Interpretation of radiological images: towards a framework of knowledge and skills.
The knowledge and skills that are required for radiological image interpretation are not well documented, even though medical imaging is gaining importance. This study aims to develop a comprehensive framework of knowledge and skills, required for two-dimensional and multiplanar image interpretation in radiology. A mixed-method study approach was applied. First, a literature search was performed to identify knowledge and skills that are important for image interpretation. Three databases, PubMed, PsycINFO and Embase, were searched for studies using synonyms of image interpretation skills or visual expertise combined with synonyms of radiology. Empirical or review studies concerning knowledge and skills for medical image interpretation were included and relevant knowledge and skill items were extracted. Second, a preliminary framework was built and discussed with nine selective experts in individual semi-structured interviews. The expert team consisted of four radiologists, one radiology resident, two education scientists, one cognitive psychologist and one neuropsychologist. The framework was optimised based on the experts comments. Finally, the framework was applied to empirical data, derived from verbal protocols of ten clerks interpreting two-dimensional and multiplanar radiological images. In consensus meetings adjustments were made to resolve discrepancies of the framework with the verbal protocol data. We designed a framework with three main components of image interpretation: perception, analysis and synthesis. The literature study provided four knowledge and twelve skill items. As a result of the expert interviews, one skill item was added and formulations of existing items were adjusted. The think-aloud experiment showed that all knowledge items and three of the skill items were applied within all three main components of the image interpretation process. The remaining framework items were apparent only within one of the main components. After combining two knowledge items, we finally identified three knowledge items and thirteen skills, essential for image interpretation by trainees. The framework can serve as a guideline for education and assessment of two- and three-dimensional image interpretation. Further validation of the framework in larger study groups with different levels of expertise is needed.


Public health risks associated with the utilisation of wildlife products in certain regions of Africa.
The authors describe the public health risks associated with wildlife products in certain regions of Africa. Most of the information presented is obtained from the Republic of South Africa, particularly the Kruger National Park. There are no statutory requirements in South Africa regarding the general inspection of game carcasses prior to sale: however, current regulatory inspection requirements are explained. Game farming systems in southern Africa are generally extensive systems with wild herbivores living in a near-natural 'free-ranging' state. Several pathological processes and disease entities have been confirmed in wildlife carcasses and these are listed with zoonotic implications.


A 1-year follow-up study on leakage of four root canal sealers at different thicknesses.
Determination of leakage using a fluid transport model allows measurement of leakage in a longitudinal manner. Leakage of four sealers at three different thicknesses in 225 bovine root sections, after storage in water for 1 year, was measured again using the same methodology. The change in seal over time for each sealer was observed. The results after the second measurement showed that every sealer produced the best seal when the sealer layer was the thinnest. AH26, Ketac-Endo and Tubli-Seal showed a reduction in leakage over time and gave significantly less leakage than Sealapex (P<0.005). Sealapex showed significantly more leakage after storing in water for 1 year (P<0.005). Therefore, the long-lasting seal of sealer may, among other influencing factors, depend on the layer thickness and the solubility of the material.


BH4− self-diffusion in liquid LiBH4.
The hydrogen dynamics in solid and in liquid LiBH4 was studied by means of incoherent quasielastic neutron scattering. Rotational jump diffusion of the BH4- subunits on the picosecond scale was observed in solid LiBH4. The characteristic time constant is significantly shortened when the system transforms from the low-temperature phase to the high-temperature phase at 383 K. In the molten phase of LiBH4 above 553 K, translational diffusion of the BH4- units is found. The measured diffusion coefficients are in the 10(-5)cm2/s range at temperatures around 700 K, which is in the same order of magnitude as the self-diffusion of liquid lithium or the diffusion of ions in molten alkali halides. The temperature dependence of the diffusion coefficient shows an Arrhenius behavior, with an activation energy of Ea = 88 meV and a prefactor of D0 = 3.1 × 10(-4)cm2/s.


Validity and repeatability of the IUATLD (1984) Bronchial Symptoms Questionnaire: an international comparison.
The International Union against Tuberculosis and Lung Disease (IUATLD) Bronchial Symptoms Questionnaire (1984) was developed for use in studies of asthma and its reliability measured in an earlier survey in England. The association of the symptoms elicited by this questionnaire to bronchial response to histamine has also been described. This paper presents the results of studies of the questionnaire in four clinical centres in Europe. The reliability of the questionnaire and its ability to predict the bronchial response to histamine were compared for English, Finnish, French and German translations of the questionnaire in samples of diagnosed asthmatics and controls in Nottingham, Berlin, Helsinki and Paris. The answers to questions showed good repeatability, especially in Finland and Germany, particularly those questions on asthma and wheeze. The most sensitive symptom for predicting hyperresponsiveness was the question on wheeze, the most specific questions were those on waking at night with shortness of breath (Paris and Nottingham) and morning tightness (Helsinki and Berlin). This study shows that the IUATLD (1984) questionnaire may provide useful, valid and comparable data even in translation but these studies will need to be repeated in representative samples before such a possibility is accepted as fully demonstrated.


Patients' Perspective on Participation in Care With or Without the Support of a Smartphone App During Radiotherapy for Prostate Cancer: Qualitative Study.
Patients with prostate cancer are often cared for as outpatients during radiotherapy, which can be an aggravating circumstance for patient participation. There is a need to evaluate whether an interactive smartphone app could enable participation in care, specifically during treatment for prostate cancer. The interactive app (Interaktor) used in this study is developed in codesign with patients and health care professionals; it includes daily reports of symptoms, a risk assessment model, evidence-based self-care advice, along with the provision of immediate access to clinicians. The aim of this study was to explore how patients with prostate cancer perceived their participation with or without the support of the smartphone app during radiotherapy. A total of 28 prostate cancer patients receiving adjuvant radiotherapy were interviewed about their perceived participation in their own care. All the patients interviewed in this study participated in an intervention study where the control group received standard care that comprised having access to a contact nurse to turn to with any concerns during their treatment. In addition to standard care, the patients in the intervention group received the app downloaded in a smartphone. The patients' age ranged between 57 and 77 years; 17 patients used the smartphone app. The interviews were analyzed with directed qualitative content analysis. The four dimensions of patient participation, which include mutual participation, fight for participation, requirement for participation, and participation in getting basic needs satisfied, were confirmed as valid perspectives in the interviews with the patients with prostate cancer, irrespective of whether they used the smartphone app. However, the patients who had used the smartphone app described it as a facilitating factor, especially for mutual participation. Using innovative ways to communicate with patients, such as an interactive app for symptom management with contact with health care in real time, can successfully help achieve increased patient participation in care.


Attitudes toward benzodiazepines over the years.
Benzodiazepines have been used extensively for the treatment of anxiety and related disorders since the 1960s. Although they have been proven to be effective as first-line treatment for anxiety disorders, during the 1980s public perception and concern for abuse liability and physical dependence with long-term use gave rise to a great deal of controversy. Negative perceptions toward the use of benzodiazepines for treating anxiety not only caused severely ill patients to go untreated or under-treated but also called into question whether the illness itself was worthy of treatment. Although new pharmacologic and psychological treatments for anxiety are available, psychopharmacologists continue to endorse benzodiazepines as primary or adjunct treatment for anxiety disorders. The intent of this article is to provide a historic overview of these issues and to offer some general clinical principles to help minimize the risk of abuse and dependence with benzodiazepine use.


Hepatocyte Growth Factor/c-Met Signaling in Head and Neck Cancer and Implications for Treatment.
Aberrant signaling of the hepatocyte growth factor (HGF)/c-Met pathway has been identified as a promoter of tumorigenesis in several tumor types including head and neck squamous cell carcinoma (HNSCC). Despite a relatively low c-Met mutation frequency, overexpression of HGF and its receptor c-Met has been observed in more than 80% of HNSCC tumors, with preclinical and clinical studies linking overexpression with cellular proliferation, invasion, migration, and poor prognosis. c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition, contributing to metastasis. The HGF/c-Met pathway may also act as a resistance mechanism against epidermal growth factor receptor (EGFR) inhibition in advanced HNSCC. Furthermore, with the identification of a biologically distinct subset of HNSCC tumors acquired from human papillomavirus (HPV) infection that generally portends a good prognosis, high expression of HGF or c-Met in HPV-negative tumors has been associated with worse prognosis. Dysregulated HGF/c-Met signaling results in an aggressive HNSCC phenotype which has led to clinical investigations for targeted inhibition of this pathway. In this review, HGF/c-Met signaling, pathway alterations, associations with clinical outcomes, and preclinical and clinical therapeutic strategies for targeting HGF/c-Met signaling in HNSCC are discussed.


An unprecedented amplification of near-infrared emission in a Bodipy derived π-system by stress or gelation.
We report an unprecedented strategy to generate and amplify near-infrared (NIR) emission in an organic chromophore by mechanical stress or gelation pathways. A greenish-yellow emitting film of π-extended Bodipy-1, obtained from n-decane, became orange-red upon mechanical shearing, with a 15-fold enhancement in NIR emission at 738 nm. Alternatively, a DMSO gel of Bodipy-1 exhibited a 7-fold enhancement in NIR emission at 748 nm with a change in emission color from yellow to orange-red upon drying. The reason for the amplified NIR emission in both cases is established from the difference in chromophore packing, by single crystal analysis of a model compound (Bodipy-2), which also exhibited a near identical emission spectrum with red to NIR emission (742 nm). Comparison of the emission features and WAXS and FT-IR data of the sheared n-decane film and the DMSO xerogel with the single crystal data supports a head-to-tail slipped arrangement driven by the N-H···F-B bonding in the sheared or xerogel states, which facilitates strong exciton coupling and the resultant NIR emission.


COMPUTER SCIENCE: Flushing Out Nasty Viruses in the Balkans.
Bulgaria created a pioneering center in late 1990 to tackle the threat that its homegrown computer viruses posed to the world; according to experts, it has been a major force in reining in that threat. Now the lab is struggling to stave off obsolescence on a budget of roughly half of what a single Western whiz kid fresh out of college might earn in a year.


Anterior cerebral blood velocity and end-tidal CO2 responses to exercise differ in children and adults.
Little is known about the response of the cerebrovasculature to acute exercise in children and how these responses might differ with adults. Therefore, we compared changes in middle cerebral artery blood velocity (MCAVmean), end-tidal Pco2 ([Formula: see text]), blood pressure, and minute ventilation (V̇e) in response to incremental exercise between children and adults. Thirteen children [age: 9 ± 1 (SD) yr] and thirteen sex-matched adults (age: 25 ± 4 yr) completed a maximal exercise test, during which MCAVmean, [Formula: see text], and V̇e were measured continuously. These variables were measured at rest, at exercise intensities specific to individual ventilatory thresholds, and at maximum. Although MCAVmean was higher at rest in children compared with adults, there were smaller increases in children (1-12%) compared with adults (12-25%) at all exercise intensities. There were alterations in [Formula: see text] with exercise intensity in an age-dependent manner [F(2.5,54.5) = 7.983, P < 0.001; η2 = 0.266], remaining stable in children with increasing exercise intensity (37-39 mmHg; P > 0.05) until hyperventilation-induced reductions following the respiratory compensation point. In adults, [Formula: see text] increased with exercise intensity (36-45 mmHg, P < 0.05) until the ventilatory threshold. From the ventilatory threshold to maximum, adults showed a greater hyperventilation-induced hypocapnia than children. These findings show that the relative increase in MCAVmean during exercise was attenuated in children compared with adults. There was also a weaker relationship between MCAVmean and [Formula: see text] during exercise in children, suggesting that cerebral perfusion may be regulated by different mechanisms during exercise in the child.NEW & NOTEWORTHY These findings provide the first direct evidence that exercise increases cerebral blood flow in children to a lesser extent than in adults. Changes in end-tidal CO2 parallel changes in cerebral perfusion in adults but not in children, suggesting age-dependent regulatory mechanisms of cerebral blood flow during exercise.


Parallel confocal microscopy using high-order axially symmetric polarized beams.
A novel scheme of parallel confocal microscopy using high-order axially symmetric polarized beams (ASPBs) is proposed. The basic concept of ASPBs is introduced first, then the principle of the scheme is presented, finally some numerical results are shown to verify the feasibility of the scheme. Seen from the results, multiple imaging spots are obtained and the size of spots is about 70% of the spot size in the single lens microscopy, and a kind of high temporal and spatial resolution parallel confocal microscopy is achieved, which may find wide applications in the fields of 3D profile measurement and biomedical imaging.


GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.
Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.


Non-invasive Imaging Techniques for Monitoring Cellular Response to Treatment in Stable Vitiligo.
Punch grafting procedures, where small pieces of normal skin are transplanted into stable vitiligo patches, results in repigmentation in only half of patients treated, yet the factors that determine whether a patient responds to treatment or not are still unknown. Reflectance confocal microscopy (RCM) is adept at visualizing melanocyte migration and epidermal changes over large areas while multiphoton microscopy (MPM) can capture metabolic changes in keratinocytes. With the overall goal of identifying optical biomarkers for early treatment response, we followed 12 vitiligo lesions undergoing punch grafting. Dendritic melanocytes adjacent to the graft site were observed before clinical evidence of repigmentation in treatment responsive patients but not in treatment non-responsive patients, suggesting that the early visualization of melanocytes is indicative of a therapeutic response. Keratinocyte metabolic changes in vitiligo skin adjacent to the graft site also correlated with treatment response, indicating that a keratinocyte microenvironment that more closely resembles normal skin is more hospitable for migrating melanocytes. Taken together, these studies suggest that successful melanocyte transplantation requires both the introduction of new melanocytes and modulation of the local tissue microenvironment.


Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors.
To monitor the prevalence of hepatitis B and hepatitis C a cross-sectional survey was conducted in 2004 among French metropolitan residents. A complex sampling design was used to enroll 14,416 adult participants aged 18-80 years. Data collected included demographic and social characteristics and risk factors. Sera were tested for anti-HCV, HCV-RNA, anti-HBc and HBsAg. Data were analyzed with SUDAAN software to provide weighted estimates for the French metropolitan resident population. The overall anti-HCV prevalence was 0.84% (95% CI: 0.65-1.10). Among anti-HCV positive individuals, 57.4% (95% CI: 43.2-70.5) knew their status. Factors associated independently with positive anti-HCV were drug use (intravenous and nasal), blood transfusion before 1992, a history of tattoos, low socioeconomic status, being born in a country where anti-HCV prevalence >2.5%, and age >29 years. The overall anti-HBc prevalence was 7.3% (95%: 6.5-8.2). Independent risk factors for anti-HBc were intravenous drug use, being a man who has sex with men, low socioeconomic status, a stay in a psychiatric facility or facility for the mentally disabled, <12 years of education, being born in a country where HBsAg prevalence >2%, age >29 and male sex. The HCV RNA and HBsAg prevalence were 0.53% (95% CI: 0.40-0.70) and 0.65% (95% CI: 0.45-0.93), respectively. Among HBsAg positive individuals, 44.8% (95% CI: 22.8-69.1) knew their status. Anti-HCV prevalence was close to the 1990s estimates whereas HBsAg prevalence estimate was greater than expected. Screening of hepatitis B and C should be strengthened and should account for social vulnerability.


Four genes from Pseudomonas fluorescens that encode the biosynthesis of pyrrolnitrin.
Pyrrolnitrin is a secondary metabolite of Pseudomonas and Burkholderia sp. strains with strong antifungal activity. Production of pyrrolnitrin has been correlated with the ability of some bacteria to control plant diseases caused by fungal pathogens, including the damping-off pathogen Rhizoctonia solani. Pseudomonas fluorescens BL915 has been reported to produce pyrrolnitrin and to be an effective biocontrol agent for this pathogen. We have isolated a 32-kb genomic DNA fragment from this strain that contains genes involved in the biosynthesis of pyrrolnitrin. Marker-exchange mutagenesis of this DNA with Tn5 revealed the presence of a 6.2-kb region that contains genes required for the synthesis of pyrrolnitrin. The nucleotide sequence of the 6.2-kb region was determined and found to contain a cluster of four genes that are required for the production of pyrrolnitrin. Deletion mutations in any of the four genes resulted in a pyrrolnitrin-nonproducing phenotype. The putative coding sequences of the four individual genes were cloned by PCR and fused to the tac promoter from Escherichia coli. In each case, the appropriate tac promoter-pyrrolnitrin gene fusion was shown to complement the pyrrolnitrin-negative phenotype of the corresponding deletion mutant. Transfer of the four gene cluster to E. coli resulted in the production of pyrrolnitrin by this organism, thereby demonstrating that the four genes are sufficient for the production of this metabolite and represent all of the genes required to encode the pathway for pyrrolnitrin biosynthesis.


[Malignant cell transformation and oncogenes].
In genome of all transforming retroviruses special genes (oncogenes) have been identified which play a key role in malignant conversion of the cells, infected with these viruses. The homologues of these genes (protooncogenes) are persist in all normal cells. During transformation protooncogenes can be activated as a result of one of following processes: insertion of promotor-like elements, mutations, translocations, amplifications or rearrangements. Using transfection technique the transforming genes were isolated from different human tumors. The activation of one of the cellular oncogenes may switch on the other genes and malignant cell transformation may be characterized as a multifactor and multistage process.


Metal-based inhibition of poly(ADP-ribose) polymerase--the guardian angel of DNA.
The inhibition activity of a series of anticancer metal complexes based on platinum, ruthenium, and gold metal ions was evaluated on the zinc-finger protein PARP-1, either purified or directly on protein extracts from human breast cancer MCF7 cells. Information on the reactivity of the metal complexes with the PARP-1 zinc-finger domain was obtained by high-resolution ESI FT-ICR mass spectrometry. An excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc-finger motif (in competition with zinc) was established. The results support a model whereby displacement of zinc from the PARP-1 zinc finger by other metal ions leads to decreased PARP-1 activity. In vitro combination studies of cisplatin with NAMI-A and RAPTA-T on different cancer cell lines (MCF7, A2780, and A2780cisR) showed that, in some cases, a synergistic effect is in operation.


A method of phenomenological interviewing.
In this article I propose a method of interviewing for descriptive phenomenological research that offers an explicit, theoretically based approach for researchers. My approach enables application of descriptive phenomenology as a total method for research, and not one just focused on data analysis. This structured phenomenological approach to interviewing applies questions based on themes of experience contextualization, apprehending the phenomenon and its clarification. The method of questioning employs descriptive and structural questioning as well as novel use of imaginative variation to explore experience. The approach will help researchers understand how to undertake descriptive phenomenological research interviews.


Thrombosis in systemic lupus erythematosus. Relation to the presence of circulating anticoagulants.
In an earlier report on the kidney in systemic lupus erythematosus (SLE), we described a subset of patients with circulating anticoagulants; many had glomerular and arteriolar thrombosis in the absence of necrosis and subendothelial deposits. The present study extends these observations to a larger group of patients with SLE and a circulating anticoagulant, and compares its findings with those in patients with SLE without evidence of an anticoagulant. It demonstrates (1) a higher prevalence of clinically recognizable thrombotic events in the venous and arterial circulations in patients with SLE and a detectable anticoagulant; (2) a probable shortening in life span; (3) a higher prevalence of glomerular thrombi; (4) elevated levels of factor VIII antigen and von Willebrand factor; and (5) significantly lower platelet counts and decreased in vitro platelet aggregation in response to adenosine diphosphate, epinephrine, and collagen. Since prednisone treatment often results in improvement or disappearance of a prolonged partial thromboplastin time, the test most commonly used for screening of a circulating anticoagulant, we suggest that the prevalence of this abnormality may be underestimated in patients with SLE.


Agricultural, socioeconomic and environmental variables as risks for human verotoxigenic Escherichia coli (VTEC) infection in Finland.
Verotoxigenic E. coli (VTEC) is the cause of severe gastrointestinal infection especially among infants. Between 10 and 20 cases are reported annually to the National Infectious Disease Register (NIDR) in Finland. The aim of this study was to identify explanatory variables for VTEC infections reported to the NIDR in Finland between 1997 and 2006. We applied a hurdle model, applicable for a dataset with an excess of zeros. We enrolled 131 domestically acquired primary cases of VTEC between 1997 and 2006 from routine surveillance data. The isolated strains were characterized by virulence type, serogroup, phage type and pulsed-field gel electrophoresis. By applying a two-part Bayesian hurdle model to infectious disease surveillance data, we were able to create a model in which the covariates were associated with the probability for occurrence of the cases in the logistic regression part and the magnitude of covariate changes in the Poisson regression part if cases do occur. The model also included spatial correlations between neighbouring municipalities. The average annual incidence rate was 4.8 cases per million inhabitants based on the cases as reported to the NIDR. Of the 131 cases, 74 VTEC O157 and 58 non-O157 strains were isolated (one person had dual infections). The number of bulls per human population and the proportion of the population with a higher education were associated with an increased occurrence and incidence of human VTEC infections in 70 (17%) of 416 of Finnish municipalities. In addition, the proportion of fresh water per area, the proportion of cultivated land per area and the proportion of low income households with children were associated with increased incidence of VTEC infections. With hurdle models we were able to distinguish between risk factors for the occurrence of the disease and the incidence of the disease for data characterised by an excess of zeros. The density of bulls and the proportion of the population with higher education were significant both for occurrence and incidence, while the proportion of fresh water, cultivated land, and the proportion of low income households with children were significant for the incidence of the disease.


Impact of Menopausal Status, Metabolic Syndrome and its Risk Factors on Impaired Quality of Life above Middle-aged Women.
This study explored influencing factors on quality of life (QoL) above middle-aged women in relation to demographic factors, health-related factors, menopausal status, metabolic syndrome (MS) and its risk factors. This study was secondary data analysis from the Sixth Korea National Health and Nutrition Examination Survey 2013~2015 that utilized a complex, multi-stage probability sample design. Study sample of 2,310 was inclusive of (28.8%) of women who were over 40. To evaluate the factors that would influence an impaired quality of life, χ² test, GLM, and logistic regression analysis were done. Level of quality of life was lower in women with late post-menopause(over 10 years since menopause) than women with pre-menopause. Factors influencing impaired QoL were as follows: graduated middle school and elementary school or less (OR=2.43, 4.42, respectively, p<.05), no job (OR=1.92, p<.001), stress (OR=1.92, p=.001), depression (OR=1.93, p=.001), insufficient sleep (OR=1.64, p=.003), late post-menopause (OR=2.61, p=.044) and over 85cm of waist circumference (OR=1.76, p=.01). These results suggest that late post-menopause may be an independent factor influencing an impaired QoL. To promote post-menopausal womens' health, a nursing strategy is required to teach women how to manage levels of stress, depression, insufficient sleep, and abdominal obesity through health education, nutritional counselling, and physical activity program.


Sibling comparison of differential parental treatment in adolescence: gender, self-esteem, and emotionality as mediators of the parenting-adjustment association.
This study employs findings from social comparison research to investigate adolescents' comparisons with siblings with regard to parental treatment. The sibling comparison hypothesis was tested on a sample of 516 two-child families by examining whether gender, self-esteem, and emotionality-which have been found in previous research to moderate social comparison-also moderate sibling comparison as reflected by siblings' own evaluations of differential parental treatment. Results supported a moderating effect for self-esteem and emotionality but not gender. The sibling comparison process was further examined by using a structural equation model in which parenting toward each child was associated with the adjustment of that child and of the child's sibling. Evidence of the "sibling barricade" effect-that is, parenting toward one child being linked with opposite results on the child's sibling as on the target child-was found in a limited number of cases and interpreted as reflecting a sibling comparison process. For older siblings, emotionality and self-esteem moderated the sibling barricade effect but in the opposite direction as predicted. Results are discussed in terms of older siblings' increased sensitivity to parenting as well as the report of differential parenting reflecting the child's level of comfort and benign understanding of differential parenting, which buffers the child against environmental vicissitudes evoking sibling comparison processes.


Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1.
DNA-based mutation analysis on the connexin 32 gene was performed in 49 families with Charcot-Marie-Tooth disease (CMT) type 1 but without duplication involving the chromosomal region, 17p12-p11.2. Mutations were identified in five of the 49 families, and four of the five mutations were hitherto undescribed: Va137Met, Glu57His, Arg142Glu, Val177Ala. X-linked CMT sometimes lacks evidence for X-linked transmission and cannot be differentiated from CMT type 2, especially in females with mildly decreased nerve conduction velocity. Therefore, molecular analysis is useful for molecular pathology of their disease.


Estimating the time since the fixation of a beneficial allele.
The fixation of a beneficial allele in a population leaves a well-characterized signature in patterns of nucleotide variation at linked sites. This signature can be used to estimate the time since fixation from patterns of polymorphism in extant individuals. I introduce a method to assess the support in polymorphism data for a recent episode of directional positive selection and to estimate the time since fixation. I summarize the polymorphism data by three statistics that carry information about levels of diversity, the allele frequency spectrum, and the extent of allelic associations. Simulations are then used to obtain a sample from the posterior distribution of the time since fixation, conditional on the observed summaries. I test the performance of the approach on simulated data and apply it to the gene tb1 in maize. The data support the recent fixation of a favored allele, consistent with what is known about the importance of tb1 in the domestication process of maize.


[Effects of metoprolol on the signal averaged electrocardiogram and QT dispersion in acute myocardial infarction].
The determination of high risk patients for sudden death and sustained ventricular tachycardia after acute myocardial infarction constitutes the main goal to decrease morbidity and mortality. Every attempt that decreases the frequency of late potentials (LPs) on signal averaged ECG (SAECG) and corrected QT dispersion (QTc-d) may improve prognosis of patients. In this study, the effect of metoprolol on frequency of LPs and QTc-d was investigated. Thirty-five patients (mean age 53 +/- 9 years) with acute myocardial infarction who were not given thrombolytic therapy were enrolled. Patients in whom metoprolol was not administered formed group I (n = 20) and patients who were given metoprolol constituted group II (n = 15). Metoprolol was administered as an initial dose of 15 mg intravenously, following 6-8 hours 100 mg/d orally. To determine the frequency of LPs, SAECG records were performed on admission and at the end of the first week. At the same time, resting ECG recordings (12 leads, 50 mm/s) were obtained to calculate QTc-d. Variance analysis was used for statistical analysis. In group I; frequency of LPs were found 30% on admission and at the end of the first week. In group II; frequency of LPs were 6% on admission and at the end of the first week there was no LPs. There was no statistically significant difference between two groups according to TQRS, RMS-40, LAS40 and QTc-d Metoprolol decreases the frequency of LPs. It has no effect on cQT-d.


Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions.
Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. However, their limited in vitro lifespan in culture systems hinders their therapeutic application. Some somatic stem cells, including hADMPCs, are known to be localized in hypoxic regions; thus, hypoxia may be beneficial for ex vivo culture of these stem cells. These cells exhibit a high level of glycolytic metabolism in the presence of high oxygen levels and further increase their glycolysis rate under hypoxia. However, the physiological role of glycolytic activation and its regulatory mechanisms are still incompletely understood. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multipotency of hADMPCs. Intriguingly, these effects were not mediated by hypoxia-inducible factor (HIF), but rather by the Notch signaling pathway. Five percent O2 significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2 markedly increased glucose consumption and lactate production of hADMPCs, which decreased back to normoxic levels on treatment with a γ-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions and, thus, likely affects the cell lifespan via glycolysis.


Preferred Place of Death for Patients With Incurable Cancer and Their Family Caregivers in Egypt.
Little is known about the place of death of patients with cancer in Eastern Mediterranean countries including Egypt, where palliative care is underdeveloped. Identifying the preferred place of death (PPoD) is important for the development of appropriate palliative care models in these countries. To know the PPoD of Egyptian patients with incurable cancer and their family caregivers (FCGs) and to determine the factors that may impact their preferences. An observational cross-sectional study that included 301 dyads of patients with incurable cancer and one of their FCGs. A questionnaire was designed to collect data about the characteristics of patients and FCGs as well as their preferences. The majority of dyads (272/301, 90.4%) answered the PPoD question. Home was the PPoD in 93% of patients and 90.1% of FCGs ( P = .218). The congruence between patients' and FCGs' PPoD was 92.7% (κ = 0.526). In multivariate analysis, poorer performance status (Eastern Cooperative Oncology Group 3 or 4) and full employment of FCGs associated significantly with patients' preference to die in hospital (odds ratio [OR] = 3.015 [95% confidence interval [CI]: 1.004-9.054], P = .049 and OR = 4.402 [95% CI: 1.561-12.417], P = .005, respectively), while poorer performance status and nonreferral to the palliative medicine unit were associated with FCGs' preference of hospital death (OR = 2.705 [95% CI: 1.105-6.626], P = .029 and OR = 2.537 [95% CI: 1.082-5.948], P = .032, respectively). The results of the current study suggest that home is the PPoD for the vast majority of Egyptian patients with incurable cancer and their FCGs. Palliative care interventions that promote home death of patients with incurable cancer are needed in Egypt.


A 21 point unifying hypothesis on the etiology and treatment of multiple sclerosis.
Multiple sclerosis (MS) is postulated to be a cell mediated autoimmune disease directed against central nervous system myelin components. Our understanding of the disease has been enhanced by a number of factors: 1) advances in our understanding of the immune system; 2) clinical trials which are beginning to identify treatments which can affect MS; 3) a better understanding of the clinical features of MS; and 4) advances in MRI imaging of the brain. Based on the current state of knowledge, this paper proposes a 21 point unifying hypothesis on the etiology and treatment of the disease. This hypothesis makes a series of assumptions, many of which are unproven, and is presented as a framework from which to investigate and treat the disease, not as a established biology. It is hypothesized that the underlying pathogenesis of MS is related to an inappropriate class of immune response against myelin antigens favoring proinflammatory Th1 versus anti-inflammatory Th2 or Th3 type responses. Environmental and genetic factors predispose toward MS by affecting the class of response and effectiveness of treatment is also related to how it impacts on this common final pathway. Because of epitope spreading, there is not one autoantigen involved in MS and the progressive form of MS differs immunologically from the relapsing remitting form. Viruses trigger and perpetuate MS, although MS is not related to a persistent viral infection. Because MS is a multifactorial disease, there are clinical and perhaps immunological subtypes of MS and a single type of treatment is unlikely to control the disease in all patients. Thus, there will be responders and non-responders to each effective therapy and ultimately combination therapy will be required to cure the disease.


Partial portal arterialization in complete en bloc resection of the hepatoduodenal ligament and left lobe of the liver for hepatic hilar cancer.
The complete resection of the hepatoduodenal ligament is associated with enormous surgical invasion, which frequently results in postoperative hepatic dysfunction secondary to interruption of the reconstructed artery. We administered partial portal arterialization by anastomosis of the gastroduodenal artery to the portal vein without reconstruction of the hepatic artery in the complete resection of the hepatoduodenal ligament with resection of the left lobe of the liver in a patient with hilar bile duct carcinoma. After division of the proper hepatic artery, the gastroduodenal artery was anastomosed in an end-to-side fashion to the trunk of the portal vein. After division of the portal vein, to prevent ischemia, a single catheter bypass was inserted into a branch of the mesenteric vein and the another side of the catheter was attached to the hepatic end, of the portal vein. The portal vein was reconstructed with the superficial femoral vein graft. The blood supply to the remaining liver was interrupted for only 15 min during which the proximal end of the superficial femoral graft was anastomosed to the hepatic end of the portal vein. Postoperative liver function has been stabilized and his postoperative course is uneventful without portal hypertension. One month postoperatively, angiography through the vessels nourishing the raised jejunum visualized intrahepatic arteries.


Attention deficit/hyperactivity disorders with co-existing substance use disorder is characterized by early antisocial behaviour and poor cognitive skills.
Attention Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of co-existing substance abuse. The Swedish legislation on compulsory healthcare can be applied to persons with severe substance abuse who can be treated involuntarily during a period of six months. This context enables a reliable clinical assessment of ADHD in individuals with severe substance use disorder (SUD). In the context of compulsory care for individuals with severe SUD, male patients were assessed for ADHD, co-morbid psychiatric symptoms, psychosocial background, treatment history, and cognition. The data from the ADHD/SUD group (n = 60) was compared with data from (1) a group of individuals with severe substance abuse without known ADHD (SUD group, n = 120), as well as (2) a group with ADHD from an outpatient psychiatric clinic (ADHD/Psych group, n = 107). Compared to the general SUD group in compulsory care, the ADHD/SUD group had already been significantly more often in compulsory care during childhood or adolescence, as well as imprisoned more often as adults. The most common preferred abused substance in the ADHD/SUD group was stimulant drugs, while alcohol and benzodiazepine abuse was more usual in the general SUD group. Compared to the ADHD/Psych group, the ADHD/SUD group reported more ADHD symptoms during childhood and performed poorer on all tests of general intellectual ability and executive functions. The clinical characteristics of the ADHD/SUD group differed from those of both the SUD group and the ADHD/Psych group in several respects, indicating that ADHD in combination with SUD is a particularly disabling condition. The combination of severe substance abuse, poor general cognitive ability, severe psychosocial problems, including indications of antisocial behaviour, and other co-existing psychiatric conditions should be considered in treatment planning for adults with ADHD and SUD.


Genome-wide analysis of natural selection on human cis-elements.
It has been speculated that the polymorphisms in the non-coding portion of the human genome underlie much of the phenotypic variability among humans and between humans and other primates. If so, these genomic regions may be undergoing rapid evolutionary change, due in part to natural selection. However, the non-coding region is a heterogeneous mix of functional and non-functional regions. Furthermore, the functional regions are comprised of a variety of different types of elements, each under potentially different selection regimes. Using the HapMap and Perlegen polymorphism data that map to a stringent set of putative binding sites in human proximal promoters, we apply the Derived Allele Frequency distribution test of neutrality to provide evidence that many human-specific and primate-specific binding sites are likely evolving under positive selection. We also discuss inherent limitations of publicly available human SNP datasets that complicate the inference of selection pressures. Finally, we show that the genes whose proximal binding sites contain high frequency derived alleles are enriched for positive regulation of protein metabolism and developmental processes. Thus our genome-scale investigation provides evidence for positive selection on putative transcription factor binding sites in human proximal promoters.


STM contrast of a CO dimer on a Cu(1 1 1) surface: a wave-function analysis.
We present a method used to intuitively interpret the scanning tunneling microscopy (STM) contrast by investigating individual wave functions originating from the substrate and tip side. We use localized basis orbital density functional theory, and propagate the wave functions into the vacuum region at a real-space grid, including averaging over the lateral reciprocal space. Optimization by means of the method of Lagrange multipliers is implemented to perform a unitary transformation of the wave functions in the middle of the vacuum region. The method enables (i) reduction of the number of contributing tip-substrate wave function combinations used in the corresponding transmission matrix, and (ii) to bundle up wave functions with similar symmetry in the lateral plane, so that (iii) an intuitive understanding of the STM contrast can be achieved. The theory is applied to a CO dimer adsorbed on a Cu(1 1 1) surface scanned by a single-atom Cu tip, whose STM image is discussed in detail by the outlined method.


The experiences and adaptations of abortion providers practicing under a new TRAP law: a qualitative study.
Abortion laws are proliferating in the United States, but little is known about their impact on abortion providers. In 2011, North Carolina instituted the Woman's Right to Know (WRTK) Act, which mandates a 24-h waiting period and counseling with state-prescribed information prior to abortion. We performed a qualitative study to explore the experiences of abortion providers practicing under this law. We conducted semistructured interviews with 31 abortion providers (17 physicians, 9 nurses, 1 physician assistant, 1 counselor and 3 clinic administrators) in North Carolina. Interviews were audio-recorded and transcribed. Interview transcripts were analyzed using a grounded theory approach. We identified emergent themes, coded all transcripts and developed a thematic framework. Two major themes define provider experiences with the WRTK law: provider objections/challenges and provider adaptations. Most providers described the law in negative terms, though providers varied in the extent to which they were affected. Many providers described extensive alterations in clinic practices to balance compliance with minimization of burdens for patients. Providers indicated that biased language and inappropriate content in counseling can negatively impact the patient-physician relationship by interfering with trust and rapport. Most providers developed verbal strategies to mitigate the emotional impacts for patients. Abortion providers in North Carolina perceive WRTK to have a negative impact on their clinical practice. Compliance is burdensome, and providers perceive potential harm to patients. The overall impact of WRTK is shaped by interaction between the requirements of the law and the adaptations providers make in order to comply with the law while continuing to provide comprehensive abortion care. Laws like WRTK are burdensome for providers. Providers adapt their clinical practices not only to comply with laws but also to minimize the emotional and practical impacts on patients. The effects on providers, frequently not a central consideration, should be considered in ongoing debates regarding abortion regulation.


The Adverse Drug Reactions from Patient Reports in Social Media Project: Five Major Challenges to Overcome to Operationalize Analysis and Efficiently Support Pharmacovigilance Process.
Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Classical Pharmacovigilance process is limited by underreporting which justifies the current interest in new knowledge sources such as social media. The Adverse Drug Reactions from Patient Reports in Social Media (ADR-PRISM) project aims to extract ADRs reported by patients in these media. We identified 5 major challenges to overcome to operationalize the analysis of patient posts: (1) variable quality of information on social media, (2) guarantee of data privacy, (3) response to pharmacovigilance expert expectations, (4) identification of relevant information within Web pages, and (5) robust and evolutive architecture. This article aims to describe the current state of advancement of the ADR-PRISM project by focusing on the solutions we have chosen to address these 5 major challenges. In this article, we propose methods and describe the advancement of this project on several aspects: (1) a quality driven approach for selecting relevant social media for the extraction of knowledge on potential ADRs, (2) an assessment of ethical issues and French regulation for the analysis of data on social media, (3) an analysis of pharmacovigilance expert requirements when reviewing patient posts on the Internet, (4) an extraction method based on natural language processing, pattern based matching, and selection of relevant medical concepts in reference terminologies, and (5) specifications of a component-based architecture for the monitoring system. Considering the 5 major challenges, we (1) selected a set of 21 validated criteria for selecting social media to support the extraction of potential ADRs, (2) proposed solutions to guarantee data privacy of patients posting on Internet, (3) took into account pharmacovigilance expert requirements with use case diagrams and scenarios, (4) built domain-specific knowledge resources embeding a lexicon, morphological rules, context rules, semantic rules, syntactic rules, and post-analysis processing, and (5) proposed a component-based architecture that allows storage of big data and accessibility to third-party applications through Web services. We demonstrated the feasibility of implementing a component-based architecture that allows collection of patient posts on the Internet, near real-time processing of those posts including annotation, and storage in big data structures. In the next steps, we will evaluate the posts identified by the system in social media to clarify the interest and relevance of such approach to improve conventional pharmacovigilance processes based on spontaneous reporting.


HIV TAT Protein Transduction Domain Mediated Cell Binding and Intracellular Delivery of Nanoparticles.
Intracellular delivery of non-transported therapeutic agents has traditionally been thought possible only for low molecular weight (<500 DA) hydrophobic molecules. Higher molecular weight agents including oligonucleotides, proteins, DNA, liposomes, and nanoparticles do not readily enter the cytoplasm. However, the human immunodeficiency virus (HIV) trans-acting transcriptional activator (TAT) protein enters the cytosol by way of an 11 amino acid cationic peptide (TATp). When this cationic sequence is attached to a variety of small pharmacological agents, including paramagnetic ions[1,2] and proteins,[3-6] they are delivered into cells. Further, TATp modification of large cargo, such as proteins, polymers, and nanoparticles, may enable them to internalize into cells as well. The size limitations for cargo delivered by a single TATp are currently undetermined, but multiple TATp attached to polymers, nanoparticles, liposomes, and phage can definitely mediate their internalization. This process appears to follow an endocytotic or potocytic pathway and does not directly transfer the cargo into the cytoplasm of the cell. Here we review recent publications in which multiple TATp have been attached to and resulted in the successful intracellular delivery of nanoparticles.


Tuberculosis presenting with pelvic mass, peritoneal lesions, and elevation of serum CA125 mimicking malignant tumor: a case report.
Tuberculosis is a curable infective disease which can mimic a malignant tumor. We report on a young woman who presented with abdominal fullness, body weight loss, and microcytic anemia. A pelvic mass and peritoneal lesions were found. The serum CA125 level was high. The initial gynecologic echo and abdominal CT scan revealed bilateral ovarian mass with peritoneal lesions, and malignancy was highly suspected. Diagnostic laparoscopy was performed, and peritoneal tuberculosis was pathologically proven. Combination anti-tuberculosis therapy was prescribed for one year. She was followed up in the outpatient clinic regularly with symptom improvement, body weigh gain, and improvement of anemia. We suggest that in cases of a pelvic mass and peritoneal lesions, with elevation of the serum CA125 level, tuberculosis should always be kept on the list of differential diagnoses. A tissue diagnosis should always be obtained before treatment, regardless of initial image study and laboratory findings.


High-throughput screening of bacterial pathogens in clinical specimens using 16S rDNA qPCR and fragment analysis.
Molecular-based detection of bacterial pathogens directly from clinical specimens permits rapid initiation of effective antimicrobial treatment and adequate patient management. Broad-range polymerase chain reaction (PCR) amplification of the 16S rRNA gene (16S rDNA qPCR) is used in many diagnostic laboratories as a complement to cultural identification of bacterial pathogens. However, efforts for automation of 16S rDNA PCR workflows are needed in order to reduce turnaround times and to enhance reproducibility and standardization of the technique. In this retrospective method evaluation study, clinical specimens (N = 499) from patients with suspected bacterial infections were used to evaluate 2 diagnostic semiautomated workflows for rapid bacterial pathogen detection. The workflows included automated DNA extraction (QIASymphony), 16S rDNA qPCR, fragment or melting curve analysis, and amplicon sequencing. Our results support the use of the 16S rDNA qPCR and fragment analysis workflow as it enabled rapid and accurate identification of bacterial pathogens in clinical specimens.


Transport and assembly of gag proteins into Moloney murine leukemia virus.
We have studied the process of Moloney murine leukemia virus (M-MuLV) assembly by characterization of core (gag) protein mutants and analysis of wild-type (wt) gag proteins produced by cells in the presence of the ionophore monensin. Our genetic studies involved examination of linker insertion mutants of a Gag-beta-galactosidase (Gag-beta-gal) fusion protein, GBG2051, which is incorporated into virus particles when expressed in the presence of wt viral proteins. Analysis indicated that the amino-terminal two-thirds of the gag matrix domain is essential for targeting of proteins to the plasma membrane; mutant proteins localized to the cytoplasm or were trapped on intracellular membranes. Mutations through most of the coding region of the gag capsid domain generated proteins which were released from cells in membrane vesicles but not in virions. In contrast, linker insertions into p12gag or carboxy-terminal portions of the matrix or capsid coding regions did not affect assembly of fusion proteins into virus particles. Monensin, which blocks vesicular transport, inhibited gag protein intracellular transport and release from cells. Our results suggest that a significant proportion of M-MuLV myristylated gag proteins travel via vesicles to the cell surface. Specific matrix protein polypeptide regions and myristic acid modification are both necessary for appropriate gag protein transport, while capsid protein interactions appear to mediate the final phase of virion formation.


Cell cycle regulation and hematologic malignancies.
A complex network precisely regulates the cell cycle through the G1, S, G2, and M phases and is the basis for cell division under physiological and pathological conditions. On the one hand, the transition from one phase to another as well as the progression within each phase is driven by the specific cyclin-dependent kinases (CDKs; e.g., CDK1, CDK2, CDK4, CDK6, and CDK7), together with their exclusive partner cyclins (e.g., cyclin A1, B1, D1-3, and E1). On the other hand, these phases are negatively regulated by endogenous CDK inhibitors such as p16ink4a, p18ink4c, p19ink4d, p21cip1, and p27kip1. In addition, several checkpoints control the commitment of cells to replicate DNA and undergo mitosis, thereby avoiding the passage of genomic errors to daughter cells. CDKs are often constitutively activated in cancer, which is characterized by the uncontrolled proliferation of transformed cells, due to genetic and epigenetic abnormalities in the genes involved in the cell cycle. Moreover, several oncogenes and defective tumor suppressors promote malignant changes by stimulating cell cycle entry and progression or disrupting DNA damage responses, including the cell cycle checkpoints, DNA repair mechanisms, and apoptosis. Thus, genes or proteins related to cell cycle regulation remain the main targets of interest in the treatment of various cancer types, including hematologic malignancies. In this context, advances in the understanding of the cell cycle regulatory machinery provide a basis for the development of novel therapeutic approaches. The present article summarizes the pathways as well as their genetic and epigenetic alterations that regulate the cell cycle; moreover, it discusses the various approved or potential therapeutic targets associated with the cell cycle, focusing on hematologic malignancies.


Use of the Alvarado Score in Elderly Patients with Complicated and Uncomplicated Appendicitis.
The purpose of this study was to determine whether the Alvarado score is beneficial in identifying complicated versus uncomplicated acute appendicitis in elderly patients. A retrospective review was conducted of patients aged 65 years and older who underwent an appendectomy for pathologically confirmed appendicitis. A review of 310 operative reports and patient charts from October 2012 to December 2016 yielded 216 patients. Patients were grouped based on complicated versus uncomplicated appendicitis. One hundred ten patients had complicated appendicitis, whereas 106 patients were uncomplicated. Among the complicated appendicitis patients, 76.4 per cent were perforated, 38.2 per cent were gangrenous, and 34.5 per cent had an abscess. The complicated appendicitis group had a higher mean duration of symptoms (2.70 ± 3.41 days vs 2.09 ± 3.08 days, P = 0.011). Appendectomies that were open or converted to open were more likely to be associated with complicated appendicitis (75% vs 48%, P = 0.012). Mean hospital length of stay was greater in those with complicated appendicitis (5.34 ± 5.56 days vs 3.12 ± 2.86 days, P < 0.001). The two groups did not differ on mean Alvarado score (complicated = 6.96 ± 1.99 vs uncomplicated = 6.72 ± 1.85, P = 0.36). Only 62.5 per cent of patients had an Alvarado score that met the cutoff for acute appendicitis. The Alvarado score was not able to differentiate complicated from uncomplicated appendicitis in elderly patients.


Fermentation of five sucrose isomers by human dental plaque bacteria.
Sucrose has five structural isomers: palatinose, trehalulose, turanose, maltulose and leucrose. Although these isomers have been reported to be noncariogenic disaccharides, which cannot be utilized by mutans streptococci, there is no information about their fermentability by other bacteria in dental plaque. The purpose of the present study was to examine whether these isomers were fermented by predominant bacteria in human dental plaque. Clinical bacterial isolates obtained from dental plaque from 3 children aged 22 months to 50 months (146 strains) were inoculated into 3 ml of peptone-yeast extract (PY medium) containing glucose for 1 day, then an aliquot of 20 microl of culture medium was inoculated into 1 ml of PY medium containing 1% (w/v) of the respective test carbohydrates. After incubation for 1 day, the pH values and the optical density at 660 nm of the cultures were measured. Fermentation ability was measured by pH <or=5.5, growth by an OD(660) of >or=0.5. Of the clinical isolates, 33% fermented palatinose, and 69% of these were Actinomyces species. All of the palatinose-fermenting bacterial strains fermented trehalulose, 25% fermented turanose, 70% fermented maltulose and 23% fermented leucrose. We therefore conclude that, in human dental plaque, there are significant numbers of bacteria that are able to ferment sucrose isomers.


Phenotypic and genomic characterization of pneumococcus-like streptococci isolated from HIV-seropositive patients.
Accurate differentiation between pneumococci and other viridans streptococci is essential given their differences in clinical significance. However, classical phenotypic tests are often inconclusive, and many examples of atypical reactions have been reported. In this study, we applied various phenotypic and genotypic methods to discriminate between a collection of 12 streptococci isolated from the upper respiratory tract of HIV-seropositive individuals in 1998 and 1999. Conventional phenotypic characterization initially classified these streptococci as Streptococcus pneumoniae, as they were all sensitive to optochin and were all bile soluble. However, they did not agglutinate with anti-pneumococcal capsular antibodies and were also far more resistant to antimicrobial agents than typeable pneumococci isolated in the same period. Genotypic characterization of these isolates and control isolates by both multilocus sequence analysis (MLSA) and comparative genomic hybridization (CGH) showed that only a single isolate was genetically considered to be a true S. pneumoniae isolate, and that the remaining 11 non-typable isolates were indeed distinct from true pneumococci. Of these, 10 most closely resembled a subgroup of Streptococcus mitis isolates genetically, while one strain was identified as a Streptococcus pseudopneumoniae isolate. CGH also showed that a considerable part of the proposed pneumococcal core genome, including many of the known pneumococcal virulence factors, was conserved in the non-typable isolates. Sequencing of part of the 16S rRNA gene and investigation for the presence of ply by PCR corroborated these results. In conclusion, our findings confirm the close relationship between streptococci of the Mitis group, and show that both MLSA and CGH enable pneumococci to be distinguished from other Mitis group streptococci.


Validity and calibration of the FFQ used in the Melbourne Collaborative Cohort Study.
To evaluate the reliability and validity of the FFQ administered to participants in the follow-up of the Melbourne Collaborative Cohort Study (MCCS), and to provide calibration coefficients. A random sample stratified by country of birth, age, sex and BMI was selected from MCCS participants. Participants completed two FFQ and three 24 h recalls over 1 year. Reliability was evaluated by intraclass correlation coefficients (ICC). Validity coefficients (VC) were estimated from structural equation models and calibration coefficients obtained from regression calibration models. Adults born in Australia, Greece or Italy. Nine hundred and sixty-five participants consented to the study; of these, 459 participants were included in the reliability analyses and 615 in the validity and calibration analyses. The FFQ showed good repeatability for twenty-three nutrients with ICC ranging from 0·66 to 0·80 for absolute nutrient intakes for Australian-born and from 0·51 to 0·74 for Greek/Italian-born. For Australian-born, VC ranged from 0·46 (monounsaturated fat) to 0·83 (Ca) for nutrient densities, comparing well with other studies. For Greek/Italian-born, VC were between 0·21 (Na) and 0·64 (riboflavin). Calibration coefficients for nutrient densities ranged from 0·39 (retinol) to 0·74 (Mg) for Australian-born and from 0·18 (Zn) to 0·54 (riboflavin) for Greek/Italian-born. The FFQ used in the MCCS follow-up study is suitable for estimating energy-adjusted nutrients for Australian-born participants. However, its performance for estimating intakes is poorer for southern European migrants and alternative dietary assessment methods ought to be considered if dietary data are to be measured in similar demographic groups.


Empirical treatment of bacteraemic urinary tract infection. Evaluation of a decision support system.
In a Danish county with a low prevalence of antibiotic resistance to most antibiotics, we have constructed and evaluated a decision support system (DSS) for guidance of empirical antibiotic therapy in patients with bacteraemia originating from the urinary tract. The DSS was based upon a causal probabilistic network, and a decision theoretic approach was used to balance the costs of antibiotic therapy against the therapeutic benefit. The costs included direct cost of purchasing antibiotics, side effects, and the risk of development of antibiotic resistance. The therapeutic benefit was defined as the increase in life-expectancy caused by antibiotic therapy. Life-years were chosen as the common currency unit. Four hundred and ninety-one bacteraemias seen during 1992-1994 were used to construct the DSS (derivation set), and 426 bacteraemias during 1995-1996 were used for evaluation (validation set). The cases were identified in a regional register of bacteraemias. The study was non-interventional. The DSS suggested antibiotics which would provide coverage in 377 of the 426 episodes (88.5%) compared to 259 episodes (60.8%) for which empirical therapy actually provided coverage (p < 0.01, McNemar-test). The regimens suggested by the DSS included mecillinam as monotherapy in 240 episodes (56.3%), gentamicin as monotherapy in 81 (19.0%), and a combination of gentamicin and ampicillin in 80 (18.8%). A decision theoretic approach shows promise of improving empirical antibiotic treatment, and may be a measure to support an antibiotic policy.


Mutational screening of SCN5A linked disorders in Polish patients and their family members.
Mutations in SCN5A lead to a broad spectrum of phenotypes, including the Long QT syndrome, Brugada syndrome, Idiopathic ventricular fibrillation (IVF), Sudden infant death syndrome (SIDS) (probably regarded as a form of LQT3), Sudden unexplained nocturnal death syndrome (SUNDS) and isolated progressive cardiac conduction defect (PCCD) (Lev-Lenegre disease). Brugada Syndrome (BS) is a form of idiopathic ventricular fibrillation characterized by the right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. In this study sequences of the coding region of the SCN5A gene were analysed in patients with the LQT3, Brugada Syndrome and other arrythmogenic disorders. Different mSSCP patterns are described with no disease-related SSCP conformers in any sample. Direct sequencing of the SCN5A gene confirmed the absence of mutations. This suggests that the analysed region of the SCN5A gene is not commonly involved in the pathogenesis of the Brugada Syndrome and associated disorders.


Radiation flavor--fact or fancy.
Experimental results indicate that sensory evaluations in different laboratories give equivalent results if standardized procedures and a standard sample are used. Conflicting results concerning the flavor of irradiated foods are due largely to different methods of evaluation and to incorrect interpretation of results. Unusual flavor due to irradiation should be considered different, not necessarily objectionable.


Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations?
A short course of systemic corticosteroids is an important therapy in the treatment of pediatric asthma exacerbations. Although a 5-day course of oral prednisone or prednisolone has become the most commonly used regimen, dexamethasone has also been used for a shorter duration (1-2 days) with potential for improvement in compliance and palatability. We reviewed the literature to determine if there is sufficient evidence that dexamethasone can be used as an effective alternative in the treatment of pediatric asthma exacerbations in the inpatient setting. A Medline search was conducted on the use of dexamethasone in the treatment of asthma exacerbations in children. The studies selected were clinical trials comparing the efficacy of dexamethasone with prednisone. Meta-analysis was performed examining physician revisitation rates and symptomatic return to baseline. Six completed pediatric clinical trials met the inclusion criteria. All of the pediatric trials found that prednisone is not superior to dexamethasone in treating mild to moderate asthma exacerbations. Meta-analysis demonstrated homogeneity between the dexamethasone and prednisone groups when examining symptomatic return to baseline and unplanned physician revisits after the initial emergency department encounter. Some studies found potential additional benefits of dexamethasone, including improved compliance and less vomiting. The current literature suggests that dexamethasone can be used as an effective alternative to prednisone in the treatment of mild to moderate acute asthma exacerbations in children, with the added benefits of improved compliance, palatability, and cost. However, more research is needed to examine the role of dexamethasone in hospitalized children.


Atomistic Polarizable Embeddings: Energy, Dynamics, Spectroscopy, and Reactivity.
The computational modeling of realistic extended systems, relevant in, e.g., Chemistry and Biophysics, is a fundamental problem of paramount importance in contemporary research. Enzymatic catalysis and photoinduced processes in pigment-protein complexes are typical problems targeted by computer-aided approaches, to complement experiments as interpretative tools at a molecular scale. The daunting complexity of this task lies in between the opposite stringent requirements of results' reliability for structural/dynamical properties and related intermolecular interactions, and a mandatory principle of realism in the modeling strategy. Therefore, in practice, a truly realistic computational model of a biologically relevant system can easily fail to meet the accuracy requirement, in order to balance the excessive computational cost necessary to reach the desired precision.To address such an "accuracy vs reality" dualistic requirement, mixed quantum mechanics/classical mechanics approaches within Atomistic (i.e., preserving the discrete particle configuration) Polarizable Embeddings (QM/APEs) methods have been proposed over the years. In this Account, we review recent developments in the design and application of general QM/APE methods, targeting situations where a local intrinsically quantum behavior is coupled to a large molecular system (i.e., an environment), often involving processes with different dynamical time scales, in order to avoid brute-force, unpractical quantum chemistry calculations on the complete system.In the first place, our interest is devoted to the available APEs models presently implemented in computational software, highlighting the quantum chemistry methods that can be used to treat the QM subsystem. We review the coupling strategy between the QM subsystem and the APE, which requires to examine the way the QM/MM mutual interactions are accounted for and how the polarization of the classical environment is considered with respect to (wrt) the quantum variables. Because of the need of reliable molecular and macromolecular structures, a pivotal aspect to address here is the handling of the system dynamics (i.e., gradients wrt nuclear positions are required), especially for large molecular assemblies composed by an overwhelming number of atoms, exploring many conformations on a complex energy landscape.Alongside, we highlight our views on the necessary steps to take toward more accurate general-purposes and transferable explicit embeddings. The main objective to achieve here is to design a more physically grounded multiscale approach. To do so, one should apply advanced new generation classical models to account for refined induction effects that are able to (i) improve the quality of QM/MM interaction energies; (ii) enhance transferability by avoiding the compulsory partial (or total) reparameterization of the classical model. Moreover, the extension of recent developments originating from the field of advanced classical molecular dynamics (MD) to the realm of QM/APE methods is a key direction to improve both speed and efficiency for the phase space exploration of systems of growing size and complexity.Lastly, we point out specific research topics where an advanced QM/APE dynamics can certainly shed some light. For example, we discuss chemical reactions in "harsh" environments and the case of spectroscopic theoretical modeling where the inclusion of refined environment effects is often mandatory.


A recurrent fibrillin-1 mutation in severe early onset Marfan syndrome.
The recurrent substitution of isoleucine for threonine at codon 1048 (I1048T) substitution has been linked to severe, early onset Marfan syndrome, however, the existence of strong genotype-phenotype associations in Marfan syndrome (MFS) is not widely agreed upon. Our aim is to substantiate the association between the I1048T substitution and a severe clinical presentation to facilitate care planning and genetic counseling. We review the clinical findings from seven cases of early-onset MFS with a recurrent I1048T substitution. The presented findings include those from one newly diagnosed case, significant new detail from three additional cases, and a review of published findings in three cases. All seven individuals with the I1048T substitution had mitral insufficiency, arachnodactyly and characteristic facies consistent with early-onset MFS. Our findings support the existence of a genotype-phenotype correlation between the I1048T substitution and early-onset MFS. Recognition of this relationship has implications for genetic counseling and clinical care. Additionally, exploration of how the I1048T substitution results in a severe phenotype may lead to further insight into the pathophysiology of MFS.


Fibrinogen deficiency is compatible with the development of atherosclerosis in mice.
A critical role of the coagulation system in the development of atherosclerosis has been frequently postulated based on a variety of indirect observations, including the expression of procoagulants and fibrinolytic factors within atherosclerotic vessels, the presence of substantial amounts of fibrin(ogen) and fibrin degradation products within intimal lesions, the cellular infiltration and assimilation of mural thrombi into developing plaques, and the identification of high plasma fibrinogen (Fib) levels as an independent risk factor for the development of ischemic heart disease. To directly examine the role of fibrin(ogen) in atherogenesis, Fib-deficient mice were crossed to atherosclerosis-prone apolipoprotein E (apo E)-deficient mice. Both apo E-/- and apo E-/-/Fib-/- mice developed lesions throughout the entire aortic tree, ranging in appearance from simple fatty streaks to complex fibrous plaques. Furthermore, remarkably little difference in lesion size and complexity was observed within the aortae of age- and gender-matched apo E-/- and apo E-/-/Fib-/- mice. These results indicate that the contribution of fibrin(ogen) to intimal mass and local cell adhesion, migration, and proliferation is not strictly required for the development of advanced atherosclerotic disease in mice with a severe defect in lipid metabolism.


Endo-parasitic helminthes of four mormyrid species (Osteichthyes: Mormyridae) from a West African flood river system.
Mormyrus rume rume, Hyperopisus bebe bebe, Campylomormyrus tamandua and Gnathonemus petersii sampled from the Anambra river with a fleet of gill nets, traps and hook and line were examined for endo-parasitic helminthes from October 2005 to September 2006. Recovered helminthes were Rhadinorhynchus horridus from the intestine of H. bebe bebe and G. petersii; Procamallanus laeviconchus from the stomach of M. rume rume and C. tamandua; Spinitectus mormyri from the stomach of M. rume rume; Contracaecum sp. from the coelom of H. bebe bebe, G. petersii and C. tamandua, whereas an unidentified cestode infected the intestine of all the mormyrids. G. petersii constitutes a new host record for R. horridus; M. rume rume for S. mormyri and M. rume rume and C. tamandua for P. laeviconchus. In cases of mixed infection the parasites occupied their preferred habitats. The overall prevalence of the endo-parasites in the fish hosts was 41.9%, which is within the range (< 50%) typical of southern Nigerian freshwater lotic habitats. Prevalence, mean intensity and mean abundance of R. horridus in its host fishes were higher in the dry (October/November-March) than the rainy season (April-September/October); in the nematodes (P. laeviconchus, S. mormyri and Contracaecum) the reverse was the case, whereas no definite pattern was exhibited by the unidentified cestode. P. laeviconchus appeared reddish from engorgement of blood but no damage was evident at the point of attachment. Local inflammation where R. horridus was attached to the mucosa of the intestine was not considered severe. R. horridus and P. laeviconchus are probably the most important parasites of the mormyrids in terms of fishery management in the Anambra river system.


Topical steroid treatment of allergic rhinitis decreases nasal fluid TH2 cytokines, eosinophils, eosinophil cationic protein, and IgE but has no significant effect on IFN-gamma, IL-1beta, TNF-alpha, or neutrophils.
Topical treatment with glucocorticoids (GCs) is known to decrease eosinophils but not neutrophils in patients with allergic rhinitis. We sought to examine whether the differential effects of GC treatment on eosinophils and neutrophils are mirrored by differential effects on T(H)1/T(H)2 cytokines and the neutrophil-associated cytokines IL-1beta and TNF-alpha. Differential counts of eosinophils and neutrophils in nasal fluids from 60 children with seasonal allergic rhinitis treated with a topical GC were examined after staining with May-Grünwald-Giemsa stain. Nasal fluid levels of IFN-gamma, IL-4, IL-6, IL-10, IL-1beta, and TNF-alpha were examined with ELISA, and IgE and eosinophil cationic protein (ECP) levels were examined with RIA. After GC treatment, there was a statistically significant decrease of the T(H)2 cytokines IL-4, IL-6, and IL-10, as well as ECP and IgE. By contrast, there were no significant changes of the levels of IFN-gamma, IL-1beta, TNF-alpha, or neutrophils. In the GC-treated patients IL-1beta and TNF-alpha levels correlated with neutrophils and ECP, and IL-1beta correlated with eosinophils. Furthermore, ECP correlated with both eosinophils and neutrophils. Neither IL-1beta nor TNF-alpha correlated with IgE. Patients with high neutrophil counts after GC treatment were found to have significantly higher eosinophil counts and ECP than patients with low counts. The beneficial effects of topical treatment with GC in patients with allergic rhinitis could be attributed to downregulation of T(H)2 cytokines, with an ensuing decrease of eosinophils, ECP, and IgE. It is possible that neutrophils could counteract the beneficial effects of GCs by releasing the proinflammatory cytokines IL-1beta and TNF-alpha.


THz-bandwidth tunable slow light in semiconductor optical amplifiers.
We report tunable fractional delays of 250% for 700 fs pulses propagating in a 1.55 mum semiconductor optical amplifier at room temperature. This large fractional delay is attributed to a spectral hole created by the propagating pulses for pulses with duration shorter than the carrier heating relaxation time. Delay can be tuned electrically by adjusting the current with low amplitude variation across the tuning range.


The Iceberg Nature of Fibromyalgia Burden: The Clinical and Economic Aspects.
This review has focused on important but less visible aspects of fibromyalgia (FM) with respect to the high impact of this disorder on patients and societies. FM is a common but challengeable illness. It is characterized by chronic widespread pain, which can be accompanied by other symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and depressive episodes. While our understanding of this debilitating disorder is limited, diagnosis and treatment of this condition is very difficult, even in the hands of experts. Due to the nature of disease, where patients experience invalidation by medical services, their families and societies regarding the recognition and management of disease, direct, indirect and immeasurable costs are considerable. These clinical and economic costs are comparable with other common diseases, such as diabetes, hypertension and osteoarthritis, but the latter usually receives much more attention from healthcare and non-healthcare resources. Present alarming data shows the grave and "iceberg-like" burden of FM despite the benign appearance of this disorder and highlights the urgent need both for greater awareness of the disease among medical services and societies, as well as for more research focused on easily used diagnostic methods and target specific treatment.


Collaborative computational anatomy: an MRI morphometry study of the human brain via diffeomorphic metric mapping.
This article describes a large multi-institutional analysis of the shape and structure of the human hippocampus in the aging brain as measured via MRI. The study was conducted on a population of 101 subjects including nondemented control subjects (n = 57) and subjects clinically diagnosed with Alzheimer's Disease (AD, n = 38) or semantic dementia (n = 6) with imaging data collected at Washington University in St. Louis, hippocampal structure annotated at the Massachusetts General Hospital, and anatomical shapes embedded into a metric shape space using large deformation diffeomorphic metric mapping (LDDMM) at the Johns Hopkins University. A global classifier was constructed for discriminating cohorts of nondemented and demented subjects based on linear discriminant analysis of dimensions derived from metric distances between anatomical shapes, demonstrating class conditional structure differences measured via LDDMM metric shape (P < 0.01). Localized analysis of the control and AD subjects only on the coordinates of the population template demonstrates shape changes in the subiculum and the CA1 subfield in AD (P < 0.05). Such large scale collaborative analysis of anatomical shapes has the potential to enhance the understanding of neurodevelopmental and neuropsychiatric disorders.


Low-hysteresis, pressure-insensitive, and transparent capacitive strain sensor for human activity monitoring.
Wearable strain sensors have been widely used for human activity monitoring. Most reported strain sensors have mainly focused on material engineering, high stretchability and large gauge factors. Few works have focused on strain sensor's robustness and reliability, including low hysteresis, good long-term stability, good electrode material stability, and low coupling effects under multi-input signals, which are the factors that limit practical strain sensor applications. To develop a high-performance strain sensor, we propose a flexible capacitive sensor structure with three-dimensional (3D) interdigital electrodes fabricated by vertically aligned carbon nanotubes. Compared with a traditional resistive strain sensor and a capacitive strain sensor with vertical sandwich electrodes, a strain sensor with horizontal parallel interdigital electrodes can benefit from low cross talk in terms of the normal force and improve substrate transparency. Additionally, embedding 3D electrodes into the substrate improves ultrahigh robustness with a low-pressure coupling effect under normal force. Moreover, compared with other reported works, the electrode variation under strain is small (less than 1.6%), which means that the perturbation of inert properties on device performance is small. Finally, the fabricated strain sensor achieves an ultralow hysteresis (0.35%), excellent pressure-insensitive performance (less than 0.8%), fast response (60 ms), good long-term stability, and good transparency. As an application example, a flexible strain sensor was successfully demonstrated as a wearable device for the precise monitoring of different types of human activities, including bending of the finger, knee, elbow, wrist, and neck with large strain signals and small strain signals generated by a mouth-opening activity. This excellent performance indicates that the flexible strain sensor is a promising candidate for human motion detection, soft robotics, and medical care.


A novel kernel for correcting size bias in the logistic kernel machine test with an application to rheumatoid arthritis.
The logistic kernel machine test (LKMT) is a testing procedure tailored towards high-dimensional genetic data. Its use in pathway analyses of case-control genome-wide association studies results from its computational efficiency and flexibility in incorporating additional information via the kernel. The kernel can be any positive definite function; unfortunately, its form strongly influences the test's power and bias. Most authors have recommended the use of a simple linear kernel. We demonstrate via a simulation that the probability of rejecting the null hypothesis of no association just by chance increases with the number of SNPs or genes in the pathway when applying a simple linear kernel. We propose a novel kernel that includes an appropriate standardization in order to protect against any inflation of false positive results. Moreover, our novel kernel contains information on gene membership of SNPs in the pathway. When applying the novel kernel to data from the North American Rheumatoid Arthritis Consortium, we find that even this basic genomic structure can improve the ability of the LKMT to identify meaningful associations. We also demonstrate that the standardization effectively eliminates problems of size bias. We recommend the use of our standardized kernel and urge caution when using non-adjusted kernels in the LKMT to conduct pathway analyses.


ATP functions as a primary alarmin in allergen-induced type 2 immunity.
Environmental allergens that interact with the airway epithelium can activate cellular stress pathways that lead to the release of danger signals known as alarmins. The mechanisms of alarmin release are distinct from damage-associated molecular patterns (DAMPs), which typically escape from cells after loss of plasma membrane integrity. Oxidative stress represents a form of allergen-induced cellular stress that stimulates oxidant-sensing mechanisms coupled to pathways, which facilitate alarmin mobilization and efflux across the plasma membrane. In this review, we highlight examples of alarmin release and discuss their roles in the initiation of type 2 immunity and allergic airway inflammation. In addition, we discuss the concept of alarmin amplification, where "primary" alarmins, which are directly released in response to a specific cellular stress, stimulate additional signaling pathways that lead to secretion of "secondary" alarmins that include proinflammatory cytokines, such as IL-33, as well as genomic and mitochondrial DNA that coordinate or amplify type 2 immunity. Accordingly, allergen-evoked cellular stress can elicit a hierarchy of alarmin signaling responses from the airway epithelium that trigger local innate immune reactions, impact adaptive immunity, and exacerbate diseases including asthma and other chronic inflammatory conditions that affect airway function.


Systematic Literature Review of Text Messaging Interventions to Promote Medication Adherence Among People With Serious Mental Illness.
Mobile health tools are feasible options to encourage behavior change among patients with serious mental illness. Mobile health tools vary widely, both in platforms used and content delivered. This literature review assessed the use of text messaging interventions to promote medication adherence among patients with serious mental illness. A systematic literature review using PRISMA guidelines examined short message service (SMS) text messaging interventions promoting medication adherence to people with a serious mental illness diagnosis. Databases included PubMed, Cochrane, CINAHL, and PsycINFO. Data extraction included demographic information, participant diagnoses, intervention components, medication class, adherence measures, research design, and study outcomes. Study quality was also assessed. Of 114 full-text articles screened, 10 articles were selected from nine unique interventions (N=937 people with serious mental illness). Study durations ranged from 30 days to 18 months, with frequency of SMS ranging from twice weekly to 12 times daily. Of the nine unique trials, most reported using an automated server to deliver SMS messages (N=7), two-way SMS capabilities (N=6), customized message content or timing (N=7), and additional components (e.g., provider contact, educational content, and monetary rewards) (N=7). Seven of the 10 articles reported statistically significant improvement in medication adherence and in at least one clinical outcome. Evidence to date indicates that text messaging interventions are feasible and appear to improve medication adherence and clinical outcomes among patients with serious mental illness. Future research should assess implementation approaches and how to scale up efforts in nonresearch settings.


A surgical technique for buttockectomy.
The buttockectomy is an en bloc resection of the gluteus maximus muscle and is usually performed for low-grade malignancy tumors of the buttocks that are encompassed by the muscle excised. After the incision of the skin widely around the tumor, skin flaps are created to expose the entire gluteus maximus muscle; the inferior rolled edge of the muscle is identified and traced laterally to its insertion on the iliotibial tract. For a left buttockectomy the operator proceeds clockwise, first releasing the insertions of the muscle from the iliotibial tract and greater trochanter and the origins from the crest of ilium and sacrum. For a right buttockectomy one proceeds in a counterclockwise fashion, again starting at the inferior aspect of the gluteus maximus muscle. Care must be taken to avoid damage to the sciatic nerve and to secure the inferior and superior gluteal vessels before they are transected. Suction drainage is secured to remove serum and ensure adherence of skin flaps to the resection site. If the skin closure is tight, retention sutures may be needed.


Co-emergence and Collapse: The Mesoscopic Approach for Conceptualizing and Investigating the Functional Integration of Organisms.
The fall of reductionist approaches to explanation leaves biology with an unescapable challenge: how to decipher complex systems. This entails a number of very critical questions, the most basic ones being: "What do we mean by 'complex'?" and "What is the system we should look for?" In complex systems, constraints belong to a higher level that the molecular one and their effect reduces and constrains the manifold of the accessible internal states of the system itself. Function is related but not deterministically imposed by the underlying structure. It is quite unlikely that such kind of complexity could be grasped by current approaches focusing on a single organization scale. The natural co-emergence of systems, parts and properties can be adopted as a hypothesis-free conceptual framework to understand functional integration of organisms, including their hierarchical or multilevel patterns, and including the way scientific practice proceeds in approaching such complexity. External, "driving" factors - order parameters and control parameters provided by the surrounding microenvironment - are always required to "push" the components' fate into well-defined developmental directions. In the negative, we see that in pathological processes such as cancer, organizational fluidity, collapse of levels and dynamic heterogeneity make it hard to even find a level of observation for a stable explanandum to persist in scientific practice. Parts and the system both lose their properties once the system is destabilized. The mesoscopic approach is our proposal to conceptualizing, investigating and explaining in biology. "Mesoscopic way of thinking" is increasingly popular in the epistemology of biology and corresponds to looking for an explanation (and possibly a prediction) where "non-trivial determinism is maximal": the "most microscopic" level of organization is not necessarily the place where "the most relevant facts do happen." A fundamental re-thinking of the concept of causality is also due for order parameters to be carefully and correctly identified. In the biological realm, entities have relational properties only, as they depend ontologically on the context they happen to be in. The basic idea of a relational ontology is that, in our inventory of the world, relations are somehow prior to the relata (i.e., entities).


Keratoprosthesis surgery as an alternative to keratoplasty.
Corneal transplant surgery after chemical or thermal burns has a very low success rate. Vision in these patients can be restored by using an artificial cornea (keratoprosthesis). In this report, we present 5 clinical cases of implanting a fresh corneal graft with Boston type 1 keratoprosthesis in patients with corneas inappropriate for standard corneal transplantation. The mean follow-up was 26.4 months (range, 12 to 36 months; SD, 13.1). The main measures of outcomes were visual acuity and keratoprosthesis stability. At least 1 year after the operation (5 eyes), vision acuity was >0.1 in 100% of the eyes and >0.4 in 50% of the eyes. Retention of the initial keratoprosthesis was 100%. The results of this study seem to be similar to those reported internationally. The anatomical and visual functions of the eyes were stable after keratoprosthesis implantation, though for a longer follow-up period, additional surgical procedures may be required.


Proteomic and metabolomic profiling of acupuncture for migraine reveals a correlative link via energy metabolism.
Migraine is a neurovascular disease with a high disability rate. Acupuncture treatment has emerged as a safe and viable alternative prophylactic therapy that can effectively alleviate the duration and frequency of migraine attacks. However, the therapeutic mechanisms underlying the effects of acupuncture are yet to be systematically elucidated. In this study, we enrolled female patients with migraine without aura (n = 20) and healthy controls (n = 10). Patients received acupuncture treatment on DU20, DU24, bilateral GB13, GB8, and GB20, applied three times per week over the course of 4 weeks for 12 sessions in total. Blood samples were collected from the median cubital vein before and after acupuncture treatment. Proteomic and metabolomic profiling was performed using liquid chromatography-mass spectrometry to determine the characteristics of differentially expressed molecules and expression of their corresponding biological pathways as well as to elucidate the pathogenesis of migraine and the biological effects underlying the treatment of migraine with acupuncture. Proteomic and metabolomic profiling of plasma samples from patients with migraine without aura before and after acupuncture treatment revealed enrichment of immune-related pathway functions and the arginine synthesis pathway. Joint pathway analyses revealed significant enrichment of the pentose phosphate and glycolysis/gluconeogenesis pathways in patients with migraine. The glycolysis/gluconeogenesis and riboflavin metabolism pathways were significantly enriched after acupuncture treatment. The expression levels of various key proteins and metabolites, including α-D-glucose, flavin adenine dinucleotide, biliverdin reductase B, and L-glutamate, were significantly differentially expressed before and after acupuncture treatment in patients with migraine without aura. Treatment of migraine with acupuncture was associated with significant changes in key molecules and pathways, indicative of physiological changes in the trigeminovascular system, glutamate neurotoxicity, and other migraine-related physiological changes. Overall, our comprehensive analysis using proteomic and metabolomic profiling demonstrates that energy metabolism may serve as a key correlative link in the occurrence of migraine and the therapeutic effects of acupuncture treatment. Our findings may facilitate the identification of diagnostic and therapeutic modalities in the ongoing search for effective treatments for migraine attacks.