Atomistic view of base flipping in DNA.
Base flipping is essential for the enzyme-catalysed methylation of DNA. In our previous studies, the flipping of bases out of duplex DNA in DNA alone and when bound to the (cytosine-C5)-methyltransferase from HhaI (M.HhaI) were investigated via potential of mean force calculations. Insights into various experimental observations were obtained. In the present paper we present an overview of previous computational studies of base flipping along with new detailed structural and energetic analysis on atomic events that contribute to the free energy surfaces. The contributions from different intrinsic and environmental effects to the base-flipping process are explored, and experimental data derived from a variety of methods are reconciled. A detailed protein-facilitated base-flipping mechanism is proposed. Ground-state destabilization is achieved via disruption of the target base Watson-Crick interactions by substitution with favourable DNA-protein interactions. In addition, specific DNA-protein interactions and favourable solvation effects further promote target base flipping along the major groove through the protein matrix, and maximal interactions occur between the DNA and the protein upon reaching the fully flipped state. Other DNA binding proteins that involve distortion of DNA's conformation may use a similar mechanism to that by which M.HhaI facilitates base flipping.


Perceptions and determinants of healthy eating for people with HIV in the Dominican Republic who experience food insecurity.
The current study aimed to understand how moderate and severe food-insecure people living with HIV (PLHIV) in the Dominican Republic perceive a healthy diet and explore facilitators and barriers to engaging in healthy dietary behaviours as a means of HIV self-management. We conducted semi-structured interviews with PLHIV. We generated codes on food insecurity among PLHIV and used content analysis to organise codes for constant comparison between and within participants. Two urban HIV clinics in the Dominican Republic. Thirty-two PLHIV participated in the interviews. Factors that contributed to dietary behaviours include individual factors, such as knowledge of nutrition, views and attitudes on healthy dietary behaviours, beliefs about dietary needs for PLHIV and diet functionality. Interpersonal factors, including assistance from family and peers in providing food or funds, were deemed critical along with community and organisational factors, such as food assistance from HIV clinics, accessibility to a variety of food store types and the availability of diverse food options at food stores. Policy-level factors that influenced dietary behaviours were contingent on respondents' participation in the labour market (i.e. whether they were employed) and consistent access to government assistance. Food insecurity influenced these factors through unpredictability and a lack of control. PLHIV who experience food insecurity face various barriers to engaging in healthy dietary behaviours. Their diets are influenced at multiple levels of influence ranging from individual to structural, requiring multi-level interventions that can address these factors concurrently.


Separation of phosphorylated sugars using capillary electrophoresis with indirect photometric detection.
Adenosine monophosphate (AMP) and naphthalene disulfonate (NDS) have been characterized as electrolytes for the indirect photometric detection of phosphorylated sugars and other organophosphorus compounds of biochemical interest. This work has resulted in the CE separation on an uncoated capillary using 5 mM AMP and 100 mM boric acid at pH 7.2 of six metabolites (glucose-6-phosphate [G6P], fructose-6-phosphate [F6P]), fructose-1,6-bisphosphate [F-1,6-P], dihydroxyacetone phosphate [DHAP], glyceraldehyde-3-phosphate [G3P], and 2-phosphoglycerate [2-PG] or 3-phosphoglycerate [3-PG]) found in the glycolytic pathway. The detection limits using a 5-sec injection time were between 0.5 and 1 mg/L for these compounds, with the exception of G3P. Resolution between 3-PG and 2-PG is possible by the addition of magnesium ion, although the separation time is longer. A successful separation of five monophosphorylated sugars (G6P, F6P, ribose-5-phosphate [R5P], sucrose-6-phosphate [S6P], and 2-PG) has been performed using the same conditions as for the glycolytic pathway separation. A separation of bisphosphorylated sugars (glucose-1,6-bisphosphate [G-1,6-P],F-1,6-P, ribulose-1,5-bisphosphate [Ru-1, 5P], and sedoheptulose-1,7-bisphosphate [S-1, 7P]) could not be performed with AMP unless magnesium chloride was added. With NDS, a separation of these bisphosphorylated sugars can be obtained without the addition of magnesium chloride.


CaMKIV over-expression boosts cortical 4-7 Hz oscillations during learning and 1-4 Hz delta oscillations during sleep.
Mounting evidence suggests that neural oscillations are related to the learning and consolidation of newly formed memory in the mammalian brain. Four to seven Hertz (4-7 Hz) oscillations in the prefrontal cortex are also postulated to be involved in learning and attention processes. Additionally, slow delta oscillations (1-4 Hz) have been proposed to be involved in memory consolidation or even synaptic down scaling during sleep. The molecular mechanisms which link learning-related oscillations during wakefulness to sleep-related oscillations remain unknown. We show that increasing the expression of calcium/calmodulin dependent protein kinase IV (CaMKIV), a key nucleic protein kinase, selectively enhances 4-7.5 Hz oscillation power during trace fear learning and slow delta oscillations during subsequent sleep. These oscillations were found to be boosted in response to the trace fear paradigm and are likely to be localized to regions of the prefrontal cortex. Correlation analyses demonstrate that a proportion of the variance in 4-7.5 Hz oscillations, during fear conditioning, could account for some degree of learning and subsequent memory formation, while changes in slow delta power did not share this predictive strength. Our data emphasize the role of CaMKIV in controlling learning and sleep-related oscillations and suggest that oscillatory activity during wakefulness may be a relevant predictor of subsequent memory consolidation.


T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission.
Acquired HIV-specific cell-mediated immune responses have been observed in exposed-uninfected individuals, and it has been inferred, but not demonstrated, that these responses constitute a part of natural protective immunity to HIV. This inference was tested prospectively in the natural exposure setting of maternal-infant HIV transmission in a predominantly breast-fed population. Cord blood from infants of HIV-seropositive women in Durban, South Africa, were tested for in vitro reactivity to a cocktail of HIV envelope peptides (Env) using a bioassay measuring interleukin-2 production in a murine cell line. Infants were followed with repeat HIV RNA tests up to 18 months of age to establish which ones acquired HIV-infection. T-helper cell responses to Env were detected in 33 out of 86 (38%) cord blood samples from infants of HIV-seropositive women and in none of nine samples from seronegative women (P = 0.02). Among infants of HIV-seropositive mothers, three out of 33 with T-helper responses to Env were already infected before delivery (HIV RNA positive on the day of birth), two were lost to follow-up, and none of the others (out of 28) were found to be HIV infected on subsequent tests. In comparison, six out of 53 infants unresponsive to Env were infected before delivery, and eight out of 47 (17%) of the others were found to have acquired HIV infection intrapartum or post-partum through breast-feeding (P = 0.02). T-helper cell responses to HIV envelope peptides were detected in more than one-third of newborns of HIV-infected women; no new infections were acquired by these infants at the time of delivery or post-natally through breast-feeding if these T-helper cell responses were detected in cord blood.


Using hydraulic head measurements in variable-density ground water flow analyses.
The use of hydraulic head measurements in ground water of variable density is considerably more complicated than for the case of constant-density ground water. A theoretical framework for dealing with these complications does exist in the current literature but suffers from a lack of awareness among many hydrogeologists. When corrections for density variations are ignored or not properly taken into account, misinterpretation of both ground water flow direction and magnitude may result. This paper summarizes the existing theoretical framework and provides practical guidelines for the interpretation of head measurements in variable-density ground water systems. It will be argued that, provided that the proper corrections are taken into account, fresh water heads can be used to analyze both horizontal and vertical flow components. To avoid potential confusion, it is recommended that the use of the so-called environmental water head, which was initially introduced to facilitate the analysis of vertical ground water flow, be abandoned in favor of properly computed fresh water head analyses. The presented methodology provides a framework for determining quantitatively when variable-density effects on ground water flow need to be taken into account or can be justifiably neglected. Therefore, we recommend that it should become part of all hydrogeologic analyses in which density effects are suspected to play a role.


Interaction of photosynthetic pigments with various organic solvents. Magnetic circular dichroism approach and application to chlorosomes
Magnetic circular dichroism (MCD) and absorption spectra have been measured on three intact photosynthetic pigments with the chlorin ring as macrocycle: chlorophyll a, bacteriochlorophyll c and d, in various hydrophilic organic solvents. The MCD intensity of a Qy(0-0) transition for the Mg chlorin derivative was sensitive to the coordination state of the central Mg atom by the solvent molecules. The coordination number has been characterized in terms of the relationship between the ratio of Qy(0-0) MCD intensity to its dipole strength (B/D) and the difference in energies of Qx(0-0) and Qy(0-0) transitions. This relationship depends not only on the coordination number of the magnesium (Mg) atom but also on the coordination interaction of the solvent molecules to the Mg atom, and can clarify the spectroscopic change of chlorosomes by alcohol treatment. We propose that the correlation between the MCD intensity of Qy(0-0) transition and the energy difference can be used as a new measure for determining the coordination number of the Mg atom and for estimating the interaction strength of the Mg atom with solvent molecules.


Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita.
Dyskeratosis congenita (DC) is an inherited bone marrow (BM) failure syndrome associated with mutations in telomerase genes and the acquisition of shortened telomeres in blood cells. To investigate the basis of the compromised hematopoiesis seen in DC, we analyzed cells from granulocyte colony-stimulating factor mobilized peripheral blood (mPB) collections from 5 members of a family with autosomal dominant DC with a hTERC mutation. Premobilization BM samples were hypocellular, and percentages of CD34(+) cells in marrow and mPB collections were significantly below values for age-matched controls in 4 DC subjects. Directly clonogenic cells, although present at normal frequencies within the CD34(+) subset, were therefore absolutely decreased. In contrast, even the frequency of long-term culture-initiating cells within the CD34(+) DC mPB cells was decreased, and the telomere lengths of these cells were also markedly reduced. Nevertheless, the different lineages of mature cells were produced in normal numbers in vitro. These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs.


Subcortical volumes in girls with tourette syndrome: support for a gender effect.
To test whether girls with Tourette syndrome (TS) show subcortical morphology that differentiates them from control subjects. MRI-based subcortical assessment was completed on 19 girls with TS age 7 to 15 years, 11 with TS only, and 8 with TS plus attention deficit hyperactivity disorder (TS + ADHD), and on 21 age- and sex-matched controls. The structures measured were the caudate, putamen, globus pallidus, and lateral ventricle volumes. Whole-brain-corrected volumes and asymmetry indices were compared using two- and three-group designs (i.e., TS versus control; TS-only versus TS + ADHD versus control). Two-group comparisons demonstrated no robust significant differences between girls with TS and gender-matched controls. Three-group comparisons demonstrated that TS-only subjects had significantly small lateral ventricles compared with TS + ADHD and control subjects. Because the two-group comparisons of the current study differed from previous reports of putamen asymmetry index as a marker for TS, retrospective comparisons with data from boys were performed. These additional comparisons showed that girls with TS had putamen asymmetry indices similar to those of boys with TS; however, control girls also showed those same patterns. Basal ganglia volume and asymmetry differences do not distinguish the girls with TS from matched controls. Gender differences confound the association between putamen asymmetry and TS. Although the numbers are small and the clinical significance is unclear, this study further indicates that girls with TS-only have smaller lateral ventricular volumes than control subjects and those with TS + ADHD.


Treatment for liver metastases from breast cancer: results and prognostic factors.
Liver metastases from breast cancer (BCLM) are associated with poor prognosis. Cytotoxic chemotherapy can result in regression of tumor lesions and a decrease in symptoms. Available data, in the literature, also suggest a subgroup of patients may benefit from surgery, but few talked about transcatheter arterial chemoembolization (TACE). We report the results of TACE and systemic chemotherapy for patients with liver metastases from breast cancer and evaluate the prognostic factors. Forty-eight patients with liver metastases, from proved breast primary cancer were treated with TACE or systemic chemotherapy between January 1995 and December 2000. Treatment results were assessed according to WHO criteria, along with analysis of prognostic factors for survival using Cox regression model. The median follow-up was 28 mo (1-72 mo). Response rates were calculated for the TACE group and chemotherapy group, being 35.7% and 7.1%, respectively. The difference was significant. The one-, two- and three-year Survival rates for the TACE group were 63.04%, 30.35%, and 13.01%, and those for the systemic chemotherapy group were 33.88%, 11.29%, and 0%. According to univariate analysis, variables significantly associated with survival were the lymph node status of the primary cancer, the clinical stage of liver metastases, the Child-Pugh grade, loss of weight. Other factors such as age, the intervals between the primary to the metastases, the maximal diameter of the liver metastases, the number of liver metastases, extrahepatic metastasis showed no prognostic significances. These factors mentioned above such as the lymph node status of the primary cancer, the clinical stage of liver metastases, the Child-Pugh grade, loss of weight were also independent factors in multivariate analysis. TACE treatment of liver metastases from breast cancer may prolong survival in certain patients. This approach offers new promise for the curative treatment of the patients with metastatic breast cancer.


A 9-Week Aerobic and Strength Training Program Improves Cognitive and Motor Function in Patients with Dementia: A Randomized, Controlled Trial.
To compare training and follow-up effects of combined aerobic and strength training versus aerobic-only training on cognitive and motor function in institutionalized patients with dementia and to explore whether improved motor function mediates improved cognitive function. Using a 9-week, parallel, three-group, single-blind, randomized, controlled trial with a follow-up assessment at week 18, we assessed 109 patients with dementia (age 85.5 ± 5.1 years) in a psycho-geriatric nursing home. Each 9-week intervention consisted of 36, 30-minute sessions. A combined group (N = 37) received and completed two strength and two walking sessions per week, an aerobic group (N = 36) completed four walking sessions, and a social group (N = 36) completed four social visits per week. Cognitive and motor functions were assessed at baseline, after the 9-week intervention, and after a consecutive 9 weeks of usual care. Baseline corrected post-test scores in the combined versus the social group were higher for global cognition, visual memory, verbal memory, executive function, walking endurance, leg muscle strength, and balance. Aerobic versus social group scores were higher for executive function. Follow-up effects reversed toward baseline values. Motor improvement did not significantly mediate cognitive improvement. Compared with a nonexercise control group, a combination of aerobic and strength training is more effective than aerobic-only training in slowing cognitive and motor decline in patients with dementia. No mediating effects between improvements in cognitive function via improved motor function were found. Future research into the underlying mechanistic associations is needed.


Pathophysiologic interactions in skeletal metastasis.
This review summarizes evidence that the formation of bone metastases is the result of multiple synergistic cellular and molecular interactions between metastatic cells and the unique microenvironment in bone. Molecular technologies have been used to detect cancer cells in bone and to define their genotypic and phenotypic properties. Bone organ cultures have been employed to analyze the ability of tumor cells to modulate bone resorption and to study the effects of resorption products on the phenotypic properties of cancer cells. Experimental models of bone metastasis provide the ability to examine the effects of modulating specific host or tumor properties in vivo by quantifying their effects on the formation of bone tumors. By means of the blood stream, cells from many common neoplasms seed bone marrow as an early clinical event. The subsequent growth of these cells into clinically significant metastatic lesions is associated with their ability to stimulate bone resorption through osteoclasts and macrophages or through a direct action on bone. In turn, the products of bone resorption, which include matrix-derived growth factors, act on the tumor cells to stimulate the expression of properties that promote their metastatic competence. These include the induction of integrin adhesion molecules, the stimulation of cell motility and chemotaxis, the enhanced expression of matrix metalloproteinases, and the stimulation of tumor cell growth. The interdependency of tumor cells and bone was recognized by Steven Paget over 100 years ago, and it provides a rational basis for the development of current therapeutic strategies against bone metastasis.


Influence of a Flat Polyimide Inlay on the Propagation of Guided Ultrasonic Waves in a Narrow GFRP-Specimen.
Structural health monitoring systems for composite laminates using guided ultrasonic waves become more versatile with the structural integration of sensors. However, the data generated within these sensors have to be transmitted from the laminate to the outside, where polyimide-based printed circuit boards play a major role. This study investigates, to what extent integrated polyimide inlays with applied sensor bodies influence the guided ultrasonic wave propagation in glass fiber-reinforced polymer specimens. For reasons of resource efficiency, narrow specimens are used. Numerical simulations of a damping-free specimen indicate reflections of the S0-mode at the integrated inlay. This is validated experimentally with an air-coupled ultrasonic technique and a 3D laser Doppler vibrometry measurement. The experimental data are evaluated with a method including temporal and spatial continuous wavelet transformations to clearly identify periodically occurring wave packages as edge reflections and distinguish them from possible inlay reflections. However, even when separating in-plane and out-of-plane movements using the 3D measurement, no reflections at the inlays are detected. This leads to the conclusion that polyimide inlays are well suited as substrates for printed circuit boards integrated into fiber-reinforced polymer structures for structural health monitoring, since they do not significantly influence the wave propagation.


[Morphofunctional changes in the intestines of rabbits as affected by cholera vibrio toxins].
Forty adult rabbits were inoculated with cholera vibrio toxins (endotoxin and enterotoxin) intravenously or into the operatively pre-isolated segments of the jejunum some of which remained intact. The examinations were carried out 3--5 hours after intravenous and 18--24 hours after intraintestinal inoculation of the toxins. Irrespective of the route of endotoxin inoculation, circulation disorders developed predominantly in the jejunum mucosa. Its content did not change in volume but the potassium ions concentration increased. Active hypersecretion in the epithelial cells of the jejunum mucosa was observed after inoculations of enterotoxin by both routes. It was followed by both quantitative and qualitative changes of its contents: increased concentration of potassium, sodium, chlorine ions and bicarbonates only in the ileum. Histopathological lesions in ;the jejunum mucosa were absent after inoculation of cholera vibrio toxins by both routes.


The quality of work life of people with severe mental disorders working in social enterprises: a qualitative study.
The aim of this phenomenological study is to provide an in-depth understanding of the meaning that people with severe mental disorders give about their quality of work life (QWL) while working in social enterprises. Semi-structured interviews with 14 participants were conducted. All interviews were recorded and transcribed verbatim. Colaizzi's framework for data analysis was used. Eight sub-themes emerged and can be better understood within two larger themes: (A) interpersonal and intrapersonal aspects of QWL and (B) structural and physical aspects. Within theme A, sub-themes were (1) having a sense of belonging to the enterprise, (2) having the feeling of being a good worker, (3) establishing relationships with co-workers, and (4) establishing relationships with supervisors. Within theme B, sub-themes were (5) working tasks, (6) working conditions, (7) working environment, and (8) organizational management. The findings highlight the importance of understanding the perspective of people with severe mental disorders regarding their QWL in order to better tailor interventions that enhance it. Although some sub-themes of QWL identified in the present study were similar to those found in previous studies conducted with other populations, a unique sub-theme of QWL was identified: having the feeling of being a good worker. Specific QWL measurement that addresses this unique sub-theme is needed when assessing QWL of people with severe mental disorders.


Morphological pattern of intrinsic nerve plexus distributed on the rabbit heart and interatrial septum.
Although the rabbit is routinely used as the animal model of choice to investigate cardiac electrophysiology, the neuroanatomy of the rabbit heart is not well documented. The aim of this study was to examine the topography of the intrinsic nerve plexus located on the rabbit heart surface and interatrial septum stained histochemically for acetylcholinesterase using pressure-distended whole hearts and whole-mount preparations from 33 Californian rabbits. Mediastinal cardiac nerves entered the venous part of the heart along the root of the right cranial vein (superior caval vein) and at the bifurcation of the pulmonary trunk. The accessing nerves of the venous part of the heart passed into the nerve plexus of heart hilum at the heart base. Nerves approaching the heart extended epicardially and innervated the atria, interatrial septum and ventricles by five nerve subplexuses, i.e. left and middle dorsal, dorsal right atrial, ventral right and left atrial subplexuses. Numerous nerves accessed the arterial part of the arterial part of the heart hilum between the aorta and pulmonary trunk, and distributed onto ventricles by the left and right coronary subplexuses. Clusters of intrinsic cardiac neurons were concentrated at the heart base at the roots of pulmonary veins with some positioned on the infundibulum. The mean number of intrinsic neurons in the rabbit heart is not significantly affected by aging: 2200 ± 262 (range 1517-2788; aged) vs. 2118 ± 108 (range 1513-2822; juvenile). In conclusion, despite anatomic differences in the distribution of intrinsic cardiac neurons and the presence of well-developed nerve plexus within the heart hilum, the topography of all seven subplexuses of the intrinsic nerve plexus in rabbit heart corresponds rather well to other mammalian species, including humans.


Mapping of neurotrophins and their receptors in the adult mouse brain and their role in the pathogenesis of a transgenic murine model of bovine spongiform encephalopathy.
Neurotrophins are a family of growth factors that act on neuronal cells. The neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3, -4 and -5. The action of neurotrophins depends on two transmembrane-receptor signalling systems: (1) the tropomyosin-related kinase (Trk) family of tyrosine kinase receptors (Trk A, Trk B and Trk C) and (2) the p75 neurotrophin receptor (p75(NTR)). The interaction between neurotrophic factors and their receptors may be involved in the mechanisms that regulate the differential susceptibility of neuronal populations in neurodegenerative diseases. The aim of the present study was to evaluate the role of neurotrophins in the pathogenesis of bovine spongiform encephalopathy (BSE) using a transgenic mouse overexpressing bovine prnp (BoTg 110). Histochemistry for Lycopersicum esculentum agglutinin, haematoxylin and eosin staining and immunohistochemistry for the abnormal isoform of the prion protein (PrP(d)), glial fibrillary acidic protein (GFAP), NGF, BDNF, NT-3 and the receptors Trk A, Trk B, Trk C and p75(NTR) was performed. The lesions and the immunolabelling patterns were assessed semiquantitatively in different areas of the brain. No significant differences in the immunolabelling of neurotrophins and their receptors were observed between BSE-inoculated and control animals, except for p75(NTR), which showed increased expression correlating with the distribution of lesions, PrP(d) deposition and gliosis in the BSE-inoculated mice.


Analytical comparison of sensor signal processing enhancements for NDT synthetic aperture ultrasonic imaging.
The results of a detailed analytical study of the effects of sensor processing techniques on clutter suppression and image enhancement for nondestructive testing (NDT) systems are presented. A relatively simple beamforming/diffraction model is developed for near-field, wideband, synthetic aperture ultrasonic imaging in NDT systems. The physical model is used to quantitatively evaluate a variety of front-end sensor signal processing tradeoffs for the enhanced detection and sizing of defects. It is shown using statistical microscopic scattering calculations that a combination of increased spatial sampling and rectangular windowing can increase the signal-to-clutter ratio by ~10 dB while maintaining crack size resolutions well below future projected specifications. The sensor signal processing image enhancements are demonstrated by the construction of simulated strip-map SAFT (synthetic aperture focusing technique) images of metallic crack defects in the presence of large numbers of randomly distributed clutter (simulated grain boundary) scatterers.


Gadolinium based contrast agents in current practice: Risks of accumulation and toxicity in patients with normal renal function.
Despite being decked as the most prized compounds in the nugget box of contrast agents for clinical radiologists, and carrying an indisputable tag of safety of the US Food and Drug Administration for close to three decades, all may not be seemingly well with the family of gadolinium compounds. If the first signs of violations of primum non nocere in relation to gadolinium-based contrast agents (GBCAs) appeared in the millennium year with the first published report of skin fibrosis in patients with compromised renal function, the causal relationship between the development of nephrogenic systemic fibrosis (NSF) and GBCAs, first proposed by two European groups in 2006, further precluded their use in renocompromised patients. The toxicity, pharmacokinetics, and pharmacodynamics of GBCAs, however, has come under hawk-eyed scrutiny with recent reports that gadolinium tends to deposit cumulatively in the brain of patients with normal hepatobiliary function and intact blood-brain barrier. While the jury on the long-term hazard significance of this critical scientific finding is still out, the use of GBCAs must be guided by due clinical diligence, avoidance of repeated doses, and preferring GBCAs with the best safety profiles.


Simultaneous determination of ethylene glycol and its major toxic metabolite, glycolic acid, in serum by gas chromatography.
We developed a gas-chromatographic procedure for the simultaneous determination of ethylene glycol (EG) and its major toxic metabolite, glycolic acid (GA), suitable for clinical use in instances of EG intoxication. After serum protein precipitation with acetonitrile (containing internal standard), the supernate is treated with 2,2-dimethoxypropane (containing dimethylformamide) to remove water, and the volume is then reduced by evaporation to <100 microL of dimethylformamide (but not to dryness). After trimethylsilyl derivatization, the resulting derivatives are analyzed by capillary column gas chromatography. Only 100 microL of serum is required and the entire determination, including calibrators and controls, takes <2 h. The method gives a linear response to at least 10 g/L EG and 5 g/L GA and has a limit of detection <10 mg/L. Intraassay CV is < or = 2.8% for EG (100 and 1000 mg/L) and GA (100 and 500 mg/L); between-day CV is < or = 6.5%. The absolute recovery from serum was 91% for EG and 77-82% for GA (200 and 2000 mg/L each). Relative to calibrators prepared bovine serum albumin (70 g/L), the recovery was 99-104% for EG (100 - 5000 mg/L) and 95-105% for GA (50 - 2500 mg/L). No clinically important interference was detected for >60 exogenous or endogenous compounds and drugs.


Acute promyelocytic leukemia with marrow fibrosis at initial presentation: possible involvement of transforming growth factor-beta(1).
Although the occurrence of marrow fibrosis in acute myeloid leukemia has been described, there have been no reports of acute promyelocytic leukemia (APL) associated with marrow fibrosis. Here we describe an APL patient with severe marrow fibrosis at initial presentation. He had the typical manifestations of APL, except for marrow fibrosis. Complete remission was achieved by treatment with all-trans retinoic acid plus chemotherapy, and his marrow fibrosis gradually improved concomitantly with the decrease in leukemic cells. To clarify the mechanism of marrow fibrosis in this patient, we investigated the expression of genes for several cytokines promoting fibrosis by the reverse transcriptase polymerase chain reaction methods. An overexpression of transforming growth factor-beta(1) was noted in his leukemic cells at initial presentation, whereas no increase in expression was observed at the time of relapse when he no longer had marrow fibrosis. These findings suggest that overexpression of transforming growth factor-beta(1) was involved in the development of marrow fibrosis in this APL patient.


Association between initial continuity of care status and diabetes-related health outcomes in older patients with type 2 diabetes mellitus: A nationwide retrospective cohort study in South Korea.
Timely and continuous care is necessary for patients with diabetes to prevent hospitalization and complications. This study investigated the association between initial Continuity of Care Index (COCI) status after diagnosis of type 2 diabetes mellitus (T2DM) and short- and long-term diabetes-related health outcomes. It targeted elderly patients aged 60 years and above diagnosed with T2DM and used the National Health Insurance Service Senior cohort data from 2008 to 2019. The outcome measures were diabetic avoidable hospitalization and diabetic complication incidence for a five-year period. The main independent variable was the first-year COCI status after T2DM diagnosis. Survival analyses were performed using the Cox proportional hazards model. Participants with a good COCI status within the first year of being diagnosed with T2DM experienced a reduced risk of diabetes-induced avoidable hospitalization (five years: Hazard ratio (HR) 0.39, 95 % Confidence interval (CI) 0.27-0.57; overall period: HR 0.56, 95 % CI 0.43-0.72) and diabetic complications (five years: HR 0.74, 95 % CI 0.68-0.80; overall period: HR 0.77, 95 % CI 0.71-0.82). In the short- and long-term, there is a need for early management and improved healthcare accessibility of diabetes to prevent diabetes-avoidable hospitalization and diabetes-related complications.


Modeling mode characteristics of transverse anisotropic waveguides using a vector pseudospectral approach.
I extend the full vector pseudospectral-based eigenvalue scheme, based on the transverse magnetic field components, to analyze the mode behaviors of dielectric optical waveguides with transverse, nondiagonal anisotropy. One of the principal axes of the anisotropic materials is thus constrained to point in the longitudinal direction of the waveguide. I expand the guided mode fields in the interior subdomains with finite extent by using Chebyshev polynomials and those in the exterior subdomains with semi-infinite extent by using Laguerre-Gaussian functions with an accurately determined scaling factor. This study analyzes two examples: (1) the circularly-polarized modes of a magneto-optical raised strip waveguide and (2) the guided mode patterns of a nematic liquid-crystal channel waveguide under different orientations of the liquid-crystal molecule. The comparison of the numerical results with those from the vector finite difference approach demonstrates that my numerical approach has a higher computational efficiency and requires less computer memory.


International virtual e-hospital: the Balkans journey.
What started in Berlin in May of 2000 as an idea to create the telemedicine program of Kosova in order to help the country rebuild the broken medical system and change the miserable face of medicine, has now spread to other countries in the Balkans. Today, June 29, 2007, as I am rewriting this chapter, ten doctors and engineers from Kosova, Montenegro and Macedonia graduated from a three weeks intensive course on telemedicine, e-health and medical electronic library. This international telemedicine fellowship is organized by the very entity that was created in Berlin 7 years ago: The International Virtual e-Hospital (IVEH). This time, however they are part of a project called "Improving Health Care in the Balkans Using Telemedicine, Advanced Technologies and Cultural Exchange Programs as a Platform" funded by the Bureau of Education and Cultural Exchange of the State department of USA, and is being implemented in collaboration with Arizona Telemedicine Program and University of Arizona Health Science Center Library, as well as Alaska Telemedicine program in Anchorage. The goal of the program is to create the medical and technical leadership that will significantly enhance health care access and quality in the region. This program is creating a powerful international medical education network in the Balkans for further collaboration and development. As part of the project, 48 physicians, nurses and engineers from Kosova, Montenegro, Macedonia and Albania are being trained in telemedicine, e-health, electronic library management, trauma and surgical critical care. A group of experts in these same medical disciplines will conduct workshops, seminars and other cultural and educational activities in the Balkan region. We can say now with certainty that the Telemedicine Program of Kosova is having an impact in the region that goes far beyond telemedicine applications and advanced technologies in the Balkans. It is creating leadership that will take the future in their own hands, as they become the true champions of telemedicine and rebuilding the dream of advancing the health care in their own countries. As we say at IVEH, it is "one country at a time." In October, we will inaugurate the Second Phase of the Telemedicine Program of Kosova. On October 21-23, in Tirana, Albania, we will organize the Second Intensive Balkan Telemedicine and e-health seminar, a three-day workshop on current principles and practices of telemedicine, e-health, and medical informatics. The journey that started in Berlin is continuing. Soon we will be traveling to Atalaya, Peru and other communities of Amazon River, then Africa. We will not stop. One country at a time!


Electron imaging of pyrrhotite superstructures.
Natural pyrrhotites, when studied by high resolution electron microscopy, yield crystallographic information on a unit cell scale. Structural heterogeneity is prominent. The many reported superstructures are interpretable through an antiphase model. The 5C pyrrhotite superstructure results from an ordered sequence of antiphase domains while the higher temperature NC type results from a disordered sequence.


Just run: Development of a theory-based motivational online intervention for promoting ongoing running participation.
Running is a popular form of physical activity yet discontinuation is common. Interventions targeting physical activity adoption have shown modest effects, often with little translation into long-term participation, which may limit the health benefits available to the wider community. This paper details the development of a new online running intervention (Just Run) aimed at improving continuation of running activity in new runners through a motivational and psychological lens, including aspects of design, content, refinement, and usability testing. A six-step intervention mapping process was used to develop a theory-based online intervention using a mix of research designs. Key stakeholders including runners, coaches and relevant experts in physical activity and behavior change provided valuable insight, feedback and refinement of the education to be delivered. The final Just Run intervention included 10 modules delivered online over 12 weeks to promote ongoing running participation through videos, testimonials, and activities. Key themes identified through the literature and stakeholder engagement process related to goal setting, self-efficacy, intrinsic motivation, social support and overcoming barriers to running participation. Usability testing confirmed the quality and suitability of the education to the target population. Just Run has been developed with a range of stakeholders to address an area of unmet need in the adoption and promotion of running as a form of physical activity in the community. Just Run is a robust online intervention that has been designed and pre-tested with positive feedback and unique insights from key stakeholders. Further investigation is required to support its implementation to the wider community.


Transcriptomic analysis supports similar functional roles for the two thymuses of the tammar wallaby.
The thymus plays a critical role in the development and maturation of T-cells. Humans have a single thoracic thymus and presence of a second thymus is considered an anomaly. However, many vertebrates have multiple thymuses. The tammar wallaby has two thymuses: a thoracic thymus (typically found in all mammals) and a dominant cervical thymus. Researchers have known about the presence of the two wallaby thymuses since the 1800s, but no genome-wide research has been carried out into possible functional differences between the two thymic tissues. Here, we used pyrosequencing to compare the transcriptomes of a cervical and thoracic thymus from a single 178 day old tammar wallaby. We show that both the tammar thoracic and the cervical thymuses displayed gene expression profiles consistent with roles in T-cell development. Both thymuses expressed genes that mediate distinct phases of T-cells differentiation, including the initial commitment of blood stem cells to the T-lineage, the generation of T-cell receptor diversity and development of thymic epithelial cells. Crucial immune genes, such as chemokines were also present. Comparable patterns of expression of non-coding RNAs were seen. 67 genes differentially expressed between the two thymuses were detected, and the possible significance of these results are discussed. This is the first study comparing the transcriptomes of two thymuses from a single individual. Our finding supports that both thymuses are functionally equivalent and drive T-cell development. These results are an important first step in the understanding of the genetic processes that govern marsupial immunity, and also allow us to begin to trace the evolution of the mammalian immune system.


A difference in timing for the onset of visual and chemosensory systems during embryonic development in two closely related cuttlefish species.
Embryos perceive environmental stimuli, thanks to their almost mature sensory systems. In cuttlefish, the embryonic development of Sepia officinalis and Sepia pharaonis is similar but the egg capsule transparency is different. S. officinalis' eggs are black (ink), which provide protection from predators. Conversely, those of S. pharaonis are translucent. The aim of this study was to test the visual and chemosensory perception abilities of these two cuttlefish embryos by observation of the ventilation rate (VR) before and after stimulation. Our results show that S. pharaonis responds to light at stage 22 and S. officinalis at stage 24. Conversely, S. pharaonis responds to predator odor at stage 23 and S. officinalis at stage 22. Both species are able to respond to these stimuli before hatching but do not have the same developmental schedule. Neither are the responses of the two cuttlefish exactly the same. In S. officinalis, VR increases after stimulations. In S. pharaonis, VR increases after light stimulation and decreases following the odor stimulation after stage 25. This result could reveal an ability to recognize stimuli at stage 25. The decrease could be identified as freezing-like behavior which would be more adaptive than an increase, since the embryos are visible.


Untying the knot: protein quality control in inherited cardiomyopathies.
Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity worldwide. Although genetic screening procedures for early disease detection have been improved significantly, treatment to prevent or delay mutation-induced cardiac disease onset is lacking. Recent findings indicate that loss of protein quality control (PQC) is a central factor in the disease pathology leading to derailment of cellular protein homeostasis. Loss of PQC includes impairment of heat shock proteins, the ubiquitin-proteasome system, and autophagy. This may result in accumulation of misfolded and aggregation-prone mutant proteins, loss of sarcomeric and cytoskeletal proteins, and, ultimately, loss of cardiac function. PQC derailment can be a direct effect of the mutation-induced activation, a compensatory mechanism due to mutation-induced cellular dysfunction or a consequence of the simultaneous occurrence of the mutation and a secondary hit. In this review, we discuss recent mechanistic findings on the role of proteostasis derailment in inherited cardiomyopathies, with special focus on sarcomeric gene mutations and possible therapeutic applications.


[Cefixime versus amoxicillin plus netilmicin in the treatment of community-acquired non-complicated acute pyelonephritis].
Community-acquired non-complicated acute pyelonephritis (APN) is a frequent, occasionally serious infection (around 20% of the cases are bacteremic) that usually requires hospital admission. The third generation oral cephalosporins which are active against more than 95% of E. coli strains should allow the outpatient management of these patients. To evaluate the bacteriological and clinical efficacy of oral cefixime in comparison to amoxicilin plus netilcilin in the treatment of APN. Patients older than 18 years affected by APN were included in a fourteen month prospective study. According to a random numbers chart, the patients received cefixime (400 mg/24 h in a single daily dose for 12 days) or amoxicilin (1 g/8 h per os) plus netilmicin (4 mg/kg/24 h in a single intramuscular daily dose) during five days followed by 7 days of an oral treatment chosen according to the susceptibility pattern of isolated microorganism. Sixty-one patients received cefixime and 65 amoxicillin plus retilmicin. There were no significant differences between both groups of patients. Thirty-two patients presented bacteremia (25.4%). The mean (SD) eak and trough concentrations of netilmicin were 11.4 (2.8) mg/l and 0.38 (0.4) mg/l, respectively. Clinical response was favorable in 97% of patients treated with cefixime and in 98% of those treated with amoxicilin plus netilmicin (p = NS). The infection recurred in 10 out of 59 patients (16.9%) in the cefixime arm of the study and in 9 out of 64 patients (14%) treated with amoxicillin plus netilmicin (p = NS). Tolerance to the study drugs was good in both arms of the study, and renal function remained normal. Cefixime seems to be an acceptable alternative to the regimens containing an aminopenicillin and an aminoglycoside for the treatment of community-acquired non-complicated APN.


Cell stress is related to re-localization of Argonaute 2 and to decreased RNA interference in human cells.
Various kinds of stress on human cells induce the formation of endogenous stress granules (SGs). Human Argonaute 2 (hAgo2), the catalytic core component of the RNA-induced silencing complex (RISC), can be recruited to SGs as well as P-bodies (PBs) indicating that the dynamic intracellular distribution of hAgo2 in SGs, in PBs or at other sub-cellular sites could be related to the efficiency of the RNA interference (RNAi) machinery. Here, we studied the influence of heat shock, sodium arsenite (NaAsO2), cycloheximide (CHX) and Lipofectamine 2000-mediated transfection of phosphorothioate (PS)-modified oligonucleotides (ON) on the intracellular localization of hAgo2 and the efficiency of RNAi. Fluorescence microscopy and sedimentation analysis of cell fractions indicate stress-induced accumulation of hAgo2 in SGs and the loss of distinctly composed complexes containing hAgo2 or their sub-cellular context. Transfection of cells with PS-ON induces cell stress that is phenotypically similar to the established inducers heat shock and NaAsO2. The intracellular re-distribution of hAgo2 is related to its increased metabolic stability and to decreased RNAi directed by microRNA or by short interfering RNA. Here, we propose a functional model of the relationship between cell stress, translocation of hAgo2 to SGs providing a depot function, and loss of RNAi activity.


A patient-led educational program on Tourette Syndrome: impact and implications for patient-centered medical education.
Graduate medical education about Tourette Syndrome does not typically focus on understanding the perspectives and perceptions of individuals with the condition. Explore the impact of patient-centered, patient-led education programs on participant knowledge and empathy for patients. Seventy-nine medical residents and students at five training sites in New Jersey attended patient-led presentations. Results were obtained using a pretest-posttest design assessing physician empathy, using the 10 perspective-taking items from the Jefferson Scale of Empathy. Additional understanding of residents' experience was obtained by analyzing participant generated reaction statements. A factorial ANOVA (pretest, Posttest × Gender × Specialty) revealed a significant increase (p < .05) from total pre-presentation scores to total post-presentation scores indicating that participants endorsed a more empathic view following the patient-led presentation. Participant statements revealed themes concordant with the practice of patient-centered medicine. Providing patient-led educational presentations to medical residents can increase physician empathy, increase knowledge of Tourette Syndrome, and support the advancement of patient-centered medical education.


Antitoxic immunity in experimental cholera: observations with purified antigens and the ligated ileal loop model.
Rabbits immunized with purified antigens, choleragen and choleragenoid (cholera exo-enterotoxin and natural toxoid), were found to resist intra-intestinal challenge with a variety of strains of cholera vibrios. The resistance occurred in the absence of a significant antibacterial antibody response. In fact, the antigens were incapable of protecting mice against the septicemic infection of the standard mouse protection test used for bioassay of conventional cholera vaccines. The immunized rabbits did, however, develop a significant antitoxin titer demonstrable by passive hemagglutination, although the presence of antitoxic coproantibody could not be established conclusively. The results suggest the potential value of antitoxic immunity in cholera and are consistent with the existence of only one serological type of cholera exo-enterotoxin.


Perioperative music may reduce pain and fatigue in patients undergoing laparoscopic cholecystectomy.
Acute post-operative pain is a predictor in the development of chronic pain after laparoscopic cholecystectomy. Music has been shown to reduce surgical stress. In a randomized, clinical trial, we wanted to test the hypothesis that perioperative and post-operative soft music reduces pain, nausea, fatigue and surgical stress in patients undergoing laparoscopic cholecystectomy as day surgery. The study was performed in otherwise healthy Danish patients eligible for day surgery. Ninety-three patients were included and randomized to either soft music or no music perioperatively and post-operatively. Using visual analog score pain, nausea and fatigue at baseline, 1 h, 3 h, 1 day and 7 days after surgery were recorded. C-reactive protein and cortisol were sampled before and after surgery. Music did not lower pain 3 h after surgery, which was the main outcome. The music group had less pain day 7 (P = 0.014). Nausea was low in both groups and was not affected by music. The music group experienced less fatigue at day 1 (P = 0.042) and day 7 (P = 0.015). Cortisol levels decreased during surgery in the music group (428.5-348.0 nmol/l), while it increased in the non-music group (443.5-512.0 nmol/l); still, the difference between the two groups were only significant using general linear models as post-hoc analysis. Soft music did not affect C-reactive protein levels. Soft music did not reduce pain 3 h after laparoscopic cholecystectomy. Soft music may reduce later post-operative pain and fatigue by decreasing the surgical stress response.


The microcomputer-based color image analyzer and its application to histochemistry.
For quantification of histochemical reactions, color image analysis, as well as cytophotometry, is important. However, the extremely large amount of information, usually more than one million bits per image, involved in one microscopic picture of a colored histochemical specimen, when digitalized, has inhibited attempts to develop a more convenient system of color image analysis. Recent advances in microcomputer technology have now made it possible to build, at a reasonable cost, an intelligent color terminal equipped with array-processing hardware, a sufficiently large video random-access memory to represent 4096 colors in each pixel, and packages of machine language subroutines called "macro-commands" in the form of read-only memory that can process color images within a few seconds. This intelligent terminal can easily be controlled by a small personal computer via an IEEE-488 interface bus. The digitalized color image can be stored in and retrieved from a floppy disk. As the macro-commands in this system are controlled by BASIC program through CALLS with parameters, it is highly flexible and adapts readily to the varied needs of histochemists. Reported on herein will be the instrumentation of the microcomputer-based color image analyzer and a few examples of applications of this system to histochemistry: color intensification of cytochemical reactions, quantification of enzyme (e.g., horseradish peroxidase) reaction products, periodic acid-Schiff staining, collagen fibers visualized by Azan-Mallory stain, etc. Possible future applications of this color image analyzer will also be discussed.


What is in the toolkit (and what are the tools)? How to approach the study of doctor-patient communication.
Doctor-patient communication is important, but is challenging to study, in part because it is multifaceted. Communication can be considered in terms of both the aspects of the communication itself, and its measurable effects. These effects are themselves varied: they can be proximal or distal, and can focus on subjective measures (how patients feel about communication), or objective measures (exploring more concrete health outcomes or behaviours). The wide range of methodologies available has resulted in a heterogeneous literature which can be difficult to compare and analyse. Here, we provide a conceptual approach to studying doctor-patient communication, examining both variables which can controlled and different outcomes which can be measured. We present methodologies which can be used (questionnaires, semistructured interviews, vignette studies, simulated patient studies and observations of real interactions), with particular emphasis on their respective logistical advantages/disadvantages and scientific merits/limitations. To study doctor-patient communication more effectively, two or more different study designs could be used in combination. We have provided a concise and practically relevant review of the methodologies available to study doctor-patient communication to give researchers an objective view of the toolkit available to them: both to understand current research, and to conduct robust and relevant studies in the future.


Oncology Patients Are High Cost Outliers in Total Joint Replacement Bundled Payment Systems.
In 2016, the Centers for Medicare and Medicaid Services began its first mandatory bundled payment program, the Comprehensive Care for Joint Replacement (CJR) model, which covers a 90-day episode of care. This study determined whether oncology patients enrolled in the CJR bundle incur higher hospital costs than patients with osteoarthritis (OA). A retrospective review of all patients enrolled in the CJR bundled payments system from April 1, 2016 to June 31, 2018 at a single academic medical center was conducted. To determine whether tumor patients had higher total episode costs, this group was compared to patients diagnosed with OA using a 2-tailed t-test. To adjust for moderators of total hospital costs, we used generalized linear regression with a log-link, including multiple variables abstracted from chart review. Three hundred fourteen patients met inclusion criteria (12 primary or metastatic tumors, 302 OA). Fifty-eight percent of tumor patients were over the target price vs 16% of OA patients. The mean tumor patient had $40,862 for total internal hospital costs compared to $16,356 in the OA group (P < .001). Length of stay was greater in the tumor group (6.75 vs 2.0 days, P < .001). A greater percentage of tumor patients were discharged to a skilled nursing facility (67% vs 27%, P = .006) with significantly higher skilled nursing facility episode costs ($18,852 vs $7731, P = .04). With adjustment for fracture status, tumor patients were 5.36 times more likely to exceed the CJR target price than OA patients (risk ratio 5.36, confidence interval 3.44-8.35, P < .001) and 50 times more likely to be outliers over the regional threshold than OA patients (risk ratio 50.33, confidence interval 16.33-155.19, P < .001). Oncology patients enrolled in the CJR bundled payment model incur significantly higher costs and have higher cost variability than patients with OA. We recommend that oncology patients be excluded from the CJR bundle.


The Modern Use of an Ancient Plant: Exploring the Antioxidant and Nutraceutical Potential of the Maltese Mushroom (Cynomorium Coccineum L.).
In the continuous scientific search for new safe and effective drugs, there has recently been a rediscovery of natural substances as a potential reservoir of innovative therapeutic solutions for human health, with the prospect of integrating with and sometimes replacing conventional drugs. Cynomorium coccineum subsp. coccineum is a holoparasitic plant well known in ethnopharmacology, although its current use as a curative remedy is reported only in some ethnic groups of North Africa and the Arabian Peninsula. Often known as 'Maltese mushroom' due to its unique appearance and the absence of chlorophyll, C. coccineum is present in almost all of the Mediterranean Basin. It is only recently that a few research groups have begun to look for confirmation of some of its traditional uses to highlight previously unknown biological activities. Here, we review the recent scientific findings on the plant's phytochemistry and the most significant descriptions of some of its antioxidant and biological activities (antimicrobial, anticancer, pro-erectile, and anti-tyrosinase enzyme) both in vivo and in vitro. Some of these may be promising from the perspective of food and cosmetic formulations. The purpose of this review is to provide an initial impetus to those who, in the foreseeable future, will want to increase the knowledge and possible applications of this plant full of history, charm, and mystery.


Ecological niche modelling of bank voles in Western Europe.
The bank vole (Myodes glareolus) is the natural host of Puumala virus (PUUV) in vast areas of Europe. PUUV is one of the hantaviruses which are transmitted to humans by infected rodents. PUUV causes a general mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Vector-borne and zoonotic diseases generally display clear spatial patterns due to different space-dependent factors. Land cover influences disease transmission by controlling both the spatial distribution of vectors or hosts, as well as by facilitating the human contact with them. In this study the use of ecological niche modelling (ENM) for predicting the geographical distribution of bank vole population on the basis of spatial climate information is tested. The Genetic Algorithm for Rule-set Prediction (GARP) is used to model the ecological niche of bank voles in Western Europe. The meteorological data, land cover types and geo-referenced points representing the locations of the bank voles (latitude/longitude) in the study area are used as the primary model input value. The predictive accuracy of the bank vole ecologic niche model was significant (training accuracy of 86%). The output of the GARP models based on the 50% subsets of points used for testing the model showed an accuracy of 75%. Compared with random models, the probability of such high predictivity was low (χ(2) tests, p < 10(-6)). As such, the GARP models were predictive and the used ecologic niche model indeed indicates the ecologic requirements of bank voles. This approach successfully identified the areas of infection risk across the study area. The result suggests that the niche modelling approach can be implemented in a next step towards the development of new tools for monitoring the bank vole's population.


The efficacy of the combined procedure in involutional entropion surgery: a comparative study.
To evaluate the efficacy of the combined procedure in the management of involutional entropion. In this study, we reviewed 45 eyes of 36 patients who underwent the combined procedure (lateral tarsal strip, retractor tightening, and everting sutures) for the management of involutional lower eyelid entropion and compared the results with 31 eyes of 25 patients who underwent the Wies procedure. Exclusion criteria included previous lower eyelid surgery and follow-up of less than 6 months. No patients demonstrated entropion on the first postoperative day. The mean follow-up period was 18.4 months (6 to 52 months) in the Wies group and 22.6 months (6 to 59 months) in the combined procedure group. During the follow-up period, 9 of 31 eyes in the Wies group presented with recurrence and only 1 of 45 eyes in the combined procedure group presented with recurrence (p = 0.001). The average time of recurrence was 4.8 months in the Wies group. Recurrence occurred at 2 months postoperatively in the patient in the combined procedure group. Six of the 9 recurrences in the Wies group were managed by the combined procedure. None of these patients had further recurrence after correction. Three patients complained about a visible incision line after the Wies procedure. The combined procedure seems to be more effective than the Wies procedure in the management of involutional entropion. The combined procedure addresses the three major causative factors in involutional entropion and makes it possible to perform the surgery using a small incision.


Osteogenesis regulation of mesenchymal stem cells via autophagy induced by silica-titanium composite surfaces with different mechanical moduli.
The high surface elastic modulus of the titanium (Ti) implant is one of the critical factors causing poor osteointegration between the implant surface and surrounding bone tissue. To address this challenge, spherical silica nanoparticles (SSNs) and spherical titania nanoparticles (STNs) with different sizes were synthesized and embedded into Ti surfaces via a micro-arc oxidation (MAO) technique. There were no significant changes in the surface roughness and protein adsorption behaviors before and after the embedding of spherical silica nanoparticles and titania nanoparticles into the Ti implant. However, the surface elastic modulus of Ti-SSNs decreased from 93 GPa to 6.7 GPa, while there was still no change in surface elastic modulus between Ti and Ti-STN groups. In vitro experiments showed that Ti-SSNs, especially Ti-SSN3, significantly stimulated the expression level and nuclear localization of the transcription factor YAP. YAP/TAZ could further inhibit the phosphorylation of AKT and mTOR proteins in MSCs, leading to higher LC3-II protein expression and osteogenic differentiation of MSCs. Ti-SSNs also showed a higher level of autophagosome formation, ALP activity and mineralization capability compared to the other groups. Our results showed that the surface elasticity modulus of an implant plays an important role in the regulation of MSC behaviors. Therefore, designing an implant with an optimal elastic modulus at the surface might have great clinical potential in the bone repair field.


The effect of feature selection on multivariate pattern analysis of structural brain MR images.
Clinical predictions performed using structural magnetic resonance (MR) images are crucial in neuroimaging studies and can be used as a successful complementary method for clinical decision making. Multivariate pattern analysis (MVPA) is a significant tool that helps correct predictions by exhibiting a compound relationship between disease-related features. In this study, the effectiveness of determining the most relevant features for MVPA of the brain MR images are examined using ReliefF and minimum Redundancy Maximum Relevance (mRMR) algorithms to predict the Alzheimer's disease (AD), schizophrenia, autism, and attention deficit and hyperactivity disorder (ADHD). Three state-of-the-art MVPA algorithms namely support vector machines (SVM), k-nearest neighbor (kNN) and backpropagation neural network (BP-NN) are employed to analyze the images from five different datasets that include 1390 subjects in total. Feature selection is performed on structural brain features such as volumes and thickness of anatomical structures and selected features are used to compare the effect of feature selection on different MVPA algorithms. Selecting the most relevant features for differentiating images of healthy controls from the diseased subjects using both ReliefF and mRMR methods significantly increased the performance. The most successful MVPA method was SVM for all classification tasks.


Shared Genetic Contribution of Type 2 Diabetes and Cardiovascular Disease: Implications for Prognosis and Treatment.
The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes. Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap. Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses.


Outcomes of patients admitted to the intensive care unit with community-acquired pneumonia in a tertiary care center in Riyadh, Saudi Arabia.
Community-acquired pneumonia (CAP) is a leading cause of intensive care unit (ICU) morbidity and mortality. Despite extensive international epidemiological and clinical studies to improve those patients' outcomes, local statistics in Saudi Arabia are limited. The objective of this study is to describe the clinical characteristics and outcomes of patients admitted to the ICU with the diagnosis of CAP reflecting the experience of a tertiary center over an 18-year period. A retrospective cohort study included all consecutive adult ICU patients diagnosed with CAP between 1999 and 2017. Baseline demographics, patients' risk factors, and initial admission laboratory investigations were compared between survivors and nonsurvivors. A multivariate regression model was used to predict mortality. During the study period, there were 3438 patients admitted to the ICU with CAP (median age 67 [Quartile 1, 3 (Q1, Q3) 51, 76] years) and 54.4% were males, of whom 1007 (29.2%) died. The survivors compared with nonsurvivors were younger (65 vs. 70 years), less likely to have chronic liver disease (2.4% vs. 10.5%), chronic renal failure (8.1% vs. 14.4%), and be immunocompromised (10.2% vs. 18.2%), and less frequently required mechanical ventilation or vasopressors (46.2% vs. 80.5% and 29.6% vs. 55.9%, respectively). Acute Physiology and Chronic Health Evaluation (APACHE) II score was significantly higher among nonsurvivors (median score 26 vs. 20) with a longer duration of mechanical ventilation and ICU stay. Using a multivariate regression model, age, APACHE II score, bilirubin level, vasopressors, and mechanical ventilation were significantly associated with increased mortality, while diabetes was associated with lower mortality. Around one-third of patients admitted to the ICU with CAP died. Mortality was significantly associated with age, APACHE II score, vasopressor use, and mechanical ventilation. A comprehensive national registry is needed to enhance epidemiological data and to guide initiatives for improving CAP patients' outcomes.


Heat shock regulatory gene rpoH mRNA level increases after heat shock in Escherichia coli.
The Escherichia coli rpoH gene product sigma 32 is essential for the increase in heat shock gene transcription found after exposure of the bacteria to a sudden temperature increase. It is not known how the concentration of active sigma 32 is modulated. We showed that rpoH transcript levels increased after heat shock and that the magnitude of the increase in the level of mRNA was correlated with the magnitude of the temperature shift. The increase in the level of rpoH mRNA was still found in rpoH mutants so the mechanism of induction differed from that of the set of previously identified heat shock genes. The increased concentration of rpoH mRNA should result in a higher level of sigma 32, which is likely to be important for increasing heat shock gene transcription.


Life after placement: experiences of older rural caregivers after placing a family member into residential care.
The community care philosophy in Australia has led to a number of older people remaining in their own homes, dependant on others for the majority of their care needs. A small number of older people being cared for by a family member or friend will move into residential aged care facilities for full-time care. This article describes a qualitative study that explored the meanings that older rural Australian caregivers gave to their day-to-day lives after their care-receiver had entered full-time residential aged care. Semi-structured interviews with seven older caregivers were conducted to gain understandings about their 'life after placement'. Thematic analysis was employed to identify common themes. Quality of life concepts provided the boundaries to the research questions. The sample included four men and three women. In the study, the men reported spending more time continuing their carer role, while the women reported being more focussed on reconnecting with the community. Both men and women reported that their own health was a major constraint in being able to maintain these two tasks. The findings mirrored those of similar studies with one notable exception: this study highlighted the meanings that caregivers gave to their lives after placement in a more holistic way, as opposed to focussing on caregivers in relation to the residential aged care facility context alone. This study demonstrated that there are differences found in relation to gender and tasks after in-home caring roles have ended. Worry about loss of driving ability was a major concern in the caregivers' lives. The experiences of the caregivers in this study give a better understanding of what life is like for caregivers after in-home caring has ceased. Understanding of 'life after placement' expands our knowledge about carers and the role of carer. The findings suggest a need for funding and programs for caregivers after their in-home carer role has ended to assist caregivers (particularly men) in reconnecting with people and activities outside their immediate family. The findings may direct rural community development workers to appreciate the challenges that older rural caregivers face when their in-home caring role ends and visiting and socializing is dependant on their ability to drive. This study also offers a perspective for residential aged care staff to consider as they work with families placing an older family member into full-time care. If aged care staff recognise the value of the continuing caring role of the caregiver and integrate them into the care plan, enhanced positive outcomes could transpire for both caregiver and care-recipient.


Bone scan in mastocytosis: case report.
A 45-year old man with well-documented systemic mastocytosis showed generalized symmetric increased activity on bone imaging. These scan findings are grossly indistinguishable from those of patients with renal osteodystrophy or secondary hyperparathyroidism. The images of the hands, however, failed to show the changes observed in secondary hyperparathyroidism. The mechanism for this intense activity is thought to be due to aberrant new-bone formation.


A non-enzymatic glucose sensor with enhanced anti-interference ability based on a MIL-53(NiFe) metal-organic framework.
Non-enzymatic glucose sensors are attracting significant attention owing to their low cost, storage convenience and reusability; however, their poor anti-interference caused by their weak selectivity towards glucose limits their practicability. In the present study, a MIL-53(NiFe) metal-organic framework (MOF) was prepared on Ni foam to serve as a self-supported electrode for non-enzymatic glucose detection. Due to the abundant active sites in the MIL-53(NiFe) MOF and its good stability in an alkaline solution, the sensors exhibited a high sensitivity (41.95 mA mM-1 cm-2) and a low detection limit (0.67 μM). Moreover, the molecular sieve effect of the MIL-53(NiFe) MOF led to a remarkable anti-interference ability, even at the interference concentrations of up to 20% glucose, a higher value than that in human serum. In addition, a heat treatment was carried out to remove the residual terephthalic acid in the MOF tunnels, and this promoted the detection linear range to 2-1600 μM. The reusability, reproducibility and long-term stability of the sensors were also studied, and the results implied good practicability of the MIL-53(NiFe) MOF-based sensors. Furthermore, the good practicability of the sensors was verified by testing human serum samples. The results showed the relative standard deviation of 2.73% from the hospital results, and the standard recovery was nearly 100%.


The impact of funding changes on the implementation of primary health care policy.
To ascertain how new funding arrangements, introduced in New Zealand's 2001 Primary Health Care (PHC) Strategy, have impacted on the expansion of nurses' role in general practice. Nurses are central to the new policy that was designed to improve the health status of New Zealanders and reduce inequalities in health. Nurses were to be a crucial part of the PHC team, expanding their current roles to provide increased access to appropriate services. This paper investigates how the new funding arrangements, introduced as part of the policy, have impacted on the expansion of nurses' roles and consequently the realisation of the policy goals. Semi-structured interviews were undertaken with 128 key stakeholders five years after the introduction of the PHC Strategy, and surveys were completed by practice nurses, general practitioners and practice managers in purposively selected practices within the 20 participating Primary Health Organisations. There has been substantial growth in the development of nursing roles for some nurses in general practice; however, this expansion has not been universal and one of the main reasons for this is the way funding devolves at the practice level. One of the consequences of the policymakers not taking into account the business model of the majority of general practices, is the resulting overarching goal of the strategy not being realised, and inequalities in health status remaining.


Comparative Evaluation of Combinatory Interaction between Endocannabinoid System Compounds and Poly-L-lysine against Streptococcus mutans Growth and Biofilm Formation.
Endocannabinoid/endocannabinoid-like (EC/EC-like) are natural endogenous compounds which have been found to affect MRSA pathogenicity. Our previous studies showed that EC/EC-like was able to impair staphylococcal biofilm formation and maintenance as well as to alter biofilm-associated virulence factors. In the present study, we investigated the combinatory effect of the selected EC/EC-like with a natural antimicrobial agent, poly-L-lysine, on cariogenic bacteria Streptococcus mutans growth and biofilm formation. Among four tested EC/EC-like, only two, anandamide (AEA) and oleoylethanolamide (OEA), exhibited synergistic combinatory effect with poly-L-lysine against S. mutans. We attribute this distinct effect to differences in the fatty acid chain structure of the selected EC/EC-like compounds. Moreover, AEA exerted a specific antibiofilm mode of action against S. mutans by effecting total inhibition of biofilm formation while still allowing bacteria viability. Finally, we postulate that the presence of EC/EC-like and poly-L-lysine could enhance the permeability and efficacy of each other via hydrophobic and electrostatic interactions with the S. mutans membrane. In conclusion, we assume that a combination of endogenous natural compounds such as EC/EC-like and poly-L-lysine may benefit oral hygiene by preventing dental plaque.


Quality of reporting of diagnostic accuracy studies.
To evaluate quality of reporting in diagnostic accuracy articles published in 2000 in journals with impact factor of at least 4 by using items of Standards for Reporting of Diagnostic Accuracy (STARD) statement published later in 2003. English-language articles on primary diagnostic accuracy studies in 2000 were identified with validated search strategy in MEDLINE. Articles published in journals with impact factor of 4 or higher that regularly publish articles on diagnostic accuracy were selected. Two independent reviewers evaluated quality of reporting by using STARD statement, which consists of 25 items and encourages use of a flow diagram. Total STARD score for each article was calculated by summing number of reported items. Subgroup analyses were performed for study design (case-control or cohort study) by using Student t tests for continuous outcomes and chi(2) tests for dichotomous outcomes. Included were 124 articles published in 2000 in 12 journals: 33 case-control and 91 cohort studies. Only 41% of articles (51 of 124) reported on more than 50% of STARD items, while no articles reported on more than 80%. A flow chart was presented in two articles. Assessment of reporting on individual items of STARD statement revealed wide variation, with some items described in 11% of articles and others in 92%. Mean STARD score (0-25 points available) was 11.9 (range, 3.5-19.5). Mean difference in STARD score between cohort studies and case-control studies was 1.53 (95% confidence interval: 0.24, 2.82). Quality of reporting in diagnostic accuracy articles published in 2000 is less than optimal, even in journals with high impact factor. Authors, editors, and reviewers should pay more attention to reporting by checking STARD statement items and including a flow diagram to represent study design and patient flow.


Anaemia in acute, Plasmodium falciparum malaria in children from Orissa state, India.
The severity of anaemia associated with acute, Plasmodium falciparum malaria and the extent to which haemolysis, bone-marrow suppression, and pre-existent iron deficiency contribute to the anaemia were assessed in 102 Indian children aged 2-12 years. Blood haemoglobin (Hb), plasma unconjugated bilirubin and haptoglobin, serum iron and transferrin concentrations and transferrin saturation, red cell morphology and reticulocyte response were investigated in the patients and in 50 control children. Twenty-three patients with severe anaemia (< 70 g Hb/litre) were investigated further, by bone-marrow biopsy followed by iron staining of sections or touch smears of the biopsy material. There was evidence of haemolysis in the malaria cases: in the peripheral blood smears and the significantly higher plasma concentrations of unconjugated bilirubin, lower plasma concentrations of haptoglobin and lower blood concentrations of Hb than those seen in the controls. Haemoglobin concentration correlated directly with haptoglobin (r = 0.489; P < 0.001) and inversely with unconjugated bilirubin in malaria patients (r = -0.526; P < 0.001) but not in controls (r = -0.140 and -0.061, respectively). Parasitaemia (parasites/microliter) was not significantly correlated with Hb, haptoglobin or unconjugated bilirubin. Compared with the earlier samples, follow-up samples from the patients, collected 2 weeks after discharge from hospital and antimalarial therapy, showed significant increase in Hb, haematocrit, haptoglobin and decreases in both total and unconjugated bilirubin. There was evidence of hypercellularity and mild-moderate erythroid hyperplasia, mainly of normoblastic maturation with adequate reticulocyte response, in the bone-marrow samples from the cases of severe anaemia; dyserythropoiesis was only noticed in one case and no stainable iron was detectable in 17 of the 23 cases. These observations indicate that haemolysis is the prime cause of the anaemia seen in acute falciparum malaria, although destruction of parasitised erythrocytes is not the sole cause of the haemolytic process. Bone-marrow suppression appears to have an insignificant role but pre-existent iron deficiency aggravates the severity of the anaemia.


Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells.
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.


Double trouble - primary biliary cholangitis and coeliac disease in a young female: a case report.
In this case report, we describe a patient who was diagnosed with both Primary Biliary Cholangitis and Coeliac Disease, presenting with symptoms and signs of severe malabsorption and portal hypertension. Extensive workup was done including duodenal and liver biopsies and our patient was ultimately found to have both autoimmune diseases. An association between the two diseases has been reported multiple times during the past four decades with current guidelines recommending screening patients with primary biliary cholangitis for coeliac disease.


Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
To identify prognostic factors and a model predictive for survival in patients with metastatic renal-cell carcinoma (RCC). The relationship between pretreatment clinical features and survival was studied in 670 patients with advanced RCC treated in 24 Memorial Sloan-Kettering Cancer Center clinical trials between 1975 and 1996. Clinical features were first examined univariately. A stepwise modeling approach based on Cox proportional hazards regression was then used to form a multivariate model. The predictive performance of the model was internally validated through a two-step nonparametric bootstrapping process. The median survival time was 10 months (95% confidence interval [CI], 9 to 11 months). Fifty-seven of 670 patients remain alive, and the median follow-up time for survivors was 33 months. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status (<80%), high serum lactate dehydrogenase (> 1.5 times upper limit of normal), low hemoglobin (< lower limit of normal), high "corrected" serum calcium (> 10 mg/dL), and absence of prior nephrectomy. These were used as risk factors to categorize patients into three different groups. The median time to death in the 25% of patients with zero risk factors (favorable-risk) was 20 months. Fifty-three percent of the patients had one or two risk factors (intermediate-risk), and the median survival time in this group was 10 months. Patients with three or more risk factors (poor-risk), who comprised 22% of the patients, had a median survival time of 4 months. Five prognostic factors for predicting survival were identified and used to categorize patients with metastatic RCC into three risk groups, for which the median survival times were separated by 6 months or more. These risk categories can be used in clinical trial design and interpretation and in patient management. The low long-term survival rate emphasizes the priority of clinical investigation to identify more effective therapy.


Macrophages direct process elongation from adult frog motorneurons in culture.
Motorneurons and macrophages have been isolated and identified in primary cultures from adult frog (Rana pipiens) spinal cord. Time-lapse video microscopy revealed that during the first two weeks migrating macrophages contact the growth cones of motorneurons. As they continue to migrate, the motorneuron processes elongate in close association with the moving macrophages. Elongating motorneuron processes are thereby brought into contact with other motorneurons and networks are formed. At later stages, the macrophages die but the motorneurons and the networks survive for at least another two weeks. These experiments show that macrophages can promote a directed elongation of motorneuron processes and suggest that they play a similar role during regeneration in vivo.


The Prescription of Mobile Apps by Primary Care Teams: A Pilot Project in Catalonia.
In Catalonia, the Fundació TIC Salut Social's mHealth Office created the AppSalut Site to showcase to mobile apps in the field of health and social services. Its primary objective was to encourage the public to look after their health. The catalogue allows primary health care doctors to prescribe certified, connected apps, which guarantees a safe and reliable environment for their use. The generated data can be consulted by health care professionals and included in the patient's clinical history. This document presents the intervention and the major findings following a five-month pilot project conducted in the Barcelona area. The objective of the pilot study was to test, in a real, controlled environment, the implementation of AppSalut. Specifically, we tested whether (1) the procedures corresponding to the prescription, transmission, and evaluation of the data functions correctly, (2) users interact successfully and accept the tool, and (3) the data travels through existing pathways in accordance with international standards. The evaluation is not based on clinical criteria, but rather on the usability and technological reliability of the intervention and its implementation in the context of primary care. The project was presented to the Primary Care Team participants to encourage the involvement of doctors. The study involved at least 5 doctors and 5 patients per professional, chosen at their discretion and in accordance with their own clinical criteria. An initial consultation took place, during which the doctor discussed the pilot project with the patient and recommended the app. The patient was sent a text message (SMS, short message service) containing an access code. When the patient arrived home, they accessed their personal health record (PHR) to view the recommendation, download the app, and enter the access code. The patient was then able to start using the app. The data was collected in a standardized manner and automatically sent to the system. In a second visit, the patient looked at the data with their doctor on their clinical station screen. The latter was able to consult the information generated by the patient and select what to include in their electronic health record. In order to assess the performance of the system, three focus groups were performed and two ad-hoc case-specific questionnaires, one for doctors and one for patients, were sent by email. Response was voluntary. A total of 32 doctors made 79 recommendations of apps to patients. On average, the patients uploaded data 13 times per prescribed app, accounting for a total of 16 different variables. Results show that data traveled through the established channels in an adequate manner and in accordance with international standards. This includes the prescription of an app by a doctor, the patient accessing the recommendation via the PHR, app download by the patient from the official app stores, linking of the patient to the public platform through the app, the generation and visualization of the data on the primary care workstation, and its subsequent validation by the clinician. First, the choice of apps to be used is fundamental; the user's perception of the utility of the proposed tool being paramount. Second, thorough face-to-face support is vital for a smooth transition towards a more intense model of telemedicine. Last, a powerful limiting factor is the lack of control over people's ability to use the apps.


Clusterin isoforms differentially affect growth and motility of prostate cells: possible implications in prostate tumorigenesis.
Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with "full-length" CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to alpha-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and alpha-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to alpha-actinin.


Case Report: Overcoming challenges in pancreatic cancer with liver metastases: a personalized therapeutic odyssey of TACE, ablation, and immunotherapy.
Pancreatic cancer represents a malignant neoplasm originating from pancreatic cells. The optimal approach to cancer treatment remains uncertain, lacking a definitive consensus. Here, we present a compelling case of a 49-year-old female with pancreatic head cancer with liver metastases, as identified by CT and confirmed by biopsy. PET-CT indicated widespread metastatic involvement. TACE therapy with gemcitabine and cisplatin was initiated, yielding a stable disease response. The patient's high PD-L1 expression prompted TACE-PD-1 monoclonal antibody combination therapy. Subsequent treatments, including ablation, sustained PD-1 immunotherapy, and consolidation TACE, culminated in a complete response, as evidenced by imaging and tumor marker dynamics. Our case underscores the potential of multifaceted strategies in managing aggressive pancreatic cancer.


Versatility of the Latissimus Dorsi Free Flap during the Treatment of Complex Postcraniotomy Surgical Site Infections.
Some intractable cases of postcraniotomy infection, which can involve compromised skin, an open frontal air sinus, and residual epidural dead space, have been reported. In such cases, reconstructing the scalp and skull is challenging. Between 2009 and 2016, the author treated 12 patients with recalcitrant postcraniotomy surgical site infections with latissimus dorsi (LD) free flaps. The patients' ages ranged from 37 to 79 years (mean, 63.5 years), and their underlying diseases included subarachnoid hemorrhaging (n = 5), brain tumors (n = 4), and cerebral arteriovenous malformations (n = 3). The LD free flap was used for scalp reconstruction in 3 cases, scalp reconstruction and separation of the intracranial and nasal cavities in 5 cases, and the obliteration of epidural dead space in 4 cases. Debridement followed by staged cranial reconstruction was carried out in 8 cases, and single-stage cranial reconstruction was conducted in 2 cases. The bone defects of the other 2 cases, which were small, were filled with LD musculo-adipose free flaps. The postoperative local appearance of the wounds was acceptable in every case, and no complications occurred. The LD free flap is a versatile tool for the treatment of complex postcraniotomy surgical site infections. This vascularized muscle flap is useful for controlling local infections because of its abundant vascularity. Moreover, its variety of uses means that it can resolve several problems in cases involving complex cranial wounds.


Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.
Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established.Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities.Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci.Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR.


Underplating and partial melting: implications for melt generation and extraction.
The quantitative assessment of underplating and concomitant partial melting of continental crust requires the use of geologically reasonable melt fraction distributions as a function of temperature. Conductive modeling indicates that simple underplating of metapelite by basalt can yield magma bodies with melt fractions above the rheological limit of extraction for almost any reasonable geotherm. Convection and subsequent homogenization are likely in these bodies. Granitic and tonalitic protoliths do not appear to yield substantial amounts of extractable magma. These results indicate that underplating involves repeated intrusion or occurs in deep crust.


[Genetics and somatoform disorders].
The nosological status of somatoform disorders has long been unclear. Only with DSM-III in 1980 did the situation become more settled. This means that earlier theoretical speculation and empirical investigations are difficult to evaluate. It has not been possible to confirm empirically many psychoanalytic notions about environmental causes of somatoform disorders; however, Freud's emphasis on a genetic basis seems to be confirmed. Furthermore, genetic research suggests a certain connection between alcoholism and criminality on the one hand and somatization disorders on the other. This does not mean that manifest alcoholism and criminality is prevalent among people with somatoform disorders. Cultural, gender-specific barriers and environmental factors prevent much co-morbidity. It should, however, be noted that little research has been taking place over the last 25-30 years; we could hardly be said to be beginning to understand the interplay between genes and environment in the development of somatoform disorders.