. The relapse-free survival (RFS) and overall survival (OS) from the resection for the first metastasis were evaluated by a Kaplan-Meyer analysis. Prognostic factors were analyzed using the log-rank test and a Cox proportional hazards model. The median RFS and the 5-year RFS rate of all patients were 12 months and 2.6 %, respectively. The median survival time (MST) and 5-year OS rate of all patients were 66 months and 48.3 %, respectively. The MST of the patients with a long (>1 year) disease-free interval (DFI) could not be calculated, but their 5-year OS rate was 73.7 %. In contrast, the MST and 5-year OS rate of the patients with a short (<1 year) DFI were 29 months and 37.5 %, respectively. The short DFI was the only prognostic factor in the multivariate analysis. Aggressive surgical resection of both hepatic and pulmonary metastases from CRC should be undertaken in selective patients, including those with a long DFI.


The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment.
Patterns of methylation at lysine 4 and 27 of histone H3 have been associated with states of gene activation and repression that are developmentally regulated and are thought to underlie the establishment of lineage specific gene expression programs. Recent studies have provided fundamental insight into the problem of lineage specification by comparing global changes in chromatin and transcription between ES and neural stem (NS) cells, points respectively of departure and arrival for neural commitment. With these maps of the differentiated state in place, a central task is now to unravel the chromatin dynamics that enables these differentiation transitions. In particular, the observation that lineage-specific genes repressed in ES cells by Polycomb-mediated H3-K27 trimethylation (H3-K27me3) are demethylated and derepressed in differentiated cells posited the existence of a specific H3-K27 demethylase.In order to gain insight into the epigenetic transitions that enable lineage specification, we investigated the early stages of neural commitment using as model system the monolayer differentiation of mouse ES cells into neural stem (NS) cells. Starting from a comprehensive profiling of JmjC-domain genes, we report here that Jmjd3, recently identified as a H3-K27me3 specific demethylase, controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage.Our results demonstrate the relevance of an enzymatic activity that antagonizes Polycomb regulation and highlight different modalities through which the dynamics of H3-K27me3 is related to transcriptional output. By showing that the H3-K27 demethylase Jmjd3 is required for commitment to the neural lineage and that it resolves the bivalent domain at the Nestin promoter, our work confirms the functional relevance of bivalent domain resolution that had been posited on the basis of the genome-wide correlation between their controlled resolution and differentiation. In addition, our data indicate that the regulation of H3-K27me3 is highly gene- and context- specific, suggesting that the interplay of methyltransferases and demethylases enables the fine-tuning more than the on/off alternation of methylation states.


[Dynamics and mechanisms of the nucleolus reorganization during mitosis].
The nucleolus is the largest and most dynamic nuclear domain in the vast majority of eukaryotic cells. The main and universal nucleolar function is participation in ribosome biogenesis, including ribosomal DNA (rDNA) transcription, pre-rRNA processing and ribosome subunit assembly. Furthermore, the nucleolus and its proteins also participate in cell cycle regulation, apoptosis and cell aging. These nucleolar functions are realized predominantly in interphase and, apparently, are abolished during mitosis, when the nucleolus disassembles. In this review, literature and our own data on the dynamics and mechanisms of the nucleolus disassembly and reassembly during mitosis in animal and plant cells are summarized. Particular attention is paid to the results obtained by analysis of the nucleolar dynamics in living cells and to modeling of the premature assembly of nucleolus upon various experimental conditions.


Rapid core-to-peripheral tissue heat transfer during cutaneous cooling.
Perioperative thermal manipulations are usually directed at the skin surface because methods of directly warming the core are invasive or ineffective. However, inadequate heat flow between peripheral and core compartments will decrease the rate at which core temperature changes. We therefore determined whether core hypothermia is delayed after initiation of surface cooling. Six volunteers were anesthetized with propofol and midazolam, and maintained under three layers of passive insulation for 2.5-4 h. Subsequently, the skin surface was cooled using forced air, 1000 L/min, at 10 degrees C. Isoflurane was added as necessary to maintain arteriovenous shunt vasodilation. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Average arm and leg (peripheral) tissue temperatures were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Overall body heat content decreased approximately 234 kcal during 2.5 h of active cooling. Core temperature, which was nearly constant before active cooling, decreased approximately 1.3 degrees C/h. There was no delay between initiation of active cooling and the decrease in core temperature. Furthermore, peripheral (arm and leg) and core (trunk and head) tissue heat contents decreased at virtually the same rates: approximately 50 kcal/h and approximately 47 kcal/h, respectively. These data indicate that there is little restriction of heat flow between peripheral and core tissues in vasodilated, anesthetized subjects.