Comparison of Receptor-Defined Breast Cancer Subtypes Between German and Sudanese Women: A Facility-Based Cohort Study.
The objective of this study was to compare tumor characteristics, biomarkers, and surrogate subtypes of breast cancer between Sudanese and German women. Tumor characteristics and immunohistochemistry markers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) were collected from the routine assessment of consecutive patients with invasive breast cancer diagnosed from 2010 to 2015 (Gezira University Pathology Laboratory, Gezira, Sudan) and from 1999 to 2013 (Breast Centre, Martin-Luther-University, Halle, Germany). A total of 2,492 patients (German [n = 1,932] and Sudanese [n = 560]) were included. Age at diagnosis ranged from 20 to 94 years. Sudanese women were, on average, 10 years younger than German women, with a mean (± standard deviation) age of 48.8 (13.5) and 58.6 (12.4) years, respectively. The Sudanese women had a higher grade, larger tumor, and more lymph node positivity compared with German women. ER-, PR-, and HER2-negative proportions were 55%, 61.8%, and 71.3%, respectively, for Sudanese women versus 22.7%, 32.3%, and 82.5%, respectively, for German women. The triple-negative subtype was more prevalent in Sudanese women (34.5%) than in German women (14.2%). The strongest factor associated with ER-negative disease was grade III (odds ratio, 19.6; 95% CI 11.6 to 33.4; P < .001). Sudanese patients were at higher risk for ER-negative breast cancer, with an odds ratio of 2.01 ( P = .001; adjusted for age, size, nodal status, histologic type, and grade). Stratified by grade, the influence of origin was observed in grade I and grade II tumors, but not in grade III tumors. Sudanese women had more aggressive tumor characteristics and unfavorable prognostic biomarkers. After adjustment, Sudanese origin was still associated with hormone receptor-negative disease, especially in grade I and II tumors. These findings suggest differences in tumor biology among these ethnic groups.


Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices.
Experimental evidence suggests that blocking the interactions between endothelial cells and extracellular matrix (ECM) components may provide a potent and general strategy to inhibit tumor neovascularization. Based on these considerations, we have focused our efforts on laminin, component of the vascular basement membrane of every tumor-associated vessel, which serves an essential role in tube formation. We screened anti-laminin single-chain antibody fragments (scFv) derived from a human phage-display library and identified one that blocks the formation of capillary-like structures in vitro. This scFv inhibits angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and prevents the establishment and growth of subcutaneous tumors in mice, either when administered as bolus protein therapy or when produced locally by gene-modified tumor cells. Our work represents the first demonstration of a direct in vivo therapeutic effect of a single-chain antibody secreted by gene-modified mammalian cells. These results open the way for a new antibody-based gene therapy strategy of cancer.


Evidence for striatal dopamine release during a video game.
Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.


Iodine and selenium carry over in milk and cheese in dairy cows: effect of diet supplementation and milk yield.
Iodine and selenium are essential trace elements involved in the regulation of thyroid metabolism and antioxidant status. Two experiments were undertaken on lactating cows to determine the milk concentrations of iodine and selenium, carry over (CO) in milk, the fraction in curdle portion and how milk yield affects the milk iodine and selenium concentrations and CO. Sources of elements were potassium iodide and sodium selenite. In Experiment 1, 12 cows were randomly allotted to three diet groups in a completely randomized design: control group (CTR) - total mixed ration (TMR) containing 1.71 and 0.08 mg/kg dry matter (DM); Group 1 (T1) - TMR plus 23.8 and 2.2 mg; Group 2 (T2) - TMR plus 45.5 and 4.3 mg, respectively, for iodine and selenium. In Experiment 2, 30 cows were allotted to three groups according to milk yield: high (H), average (A) and low (L). Within each group, cows were randomly assigned two levels of iodine and selenium: Level 1: TMR containing 1.55 and 0.15 mg/kg DM; Level 2: TMR plus 47.2 mg and 8.0 mg, respectively, iodine and selenium. In both experiments, individual milk samples were collected and analyzed for iodine and selenium contents. In Experiment 1, Grana Padano cheese was obtained at lab scale and the iodine and selenium fractions in the curd were measured. In Experiment 1, the iodine intake increased (P < 0.001) the concentration and total excretion in milk. The CO increased (P < 0.05) from 16 (CTR) to 27 (T1) and 26% (T2); the sampling time was significant (P < 0.05) with no interaction with treatments. Concentration of selenium in milk was increased (P < 0.05) by treatment and CO decreased (P < 0.01) from 26 (CTR) to 12 (T1) and 9% (T2). The iodine showed a mild enrichment factor in the curdle (about 1.7-fold), whereas selenium enriched five- to sevenfold. In Experiment 2, the level of iodine supplementation affected (P < 0.05) the concentration and total excretion in milk. No effects on milk iodine concentration were related to milk yield or milk yield × treatment interaction; however, the iodine excretion in milk was major (P < 0.05) in higher yielding groups. The iodine CO was affected (P < 0.05) by the milk yield in supplemented groups. The selenium milk concentration and excretion were affected (P < 0.01) by the milk yield, whereas the CO was affected (P < 0.05) by the milk yield and selenium supplementation. Results highlight the possibility of fortification with iodine in milk and selenium in cheese through animal feeding.


Costs of metabolic syndrome-related diseases induced by obesity in Taiwan.
The objective of this paper is to estimate the cost of obesity's contribution to the metabolic syndrome diseases in Taiwan. We used individual data from the Cardiovascular Disease Risk Factors Two-Township Study survey and medical use and expenditures data from the Bureau of National Health Insurance (NHI) of Taiwan. By adopting the prevalence-based and population attributable risk (PAR) approaches, direct costs of obesity for six kinds of obesity related metabolic syndrome diseases have been estimated. Comorbidities used in our analysis included ischemic heart diseases, congestive heart failure, cerebrovascular disease accident, diabetes, hyper-cholesterolaemia and hypertension. The results indicate that overweight and obesity are associated with a higher prevalence and costs of the metabolic syndrome related diseases. PAR increases as the obese [body mass index (BMI)] prevalence increases. About 4-9% of the costs of those diseases can be attributed to overweight (24 < or = BMI < 27) and about 7-13% and 8-19% of such costs are attributable to the first and second degree obesity (27 < or = BMI < 30 and BMI > or = 30). The cost of obesity derived from the PAR and medical costs of metabolic syndrome diseases accounts for 2.9% of the national total healthcare expenditure. We therefore conclude that overweight and obesity have increased health costs and resulted in higher prevalence of and greater costs from metabolic syndrome related diseases in Taiwan. These findings provide important support for implementing obesity prevention programs in Taiwan.


Local worlds: Vulnerability and food insecurity in the Eastern Cape province of South Africa.
The overwhelming finding is that after more than a decade of democracy, the Eastern Cape (EC) province remains trapped in structural poverty. This shows in all aspects of its demographic, health and socio-economic profiles. Methods, measurements and statistics vary, but from the various studies and data sets one can attest that the majority of the population still lives in poverty. Despite the democratic transformation that began in South Africa in 1994, poverty, unemployment and inequality exist today along with the food insecurity that is symptomatic of them. Food insecurity in South Africa varies across its nine provinces, with the EC province frequently measured as the poorest province in the country. This article examines the extent to which the EC can be defined as vulnerable to food insecurity by using a review of current literature. These vulnerabilities are compounded by the environmental vulnerability factors of climate change and drought, which affect households' ability to grow food. The elderly and children are affected by life cycle vulnerability factors, with children prone to malnutrition and the elderly unable to work to produce food. Race and gender are associated with vulnerability to food insecurity. Most of the people in the EC who are poor and are African, and a high percentage of women-headed households is poor. The vulnerability factors identified suggest that job creation and agricultural productivity may be useful ways of targeting food insecurity. Interventions need to take local contexts into account and focus on particular communities and their unique needs.


Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma.
Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/ APO-1-associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIP(L)) in resistant cells and the ratio of caspase-8 to FLIP(L) measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. In addition, modification of the caspase-8/FLIP(L) ratio by caspase-8 or FLIP(L) overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIP(L) are an important determinant of susceptibility to Fas-mediated apoptosis.


Diagnostic potential of inflammatory markers in septic arthritis and periprosthetic joint infections: a clinical study with 719 patients.
The aim of this study was to investigate which markers in serum and in the synovial fluid have the highest diagnostic potential for predicting septic arthritis and periprosthetic joint infections (PJIs). The likelihood ratio assesses the diagnostic utility of a diagnostic test and the likelihood that a patient has a disease. The levels of inflammatory markers in serum [white blood cells, C-reactive protein (CRPS)] and synovial fluid [synovial fluid white blood cell count (SFWBC), percentage of polymorphonuclear cells (%PMN), lactic acid, lactate dehydrogenase (LDH), glucose, total protein] of patients suffering from septic arthritis (n = 114), PJI (n = 67), non-infectious joint diseases (n = 495) and arthralgia after total joint arthroplasty (n = 43) were determined. The arithmetical means, cut-off values, sensitivities, specificities, positive and negative likelihood ratios (+ LR, -LR), interval likelihood ratios and receiver operating characteristic curves with corresponding area under the curve (AUC) of inflammatory markers were calculated. The parameters with the highest diagnostic potential for differing between septic arthritis and non-infectious arthritis were the SFWBC (AUC = 0.850, cut-off value = 6.7 × 10(3)/μl, sensitivity = 81.8%, specificity = 76.5%,+ LR = 3.41, -LR = 0.24), CRPS (AUC = 0.797), %PMN (AUC = 0.766) and synovial lactate (AUC = 0.760). The highest diagnostic potential for predicting a PJI was shown by LDH (AUC = 0.833) and the SFWBC (AUC = 0.828). The SFWBC, CRPS, %PMN and synovial lactate were the best inflammatory markers in predicting septic arthritis. Synovial lactate levels > 10 mmol/l or an SFWBC > 50 × 10(3)/μl substantially increased disease probability, while SFWBC < 1.0 × 10(3)/μl or CRPS < 0.5 mg/dl diminished the post-test probability of septic arthritis considerably. An SFWBC < 1.1 × 10(3)/μl or a %PMN < 70% made a PJI unlikely, while SFWBC > 20 × 10(3)/μl or %PMN > 86% increased the post-test probability of a PJI. The use of the corresponding interval likelihood ratios could help physicians to estimate the probability of septic arthritis and PJI more accurately.


Isolation of a retroviruslike sequence from the TL locus of the C57BL/10 murine major histocompatibility complex.
Two retroviruslike sequences have been isolated from the TL locus of the major histocompatibility complex of C57BL/10 mice. One sequence (TLev2) hybridizes only with probes derived from the pol region of the murine leukemia provirus AKR; the other sequence (TLev1) hybridizes with gag, pol, and env AKR region probes. This 9-kilobase endogenous, TL region-associated virus (TLev1) has been further characterized. The TLev1 genome has been shown to contain murine leukemia virus-related sequences bounded by retroviruslike, VL30 long terminal repeats. Hybridization of TLev1-derived probes to mouse genomic digests reveals multiple copies which show distinct patterns compared with those observed with murine leukemia virus probes. The study of TLev1 may prove significant with respect to the interaction of retroviral sequences within the genome, expression of genes within the TL locus, and polymorphisms within the major histocompatibility complex.


Resin-bonded fixed partial dentures--a literature review with presentation of a novel approach.
Resin-bonded fixed partial dentures (RBFPD) have been in our profession for over 20 years. The aim of this work was to provide some background about their development and the factors that influence their clinical longevity. A recent literature search conducted using MEDLINE along with analysis of bibliographies of published papers revealed a considerable number of publications of RBFPDs since their first introduction in the mid-1970s. Critical analysis of these publications revealed some important and interesting key facts. These were divided into sections about developments in the treatment of the fit surface of the casting, bonding systems, and prosthesis design. A separate section about factors that affect the longevity of RBFPDs is included, along with a detailed description of preparation designs of an anterior and a posterior RBFPD. The typical design of RBFPDs is characterized by a high degree of conservation of tooth structure of abutments compared with designs of conventional fixed prostheses. While the early RBFPDs were associated with a high frequency of premature failure--mostly because of debonding--developments in preparation design and bonding techniques as well as better understanding of the appropriate type of metal alloy to be used and the best preparation method for enhanced bonding have led to significant improvements in their long-term survival. RBFPDs should be considered viable treatment options for those clinical situations that are best suited for their use. Preparation design, cement type, and casting alloy type as well as surface treatment are among the most important factors that influence longevity of RBFPDs.


[Diagnostics of neoplasms of the nasal cavity and paranasal sinuses].
The objective of the present work was to address earlier diagnostics of benign and malignant tumours in the nasal cavity and paranasal sinuses with a view to its improvemen. The immunohistochemical study and the analysis of its results made possible not only differential diagnostics of the tumorigenic processes in the nasal cavity and paranasal sinuses but also the estimation of the qualitative potential of each neoplasm. The immunohistochemical study demonstrated that the development of cancer of the nasal cavity and paranasal sinuses was associated with a substantial increase in the proliferative activity of epithelium and the appearance of a large amount of the mutant P53 protein in the atypical cells. The cells of inverted papilloma and unaffected epithelium exhibited only weak proliferative activity, contained cytokeratin-8 in their cytoplasm, and did not express a pathological receptor protein at the cytoplasmic membrane surface.


Salicylic acid dependent signaling promotes basal thermotolerance but is not essential for acquired thermotolerance in Arabidopsis thaliana.
Salicylic acid (SA) is reported to protect plants from heat shock (HS), but insufficient is known about its role in thermotolerance or how this relates to SA signaling in pathogen resistance. We tested thermotolerance and expression of pathogenesis-related (PR) and HS proteins (HSPs) in Arabidopsis thaliana genotypes with modified SA signaling: plants with the SA hydroxylase NahG transgene, the nonexpresser of PR proteins (npr1) mutant, and the constitutive expressers of PR proteins (cpr1 and cpr5) mutants. At all growth stages from seeds to 3-week-old plants, we found evidence for SA-dependent signaling in basal thermotolerance (i.e. tolerance of HS without prior heat acclimation). Endogenous SA correlated with basal thermotolerance, with the SA-deficient NahG and SA-accumulating cpr5 genotypes having lowest and highest thermotolerance, respectively. SA promoted thermotolerance during the HS itself and subsequent recovery. Recovery from HS apparently involved an NPR1-dependent pathway but thermotolerance during HS did not. SA reduced electrolyte leakage, indicating that it induced membrane thermoprotection. PR-1 and Hsp17.6 were induced by SA or HS, indicating common factors in pathogen and HS responses. SA-induced Hsp17.6 expression had a different dose-response to PR-1 expression. HS-induced Hsp17.6 protein appeared more slowly in NahG. However, SA only partially induced HSPs. Hsp17.6 induction by HS was more substantial than by SA, and we found no SA effect on Hsp101 expression. All genotypes, including NahG and npr1, were capable of expression of HSPs and acquisition of HS tolerance by prior heat acclimation. Although SA promotes basal thermotolerance, it is not essential for acquired thermotolerance.


CRISPR/Cas-Based Diagnostics in Agricultural Applications.
Pests and disease-causing pathogens frequently impede agricultural production. An early and efficient diagnostic tool is crucial for effective disease management. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein (Cas) have recently been harnessed to develop diagnostic tools. The CRISPR/Cas system, composed of the Cas endonuclease and guide RNA, enables precise identification and cleavage of the target nucleic acids. The inherent sensitivity, high specificity, and rapid assay time of the CRISPR/Cas system make it an effective alternative for diagnosing plant pathogens and identifying genetically modified crops. Furthermore, its potential for multiplexing and suitability for point-of-care testing at the field level provide advantages over traditional diagnostic systems such as RT-PCR, LAMP, and NGS. In this review, we discuss the recent developments in CRISPR/Cas based diagnostics and their implications in various agricultural applications. We have also emphasized the major challenges with possible solutions and provided insights into future perspectives and potential applications of the CRISPR/Cas system in agriculture.


Controlling the fate of roxarsone and inorganic arsenic in poultry litter.
A growing body of literature reports 3-nitro-4-hydroxyphenylarsonic acid (roxarsone) degradation in poultry litter (PL) to the more toxic inorganic arsenic (As). Aluminum-based drinking-water treatment residuals (WTR) present a low-cost amendment technology to reduce As availability in PL, similar to the use of alum to reduce phosphorus availability. Batch experiments investigated the effectiveness of WTR in removing roxarsone and inorganic As species from PL aqueous suspensions. Incubation experiments with WTR-amended PL evaluated the effects of WTR application rates (2.5-15% by weight) and incubation time (up to 32 d) at two incubation temperatures (23 and 35 degrees C) on As availability in PL. Batch PL aqueous experiments showed the high affinity of As(V), As(III), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), and roxarsone for the WTR. The 10% WTR amendment rate decreased As availability in PL by half of that of the unamended (no WTR) PL-incubated samples. The reduction in dissolved As concentrations during incubation of WTR-amended PL samples was kinetically limited, being complete within 13 d. Parallel reductions in roxarsone, As(V), and DMA concentrations were observed with liquid chromatography-inductively coupled plasma mass spectrometry, whereas As(III) and MMA concentrations were always <5% of dissolved As. Incubation temperature did not significantly (p > 0.05) influence dissolved As concentrations in the WTR-amended PL. Potential formation of a copper-containing roxarsone metabolite was considered in PL aqueous suspensions with the aid of electrospray mass spectrometry. Further experiments in the field are necessary to ensure that sorbed As is stable in WTR-amended PL.


Multisection CT as a valuable tool in the postoperative assessment of cochlear implant patients.
A data acquisition protocol for postoperative imaging of cochlear implants by using multisection CT (MSCT) is described. The improved image quality of MSCT allows assessment of the precise intracochlear position of the electrode array and visualization of individual electrode contacts. Such images can aid in fitting the speech processor, especially in difficult cases.


Deacylation of bacterial endotoxins by neutrophils and macrophages: early observations and hypotheses.
Gram-negative bacterial lipopolysaccharides (LPS) are thought to play a role in immunomodulation by providing signals to cells such as macrophages, lymphocytes and neutrophils. Recent structure-activity studies indicate that many of the bioactivities of lipid A, the bioactive region of LPS, can be produced by a lipid A precursor. The precursor is a glucosamine disaccharide that is phosphorylated at 1 and 4' and that has 3-hydroxytetradecanoate residues linked to the glucosamine backbone at 2, 3, 2', and 3'. In contrast, certain toxic activities (pyrogenicity, complement activation and the ability to produce the Shwartzman reaction) appear to require complete lipid A, which additionally has nonhydroxylated fatty acids substituted to the hydroxyl groups of some of the 3-hydroxytetradecanoate residues. Earlier studies have identified enzymes (acyloxyacyl hydrolases) in neutrophils and macrophages that remove the nonhydroxylated fatty acids from complete lipid A, thus converting the lipid A to a precursor-like structure. Based on the structure-activity studies described above, it is speculated that acyloxyacyl hydrolysis reduces the toxicity of lipid A. It is also possible that enzymatic removal of the nonhydroxylated fatty acids is required for some of the stimulatory activities of lipid A.


Vesicles carry most exocyst subunits to exocytic sites marked by the remaining two subunits, Sec3p and Exo70p.
Exocytosis in the budding yeast Saccharomyces cerevisiae occurs at discrete domains of the plasma membrane. The protein complex that tethers incoming vesicles to sites of secretion is known as the exocyst. We have used photobleaching recovery experiments to characterize the dynamic behavior of the eight subunits that make up the exocyst. One subset (Sec5p, Sec6p, Sec8p, Sec10p, Sec15p, and Exo84p) exhibits mobility similar to that of the vesicle-bound Rab family protein Sec4p, whereas Sec3p and Exo70p exhibit substantially more stability. Disruption of actin assembly abolishes the ability of the first subset of subunits to recover after photobleaching, whereas Sec3p and Exo70p are resistant. Immunogold electron microscopy and epifluorescence video microscopy indicate that all exocyst subunits, except for Sec3p, are associated with secretory vesicles as they arrive at exocytic sites. Assembly of the exocyst occurs when the first subset of subunits, delivered on vesicles, joins Sec3p and Exo70p on the plasma membrane. Exocyst assembly serves to both target and tether vesicles to sites of exocytosis.


Exploratory experimentation and scientific practice: metagenomics and the proteorhodopsin case.
Exploratory experimentation and high-throughput molecular biology appear to have considerable affinity for each other. Included in the latter category is metagenomics, which is the DNA-based study of diverse microbial communities from a vast range of non-laboratory environments. Metagenomics has already made numerous discoveries and these have led to reinterpretations of fundamental concepts of microbial organization, evolution, and ecology. The most outstanding success story of metagenomics to date involves the discovery of a rhodopsin gene, named proteorhodopsin, in marine bacteria that were never suspected to have any photobiological capacities. A discussion of this finding and its detailed investigation illuminates the relationship between exploratory experimentation and metagenomics. Specifically, the proteorhodopsin story indicates that a dichotomous interpretation of theory-driven and exploratory experimentation is insufficient and that an interactive understanding of these two types of experimentation can be usefully supplemented by another category, "natural history experimentation". Further reflection on the context of metagenomics suggests the necessity of thinking more historically about exploratory and other forms of experimentation.


Feeding climate and biodiversity goals with novel plant-based meat and milk alternatives.
Plant-based animal product alternatives are increasingly promoted to achieve more sustainable diets. Here, we use a global economic land use model to assess the food system-wide impacts of a global dietary shift towards these alternatives. We find a substantial reduction in the global environmental impacts by 2050 if globally 50% of the main animal products (pork, chicken, beef and milk) are substituted-net reduction of forest and natural land is almost fully halted and agriculture and land use GHG emissions decline by 31% in 2050 compared to 2020. If spared agricultural land within forest ecosystems is restored to forest, climate benefits could double, reaching 92% of the previously estimated land sector mitigation potential. Furthermore, the restored area could contribute to 13-25% of the estimated global land restoration needs under target 2 from the Kunming Montreal Global Biodiversity Framework by 2030, and future declines in ecosystem integrity by 2050 would be more than halved. The distribution of these impacts varies across regions-the main impacts on agricultural input use are in China and on environmental outcomes in Sub-Saharan Africa and South America. While beef replacement provides the largest impacts, substituting multiple products is synergistic.


Conditional human immunodeficiency virus type 1 protease mutants show no role for the viral protease early in virus replication.
The human immunodeficiency virus type 1 protease plays a critical role in the proteolytic processing of precursor polyproteins during virion maturation. Contradictory evidence has been obtained for a possible role for the protease early after infection, i.e., during DNA synthesis and/or integration. We have reexamined this question by using conditional mutants of the protease. In one set of experiments, protease mutants that confer a temperature-sensitive phenotype for processing were used to assess the need for protease activity early after infection. No significant difference from results with wild-type virus was seen when infections were carried out at either 35 or 40 degrees C. In a separate set of experiments, infections were carried out in the presence of a protease inhibitor. In this case, both wild-type virus and a drug-resistant variant were used, the latter as a control to ensure a specific effect of the inhibitor. Infection with either virus was not inhibited at drug concentrations that were up to 10-fold higher than those needed to inhibit intracellular processing by the viral protease. The results obtained by both of these experimental protocols provide evidence that the human immunodeficiency virus type 1 protease does not play a role early after infection.


Biomolecular condensates as novel antiviral targets.
Viral infections pose a significant health risk worldwide. There is a pressing need for more effective antiviral drugs to combat emerging novel viruses and the reemergence of previously controlled viruses. Biomolecular condensates are crucial for viral replication and are promising targets for novel antiviral therapies. Herein, we review the role of biomolecular condensates in the viral replication cycle and discuss novel strategies to leverage condensate biology for antiviral drug discovery. Biomolecular condensates may also provide an opportunity to develop antivirals that are broad-spectrum or less prone to acquired drug resistance.


Impact of preoperative pharmaceutical care consultation on medication errors in surgical patients: a comprehensive analysis.
Assessing the impact of introducing preoperative pharmaceutical care consultations by analyzing the severity of prevented medication errors (MEs) and their potential effects on the surgical process. Preoperative pharmaceutical care consultation was implemented in our hospital to assess the preoperative medication management of surgical patients between the pre-anesthesia consultation and the day of surgery. Pharmacists evaluated the appropriateness of medication management based on a consensus multidisciplinary institutional protocol. All errors identified between 2016 and 2020 were analyzed, and their severity and potential impact on surgery were standardized. A list of therapeutic groups was created to prioritize patients for consultations. During the study period, 3,105 patients attended the consultations and 1,179 MEs were prevented. According to severity, 30.6% of MEs were classified as category E and 26.2% as D. The Number Needed to Treat to prevent a category E or higher ME (indicating potential harm to patients) was 5 patients. 14.84% of MEs belonged to the prioritized drug groups. 113 errors would have resulted in a surgery delay of more than 24 hours, and 175 errors were classified as G-H (irreversible damage). This study highlights the effectiveness of pharmaceutical care consultations in preventing MEs and improving surgical outcomes.


Background corrections for laser-induced-fluorescence measurements of nitric oxide in lean, high-pressure, premixed methane flames.
An experimental technique is presented that both minimizes and accounts for the interference background when laser-induced-fluorescence (LIF) measurements are made of NO in lean, high-pressure, premixed, CH(4)/O(2)/N(2) flames. Measurement interferences such as fluorescence and Raman scattering from secondary species become increasingly important for high-pressure LIF studies. O(2) fluorescence interferences are particularly troublesome in lean premixed flames. An excitation-detection scheme that minimizes the effects of these interferences is identified. A procedure that corrects the resulting LIF signal so as to account for any remaining interference signal is then developed. This correction is found to vary from less than 10% of the overall NO signal at atmospheric pressure to over 40% of the overall signal at 14.6 atm for LIF measurements of NO in a series of worst-case flames (phi = 0.6, dilution ratio 2.2). The correction technique is further demonstrated to be portable over a useful range of flame conditions at each pressure.


Nonfatal Gun Use in Intimate Partner Violence: A Systematic Review of the Literature.
Guns figure prominently in the homicide of women by an intimate partner. Less is known, however, about their nonfatal use against an intimate partner. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched eight electronic databases and identified 10 original research articles that reported the prevalence of the nonfatal use of firearms against an intimate partner. Results indicate that (1) there is relatively little research on the subject of intimate partners' nonfatal gun use against women. (2) The number of U.S. women alive today who have had an intimate partner use a gun against them is substantial: About 4.5 million have had an intimate partner threaten them with a gun and nearly 1 million have been shot or shot at by an intimate partner. Whether nonfatal gun use is limited to the extreme form of abuse (battering) or whether it occurs in the context of situational violence remains to be seen. Regardless, when it comes to the likely psychological impact, it may be a distinction without a difference; because guns can be lethal quickly and with relatively little effort, displaying or threatening with a gun can create a context known as coercive control, which facilitates chronic and escalating abuse. Implications for policy, practice, and research are discussed, all of which include expanding an implicit focus on homicide to include an intimate partner's nonfatal use of a gun.


[Natural mineral and spring waters and fruit juices as food sources of silicon].
Beverages especially mineral waters are considered as one of the best nutritional sources of silicon. The aim of this work was to determine the silicon content in bottled mineral and spring waters, as well as in orange, apple, grapefruit and mixed fruit juices available on the market. The electrothermal atomic absorption spectrometry (GF-AAS) was used for the silicon determination. The silicon levels in mineral waters ranged from 3.33 - 30.05 mg Si/dm3, in spring waters ranged from 3.66- 11.23 mg/dm3, and in fruit juices ranged from 0.21- 1.93 mg/100g.


Post-Infectious Organizing Pneumonia: an Indistinguishable and Easily Misdiagnosed Organizing Pneumonia.
Post-infectious organizing pneumonia (OP) is a rare clinical entity associated with nonspecific clinical features and can be easily misdiagnosed. This study aimed to investigate the clinical feature differences between cryptogenic organizing pneumonia (COP) and post-infectious OP. We retrospectively analyzed clinical data on demographic characteristics, clinical manifestations, laboratory findings, radiological findings, treatments, outcomes, and prognosis of 31 cases of COP and 26 cases of post-infectious OP. Patients were treated in Beijing Chao-yang Hospital between July 2005 and January 2013. Compared with patients with COP, patients with post-infectious OP are more prone to show fever (88.5% vs. 38.7%, p < 0.05) and crackles (46.2% vs. 6.5%, p < 0.05). The elevation of PCT serum levels is more obvious in the early stage of post-infectious OP (5.24 ± 1.96 vs. 0.28 ± 0.09) and bilateral lung consolidations and patchy shadows are the most common radiological findings (70.2%). Pathogens are more prone to be confirmed within 48 hours after admission and the diagnosis time is longer (10.0 ± 0.8 vs. 7.2 ± 0.4 days). The incidence of mechanical ventilation (50% vs. 19.4%) and the utilization rate of antibiotics are higher (100.0% vs. 70.9%). The dosage (0.58 ± 0.04 vs. 0.78 ± 0.04 mg) and utilization time of glucocorticoids (5.7 ± 0.4 vs. 7.9 ± 0.8 months) are obviously reduced. The morbidity of post-infectious OP is not uncommon. PCT serum level is helpful in the diagnosis and differential diagnosis, but invasive procedures like bronchoscopic or surgical lung biopsy are the golden-standard methods to confirm diagnosis. Similar to COP, antibiotics are effective in the early stage of post-infectious OP, but glucocorticoids are effective in the late stage. The prognosis of post-infectious OP is good.


Treatment outcome research of enhanced cognitive behaviour therapy for eating disorders: a systematic review with narrative and meta-analytic synthesis.
Enhanced cognitive behaviour therapy (CBT-E) has recently generated interest as a potentially useful treatment for eating disorders (ED). In the current study, we conducted a systematic review of the outcome literature on CBT-E, with both narrative and meta-analytic synthesis. We included single-group uncontrolled pre-post design studies and randomised control trials (RCTs) of CBT-E, which allowed us to include a larger number of studies, and also compare the two methodologies in terms of effect size. The primary analysis included 15 CBT-E studies with a total of 948 participants. Narrative synthesis examined bingeing and purging episodes, BMI change, and follow-up results. A large, statistically significant effect supported CBT-E as a treatment for all EDs (g = 1.06). When comparing methodologies, both pre-post design studies (g = 1.26) and RCTs (g = 0.82) yielded large effects. Narrative synthesis outlined reductions in ED behaviours and increases in BMI which were maintained at follow-up. Limitations include that further RCTs of CBT-E are needed to establish clinical effectiveness of this treatment approach for all EDs; however, results from narrative exploration indicate this endeavour would be worthwhile. Despite the limitations, this study provides additional support for CBT-E as a successful treatment across the range of EDs.


Bacterial Defense Systems against the Neutrophilic Oxidant Hypochlorous Acid.
Neutrophils kill invading microbes and therefore represent the first line of defense of the innate immune response. Activated neutrophils assemble NADPH oxidase to convert substantial amounts of molecular oxygen into superoxide, which, after dismutation into peroxide, serves as the substrate for the generation of the potent antimicrobial hypochlorous acid (HOCl) in the phagosomal space. In this minireview, we explore the most recent insights into physiological consequences of HOCl stress. Not surprisingly, Gram-negative bacteria have evolved diverse posttranslational defense mechanisms to protect their proteins, the main targets of HOCl, from HOCl-mediated damage. We discuss the idea that oxidation of conserved cysteine residues and partial unfolding of its structure convert the heat shock protein Hsp33 into a highly active chaperone holdase that binds unfolded proteins and prevents their aggregation. We examine two novel members of the Escherichia coli chaperone holdase family, RidA and CnoX, whose thiol-independent activation mechanism differs from that of Hsp33 and requires N-chlorination of positively charged amino acids during HOCl exposure. Furthermore, we summarize the latest findings with respect to another bacterial defense strategy employed in response to HOCl stress, which involves the accumulation of the universally conserved biopolymer inorganic polyphosphate. We then discuss sophisticated adaptive strategies that bacteria have developed to enhance their survival during HOCl stress. Understanding bacterial defense and survival strategies against one of the most powerful neutrophilic oxidants may provide novel insights into treatment options that potentially compromise the ability of pathogens to resist HOCl stress and therefore may increase the efficacy of the innate immune response.


Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors.
Despite strong scientific evidence supporting the benefits of regular exercise for the prevention and management of cardiovascular disease (CVD), physical inactivity is highly prevalent worldwide. In addition to merely changing well-known risk factors for systemic CVD, regular exercise can also improve cardiovascular health through non-traditional mechanisms. Understanding the pathways through which exercise influences different physiological systems is important and might yield new therapeutic strategies to target pathophysiological mechanisms in CVD. This Review includes a critical discussion of how regular exercise can have antiatherogenic effects in the vasculature, improve autonomic balance (thereby reducing the risk of malignant arrhythmias), and induce cardioprotection against ischaemia-reperfusion injury, independent of effects on traditional CVD risk factors. This Review also describes how exercise promotes a healthy anti-inflammatory milieu (largely through the release of muscle-derived myokines), stimulates myocardial regeneration, and ameliorates age-related loss of muscle mass and strength, a frequently overlooked non-traditional CVD risk factor. Finally, we discuss how the benefits of exercise might also occur via promotion of a healthy gut microbiota. We argue, therefore, that a holistic view of all body systems is necessary and useful when analysing the role of exercise in cardiovascular health.


Reduced cadmium accumulation and toxicity in Daphnia magna under carbon nanotube exposure.
With increasing application and commercial production, carbon nanotubes (CNTs) will inevitably be released into aquatic environments and affect the transport and toxicity of toxic metals in ecosystems. The present study examined how CNTs affected the biokinetics and toxicity of a toxic metal, cadmium (Cd), in the freshwater zooplankton Daphnia magna. The authors quantified the dissolved uptake and the 50% lethal concentration (LC50, 48 h and 72 h) of Cd in daphnids in the presence of functionalized multiwalled nanotubes (F-CNTs) with different lengths (10-30 µm vs 0.5-2 µm) and concentrations (4 mg/L and 8 mg/L). Compared with the control treatment without CNTs, both CNTs slowed down the accumulation rate of Cd in D. magna over 8 h of exposure and further reduced the accumulation thereafter. Mechanisms for the reduced Cd uptake were mainly related to the influences of CNTs on the physiological activity of daphnids. The LC50 of D. magna in the presence of Cd and shorter CNTs was almost the same as that of the control group without CNTs. However, the LC50 of the groups with normal CNTs was significantly higher than that of the control group (i.e., F-CNTs decreased Cd toxicity significantly). Meanwhile, CNTs also decreased the tolerance of D. magna to Cd. The present study suggests that different physical properties of CNTs, such as length, need to be considered in the environmental risk assessment of CNTs.


[Changes in the amount of mineral components in bone tissue during treatment of transcondylar fractures of the humerus].
In 12 non-inbred 4-month-old puppies a closed brachial transcondylar fracture has been performed. By means of photonic absorbtiometry contents of mineral components have been estimated in the regenerate forming between the osseous broken pieces, in the osseous fragments and in the adjoining segment, depending on duration of the joint fixation during the treatment. Mineralization takes place more quickly in a mobile joint. Fixation for 5-7 days does not essentially affect the miniralization rate. Fixation for 14 days decreases intensity of the mineralization, produces deminiralization in the osseous pieces and in the adjoining segment of the bone, results in incompleteness of the brachial condyle rearrangement.


Specific characteristics of the pain/depression association in the general population.
To evaluate how the presence of a chronic painful physical condition (CPPC) lasting 6 months or more influences the frequency and severity of depressive symptoms in subjects with major depressive disorder (MDD). Random samples of 18,980 subjects aged between 15 and 100 years who were representative of the general population of 5 European countries (the United Kingdom, Germany, Italy, Portugal, and Spain) were interviewed by telephone between 1994 and 1999. Subjects answered a series of questions that allowed positive and differential diagnosis of DSM-IV mental disorders. The questionnaire also included a series of questions about painful physical conditions, medical treatment, consultations, and hospitalizations for medical conditions and a list of diseases. A total of 4% (95% CI = 3.7% to 4.3%) of the sample had MDD at the time of the interview. Nearly half of subjects with MDD (43.4%) also reported having a CPPC. Compared with MDD subjects without chronic pain, MDD subjects with a CPPC had a longer duration of depressive symptoms (7 months longer) and were more likely to report severe fatigue (OR = 5.4), insomnia nearly every night (OR = 3.3), severe psychomotor retardation (OR = 3.3), weight gain (OR = 2.3), severe difficulty concentrating (OR = 1.7), and severe feelings of sadness or depressed mood (OR = 1.8). A CPPC was present in nearly half of subjects with MDD. CPPCs increased the severity of physical symptoms of depression (fatigue, insomnia, psychomotor retardation, weight gain). Moreover, CPPCs affected the duration of depressive episodes and their recurrence. Physicians should consider CPPCs as a major factor in the expression and evolution of MDD. They must remember that MDD patients tend to amplify physical symptoms, to the detriment of their depressive symptomatology.


Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens.
Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.


[Immunopathologic mechanisms associated with granulomas and odontogenic cysts: a general review].
The authors make a general survey of the immunopathological mechanisms involved in odontogenic cysts and granulomas. The dental pulp and the sound periapical tissues contain neither inflammatory nor immunoglobin-producing cells. Dental decay associated with bacterial aggression of the dental pulp and periapical tissues might induce a nonspecific inflammation which subsequently becomes more specific. Immunoglobulins are present in fluid aspirates from odontogenic cysts and granulomas. Several investigations have pointed out nonspecific inflammatory mediators (including the C3 complement components), T lymphocytes (helpers and suppressors), B lymphocytes, protein S-100 + cells (Langerhans cells). The presence of immunoglobulins, immunocompetent cells and C3 complement components confirms that all constituents of both humoral and cell-mediated immunological reactions might play an essential role in the pathogenesis of osteolysis.


Polynesian origins: insights from the Y chromosome.
The question surrounding the colonization of Polynesia has remained controversial. Two hypotheses, one postulating Taiwan as the putative homeland and the other asserting a Melanesian origin of the Polynesian people, have received considerable attention. In this work, we present haplotype data based on the distribution of 19 biallelic polymorphisms on the Y chromosome in a sample of 551 male individuals from 36 populations living in Southeast Asia, Taiwan, Micronesia, Melanesia, and Polynesia. Surprisingly, nearly none of the Taiwanese Y haplotypes were found in Micronesia and Polynesia. Likewise, a Melanesian-specific haplotype was not found among the Polynesians. However, all of the Polynesian, Micronesian, and Taiwanese haplotypes are present in the extant Southeast Asian populations. Evidently, the Y-chromosome data do not lend support to either of the prevailing hypotheses. Rather, we postulate that Southeast Asia provided a genetic source for two independent migrations, one toward Taiwan and the other toward Polynesia through island Southeast Asia.


Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids.
Lipid accumulation is a pathological feature of every type of kidney injury. Despite this striking histological feature, physiological accumulation of lipids in the kidney is poorly understood. We studied whether the accumulation of lipids in the fasted kidney are derived from lipoproteins or NEFAs. With overnight fasting, kidneys accumulated triglyceride, but had reduced levels of ceramide and glycosphingolipid species. Fasting led to a nearly 5-fold increase in kidney uptake of plasma [14C]oleic acid. Increasing circulating NEFAs using a β adrenergic receptor agonist caused a 15-fold greater accumulation of lipid in the kidney, while mice with reduced NEFAs due to adipose tissue deficiency of adipose triglyceride lipase had reduced triglycerides. Cluster of differentiation (Cd)36 mRNA increased 2-fold, and angiopoietin-like 4 (Angptl4), an LPL inhibitor, increased 10-fold. Fasting-induced kidney lipid accumulation was not affected by inhibition of LPL with poloxamer 407 or by use of mice with induced genetic LPL deletion. Despite the increase in CD36 expression with fasting, genetic loss of CD36 did not alter fatty acid uptake or triglyceride accumulation. Our data demonstrate that fasting-induced triglyceride accumulation in the kidney correlates with the plasma concentrations of NEFAs, but is not due to uptake of lipoprotein lipids and does not involve the fatty acid transporter, CD36.


In vitro T-cell activation of monocyte-derived macrophages by soluble messengers or cell-to-cell contact in bovine tuberculosis.
The macrophage plays a dual role in tuberculosis, promoting not only protection against mycobacteria, but also survival of the pathogen. Macrophages inhibit multiplication of mycobacteria but also act in concert with lymphocytes through presentation of antigens to T cells. Studies in animal and human infections have suggested a correlation of in vitro growth rates of mycobacteria with in vivo virulence, using uracil uptake to assess mycobacterial metabolism. This study found that blood-derived, non-activated bovine macrophages were capable of controlling Mycobacterium bovis bacillus Calmette-Gurin growth for up to 96 hr, but were permissive to intracellular growth of virulent M. bovis. The present investigation compared the in vitro modulation of these macrophage activities by cytokine-rich T-cell supernatants or cell-to-cell contact. On the one hand, treatment of cultured monocytes with mitogen-produced T-cell supernatants promoted morphological changes suggestive of an activation status, enhanced the antigen presentation capabilities of monocytes and up-regulated major histocompatibility complex class II expression. However, this activation was not associated with enhanced anti-M. bovis activity. On the other hand, incubation of infected monocytes with T-cell populations resulted in proportionally increased inhibition of M. bovis uracil uptake. This inhibition was also seen using cells from uninfected animals and indicated the necessity for cell-to-cell contact to promote antimycobacterial capability.


Diffusion-weighted magnetic resonance imaging for diagnosis of post-operative paediatric cholesteatoma.
High rates of recidivism are reported after paediatric cholesteatoma surgery. Our practice has adapted to include non-echoplanar diffusion-weighted magnetic resonance imaging for the diagnosis of residual or recurrent cholesteatoma. This audit aimed to evaluate the performance of non-echoplanar diffusion-weighted magnetic resonance imaging in our paediatric population. A retrospective review was conducted of non-echoplanar diffusion-weighted magnetic resonance imaging scans performed to detect residual disease or recurrence after surgery for cholesteatoma in children from 1 January 2012 to 30 November 2017 in our centre. Follow-up diffusion-weighted magnetic resonance imaging scans were reviewed to 16 August 2019. Thirty-four diffusion-weighted magnetic resonance imaging scans were included. The sensitivity and specificity values of diffusion-weighted magnetic resonance imaging for detecting post-operative cholesteatoma were 81 per cent and 72 per cent, respectively. Positive predictive and negative predictive values were 72 per cent and 81 per cent, respectively. Use of diffusion-weighted magnetic resonance imaging is recommended as a replacement for routine second-look surgical procedures in the paediatric population. However, we would caution that patients require close follow up after negative diffusion-weighted magnetic resonance imaging findings.


Opportunities and Barriers to Breast Cancer Screening in a Rural Community in Coastal Karnataka, India: A Qualitative Analysis.
Breast cancer is reported to be the most common cancer among women in India with a high mortality to incidence ratio. Late presentation, driven by lack of awareness and limited accessibility to health services are some of the stated reasons for this. Given this context, this qualitative study was carried out to understand the perception of rural women towards the disease and factors that influenced utilization of available screening services among them. Forty-four rural women aged 20-60 years from a coastal province in southern India participated in four Focus Group Discussions (FGDs) that were conducted to understand their perception, attitudes and barriers towards breast cancer screening. Participants were identified from the community through purposive sampling and constituted of home makers and working women. The FGDs were led by trained facilitators and the discussions recorded. Ideas and concepts that emerged were listed as codes. Related and similar codes were grouped to form six themes. Women in the study belonged to low- and middle-income households with a mean age of 42.8 ± 7.8 years and almost all had attended school. Although the respondents exhibited fairly good knowledge about the disease, cultural inhibitions, forgetfulness, economic constraints and apprehension towards tertiary health care facility were some of the barriers reported in the uptake of screening services. Participants hailed the role of female health care providers as motivational figures and stressed the need for easily comprehensible information dissemination strategies besides expecting an equal participation of men in issues involving women's health. Involving cancer survivors as educators and empowering men on women's health in addition to the felt need of a patient advocate to improve accessibility were some of the highlights of the discussions. Addressing these could go a long way in improving the cancer care continuum in the region.<br />.


[Localization of Mg2+-ATPase in the membranes of the skeletal muscles and myocardium of the frog Rana temporaria].
Using differential centrifugation in sucrose density gradient, from muscles of the frog fractions were obtained which contain fragments of sarcolemma, as well as membranes of T-system tubules and sarcoplasmic reticulum. In isolated membrane fractions, studies were made on the activity of cation-stimulated ATPases (Na+, K+-, Ca2+, Mg2+- and Mg2+-ATPases). Enzymic and electrophoretic analyses showed that the highest content of Mg2+-ATPases is typical of the fractions which are located on the surface of 35% sucrose. The data obtained indicate that Mg2+-ATPase is the enzyme which is specific for the membranes of T-system tubules in skeletal muscles of not only birds but amphibians as well. From cardiac muscle of the frog, membrane fraction was isolated which is similar (with respect to its predominant content of Mg2+-ATPase) to the membranes of T-system tubules. It is suggested that the presence of Mg2+-ATPase in these membranes is a common property of phasic striated muscle fibers in all mature vertebrate animals.


Element variability in lacustrine systems of Terra Nova Bay (Antarctica) and concentration evolution in surface waters.
Major, minor and trace elements were determined in freshwater of lacustrine systems in Terra Nova Bay, along Victoria Land coast, Antarctica, as well as in algae and mosses. The samples were collected during some of the sampling campaigns between 2007 and 2011 (and the one of 2002) within the framework of the Italian National Program of Research in Antarctica (PNRA). Data were processed with chemometric techniques. Results showed that elements typically considered as potential anthropogenic pollutants (e.g. As, Pb, Zn, Cu and Ni) present a strong correlation with the lithogenic elements (e.g. Al, Si, Fe) in all matrices, suggesting that their origin is connected to natural phenomena. Metal concentrations in vegetation samples are in the same range as previously published data. The obtained results were compared with older literature data (since the early '90s) from the same lacustrine systems, in order to present a historical overview of element concentrations. This approach furnishes important information on surface water evolution as a function of time. A considerable variability was observed in metal concentrations but no clear trend was identified. This suggests that their concentration evolution is hardly correlated to specific natural or anthropic phenomena. No evidence of an increase of concentrations over time was apparent. Our results represent new important data about metal concentrations in lacustrine systems in Antarctica, furnishing ranges of values that can be considered as a reference. These data, therefore, could be used to detect or monitor future local and/or global anthropogenic contaminations.


The gonadotrophic response of Royal Marines during an operational deployment in Afghanistan.
Military training has been associated with changes in the hypothalamic-pituitary-gonadal axis consistent with central hypogonadism. Often such changes have been associated with body mass loss, though sleep deprivation and other psychological stress may also contribute. The effects of deployment in a combat zone on the hypothalamic-pituitary-gonadal axis in military personnel are not known. The objective was to investigate the hypothalamic-pituitary-gonadal axis in male military personnel deployed in Afghanistan. Eighty-nine Royal Marines were investigated pre-deployment, following 3 months in Afghanistan and following 2 weeks mid-tour leave. Testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinising hormone (LH), 17-hydroxyprogesterone, androstenedione (AD) and insulin were assayed and body mass recorded. The results showed that body mass (kg) dropped from 83.2 ± 9.2 to 79.2 ± 8.2 kg during the first 3 months of deployment (p < 0.001). Total testosterone did not change, but SHBG increased (30.7 ± 9.7 vs. 42.3 ± 14.1 nmol/L, p < 0.001), resulting in a significant (p < 0.001) fall in calculated free testosterone (435.2 ± 138 vs. 375.1 ± 98 pmol/L). Luteinising hormone and FSH increased by 14.3% (p < 0.001) and 4.9% (p = 0.003) respectively. Free testosterone, SHBG, LH and FSH returned to baseline following 2 weeks of mid-tour leave. Androstenedione (AD) decreased by 14.5% (p = 0.024), and insulin decreased by 26% (p = 0.039), over the course of deployment. In this study of lean Royal Marines, free testosterone decreased during operational deployment to Afghanistan. There was no evidence to suggest major stress-induced central hypogonadism. We postulate that reduced body mass, accompanied by a decrease in insulin and AD synthesis, may have contributed to an elevated SHBG, leading to a decrease in free testosterone.


Anomalies of midgut rotation in the adult.
Anomalies of midgut rotation in the adult are uncommon clinical entities. Knowledge of the normal embryologic development of midgut rotation and the pathologic dispositions of each anomaly is indispensible to manage properly such anomalies.


DNA recombination: holliday junctions dynamics and branch migration.
Holliday junctions are critical intermediates for homologous, site-specific recombination, DNA repair, and replication. A wealth of structural information is available for immobile four-way junctions, but the controversy on the mechanism of branch migration of Holliday junctions remains unsolved. Two models for the mechanism of branch migration were suggested. According to the early model of Alberts-Meselson-Sigal (Sigal, N., and Alberts, B. (1972) J. Mol. Biol. 71, 789-793 and Meselson, M. (1972) J. Mol. Biol. 71, 795-798), exchanging DNA strands around the junction remain parallel during branch migration. Kinetic studies of branch migration (Panyutin, I. G., and Hsieh, P. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 2021-2025) suggest an alternative model in which the junction adopts an extended conformation. We tested these models using a Holliday junction undergoing branch migration and time-lapse atomic force microscopy, an imaging technique capable of imaging DNA dynamics. The single molecule atomic force microscopy experiments performed in the presence and in the absence of divalent cations show that mobile Holliday junctions adopt an unfolded conformation during branch migration that is retained despite a broad range of motion in the arms of the junction. This conformation of the junction remains unchanged until strand separation. The data obtained support the model for branch migration having the extended conformation of the Holliday junction.


[Algorhythm for automatic analysis of electrocardiograms in a special apparatus].
An algorhythm for an automatic analysis of the ECG by using a special device is proposed for the purpose of identifying patients suffering from diseases of the cardiovascular system. The algorhythm is based on the utilization of simple electrocardiographic indications measured with sufficient accuracy on a real time scale (PQ, QRS, T1 configuration, amplitude of the R, S, T waves). With the algorhythm analysis of the ECG taken in patients with primary rheumatic heart disease, complicated mitral lesion, hypertensive disease, myocardialinfarction the ECG changes helped identify 70 per cent of the patients. The algorhythm proved highly effective in recognizing patients with ischemic heart disease. A correlation between the stages of the affection and the frequency of detected pathological ECG was established. The results of automatic evaluation were contrasted against the data subsequent to an ECG analysis made by the physician, both of these being in good accord.


Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymer and Their Nanomicelles for Nonviral Gene Delivery Applications.
The aim of this study was to synthesize and characterize fatty acid-grafted-chitosan (fatty acid-g-CS) polymer and their nanomicelles for use as carriers for gene delivery. CS was hydrophobically modified using saturated fatty acids of increasing fatty acyl chain length. Carbodiimide along with N-hydroxysuccinimide was used for coupling carboxyl group of fatty acids with amine groups of CS. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to quantify fatty acyl substitution onto CS backbone. The molecular weight distribution of the synthesized polymers was determined using size exclusion high performance liquid chromatography and was found to be in range of the parent CS polymer (∼50 kDa). The critical micelle concentration (cmc) of the polymers was determined using pyrene as a fluorescent probe. The cmc was found to decrease with an increase in fatty acyl chain length. The amphiphilic fatty acid-g-CS polymers self-assembled in an aqueous environment to form nanomicelles of ∼200 nm particle size and slightly positive net charge due to the cationic nature of free primary amino groups on CS molecule. These polymeric nanomicelles exhibited excellent hemo- and cytocompatibility, as evaluated by in vitro hemolysis and MTT cell viability assay, respectively, and showed superior transfection efficiency compared to unmodified chitosan and naked DNA. The surface of these nanomicelles can be further modified with ligands allowing for selective targeting, enhanced cell binding, and internalization. These nanomicelles can thus be exploited as potential nonviral gene delivery vectors for safe and efficient gene therapy.


Nitrogen oxides concentration and emission change detection during COVID-19 restrictions in North India.
COVID-19 related restrictions lowered particulate matter and trace gas concentrations across cities around the world, providing a natural opportunity to study effects of anthropogenic activities on emissions of air pollutants. In this paper, the impact of sudden suspension of human activities on air pollution was analyzed by studying the change in satellite retrieved NO2 concentrations and top-down NOx emission over the urban and rural areas around Delhi. NO2 was chosen for being the most indicative of emission intensity due to its short lifetime of the order of a few hours in the planetary boundary layer. We present a robust temporal comparison of Ozone Monitoring Instrument (OMI) retrieved NO2 column density during the lockdown with the counterfactual baseline concentrations, extrapolated from the long-term trend and seasonal cycle components of NO2 using observations during 2015 to 2019. NO2 concentration in the urban area of Delhi experienced an anomalous relative change ranging from 60.0% decline during the Phase 1 of lockdown (March 25-April 13, 2020) to 3.4% during the post-lockdown Phase 5. In contrast, we find no substantial reduction in NO2 concentrations over the rural areas. To segregate the impact of the lockdown from the meteorology, weekly top-down NOx emissions were estimated from high-resolution TROPOspheric Monitoring Instrument (TROPOMI) retrieved NO2 by accounting for horizontal advection derived from the steady state continuity equation. NOx emissions from urban Delhi and power plants exhibited a mean decline of 72.2% and 53.4% respectively in Phase 1 compared to the pre-lockdown business-as-usual phase. Emission estimates over urban areas and power-plants showed a good correlation with activity reports, suggesting the applicability of this approach for studying emission changes. A higher anomaly in emission estimates suggests that comparison of only concentration change, without accounting for the dynamical and photochemical conditions, may mislead evaluation of lockdown impact. Our results shall also have a broader impact for optimizing bottom-up emission inventories.


Salvage hip arthroplasty after failed fixation of proximal femur fractures.
We reviewed 46 patients who underwent salvage hip arthroplasty (SHA) for revision of failed cannulated screws (CS), sliding hip screws (SHS), or intramedullary nails (IMN). The primary objective was to determine differences in operative difficulty. SHA after failed femoral neck fixation was associated with lower intra-operative demands than after failed peri-trochanteric fractures. Similarly, analysis by the index implant found that conversion arthroplasty after failed CSs was associated with lower intra-operative morbidity than failed SHSs or IMNs; differences between SHS and IMN were not as clear. Importantly, intra-operative data in cases of failed SHSs were similar regardless of the original fracture type, showing the device played a larger role than the fracture pattern. Complications and revision surgery rates were similar regardless of fracture type or fixation device. Our results suggest that operative demands and subsequent patient morbidity are more dependent on the index device than the fracture pattern during SHA.


Some results in the processing of the holy shroud of turin.
We illustrate some new developments in the three-dimensional (3-D) processing of the image of the Shroud of Turin. After analyzing the various possibilities of obtaining a ``clean'' two-dimensional (2-D) image, i.e., without noise due to rows and spots, we present the processed image used as a starting point for the three-dimensional processing. Moreover, we describe the mathematical methods used for the processing and show the relief image of the face. This image enhances a number of new details, which were not apparent on the two-dimensional image. To obtain a woundless natural face image of the Man of the Shroud, we processed the previous image suppressing the smaller and attenuating the larger wounds without substantially changing the features. The image shown in this article will probably recall the natural face of Jesus Christ. Also the processing of the body image is shown.


Anterior Guided Growth of the Distal Femur for Knee Flexion Contracture: Clinical, Radiographic, and Motion Analysis Results.
Fixed knee flexion deformity is common in children with neuromuscular disorders. Anterior guided growth (AGG) of the distal femur can achieve gradual correction in patients who are skeletally immature. Little outcome data are available on this procedure. This is a retrospective matched cohort study. Forty-two knees (26 patients) underwent AGG surgery at our institution between 2007 and 2017. All patients underwent instrumented 3-dimensional gait analysis (3DGA). A nonsurgical control group of 49 knees (43 patients) was selected that matched for age, severity of preoperative knee contracture, and 3DGA parameters. Clinical, radiographic, and 3DGA outcomes were assessed and compared. Average preoperative knee flexion deformity in AGG group was 13±8 degrees. Following AGG, deformity improved by 8±7 degrees (P<0.001) as measured radiographically and by 7±7 degrees (P<0.001) as measured on physical examination. Average rate of correction was 0.7±0.6 degrees per month or 8±8 degrees per year. The 3DGA parameters such as minimum stance phase knee flexion and knee flexion at initial contact were also significantly improved following AGG. In contrast, flexion deformity as measured radiographically worsened by 3±3 degrees (P=0.002) in the control group. Twelve knees (29%) had failure of correction. Predictors of failure included older age, lower level of function, and greater severity of preoperative deformity. The age at time of surgery and the anteroposterior position of plate fixation relative to the distal femoral physis were associated with rate of correction. In children with neuromuscular disorders, AGG of the distal femur is effective in improving degree of fixed knee flexion deformity as well as objective gait parameters. A significant portion of knees experience inadequate correction. Addressing factors associated with correction failure (ie, age and plate placement) may improve the procedure's success. Level III-case control study.


The cachexia clinic: from staging to managing nutritional and functional problems in advanced cancer patients.
Panels of experts have agreed on the definition of cancer cachexia stages (CCS). We evaluated the clinical relevance of these stages and proposed ways to apply the CCSs to the clinical practice via standardized methods. The CCS were applied to 207 patients with advanced non-small-cell lung or gastrointestinal cancers from the Human Cancer Cachexia Database via consensus among the coauthors. Patients were categorized as noncachectic, precachectic, cachectic, and in refractory cachexia. Through analysis of variance, χ2, and Kaplan-Meier analyses, we tested the relationships between CCSs and selected outcomes. The CCS were significantly correlated (P < 0.05) with patient-centered indicators, including overall symptom burden, quality of life, tolerability to chemotherapy, body composition, hospital stay, and survival. However, precachectic and cachectic patients behaved similarly in all these outcomes but were significantly different from noncachectic and refractory cachectic patients. The average scores for the abridged Patient-Generated Subjective Global Assessment (aPG-SGA) corresponded well with the CCSs and reflected nicely the cut-off scores recommended for the nutritional triage of cancer patients. In addition to the aPG-SGA, we proposed the Edmonton Symptom Assessment System and routine laboratory tests for the triage of patients with refractory cachexia, for whom comfort care is the primary goal. The cachexia clinic hosted by the McGill Nutrition and Performance Laboratory offers a model for diagnosing more precisely the pathophysiology and severity of precachectic and cachectic conditions. The cachexia clinic, by working closely with palliative care programs, may offer the best environment for a comprehensive and personalized approach to the nutritional and functional problems in advanced cancer patients.


Facilitators and Barriers to Being Physically Active in a Rural Hawai'i Community: A Photovoice Perspective.
A large body of existing literature suggests associations between perceptions of the environment and physical activity status, but very few studies have examined perceptions among Native Hawaiian and Pacific Islander (NHPI) communities. The purpose of this study was to examine perceptions of the active living environment in Hawai'i in rural communities with a high proportion of NHPI. A total of thirteen adults were purposefully selected to participate in the study, and the Photovoice method was used to capture their perceptions. Three sessions were used to describe the purpose of the study, select and describe photographs, and identify emerging themes. A total of nine overarching themes were identified by participants and placed into three categories. Participants identified facilitators to being physically active, but also identified several barriers in their community such as the lack of available physical and built amenities, social norms, and safety. Participants proposed four action items to improve their active living environment: promote programs that are organized by community members, contact the local university to provide access to physical activity equipment, contact Honolulu City & County officials to voice concerns regarding barriers that prevent physical activity in the community, and working with employers in the community to create policies that promote physical activity at the workplace.


Pearls: stroke.
The diagnosis of ischemic stroke continues to be a clinical one, although advances in neuroimaging have expanded our understanding of the correlation between clinical symptoms and neuroanatomical localization. Careful neurologic examination allows localization in both neuroanatomical and vascular space. Findings on neuroimaging are then correlated to assess their clinical relevance. Transient ischemic attack is recognized as a warning sign for impending vascular disease, but even less specific transient neurologic symptoms are associated with increased risk. Stroke can occur at any age. For women, the postpartum period is a time of elevated risk for arterial ischemic stroke.


Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.
Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.


Lifestyle intervention and one-year prognosis of patients following open heart surgery: a randomised clinical trial.
To evaluate the one-year prognosis of a lifestyle counselling intervention (diet, smoking cessation and exercise) among patients who had open heart surgery. Cardiovascular disease is the leading cause of morbidity worldwide in both developing and developed countries. Lifestyle modification plays an important role for patients who are at a high risk of developing cardiovascular disease and for those with an established cardiovascular disease. Randomised, nonblind and lifestyle counselling intervention study with a one-year follow-up. A randomised, nonblind intervention study was performed on 500 patients who had open heart surgery. After hospital discharge, 250 patients (intervention group) were randomly allocated lifestyle counselling according to the recent guidelines provided by the European Society of Cardiology (European Journal Preventive Cardiology, 19, 2012, 585). The remaining 250 patients (control group) received the regular instructions. Primary end-point was the development of a cardiovascular disease (nonfatal event) during the first year; secondary end-points included fatal events, smoking abstinence, dietary habits and a physical activity evaluation. According to the primary end-point, the odds of having a nonfatal cardiovascular disease event are 0·56-times (95%CI 0·28, 0·96, p = 0·03) lower for the intervention group compared to the control group. One-year after surgery, it was found that participants in the intervention group were 1·96-times (95%CI 1·31, 2·93, p < 0·001) more likely to achieve dietary recommendations, 3·32-times (95%CI 2·24, 4·91, p < 0·001) more likely to achieve physical activity recommendations and 1·34-times (95%CI 1·15, 1·56, p < 0·001) more likely to return to work. Lifestyle counselling intervention following open heart surgery can improve health outcomes and reduce the risk of a new cardiac event. Health care services must recommend and organise well-structured cardiac rehabilitation programmes adjusted to the patient's needs. A well-structured cardiac rehabilitation programme adjusted to the patient's profile is a safe and cost-effective way to improve patients' outcome.


Baseline Mental Health and Psychosocial Functioning of Transgender Adolescents Seeking Gender-Affirming Hormone Therapy.
Research suggests that adolescents seeking gender-affirming hormone therapy experience elevated rates of depression, anxiety, and difficulties with peer relationships. Less is known regarding more specific aspects of mental health and psychosocial functioning. Furthermore, few studies have explored variations in mental health and psychosocial functioning by age, gender, degree of physical dysphoria, and informant type (adolescent, mother, and father). Participants are adolescents (n = 149) and parents/guardians (n = 247) who presented to a multidisciplinary gender clinic in Dallas, TX for an initial assessment before initiation of gender-affirming hormone therapy. Adolescents completed the Youth Self-Report (YSR) and the Body Image Scale (a measure of physical dysphoria), and parents/guardians completed the Child Behavior Checklist (CBCL). Approximately half of participants reported clinically significant difficulties with internalizing symptoms and psychosocial functioning (particularly engagement in activities), with approximately one-third indicating significant difficulties with depression, anxiety, obsessive compulsive, and posttraumatic stress symptoms. Parents reported fewer symptoms than adolescents across several subscales, but differences were generally small. By contrast, gender differences were found across all internalizing subscales and were generally large. Age and body dissatisfaction were not independently associated with broadband measures but, in combination with gender, were strongly associated with variance in YSR and CBCL reports of internalizing symptoms. Elevated rates of depression, anxiety, and competency difficulties were broadly consistent with the previous literature and demonstrate the need for investment in the clinical training and infrastructure to provide comprehensive care to this population. Differences in mental health and psychosocial functioning by gender and clinic location appear to be less straightforward.


Age-dependent alterations in osteoblast and osteoclast activity in human cancellous bone.
It is assumed that the activity of osteoblasts and osteoclasts is decreased in bone tissue of aged individuals. However, detailed investigation of the molecular signature of human bone from young compared to aged individuals confirming this assumption is lacking. In this study, quantitative expression analysis of genes related to osteogenesis and osteoclastogenesis of human cancellous bone derived from the distal radius of young and aged individuals was performed. Furthermore, we additionally performed immunohistochemical stainings. The young group included 24 individuals with an average age of 23.2 years, which was compared to cancellous bone derived from 11 body donators with an average age of 81.0 years. In cancellous bone of young individuals, the osteogenesis-related genes RUNX-2, OSTERIX, OSTEOPONTIN and OSTEOCALCIN were significantly up-regulated compared to aged individuals. In addition, RANKL and NFATc1, both markers for osteoclastogenesis, were significantly induced in cancellous bone of young individuals, as well as the WNT gene family member WNT5a and the matrix metalloproteinases MMP-9. However, quantitative RT-PCR analysis of BMP-2, ALP, FGF-2, CYCLIN-D1, MMP-13, RANK, OSTEOPROTEGERIN and TGFb1 revealed no significant difference. Furthermore, Tartrate-resistant acid phosphatase (TRAP) staining was performed which indicated an increased osteoclast activity in cancellous bone of young individuals. In addition, pentachrome stainings revealed significantly less mineralized bone matrix, more osteoid and an increased bone density in young individuals. In summary, markers related to osteogenesis as well as osteoclastogenesis were significantly decreased in the aged individuals. Thus, the present data extends the knowledge about reduced bone regeneration and healing capacity observed in aged individuals.


Successful treatment of atlantooccipital luxation in an alpaca (Lama pacos).
A 7-mo-old male alpaca (Lama pacos) presented with an abnormal lowered posture of the head and neck and reluctance to walk. Cervical radiographs demonstrated atlantooccipital luxation. Successful manual closed reduction was achieved while the animal was anesthetized, resulting in complete return to normal gait and posture.


miR-483-5p plays a protective role in chronic obstructive pulmonary disease.
Altered microRNA (miRNA or miR) expression has been reported in chronic obstructive pulmonary disease (COPD). The present study aimed to identify the involvement of miRNAs in the pathophysiology of COPD and to explore the effects of various miRNAs with significant alteration on COPD in vitro. We conducted high‑throughput analysis of miRNAs (miRNA microarray) in lung samples from 10 COPD patients and 10 healthy persons with a validation experiment using quantitative (real‑time) polymerase chain reaction (real‑time PCR) panels. By analyzing 3,000 miRNAs in lung samples using a microarray, we identified 341 differentially expressed miRNAs (138 with high expression and 203 with low expression) in patients with COPD in comparison with the healthy controls. Then 15 high-expression candidates and 15 low-expression candidates with at least 2‑fold difference and P<0.05 were selected randomly to validate the changes in three independent experiments in vitro using real‑time PCR. The validation test showed a positive correlation with the microarray results. Then we chose miR‑483‑5p as our target. The effect of miR‑483‑5p on cell proliferation and expression of COPD-related proteins were detected using Cell Counting Kit 8 and western blot analysis, respectively. The results showed that miR‑483‑5p, which was significantly downregulated in COPD samples, abrogated the transforming growth factor‑β (TGF‑β)‑mediated decrease in cell proliferation, and increase in α‑smooth muscle actin (α‑SMA) and fibronectin expression in pulmonary epithelial and lung fibroblast cell lines, BEAS‑2B and HFL1. These findings suggest that miR‑483‑5p may play an important and protective role in patients with COPD and may serve as a useful biomarker and for early detection of COPD as well as a potential therapeutic tool.


Earth Day plus 30 years: public concern and support for environmental health.
A clear majority of Americans are concerned about environmental threats to public health and do not want to weaken antipollution regulations. The strongest supporters for maintaining environmental regulations are affluent mainstream White suburban populations who are thriving economically, but support is also strong in every other major segment of the population. Overt attempts to weaken the basic regulations are unlikely, barring an obvious economic downturn that would cause a large proportion of the public to consider loosening standards in the belief that such changes would increase the number of available jobs. Given this context, environmental health was and will continue to be a core topic in the Journal. We will emphasize the nexus of environmental health and policy by publishing research, exemplary public health practice, and the views of key decision makers.


Teaching on the web: automated online instruction and assessment of residents in an acute care clinic.
Time pressures negatively impact teaching and learning in ambulatory settings. Web-based (online) learning may help in meeting this challenge. Although online teaching is increasingly used in medical education, few reports have evaluated online learning in postgraduate training. A pre-test/post-test cohort study was undertaken in an academic medical center acute care clinic to determine whether internal medicine residents accept, learn with and continue to use a 'stand-alone' online curriculum. The participants were 56 first-year internal medicine residents. Eight evidence-based, symptom-oriented online modules in acute ambulatory medicine were completed by residents during a one-month rotation. Fifty residents completed all modules. Pre- and post-tests were administered and scored automatically by computer. Average test score improved from 70% to 95% (p < 0.001). Feedback was very positive, with 96% of residents recommending the curriculum continue and 88% listing the modules as one of the most helpful learning resources for the rotation. Some 74% of residents referred back to the curriculum while caring for patients. This 'stand-alone' online curriculum, with automated instruction and assessment, facilitated effective and satisfying learning without requiring faculty involvement. This method could easily be reproduced in other settings.


Selecting patients for heart transplantation: which patients are too well for transplant?
In the context of contemporary medical and surgical therapy, the revolutionary procedure of cardiac transplantation should be redefined in its relative role. Based on the assumption that its goal is to prolong life while improving its quality, and in the absence of randomized clinical trial data testing its benefit, data from early breakthrough studies, more recent observational cohort studies, and studies testing other therapies in advanced heart failure must be analyzed to characterize clinical profiles of patients who should be considered too well for cardiac transplantation at specific stages of their disease processes. These profiles likely include advanced heart failure with (1) low risk according to the Heart Failure Survival Score, (2) peak oxygen consumption greater than 14 to 18 mL/kg/min without other indications, (3) left ventricular ejection fraction less than 20% alone, (4) history of New York Heart Association class III to IV symptoms alone, (5) history of ventricular arrhythmias alone, (6) no previous attempt at comprehensive neurohormonal blockade, and (7) no structured cardiac transplantation evaluation in a designated cardiac transplantation center. The evaluation may identify the potential transplant candidate, who could be placed on a national potential transplant candidate list, combining the psychologic benefit of acceptance by the program with an ongoing openness to the diversity of advanced heart failure treatment modalities.


Effect of prebiotics on biomarkers of colorectal cancer in humans: a systematic review.
Prebiotics may prevent colorectal cancer (CRC) development in humans by modifying the composition or activity of the colorectal microflora. Epidemiologic and animal studies have shown a reduction in CRC or CRC biomarkers after the administration of prebiotics. Studies using indirect chemical biomarkers of CRC in humans, however, gave mixed results. Recently, human studies measuring direct physical indices of CRC risk after prebiotic consumption have been published. The purpose of this review is to summarize those studies to provide recommendations for the use of prebiotics in CRC risk reduction. A PubMed search was conducted, revealing nine studies. One tested lactulose, two evaluated a blend of oligofructose and inulin, and six measured resistant starch. Lactulose reduced adenoma recurrence, while resistant starch had no effect on adenoma or CRC development. Crypt mitotic location, gene expression, and DNA methylation were somewhat improved after resistant starch consumption. No changes in cell proliferation and apoptosis, crypt morphology, or aberrant crypt foci were found. More human studies measuring physical changes to the gut are needed.


Inhibition of microbial sulfate reduction in a flow-through column system by (per)chlorate treatment.
Microbial sulfate reduction is a primary cause of oil reservoir souring. Here we show that amendment with chlorate or perchlorate [collectively (per)chlorate] potentially resolves this issue. Triplicate packed columns inoculated with marine sediment were flushed with coastal water amended with yeast extract and one of nitrate, chlorate, or perchlorate. Results showed that although sulfide production was dramatically reduced by all treatments, effluent sulfide was observed in the nitrate (10 mM) treatment after an initial inhibition period. In contrast, no effluent sulfide was observed with (per)chlorate (10 mM). Microbial community analyses indicated temporal community shifts and phylogenetic clustering by treatment. Nitrate addition stimulated Xanthomonadaceae and Rhizobiaceae growth, supporting their role in nitrate metabolism. (Per)chlorate showed distinct effects on microbial community structure compared with nitrate and resulted in a general suppression of the community relative to the untreated control combined with a significant decrease in sulfate reducing species abundance indicating specific toxicity. Furthermore, chlorate stimulated Pseudomonadaceae and Pseudoalteromonadaceae, members of which are known chlorate respirers, suggesting that chlorate may also control sulfidogenesis by biocompetitive exclusion of sulfate-reduction. Perchlorate addition stimulated Desulfobulbaceae and Desulfomonadaceae, which contain sulfide oxidizing and elemental sulfur-reducing species respectively, suggesting that effluent sulfide concentrations may be controlled through sulfur redox cycling in addition to toxicity and biocompetitive exclusion. Sulfur isotope analyses further support sulfur cycling in the columns, even when sulfide is not detected. This study indicates that (per)chlorate show great promise as inhibitors of sulfidogenesis in natural communities and provides insight into which organisms and respiratory processes are involved.


Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010.
The abuse of prescription drugs has led to a significant increase in emergency department (ED) visits and drug-related deaths over the past decade. Opioid pain relievers (OPRs) and benzodiazepines are the prescription drugs most commonly involved in these events. Excessive alcohol consumption also accounts for a significant health burden and is common among groups that report high rates of prescription drug abuse. When taken with OPRs or benzodiazepines, alcohol increases central nervous system depression and the risk for overdose. Data describing alcohol involvement in OPR or benzodiazepine abuse are limited. To quantify alcohol involvement in OPR and benzodiazepine abuse and drug-related deaths and to inform prevention efforts, the Food and Drug Administration (FDA) and CDC analyzed 2010 data for drug abuse-related ED visits in the United States and drug-related deaths that involved OPRs and alcohol or benzodiazepines and alcohol in 13 states. The analyses showed alcohol was involved in 18.5% of OPR and 27.2% of benzodiazepine drug abuse-related ED visits and 22.1% of OPR and 21.4% of benzodiazepine drug-related deaths. These findings indicate that alcohol plays a significant role in OPR and benzodiazepine abuse. Interventions to reduce the abuse of alcohol and these drugs alone and in combination are needed.


A novel antimycobacterial compound acts as an intracellular iron chelator.
Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.


Role of Non-coding RNA in the Pathogenesis of Intestinal Ischemia- Reperfusion Injury.
Intestinal ischemia-reperfusion injury is a relatively common clinical condition that seriously threatens the prognosis of patients; however, the exact mechanism of intestinal ischemia-reperfusion injury has not been clarified. Recent studies have found that noncoding RNAs, including but not limited to lncRNA, circRNA, and miRNA, play an important role in the pathogenesis of intestinal ischemia-reperfusion. The findings cited in this paper reveal the expression, function, and mechanism of noncoding RNAs during intestinal ischemia-reperfusion. The mechanistic roles of noncoding RNAs in the occurrence and development of intestinal ischemia-reperfusion are discussed, including cell proliferation, autophagy, oxidative stress, apoptosis, oxidative stress, iron death, and many other aspects. However, many unknown mechanisms of association between noncoding RNAs and intestinal ischemia-reperfusion remain to be investigated.