Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer.
We have used primary endocrine therapy for 61 elderly women with operable breast cancer (median age 77 years). Eleven patients (18%) had complete and 24 (39%) partial tumour regression, 12 (20%) had stable disease for a minimum of six months and 14 (23%) no response. Salvage surgery was undertaken in the 14 with no response and 8/9 with progressive disease following initial response, thus samples were available from relapse patients only. Assays for EGFr (two point radioreceptor assay) and oestrogen receptors (ER) (dextran coated charcoal method and an immunohistochemical method) were performed on 20/22 patients. Ten of these 20 tumours were EGFr+ (greater than 10 fmol mg-1 binding) and 9/13 patients progressing within six months had EGFr+ tumours. 15/22 were available for ER evaluation and there was no such association with ER status. EGFr status was also associated with early recurrence after surgery and death in the endocrine failure group (P less than 0.005 and P less than 0.05 respectively). Of a control population of 33 patients (median age 72 years) treated by primary surgery, only 6 were EGFr+. In this group early relapse was predicted by EGFr status, but not by ER status (median disease free survival for EGFr+ patients 15 months, and for EGFr- patients 40 months, P less than 0.01, logrank test). There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P less than 0.001). EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions.


Which similarity measure is better for analyzing protein structures in a molecular dynamics trajectory?
An important step in the computer simulation of the dynamics of biomolecules is the comparison of structures in a trajectory by exploiting a measure of distance. This allows distinguishing structures which are geometrically similar from those which are different. By analyzing microseconds-long all-atom molecular dynamics simulations of a polypeptide, we find that a distance based on backbone dihedral angles performs very well in distinguishing structures that are kinetically correlated from those that are not, while the widely used C(α) root mean square distance performs more poorly. The root mean square difference between contact matrices turns out instead to be the metric providing the highest clustering coefficient, namely, according to this similarity measure, the neighbors of a structure are also, on average, neighbors among themselves. We also propose a combined distance measure which, for the system considered here, performs well both for distinguishing structures which are distant in time and for giving a consistent cluster analysis.


Identification of differentiation-stage specific markers that define the ex vivo osteoblastic phenotype.
The phenotype of osteoblastic (OB) cells in culture is currently defined using a limited number of markers of low sensitivity and specificity. For the clinical use of human skeletal (stromal, mesenchymal) stem cells (hMSC) in therapy, there is also a need to identify a set of gene markers that predict in vivo bone forming capacity. Thus, we used RNA sequencing to examine changes in expression for a set of skeletally-related genes across 8 time points between 0 and 12days of ex vivo OB differentiation of hMSC. We identified 123 genes showing significant temporal expression change. Hierarchical clustering and Pearson's correlation generated 4 groups of genes: early stage differentiation genes (peak expression: 0-24h, n=28) which were enriched for extracellular matrix organisation, e.g. COL1A1, LOX, and SERPINH1; middle stage differentiating genes (peak expression days: 3 and 6, n=20) which were enriched for extracellular matrix/skeletal system development e.g. BMP4, CYP24A1, and TGFBR2; and late stage differentiation genes (peak expression days: 9 and 12, n=27) which were enriched for bone development/osteoblast differentiation, e.g. BMP2 and IGF2. In addition, we identified 13 genes with bimodal temporal expression (2 peaks of expression: days 0 and 12) including VEGFA, PDGFA and FGF2. We examined the specificity of the 123 genes' expression in skeletal tissues and thus propose a set of ex vivo differentiation-stage-specific markers (n=21). In an independent analysis, we identified a subset of genes (n=20, e.g. ELN, COL11A1, BMP4) to predict the bone forming capacity of hMSC and another set (n=20, e.g. IGF2, TGFB2, SMAD3) associated with the ex vivo phenotype of hMSC obtained from osteoporotic patients.


Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo.
Selective targeting of up-regulated integrins on tumor cells is a novel antiangiogenesis strategy for treating solid tumors. CNTO 95 is a fully human anti-alpha(v) integrin monoclonal antibody and has shown antitumor activity when used as a single agent in preclinical studies. We previously showed that radiation combined with an integrin alpha(v)beta(3) antagonist cRGD peptide increased the therapeutic efficacy of radiation in preclinical tumor models. We hypothesized that the combination of radiation and CNTO 95 would synergistically enhance the efficacy of radiation therapy. The in vitro studies showed that CNTO 95 radiosensitized and induced apoptosis in M21 cells in vitronectin-coated dishes. In mice bearing established human cancer xenograft tumors, CNTO 95 alone had only a moderate effect on tumor growth. The combined therapy of CNTO 95 and fractionated radiation significantly inhibited tumor growth and produced the longer tumor growth delay time in multiple tumor models. Maintenance dosing of CNTO 95 following irradiation contributed to efficacy and was important for continued inhibition of tumor regrowth. Immunohistochemistry studies showed that the combined use of CNTO 95 and radiation reduced the alpha(v) integrin and vascular endothelial growth factor receptor expression and the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. CNTO 95 alone and in combination with radiation did not produce any obvious signs of systemic toxicity. These results show that CNTO 95 can potentiate the efficacy of fractionated radiation therapy in a variety of human cancer xenograft tumor types in nude mice. These findings are very promising and may have high translational relevance for the treatment of patients with solid tumors.


Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility.
Since cAMP blocks meiotic maturation of mammalian and amphibian oocytes in vitro and cyclic nucleotide phosphodiesterase 3A (PDE3A) is primarily responsible for oocyte cAMP hydrolysis, we generated PDE3A-deficient mice by homologous recombination. The Pde3a(-/-) females were viable and ovulated a normal number of oocytes but were completely infertile, because ovulated oocytes were arrested at the germinal vesicle stage and, therefore, could not be fertilized. Pde3a(-/-) oocytes lacked cAMP-specific PDE activity, contained increased cAMP levels, and failed to undergo spontaneous maturation in vitro (up to 48 hours). Meiotic maturation in Pde3a(-/-) oocytes was restored by inhibiting protein kinase A (PKA) with adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS) or by injection of protein kinase inhibitor peptide (PKI) or mRNA coding for phosphatase CDC25, which confirms that increased cAMP-PKA signaling is responsible for the meiotic blockade. Pde3a(-/-) oocytes that underwent germinal vesicle breakdown showed activation of MPF and MAPK, completed the first meiotic division extruding a polar body, and became competent for fertilization by spermatozoa. We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity. Pde3a(-/-) mice represent an in vivo model where meiotic maturation and ovulation are dissociated, which underscores inhibition of oocyte maturation as a potential strategy for contraception.


Four enzymes define the incorporation of coenzyme A in thienamycin biosynthesis.
The enzymatic activities of three proteins encoded by the thienamycin gene cluster of Streptomyces cattleya (ThnR, ThnH, and ThnT) have been shown to incrementally cleave CoA to afford the active side-chain component of the beta-lactam antibiotic thienamycin. These results supersede proposals based on earlier radiochemical incorporation experiments. For 20 years it has been thought that cysteine was directly incorporated into the antibiotic. Specific, stepwise truncation of CoA to 4-phosphopantetheine, pantetheine, and finally cysteamine was observed with ThnR, ThnH, and ThnT, respectively, in a series of coupled enzymatic assays. Pantetheinylated carbapenams were synthesized to address possible thienamycin biosynthetic intermediates and were shown to be effective substrates for the pantetheine-cleaving enzyme ThnT. Finally, a fourth gene, thnF, was shown to encode a protein capable of N-acetylating a model compound containing cysteamine in the presence of acetyl-CoA, consistent with the production of the S. cattleya cometabolite, N-acetylthienamycin. Taken together, these four enzymes are proposed to siphon CoA from primary metabolism to create the side chains for the predominant S. cattleya carbapenems, thienamycin and N-acetylthienamycin, in a process likely to be general for the broader class of these antibiotics.


Climate change is predicted to negatively influence Moroccan endemic reptile richness. Implications for conservation in protected areas.
The identification of species-rich areas and their prognosticated turnover under climate change are crucial for the conservation of endemic taxa. This study aims to identify areas of reptile endemicity richness in a global biodiversity hot spot (Morocco) under current and future climatic conditions and to investigate the role of protected areas in biodiversity conservation under climate change. Species distribution models (SDM) were performed over the distribution of 21 endemic reptiles, combined to estimate current species richness at 1 × 1 km resolution and projected to years 2050 and 2080 according to distinct story lines and ensemble global circulation models, assuming unlimited and null dispersion ability. Generalized additive models were performed between species richness and geographic characteristics of 43 protected areas. SDM found precipitation as the most important factor related to current species distributions. Important reductions in future suitable areas were predicted for 50 % of species, and four species were identified as highly vulnerable to extinction. Drastic reductions in species-rich areas were predicted for the future, with considerable variability between years and dispersal scenarios. High turnover rates of species composition were predicted for eastern Morocco, whereas low values were forecasted for the Northern Atlantic coast and mountains. Species richness for current and future conditions was significantly related to the altitude and latitude of protected areas. Protected areas located in mountains and/or in the Northern Atlantic coast were identified as refugia, where population monitoring and conservation management is needed.


Vitamin D levels strongly influence bone mineral density and bone turnover markers during weight gain in female patients with anorexia nervosa.
The aim of the study was to investigate a potential role for vitamin D status on bone mineral density (BMD) during weight gain in patients with anorexia nervosa (AN). Spine and hip BMD assessed by dual-energy X-ray absorptiometry (DXA), serum vitamin D (25-OH-D), N-propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (CTX), and intact parathyroid hormone (PTH) were measured before and after a 20-week intensive weight-restoration program in ninety-one female patients with AN and secondary amenorrhoea. Ninety-one consecutive female patients (age 13-45 years; weight 39.4 ± 5.6 kg, body mass index [BMI] 15.1 ± 1.6 kg m-2 ) were included in the study. Although weight and BMI significantly increased in all patients during treatment, mean BMD only significantly increased at the spine (1.0% ± 3.6%, p = .009). The increase in spine BMD was significantly higher only above post-treatment 25-OH-D levels of 30 ng mL-1 (2.5% vs. 0.5%, respectively, for 25-OH-D ≥ and < 30 ng mL-1 , p = .026). There was a significant decrease in bone resorption (CTX; p = .043) and increased bone formation (P1NP; p < .001) after weight restoration. Nevertheless, a significant increase in PTH was also found, which was inversely correlated with decreased post-treatment 25-OH-D levels (R2 = .153, p < .001). Hypovitaminosis D may counteract the efficacy of refeeding in AN through increased bone resorption mediated by secondary hyperparathyroidism, which strongly supports the use of vitamin D supplements for bone health in AN.


Method for characterization of diffusion properties of photopolymerisable systems.
A novel approach for measuring the diffusion coefficients in photopolymerisable materials is proposed. The method is based on studying the evolution of the surface relief profile in a single illuminated spot using an interferometric surface profiler. It is shown that the observed post-exposure swelling in the illuminated spot is due to mass-transport of monomer from the unexposed to the exposed area driven by a monomer concentration gradient set up by the monomer polymerization in the exposed area. Appropriate choice of the thickness of the studied layers ensures both lateral movement of monomer and negligible contribution from the depth. The diffusion coefficient is retrieved from the standard one-dimensional diffusion equation where the height of the profile in the center of the illuminated spot is used instead of the monomer concentration. In contrast to other techniques for measuring the diffusion in photopolymerisable materials, no assumptions or preliminary information about the polymerization rates are required. It is shown how the method can be used for studying the intensity and polymer density dependence of diffusion coefficient.


A 12-year anthropometric evaluation of the nose in bilateral cleft lip-cleft palate patients following nasoalveolar molding and cutting bilateral cleft lip and nose reconstruction.
Patients with bilateral cleft lip-cleft palate have nasal deformities including reduced nasal tip projection, widened ala base, and a deficient or absent columella. The authors compare the nasal morphology of patients treated with presurgical nasoalveolar molding followed by primary lip/nasal reconstruction with age-matched noncleft controls. A longitudinal, retrospective review of 77 nonsyndromic patients with bilateral cleft lip-cleft palate was performed. Nasal tip protrusion, alar base width, alar width, columella length, and columella width were measured at five time points spanning 12.5 years. A one-sample t test was used for statistical comparison to an age-matched noncleft population published by Farkas. All five measurements demonstrated parallel, proportional growth in the treatment group relative to the noncleft group. The nasal tip protrusion, alar base width, alar width, columella length, and columella width were not statistically different from those of the noncleft, age-matched control group at age 12.5 years. The nasal tip protrusion also showed no difference in length at 7 and 12.5 years. The alar width and alar base width were significantly wider at the first four time points. This is the first study to describe nasal morphology following nasoalveolar molding and primary surgical repair in patients with bilateral cleft lip-cleft palate through the age of 12.5 years. In this investigation, the authors have shown that patients with bilateral cleft lip-cleft palate treated at their institution with nasoalveolar molding and primary nasal reconstruction, performed at the time of their lip repair, attained nearly normal nasal morphology through 12.5 years of age.


Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes.
Chromosome segregation in mammalian oocytes is driven by a microtubule spindle lacking centrosomes. Here, we analyze centrosome-independent spindle assembly by quantitative high-resolution confocal imaging in live maturing mouse oocytes. We show that spindle assembly proceeds by the self-organization of over 80 microtubule organizing centers (MTOCs) that form de novo from a cytoplasmic microtubule network in prophase and that functionally replace centrosomes. Initially distributed throughout the ooplasm, MTOCs congress at the center of the oocyte, where they contribute to a massive, Ran-dependent increase of the number of microtubules after nuclear envelope breakdown and to the individualization of clustered chromosomes. Through progressive MTOC clustering and activation of kinesin-5, the multipolar MTOC aggregate self-organizes into a bipolar intermediate, which then elongates and thereby establishes chromosome biorientation. Finally, a stable barrel-shaped acentrosomal metaphase spindle with oscillating chromosomes and astral-like microtubules forms that surprisingly exhibits key properties of a centrosomal spindle.


"Psychosomatic": a systematic review of its meaning in newspaper articles.
In this study, the authors describe the meaning of the word "psychosomatic" in U.S. and U.K. newspaper articles using a systematic text word search and a consensus rating of the contextual meaning of all articles published in 14 U.S. and U.K. newspapers between 1996 and 2002. The survey was limited to broadsheet newspapers. "Psychosomatic" had a pejorative meaning, such as "imaginary" or "made up," in 74 of 215 (34%) of the articles in which the meaning could be judged. Most commonly, "psychosomatic" was used to describe a problem that was psychological or in which the mind affects the body (56%) rather than as a reciprocal interaction (5%). "Psychosomatic medicine" is the new name for the seventh subspecialty of psychiatry. More needs to be done to educate the media about its actual meaning to make it attractive to patients.


Relationship of Cervical Sagittal Vertical Alignment After Sagittal Balance Correction in Adult Spinal Deformity: A Retrospective Radiographic Study.
Retrospective radiographic study. Predict the variability of the center of gravity of head (COG) relative to the global cervical sagittal alignment (SVA). Cervical lordosis, thoracic kyphosis, lumbar lordosis, and pelvic incidence are considered interrelated, with changes in SVA causing reciprocal changes to bring the head over pelvis. The implications of cervical deformities have generated more interest recently, and it has been shown that poor cervical alignment is associated with poor clinical outcomes. Patients were selected from the imaging server of a single institution with adult spinal deformity (ASD) and SVA, who underwent surgical correction from 2008 to 2013. Three observers performed the measurements, and intraclass correlation coefficient (ICC) was measured for inter and intraobserver reliability. Group 1 was patients with unbalanced spines (C7-SVA > 5 cm) preoperatively and corrected to full balanced spine (C7-SVA < 5 cm) until last follow-up. Group 2 was improved in sagittal balance after surgery and maintained SVA correction until last follow-up, but not fully balanced. Fifty-five patients met the inclusion criteria, 42 patients improved in SVA after surgery, and 13 showed no improvement. Twenty-three patients kept full balanced measurements until last follow-up, and 19 patients maintained not-full balanced spine. In group 1, there was no change in pre and postoperative parameters except for C2-CL (21.74° vs 16.91°, P = .033). It was similar in group 2, no differences except for C2-CL (21.67° vs 17.81°, P = .018). Parameters in this study failed to yield predictable relationships when compared to changes in SVA. The position of COG may be independent of global SVA. This study aims to improve our understanding of the dynamic changes and relationships of the regional and global spinal parameters with regard to spinal deformity corrective surgeries in adults. III.


Protecting Privacy and Security of Genomic Data in i2b2 with Homomorphic Encryption and Differential Privacy.
Re-use of patients' health records can provide tremendous benefits for clinical research. Yet, when researchers need to access sensitive/identifying data, such as genomic data, in order to compile cohorts of well-characterized patients for specific studies, privacy and security concerns represent major obstacles that make such a procedure extremely difficult if not impossible. In this paper, we address the challenge of designing and deploying in a real operational setting an efficient privacy-preserving explorer for genetic cohorts. Our solution is built on top of the i2b2 (Informatics for Integrating Biology and the Bedside) framework and leverages cutting-edge privacy-enhancing technologies such as homomorphic encryption and differential privacy. Solutions involving homomorphic encryption are often believed to be costly and immature for use in operational environments. Here, we show that, for specific applications, homomorphic encryption is actually a very efficient enabler. Indeed, our solution outperforms prior work by enabling a researcher to securely compute simple statistics on more than 3,000 encrypted genetic variants simultaneously for a cohort of 5,000 individuals in less than 5 seconds with commodity hardware. To the best of our knowledge, our privacy-preserving solution is the first to also be successfully deployed and tested in a operation setting (Lausanne University Hospital).


An eye fixation-related potentials analysis of the P300 potential for fixations onto a target object when exploring natural scenes.
The P300 event-related potential has been extensively studied in electroencephalography with classical paradigms that force observers to not move their eyes. This potential is classically used to infer whether a target or a task-relevant stimulus was presented. Few researches have studied this potential through more ecological paradigms where observers were able to move their eyes. In this study, we examined with an ecological paradigm and an adapted methodology the P300 potential using a visual search task that involves eye movements to actively explore natural scenes and during which eye movements and electroencephalographic activity were coregistered. Averaging the electroencephalography signal time-locked to fixation onsets, a P300 potential was observed for fixations onto the target object but not for other fixations recorded for the same visual search or for fixations recorded during the free viewing without any task. Our approach consists of using control experimental conditions with similar eye movements to ensure that the P300 potential was attributable to the fact that the observer gazed at the target rather than to other factors such as eye movement pattern (the size of the previous saccade) or the "overlap issue" between the potentials elicited by two successive fixations. We also proposed to model the time overlap issue of the potentials elicited by consecutive fixations with various durations. Our results show that the P300 potential can be studied in ecological situations without any constraint on the type of visual exploration, with some precautions in the interpretation of results due to the overlap issue.


Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.
Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted.


Drug prescription patterns, polypharmacy and potentially inappropriate medication in Swiss nursing homes: a descriptive analysis based on claims data.
To date, comprehensive data on drug utilisation in Swiss nursing homes are lacking. To describe drug prescription patterns, polypharmacy and potentially inappropriate medication (PIM) in Swiss nursing home residents (NHR). Using administrative claims data provided by the Swiss health insurance company Helsana, we assessed drug claims and drug costs in 2016 in individuals aged ≥65 years and insured with Helsana, who were either NHR or living in the community (reference group, RG). In particular, we analysed the prevalence of polypharmacy (≥5 claims for different drugs during a 3-month period) and PIM use according to the 2015 Beers criteria and the PRISCUS list. We standardised the results to the Swiss population. In 2016, NHR had on average nearly twice as many drug claims per capita as individuals in the RG (NHR 58.8; RG 30.8). The average per capita drug costs per day for NHR were low, but higher than in the RG (NHR CHF 8.55; RG CHF 5.45). The same pattern applied to the prevalence of polypharmacy (NHR 85.5%; RG 50.4%). Standardisation by age and sex did not materially alter these observations. Overall, 79.1% of NHR received ≥1 PIM, and 56.2% were long-term users (≥3 claims) of at least one PIM (based on the combined PRISCUS list and Beers criteria). Among all PIMs in nursing homes, quetiapine (antipsychotic agent), lorazepam (anxiolytic agent) and zolpidem (hypnotic agent) were the most prevalent (22.4, 20.2 and 13.0%, respectively). The high prevalence of polypharmacy and PIM in Swiss nursing homes may indicate a need for interventions aiming at de-prescribing drugs with an unfavourable benefit-risk profile.


Application theory of scattering and coupled mode analysis for liquid crystal diffractive grating.
This work presents a detailed analysis of a liquid crystal (LC) phase diffraction grating based on a approach combining vector theory of scattering and coupled mode analysis. In general, the coupled mode analysis gives a solution for the diffracted field regardless of aperture and the polarization state of the incident light. However, the aperture of the incident light defines the angular selectivity of the diffraction grating as well as the distribution of the intensity of the diffractive maximums. The solution of the vector theory of scattering in combination with the coupled mode analysis for diffraction of the light beam with finite aperture has allowed one to optimize the parameters of the high efficiency diffractive LC grating. The analytic solutions here were verified with experimental results for a reverse-twisted LC grating and a comparison with the standard Gooch-Tarry's method, which typically applied for a twisted nematic LC display.


Identification of Phosphorylated Cyclin-Dependent Kinase 1 Associated with Colorectal Cancer Survival Using Label-Free Quantitative Analyses.
Colorectal cancer is the most common form of cancer in the world, and the five-year survival rate is estimated to be almost 90% in the early stages. Therefore, the identification of potential biomarkers to assess the prognosis of early stage colorectal cancer patients is critical for further clinical treatment. Dysregulated tyrosine phosphorylation has been found in several diseases that play a significant regulator of signaling in cellular pathways. In this study, this strategy was used to characterize the tyrosine phosphoproteome of colorectal cell lines with different progression abilities (SW480 and SW620). We identified a total of 280 phosphotyrosine (pTyr) peptides comprising 287 pTyr sites from 261 proteins. Label-free quantitative analysis revealed the differential level of a total of 103 pTyr peptides between SW480 and SW620 cells. We showed that cyclin-dependent kinase I (CDK1) pTyr15 level in SW480 cells was 3.3-fold greater than in SW620 cells, and these data corresponded with the label-free mass spectrometry-based proteomic quantification analysis. High level CDK1 pTyr15 was associated with prolonged disease-free survival for stage II colorectal cancer patients (n = 79). Taken together, our results suggest that the CDK1 pTyr15 protein is a potential indicator of the progression of colorectal cancer.


Site-specific integration of bacteriophage VWB genome into Streptomyces venezuelae and construction of a VWB-based integrative vector.
The temperate bacteriophage VWB integrates into the chromosome of Streptomyces venezuelae ETH14630 via site-specific integration. Following recombination of the VWB attP region with the chromosomal attB sequence, the host-phage junctions attL and attR are formed. Nucleotide sequence analysis of attP, attB, attL and attR revealed a 45 bp common core sequence. In attB this 45 bp sequence consists of the 3' end of a putative tRNA Arg(AGG) gene with a 3'-terminal CCA sequence which is typical for prokaryotic tRNAs. Phage DNA integration restores the putative tRNA Arg(AGG) gene in attL. However, following recombination the CCA sequence is missing as is the case for most Streptomyces tRNA genes described so far. Adjacent to VWB attP, an ORF encoding a 427 aa protein was detected. The C-terminal region of this protein shows high similarity to the conserved C-terminal domain of site-specific recombinases belonging to the integrase family. To prove the functionality of this putative integrase gene (int), an integrative vector pKT02 was constructed. This vector consists of a 2.3 kb HindIII-SphI restriction fragment of VWB DNA containing attP and int cloned in a non-replicative Escherichia coli vector carrying a thiostrepton-resistance (tsr) gene. Integration of pKT02 was obtained after transformation of Streptomyces venezuelae ETH14630 and Streptomyces lividans TK24 protoplasts. This vector will thus be useful for a number of additional Streptomyces species in which a suitable tRNA gene can be functional as integration site.


Normal distribution pattern and physiological variants of 68Ga-PSMA-11 PET/CT imaging.
Ga-PSMA-11 is a novel PET tracer suggested to be used for imaging of advanced prostate cancer. In this study, we aimed to present a detailed biodistribution of Ga-PSMA-11, including physiological and benign variants of prostate-specific membrane antigen (PSMA) imaging. We carried out a retrospective analysis of 40 patients who underwent PSMA PET/computed tomography (CT) imaging and who had no evidence of residual or metastatic disease on the scans. In addition, 16 patients who underwent PSMA PET/CT imaging with any indication other than prostate cancer were included in the study to evaluate physiological uptake in the normal prostate gland. The median, minimum-maximum, and mean standardized uptake value (SUV) values were calculated for visceral organs, bone marrow and lymph nodes, and mucosal areas. Any physiological variants or benign lesions with Ga-PSMA-11 were also noted. Ga-PSMA-11 uptake was noted in the kidneys, parotid and submandibular glands, duodenum, small intestines, spleen, liver, and lacrimal glands, and mucosal uptake in the nasopharynx, vocal cords, pancreas, stomach, mediastinal blood pool, thyroid gland, adrenal gland, rectum, vertebral bone marrow, and testes. Celiac ganglia showed slight Ga-PSMA-11 uptake in 24 of 40 patients without the presence of any other pathologic lymph nodes in abdominal and pelvic areas. Variable uptake of Ga-PSMA-11 was observed in calcified choroid plexus, a thyroid nodule, an adrenal nodule, axillary lymph nodes and celiac ganglia, occasional osteophytes, and gallbladder. The patient group with PSMA PET/CT for indications other than prostate cancer (n=16) showed a slight radiotracer uptake in normal prostate gland (SUVmax: 5.5±1.6, range: 3.5-8.3). This study shows normal distribution pattern, range of SUVs, and physiological variants of Ga-PSMA-11. In addition, several potential pitfalls were documented to prevent misinterpretations of the scan.


Specular X-ray reflectivity and small angle neutron scattering for structure determination of ordered mesoporous dielectric films.
Specular X-ray reflectivity (SXR) and small-angle neutron scattering (SANS) are used to characterize the structure of a thin film containing cylindrical mesopores. The 3-D structure of the mesoporous film was determined from SANS measurements taken at multiple rotation angles between the incident beam and the film. The film was found to be composed of a randomly packed core and surface layers within which the hollow cylinders were regularly packed and oriented along the surface. The packing of the cylindrical mesopores was not hexagonal but rather rectangular with a conical angle of 55.7 degrees instead of 60 degrees expected for hexagonal packing. The extent of the planar orientation of the cylindrical mesopores within the surface layers was estimated from the width of the Bragg reflection in the SXR result to be about 25 repeating layers at both interfaces. This was further confirmed from cross-section transmission electron microscopy (TEM) results. The SXR results of this film exhibit an anomalous decrease in reflected intensity after each Bragg reflection. This anomaly in SXR can be modeled in a Parratt formulism using a depth profile composed of two characteristic lengths, the repeating distance among layers and the curvature of the density profile of each layer.


Complications following young femoral neck fractures.
Femoral neck fractures in patients 60 years of age or younger are challenging injuries to treat because of the high-energy trauma mechanisms and the displaced fracture patterns typically found in this patient population. Understanding the burden of disease is an important first step in addressing treatment controversies in this population. The purpose of the current study is to quantitatively pool the incidence of patient important complications following internal fixation of young femoral neck fractures. A comprehensive search of the Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Central databases was completed under the direction of a biomedical librarian. Multiple outcomes of interest (complications) were collected and included: reoperation, femoral head avascular necrosis, fracture non-union, infection, implant failure, and malunion. 1558 fractures from 41 studies were included in the meta-analysis. An18.0% pooled reoperation incidence was observed for isolated femoral neck fractures. The total pooled incidence of avascular necrosis (AVN) was 14.3%, and the total incidence of nonunion was 9.3%. When stratified for fracture displacement displaced fractures were more likely to undergo reoperation and to result in AVN or non-union. The total incidence of malunion was 7.1%, implant failure was 9.7%, and surgical site infection was 5.1%. Complications associated with a femoral neck fracture treated in conjunction with an ipsilateral femoral shaft fracture were lower overall than the pooled estimates for isolated neck fractures. The results of our analysis demonstrate that the incidence of complications experienced by young femoral neck fracture patients is relatively high. Reoperation following internal fixation of isolated femoral neck fractures occurred in nearly 20% of cases, and AVN and nonunion were the most common complications that likely contributed to repeat surgeries. These results highlight the importance of further efforts to improve the clinical outcomes in this population.


Do pregnant women follow exercise guidelines? Prevalence data among 3482 women, and prediction of low-back pain, pelvic girdle pain and depression.
We describe exercise level in mid-pregnancy, associated sociodemographic variables, and investigate the association between exercise in mid-pregnancy and subsequent low-back pain, pelvic girdle pain and depression at 32 weeks of pregnancy. The study included 3482 pregnant women participating in the Akershus Birth Cohort study (response rate 80.5%). Data were collected by a questionnaire in pregnancy weeks 17-21, pregnancy week 32 and electronic birth journal. The results were analysed by logistic regression and are presented as crude (cOR) and adjusted OR (aOR) with 95% CI. Only 14.6% of the respondents followed the current exercise prescription for exercise during pregnancy (≥3 times a week, >20 min at moderate intensity). One-third of the study sample exercised less than once a week at pregnancy weeks 17-21. Women exercising either 1-2 times or ≥3 times a week at mid-pregnancy were more often primiparous, higher-educated and had less often prepregnacy body mass index >30 kg/m2 compared with women exercising less than once a week. Women who exercised ≥3 times a week were less likely to report pelvic girdle pain (aOR: 0.76, 95% CI 0.61 to 0.96), while women exercising 1-2 times a week were less likely to report low-back pain (aOR: 0.80, 95% CI 0.66 to 0.97) and depression (aOR: 0.66, 95% CI 0.48 to 0.91). Few Norwegian women follow current exercise prescriptions for exercise in mid-pregnancy. The results may indicate an association between exercising mid-pregnancy and lower prevalence of low-back pain, pelvic girdle pain and depression in late pregnancy.


Examining the possible impact of daily transport on depression among older adults using an agent-based model.
Daily transport may impact depression risk among older adults through several pathways including facilitating the ability to meet basic needs, enabling and promoting contact with other people and nature, and promoting physical activity (e.g. through active transportation such as walking or walking to public transit). Both daily transport and depression are influenced by the neighborhood environment. To provide insights into how transport interventions may affect depression in older adults, we developed a pilot agent-based model to explore the contribution of daily transport and neighborhood environment to older adults' depression in urban areas. The model includes about 18,500 older adults (i.e. agents) between the ages of 65 and 85 years old, living in a hypothetical city. The city has a grid space with a number of neighborhoods and locations. Key dynamic processes in the model include aging, daily transport use and feedbacks, and the development of depression. Key parameters were derived from US data sources. The model was validated using empirical studies. An intervention that combines a decrease in bus fares, shorter bus waiting times, and more bus lines and stations is most effective at reducing depression. Lower income groups are likely to be more sensitive to the public transit-oriented intervention. Preliminary results suggest that promoting public transit use may be a promising strategy to increase daily transport and decrease depression. Our results may have implications for transportation policies and interventions to prevent depression in older adults.


Effect of mixed flavonoids, n-3 fatty acids, and vitamin C on oxidative stress and antioxidant capacity before and after intense cycling.
Consumption of plant flavonoids, antioxidants, and n-3 fatty acids is proposed to have many potential health benefits derived primarily through antioxidant and anti-inflammatory activities. This study examined the effects of 1,000 mg quercetin + 1,000 mg vitamin C (QC); 1,000 mg quercetin, 1,000 mg vitamin C, 400 mg isoquercetin, 30 mg epigallocatechin gallate, and 400 mg n-3 fatty acids (QFO); or placebo (P), taken each day for 2 wk before and during 3 d of cycling at 57% W(max) for 3 hr, on plasma antioxidant capacity (ferricreducing ability of plasma [FRAP], oxygen-radical absorbance capacity [ORAC]), plasma oxidative stress (F(2)-isoprostanes), and plasma quercetin and vitamin C levels. Thirty-nine athletes were recruited and randomized to QC, QFO, or P. Blood was collected at baseline, after 2 wk supplementation, immediately postexercise, and 14 hr postexercise. Statistical design used a 3 (groups) × 4 (times) repeated-measures ANOVA with post hoc analyses. Plasma quercetin was significantly elevated in QC and QFO compared with P. Plasma F(2)-isoprostanes, FRAP, and vitamin C were significantly elevated and ORAC significantly decreased immediately postexercise, but no difference was noted in the overall pattern of change. Post hoc analyses revealed that the QC and QFO groups did not exhibit a significant increase in F(2)-isoprostanes from baseline to immediately postexercise compared with P. This study indicates that combining flavonoids and antioxidants with n-3 fatty acids is effective in reducing the immediate postexercise increase in F(2)-isoprostanes. Moreover, this effect occurs independently of changes in plasma antioxidant capacity.


Cancer stem cells as a potential therapeutic target in breast cancer.
Cancer stem cells (CSCs) are defined as the small population of cancer cells that have stem cell properties as in hierarchically organized tumors. They are considered as the source of tumor initiation and maintenance. These cells are highly resistant to current cancer treatment and may be responsible for the disease recurrence after therapy as well. Therefore, considerable efforts have been made to elucidate the molecular and pathological properties of the CSCs to develop effective therapies targeting CSCs. A growing body of experimental evidence has revealed that therapeutic targeting CSCs may offer a new strategy for patients with breast cancer (BC). In this review, we summarized the evidence for existence of CSCs, followed by an overview of their molecular biomarkers, signaling pathways and potential therapeutic strategies to target these CSCs in BC.


Personal, social, and environmental factors associated with lifejacket wear in adults and children: A systematic literature review.
Drowning claims 7% of the global burden of injury-related deaths. Lifejackets are routinely recommended as a drowning prevention strategy; however, a review of related factors regarding lifejacket wear has not previously been investigated. This systematic review examined literature published from inception to December 2016 in English and German languages. The personal, social, and environmental factors associated with lifejacket wear among adults and children were investigated, a quantitative evaluation of the results undertaken, and gaps in the literature identified. Twenty studies, with sample sizes of studies ranging between 20 and 482,331, were identified. Fifty-five percent were cross-sectional studies. All studies were scored IV or V on the Australian National Health and Medical Research Council (NHMRC) grading system indicating mostly descriptive and cross-sectional levels of evidence. Factors associated with increased wear included age (mostly children), gender (mostly female), boat type (non-motorised), boat size (small boats), role modelling (children influenced by adult lifejacket wear), and activity (water-skiing, fishing). Factors not associated or inconsistent with lifejacket wear included education, household income, ethnicity, boating ability, confidence in lifejackets, waterway type, and weather and water conditions. Factors associated with reduced lifejacket wear included adults, males, discomfort, cost and accessibility, consumption of alcohol, and swimming ability. Three studies evaluated the impact of interventions. This review identified factors associated with both increased and decreased lifejacket wear. Future research should address the motivational factors associated with individuals' decisions to wear or not wear lifejackets. This, combined with further research on the evaluation of interventions designed to increase lifejacket wear, will enhance the evidence base to support future drowning prevention interventions.


IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.
We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations. © 2017 American Society for Bone and Mineral Research.


Molecular and histologic characteristics of pseudoprogression in diffuse gliomas.
During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.


Polarization of myelinating Schwann cell surface membranes: role of microtubules and the trans-Golgi network.
Schwann cells polarize their surface membranes into several biochemically and ultrastructurally discrete regions of the myelin internode. To form these membrane domains, Schwann cells must sort, transport, and target membrane proteins appropriately. In this study, microtubule disassembly, confocal microscopy, and electron microscopic immunocytochemistry were used to investigate mechanisms involved in targeting P0 protein (P0), the myelin-associated glycoprotein (MAG), and laminin to different plasma membrane domains in myelinating Schwann cells from 35-d-old rat sciatic nerve. After microtubule disassembly by colchicine, all three proteins accumulated in Schwann cell perinuclear cytoplasm, indicating that microtubules are necessary for their transport. The distributions of Golgi membranes, endoplasmic reticulum, and intermediate filaments were also altered by colchicine treatment. Electron microscopic immunocytochemical studies indicated that P0 and MAG are sorted into separate carrier vesicles as they exit the trans-Golgi network. Following microtubule disassembly, P0-rich carrier vesicles fused and formed myelin-like membrane whorls, whereas MAG-rich carrier vesicles fused and formed mesaxon-like membrane whorls. Microtubule disassembly did not result in mistargeting of either P0 or MAG to surface membranes. These results indicate that following sorting in the trans-Golgi network, certain carrier vesicles are transported along the myelin internode on microtubules; however, microtubules do not appear to target these vesicles selectively to specific sites. The targeting of P0-, MAG-, and laminin-rich carrier vesicles to specific sites most likely occurs by ligand receptor binding mechanisms that permit fusion of carrier vesicles only with the appropriate target membrane.


Comparative proteomic profiles of the marine cyanobacterium Trichodesmium erythraeum IMS101 under different nitrogen regimes.
Trichodesmium is a marine filamentous diazotrophic cyanobacterium and an important contributor of "new" nitrogen in the oligotrophic surface waters of the tropical and sub-tropical oceans. It is unique in that it exclusively fixes N(2) at daytime, although it belongs to the non-heterocystous filamentous segment of the cyanobacterial radiation. Here we present the first quantitative proteomic analysis of Trichodesmium erythraeum IMS101 when grown under different nitrogen regimes using 2-DE/MALDI-TOF-MS. Addition of combined nitrogen (NO3-) prevented development of the morphological characteristics of the N(2)-fixing cell type (diazocytes), inhibited expression of the nitrogenase enzyme subunits and consequently N(2) fixation activity. The diazotrophic regime (N(2) versus NO3- cultures) elicited the differential expression of more than 100 proteins, which represented 13.5% of the separated proteins. Besides proteins directly related to N(2) fixation, proteins involved in the synthesis of reducing equivalents and the generation of a micro-oxic environment were strongly up-regulated, as was in particular Dps, a protein related to iron acquisition and potentially other vital cellular processes. In contrast, proteins involved in the S-adenosylmethionine (SAM) cycle, synthesis of amino acids and production of carbon skeletons for storage and synthesis of amino acids were suppressed. The data are discussed in the context of Trichodesmium's unusual N(2)-fixing physiology.


Laryngeal carcinoma in a Lynch syndrome II kindred.
Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for about 4% to 6% of the total colorectal cancer burden. It is subdivided into Lynch syndrome I and II. Lynch syndrome I is characterized by an autosomal dominant inheritance pattern for site-specific, early onset, adenocarcinoma of the colon, with proximal predominance and an excess of synchronous and metachronous colonic cancers. Lynch syndrome II (cancer family syndrome) shows these same colon cancer characteristics, but differs in that there is an excess proclivity of other forms of cancer, particularly of the endometrium and ovary. This article documents a family that shows features of Lynch syndrome II. Unique aspects pertain to a patient who is in the direct genetic lineage (whose five brothers manifested colonic cancer), but who developed carcinoma of the uterine cervix at age 34 and laryngeal cancer at 60. The pedigree also shows uterine cervical carcinoma among other patients at genetic risk. Her son, who is a nonsmoker and nondrinker, manifested laryngeal cancer at age 31. These observations appear to add new information about tumor heterogeneity in HNPCC.


A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.


Novel cancer therapies and their association with diabetes.
Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, 'off target effects', in great part due to molecular pathways shared by neoplastic and normal cells. One such undesirable effect is hyperglycemia, which results from either the loss of immune tolerance and autoimmune destruction of pancreatic β-cells or dysregulation of the insulin signaling pathway resulting in insulin resistance. These distinct pathogenic mechanisms lead to clinical presentations similar to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Both types of diabetes have been reported in patients across clinical trials, and data on the mechanism(s) for developing hyperglycemia, prevalence, prognosis and effect on cancer mortality is still emerging. With the rapidly expanding list of clinical indications for new cancer therapies, it is essential to understand the impact of their adverse effects. In this review, we focus on hyperglycemia and diabetes related to cancer therapies, describe what is known about mechanism(s) leading to dysregulated glucose metabolism and provide a guide to management of complex oncology patients with a new diagnosis of diabetes.


Meningoradiculitis and encephalomyelitis due to Borrelia burgdorferi: a follow-up study of 72 patients over 27 years.
In 1987, follow-up studies were conducted on 72 patients who had had meningoradiculitis and encephalomyelitis (8 patients) due to Borrelia burgdorferi 5-27 years previously. These patients had not been treated with antibiotics, either during the acute disease or during the interval prior to follow-up studies. The patients had exhibited the typical symptoms of Bannwarth's syndrome during the acute phase. At the follow-up studies, 33 patients showed no, and 23 only mild, clinical residual symptoms including normal CSF findings and low-positive serum IgG borrelia antibody titres (IFT; ELISA). Three patients without sequelae exhibited persistent intrathecal secretion of oligoclonal B. burgdorferi-specific CSF IgG antibodies (Immunoblot; positive borrelia CSF IgG antibody titres). Thirteen patients exhibited mild-to-medium sequelae with persistent intrathecal formation of oligoclonal B. burgdorferi-specific CSF IgG antibodies, up to 21 years after the acute illness. This persistence can be interpreted as an "immunological scar syndrome". Our follow-up studies appear to indicate that neurological manifestations of B. burgdorferi infections are generally (with few exceptions) of a benign nature. Most patients can be classified as having been cured without antibiotic therapy. No late manifestations of chronic progressive CNS borreliosis comparable to that of neurosyphilis have been seen following acute untreated neuroborreliosis.


Complexity complicates lean: lessons from seven emergency services.
The purpose of this paper is to explain how different emergency services adopt and adapt the same hospital-wide lean-inspired intervention and how this is reflected in hospital process performance data. A multiple case study based on a realistic evaluation approach to identify mechanisms for how lean impacts process performance and services' capability to learn and continually improve. Four years of process performance data were collected from seven emergency services at a Swedish University Hospital: ear, nose and throat (ENT) (two), pediatrics (two), gynecology, internal medicine, and surgery. Performance patterns were linked with qualitative data collected through realist interviews. The complexity of the care process influenced how improvement in access to care was achieved. For less complex care processes (ENT and gynecology), large and sustained improvement was mainly the result of a better match between capacity and demand. For medicine, surgery, and pediatrics, which exhibit greater care process complexity, sustainable, or continual improvement were constrained because the changes implemented were insufficient in addressing the higher degree of complexity. The variation in process performance and sustainability of results indicate that lean efforts should be carefully adapted to the complexity of the care process and to the educational commitment of healthcare organizations. Ultimately, the ability to adapt lean to a particular context of application depends on the development of routines that effectively support learning from daily practices.


Toluene-induced ototoxicity by subcutaneous administration.
Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.


Thermostable biocatalytic films of enzymes and polylysine on electrodes and nanoparticles in microemulsions.
Microemulsions of oil, water and surfactant were evaluated as media for biocatalysis at high temperatures employing films of polylysine (PLL) and the enzymes horseradish peroxidase (HRP), soybean peroxidase (SBP) and the protein myoglobin (Mb). PLL was covalently linked to oxidized pyrolytic graphite electrodes or carboxylated 500 nm diameter silica nanoparticles, then cross-linked by amidization to HRP, SBP and Mb. The resulting film systems were stable at 90 degrees C for >12 h in microemulsions. Characterization of the microemulsions by conductivity, viscosity and probe diffusion coefficients suggested that these media have bicontinuous microstructures from 25 to 90 degrees C. UV circular dichroism and visible spectroscopy confirmed that the enzymes retained near-native conformation in the films at temperatures as high as 90 degrees C. Oxidation of o-methoxyphenol to 3,3'-dimethoxy-4,4'-biphenoquinone by enzyme-PLL films on silica nanoparticles gave yields 3-5-fold larger in microemulsions at 90 degrees C compared to the same reaction at 25 degrees C. The best yields were in CTAB microemulsions and were 3-fold larger than in buffers at 90 degrees C.


p73 and p63 sustain cellular growth by transcriptional activation of cell cycle progression genes.
Despite extensive studies on the role of tumor suppressor p53 protein and its homologues, p73 and p63, following their overexpression or cellular stress, very little is known about the regulation of the three proteins in cells during physiologic cell cycle progression. We report a role for p73 and p63 in supporting cellular proliferation through the transcriptional activation of the genes involved in G(1)-S and G(2)-M progression. We found that in MCF-7 cells, p73 and p63, but not p53, are modulated during the cell cycle with a peak in S phase, and their silencing determines a significant suppression of proliferation compared with the control. Chromatin immunoprecipitation analysis shows that in cycling cells, p73 and p63 are bound to the p53-responsive elements (RE) present in the regulatory region of cell cycle progression genes. On the contrary, when the cells are arrested in G(0)-G(1), p73 detaches from the REs and it is replaced by p53, which represses the expression of these genes. When the cells move in S phase, p73 is recruited again and p53 is displaced or is weakly bound to the REs. These data open new possibilities for understanding the involvement of p73 and p63 in cancer. The elevated concentrations of p73 and p63 found in many cancers could cause the aberrant activation of cell growth progression genes and therefore contribute to cancer initiation or progression under certain conditions.


A behavior change program to increase outings delivered during therapy to stroke survivors by community rehabilitation teams: The Out-and-About trial.
Australian guidelines recommend that outdoor mobility be addressed to increase participation after stroke. To investigate the efficacy of the Out-and-About program at increasing outings delivered during therapy by community teams, and outings taken by stroke survivors in real life. Cluster-randomized trial involving 22 community teams providing stroke rehabilitation. Experimental teams received the Out-and-About program (a behavior change program comprising a training workshop with barrier identification and booster session, printed educational materials, audit, and feedback). Control teams received printed clinical guidelines only. The primary outcome was the percentage of stroke survivors receiving four or more outings during therapy. Secondary outcomes included the number of outings received by stroke survivors during therapy and undertaken in real life. At 12 months after implementation of the behavior change program, 9% of audited experimental group stroke survivors received four or more outings during therapy compared with 5% in the control group (adjusted risk difference 4%, 95% CI - 9 to 17, p = 0.54). They received 1.1 (SD 0.9) outings during therapy compared with 0.6 (SD 1.0) in the control group (adjusted mean difference 0.5, 95% CI - 0.4 to 1.4; p = 0.26). After six months of rehabilitation, observed experimental group stroke survivors took 9.0 (SD 3.0) outings per week in real life compared with 7.4 (SD 4.0) in the control group (adjusted mean difference 0.5, 95% CI - 1.8 to 2.8; p = 0.63). The Out-and-About program did not change team or stroke survivor behavior.


Successful Fusion of the Proximal Tibiofibular Joint with Osteogenic Protein-1 (OP-1) Augmentation.
Proximal tibiofibular joint (PTFJ) instability is rare, but when encountered can be difficult to manage. Previously reported forms of treatment, including cast immobilization, soft tissue repairs and reconstructions, and fibular head resection have met with limited success. Another option is PTFJ arthrodesis-however, fusion can be difficult and ankle pain after surgery is not uncommon. In this report, we present a novel surgical technique used to treat PTFJ instability. It is a form of PTFJ arthrodesis that utilizes the osteoinductive agent recombinant human osteogenic protein (rhOP-1) to help achieve fusion, in conjunction with a fibular osteotomy to unload the PTFJ and to preserve normal rotator mobility of the distal fibula during ankle motion. We have used this technique in two patients with successful results; one of whom required revision after two previous failed attempts at PTFJ fusion and the other who had a previous diagnosis of underlying collagen disorder. Their case studies are presented in detail in this report.


Microfluidic-induced growth and shape-up of three-dimensional extended arrays of densely packed nanoparticles.
We use evaporation within a microfluidic device to extract the solvent of a (possibly very dilute) dispersion of nanoparticles and concentrate the dispersion until a solid made of densely packed nanoparticles grows and totally invades the microfluidic geometry. The growth process can be rationalized as an interplay between evaporation-induced flow and kinetic and thermodynamic coefficients which are system-dependent; this yields limitations to the growth process illustrated here on two main cases: evaporation- and transport-limited growth. Importantly, we also quantify how colloidal stability may hinder the growth and show that care must be taken as to the composition of the initial dispersion, especially regarding traces of ionic species that can destabilize the suspension upon concentration. We define a stability chart, which, when fulfilled, permits us to grow and shape-up solids, including superlattices and extended and thick arrays of nanoparticles made of unary and binary dispersions, composites, and heterojunctions between distinct types of nanoparticles. In all cases, the geometry of the final solid is imparted by that of the microfluidic device.


Pre-exposure Prophylaxis Adherence Measured by Plasma Drug Level in MTN-001: Comparison Between Vaginal Gel and Oral Tablets in Two Geographic Regions.
Despite strong evidence that daily oral pre-exposure prophylaxis (PrEP) reduces HIV risk, effectiveness across studies has varied. Inconsistent adherence constitutes one explanation. Efforts to examine adherence are limited when they rely on self-reported measures. We examined recent adherence as measured by plasma tenofovir (TFV) concentration in participants of MTN-001, a phase 2 cross-over trial comparing oral tablet and vaginal gel formulations of TFV among 144 HIV-uninfected women at sites in the United States (U.S.) and sub-Saharan Africa (SSA). Adherence to daily product use was higher in the U.S. than in the SSA sites. Within region, however, adherence was similar between products. In the U.S., gel adherence was higher among married women, and lower among women using male condoms and injectable contraceptives. At the SSA sites, gel adherence was lower for younger women. Inconsistent adherence points to challenges in use of daily PrEP, even during a trial of short duration.


The impact of community-based sexually transmitted infection screening results on sexual risk behaviors of African American adolescents.
To examine the effect of a community-based sexually transmitted infection (STI) screening program on sexual risk behavior among African American adolescents. We hypothesized that adolescents testing positive for an STI and receiving post-test counseling would reduce risky sexual practices, whereas STI-negative adolescents would show little or no change in protective sexual behavior after screening. From August 2006 to January 2008, we recruited 636 sexually active African American adolescents (age, 14-17) from community-based organizations in two mid-sized U.S. cities with high STI prevalence. Participants were screened for three STIs (gonorrhea, chlamydia, and trichomoniasis) and completed an audio computer-assisted self-interview. Youth who tested positive for an STI (6.6%) received treatment and counseling. Youth testing negative received no further intervention. Approximately 85% of participants completed 3- and 6-month follow-up assessments. Generalized estimating equations determined the effects of STI screening on adolescents' number of sexual partners and occurrence of unprotected sex. Adolescents who tested positive for an STI reduced their number of vaginal and oral sex partners and the probability of unprotected sex. STI-negative adolescents demonstrated no change for numbers of partners or unprotected sex. Community-based STI screening can help to reduce sexual risk behavior in youth who test positive for STIs. Alternative approaches will be needed to reduce risk behavior in youth who test negative but who are nevertheless at risk for acquiring an STI.


Caveolin-1 Controls Hyperresponsiveness to Mechanical Stimuli and Fibrogenesis-Associated RUNX2 Activation in Keloid Fibroblasts.
Keloids are pathological scars characterized by excessive extracellular matrix production that are prone to form in body sites with increased skin tension. CAV1, the principal coat protein of caveolae, has been associated with the regulation of cell mechanics, including cell softening and loss of stiffness sensing ability in NIH3T3 fibroblasts. Although CAV1 is present in low amounts in keloid fibroblasts (KFs), the causal association between CAV1 down-regulation and its aberrant responses to mechanical stimuli remain unclear. In this study, atomic force microscopy showed that KFs were softer than normal fibroblasts with a loss of stiffness sensing. The decrease of CAV1 contributed to the hyperactivation of fibrogenesis-associated RUNX2, a transcription factor germane to osteogenesis/chondrogenesis, and increased migratory ability in KFs. Treatment of KFs with trichostatin A, which increased the acetylation level of histone H3, increased CAV1 and decreased RUNX2 and fibronectin. Trichostatin A treatment also resulted in cell stiffening and decreased migratory ability in KFs. Collectively, these results suggest a role for CAV1 down-regulation in linking the aberrant responsiveness to mechanical stimulation and extracellular matrix accumulation with the progression of keloids, findings that may lead to new developments in the prevention and treatment of keloid scarring.


High resolution mapping of Y haplogroup G in Tyrol (Austria).
The distribution of Y-chromosomal haplogroup G2a (G-P15) in present-day paternal lineages in Tyrol (Austria) was analyzed by applying a high-density regional sampling scheme that also covered remote mountain areas. There is evidence from ancient genetic data for a high frequency of Y-chromosomal haplogroup G in prehistoric populations of Central Europe, whilst nowadays levels well below 10% are routinely observed. A population sample comprising ∼3700 specimens was analyzed for Y-chromosomal variation by genotyping Y-SNPs and Y-STRs. The set of binary markers included nine SNPs specific for sub-lineages of haplogroup G. The frequency of haplogroup G in 2379 unrelated men born in Tyrol amounted to 11.3%. Nearly all of these Y chromosomes belonged to haplogroup G2a. The main sub-haplogroup within G2a was defined by the SNP L497 (G2a3b1c) and reached a population frequency of 8.6%. Although this average level is higher than reported for other countries the geographical distribution of haplogroup G-L497 showed a differentiated pattern with a clustered distribution within some alpine valleys, where maxima above 40% were found. Both, the estimation of coalescent times and a principle coordinates analysis based on RST values derived from Y-STR haplotypes from different sub-regions of Tyrol revealed evidence for an old settlement history associated with Y chromosomes belonging to haplogroup G in the Tyrolean Alps.


"HIT on Trousseau" double trouble: acquired coagulopathy with femoral artery thrombosis.
Trousseau Syndrome is a paraneoplastic procoagulant phenomenon. Heparin-induced thrombocytopenia (HIT) is a rare complication of anticoagulation with heparin. To our knowledge, the coincidence of the two has not been reported so far. We report a case of an acute thrombosis of the left femoral artery and distal leg arteries in a patient with an otherwise normal cardiovascular status. Endovascular revascularization attempts using mechanical rotational thrombectomy catheter, aspiration and local thrombolysis were unsuccessful. Progressive coagulation along the intra-arterial catheter was seen. Surgical thrombectomy of the femoral-pedal axis was successful, but the patient developed an immune-mediated HIT postoperatively. An adenocarcinoma of the colon was the likely cause for the initial arterial thrombosis, and probably adversely affected endovascular revascularization attempts. Subsequent HIT with microvascular thrombosis worsened ischemic damage leading to a below knee-amputation, despite patent large vessels. Compared to venous thrombosis, arterial thrombosis is a rare manifestation of Trousseau syndrome. The coincidence of it with HIT is even rarer. There may be a causal relationship between the two.


Mass isotopomer analysis of metabolically labeled nucleotide sugars and N- and O-glycans for tracing nucleotide sugar metabolisms.
Nucleotide sugars are the donor substrates of various glycosyltransferases, and an important building block in N- and O-glycan biosynthesis. Their intercellular concentrations are regulated by cellular metabolic states including diseases such as cancer and diabetes. To investigate the fate of UDP-GlcNAc, we developed a tracing method for UDP-GlcNAc synthesis and use, and GlcNAc utilization using (13)C6-glucose and (13)C2-glucosamine, respectively, followed by the analysis of mass isotopomers using LC-MS. Metabolic labeling of cultured cells with (13)C6-glucose and the analysis of isotopomers of UDP-HexNAc (UDP-GlcNAc plus UDP-GalNAc) and CMP-NeuAc revealed the relative contributions of metabolic pathways leading to UDP-GlcNAc synthesis and use. In pancreatic insulinoma cells, the labeling efficiency of a (13)C6-glucose motif in CMP-NeuAc was lower compared with that in hepatoma cells. Using (13)C2-glucosamine, the diversity of the labeling efficiency was observed in each sugar residue of N- and O-glycans on the basis of isotopomer analysis. In the insulinoma cells, the low labeling efficiencies were found for sialic acids as well as tri- and tetra-sialo N-glycans, whereas asialo N-glycans were found to be abundant. Essentially no significant difference in secreted hyaluronic acids was found among hepatoma and insulinoma cell lines. This indicates that metabolic flows are responsible for the low sialylation in the insulinoma cells. Our strategy should be useful for systematically tracing each stage of cellular GlcNAc metabolism.


Effects of Chinese medicines for tonifying the kidney on DNMT1 protein expression in endometrium of infertile women during implantation period.
The purpose of this study was to explore the effects of Erzhi Tiangui Granule (ETG) on DNA methyltransferases (DNMT) 1 protein expression in endometrium of infertile women with Kidney-yin Deficiency syndrome. A randomized, double-blinded, placebo-controlled clinical trial was conducted. Sixty-six (66) infertile patients who had Kidney-yin Deficiency syndrome and who were to undergo in vitro fertilization-embryo transfer (IVF-ET) were randomly assigned to either a treatment group or a control group according to a random table. Besides gonadotropin (Gn) therapy in both groups, the treatment group received ETG for 3 menstrual cycles before IVF, and the control group received placebo granules. The ETG and the placebo granules were made with similar color and shape, as well as in the same packaging. The scores of the Kidney-yin Deficiency syndrome were assessed. Other outcome measures included the dosage and duration of Gn, the number of retrieved oocytes, the rate of high-quality oocytes, the rate of high-quality embryos, the fertilization rate, and the clinical pregnancy rate. DNMT1 protein expression in the endometrium was measured in the midluteal phase. The difference in the syndrome score change before and after treatment between the two groups was statistically significant (p<0.05). The dosage and duration of Gn were significantly lower in the treatment group than those in the control group (p<0.05). The high-quality oocyte and embryo rates, and clinical pregnancy rate were all higher in the treatment group than those in the control group (p<0.05). The fertilization rate was not significant when compared to the placebo group. No difference was found in the number of retrieved oocytes between the two groups. The DNMT1 protein expression in the endometrium was much more abundant in the treatment group than that in the control group (p<0.05). For the infertile patients undergoing IVF, the Chinese recipe for tonifying the Kidney as an adjunct treatment could reduce Gn dosage and treatment duration, alleviate clinical symptoms, and improve the clinical pregnancy rate. The increased level of DNMT1 protein expression after treatment may lead to enhanced endometrial receptivity. This finding may explain the improvement in clinical pregnancy rate.


Ultrasound-Based Detection of Fasciculations in Healthy and Diseased Muscles.
Involuntary muscle activations are diagnostic indicators of neurodegenerative pathologies. Currently detected by invasive intramuscular electromyography, these muscle twitches are found to be visible in ultrasound images. We present an automated computational approach for the detection of muscle twitches, and apply this to two muscles in healthy and motor neuron disease-affected populations. The technique relies on motion tracking within ultrasound sequences, extracting local movement information from muscle. A statistical analysis is applied to classify the movement, either as noise or as more coherent movement indicative of a muscle twitch. The technique is compared to operator identified twitches, which are also assessed to ensure operator agreement. We find that, when two independent operators manually identified twitches, higher interoperator agreement (Cohen's κ) occurs when more twitches are present (κ = 0.94), compared to a lower number (κ = 0.49). Finally, we demonstrate, via analysis of receiver operating characteristics, that our computational technique detects muscle twitches across the entire dataset with a high degree of accuracy (0.83 < accuracy < 0.96).


Prediction of analyte retention for ion chromatography separations performed using elution profiles comprising multiple isocratic and gradient steps.
This study addresses the simulation of ion chromatographic (IC) separations performed under conditions where the elution profile consists of a sequence of isocratic and gradient elution steps (referred to as "complex elution profiles"). First, models for prediction of retention under gradient elution conditions in IC were evaluated using an extensive database of gradient elution retention data. It is shown that one such model is preferred on the basis that it can be used to predict gradient retention times on the basis of isocratic input data. A method is then proposed for using this model for complex elution profiles whereby each step of the elution profile is treated separately and analyte movement through the column is mapped. An empirically based algorithm for predicting peak width under complex elution conditions is also proposed. Evaluation of the suggested approaches was undertaken on a set of 24 analyte anions and 13 analyte cations on 5 different Dionex columns using a range of 5-step complex elution profiles that gave R2 values for correlations between predicted and observed retention times of 0.987 for anions and 0.997 for cations. The simulation of separations of anions and cations using a 3-step complex elution profile is demonstrated, with good correlation between observed and predicted chromatograms. The proposed approach is useful for the rapid development of separations when complex elution profiles are used in IC.


The Current State of Solar Modeling
Data from the Global Oscillation Network Group (GONG) project and other helioseismic experiments provide a test for models of stellar interiors and for the thermodynamic and radiative properties, on which the models depend, of matter under the extreme conditions found in the sun. Current models are in agreement with the helioseismic inferences, which suggests, for example, that the disagreement between the predicted and observed fluxes of neutrinos from the sun is not caused by errors in the models. However, the GONG data reveal subtle errors in the models, such as an excess in sound speed just beneath the convection zone. These discrepancies indicate effects that have so far not been correctly accounted for; for example, it is plausible that the sound-speed differences reflect weak mixing in stellar interiors, of potential importance to the overall evolution of stars and ultimately to estimates of the age of the galaxy based on stellar evolution calculations.


Serotonin-dependent depression in Parkinson's disease: a role for the subthalamic nucleus?
Depression is the most common neuropsychiatric co-morbidity in Parkinson's disease (PD). The underlying mechanism of depression in PD is complex and likely involves biological, psychosocial and therapeutic factors. The biological mechanism may involve changes in monoamine systems, in particular the serotonergic (5-hydroxytryptamine, 5-HT) system. It is well established that the 5-HT system is markedly affected in the Parkinsonian brain, with evidence including pathological loss of markers of 5-HT axons as well as cell bodies in the dorsal and median raphe nuclei of the midbrain. However, it remains unresolved whether alterations to the 5-HT system alone are sufficient to confer vulnerability to depression. Here we propose low 5-HT combined with altered network activity within the basal ganglia as critically involved in depression in PD. The latter hypothesis is derived from a number of recent findings that highlight the close interaction between the basal ganglia and the 5-HT system, not only in motor but also limbic functions. These findings include evidence that clinical depression is a side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN), a treatment option in advanced PD. Further, it has recently been demonstrated that STN DBS in animal models inhibits 5-HT neurotransmission, and that this change may underpin depressive-like side effects. This review provides an overview of 5-HT alterations in PD and a discussion of how these changes might combine with altered basal ganglia network activity to increase depression vulnerability.


Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness.
H-2 dependent and virus-specific Ir genes regulate the generation of primary virus-specific K or D restricted cytotoxic T-cell responses in vivo. The following examples have been analyzed in some detail: first, Dk restricted responses to vaccinia in Sendai viruses are at least 30 times lower than the corresponding K-restricted responses irrespective of the H-2 haplotypes (k, b, d, dxs, dxq) of K and I regions; in contrast, LCMV infection generates high responses to Dk. These findings are consistent with but do not prove that this Ir gene maps to D. Second, Db restricted responses to vaccinia and Sendai viruses are high in strains possessing the Kq or KbIb, KbaIb haplotype, are very low in strains with Kk, and relatively low in mouse strains of the KdI-Ad haplotype; LCMV generates high Db restricted response in the presence of Kk. This Ir gene for the response to vaccinia and Sendai viruses maps to K since B10.BYR (KqIkdDb) is a responder and B10.A (2R) is a nonresponder (KkIkdDb). Third, virus and K or D allele specific nonresponsiveness is dominant with variable penetrance; in heterozygous mice the nonresponder Kk allele over-rides responsiveness normally found in KbDb or KqDb combinations. Fourth, when (responder X nonresponder)F1 lymphocytes are stimulated in an environment expressing vaccinia virus plus only a high responder Kb or Kq allelle and Db, response to vaccinia Db is high; in contrast when the same F1 cells are stimulated in an environment expressing the low responder allele Kk, response to vaccinia Db is low. Thus absence of Kk during immunization allows generation of high responsive Db restricted vaccinia specific cytotoxic T cells. The Dk dependent low response to vaccinia Dk can be explained by a preclusion rule or by failure of vaccinia to complex with Db; however the analysis of Kk dependent low response to vaccinia Db does not support these explanations or that self-tolerance is responsible for this Ir effect but is compatible with the interpretation that Kk vaccinia is immunodominant over Db vaccinia. These results are discussed with respect to (a) possible mechanisms of regulation by Ir genes and (b) H-2 polymorphism and HLA-disease association.


The Korean Medication Algorithm for Major Depressive Disorder (KMA-MDD): Report of the Korean Society of Depressive and Bipolar Disorders.
Objective. There are many differences in biological characteristics, clinical situations, and medical insurance systems with ethnic groups or countries. The Korean Society of Depressive and Bipolar Disorders decided to develop a Korean treatment algorithm for major depressive disorder. Methods. The Korean Medication Algorithm Project for Major Depressive Disorder (KMAP-MDD) was designed with the following principles: (1) to be an ideal algorithm, (2) to be a Korean algorithm, (3) to be a medication algorithm, (4) to be an evidence-based and formal consensus algorithm. After collecting and reviewing many literature citations and reports by evidence-based rule, we constructed a survey questionnaire for formal consensus of Korean experts. By employing panels of experts to review the evidence and survey results thoroughly, we used evidence-based algorithm development as a component of a formal consensus development process. Results. We developed two algorithms for the KMA-MDD: one for major depressive disorder without psychotic feature and the other for major depressive disorder with psychotic features. Clinical guidelines for the implementation of KMA-MDD were also developed. The KMA-MDD provides specific treatment strategies for each stage. Conclusions. The KMA-MDD is the first Korean algorithm for treatment of major depressive disorder. It is based on evidence which supports the efficacy of each treatment, and it has obtained the consensus of Korean experts. We hope that the KMA-MDD will be good practical tool for clinicians who treat major depressive disorder in Korea.


Differences of protein fractions among fresh, frozen and powdered donkey milk.
Recently donkey milk has been the focus of several studies because of its special nutritional properties and composition, which is very close to human milk. When a mother cannot breastfeed, or chooses not to breastfeed, the use of a milk substitute must provide the best option to meet the nutritional and health needs of the infant. Donkey milk has been widely used in the past to replace human milk, because chemical composition and protein content are close to that of human milk, and also because the allergenicity of donkey milk is low. The recent studies of the paediatric scientists have demonstrated that infant formulae, which are based on dairy cows milk, are less adapted than donkey milk. In fact, donkey's milk digestibility is higher than cows' milk and similar to human milk, because of the high whey proteins content and the few casein content. Since donkey milk supply is related to its seasonal availability during the year, in this study were evaluated the effects of a specific technological treatment (spray-dryer) and a particular storage temperature (-20 degrees C) on the protein fractions of donkey milk. The results obtained in fresh, frozen and powdered donkey milk showed different values in total proteins, caseins, whey proteins and lysozyme content. The article presents some promising patents on protein fractions among fresh, frozen and powdered donkey milk.


Detecting natural selection in RNA virus populations using sequence summary statistics.
At present, most analyses that aim to detect the action of natural selection upon viral gene sequences use phylogenetic estimates of the ratio of silent to replacement mutations. Such methods, however, are impractical to compute on large data sets comprising hundreds of complete viral genomes, which are becoming increasingly common due to advances in genome sequencing technology. Here we investigate the statistical performance of computationally efficient tests that are based on sequence summary statistics, and explore their applicability to RNA virus data sets in two ways. Firstly, we perform extensive simulations in order to measure the type I error of two well-known summary statistic methods - Tajima's D and the McDonald-Kreitman test - under a range of virus-like mutational and demographic scenarios. Secondly, we apply these methods to a compilation of approximately 100 RNA virus alignments that represent natural RNA virus populations. In addition, we develop and introduce a new implementation of the McDonald-Kreitman test and show that it greatly improves the test's statistical reliability on typical viral data sets. Our results suggest that variants of the McDonald-Kreitman test could prove useful in the analysis of very large sets of highly diverse viral genetic data.


Estimation of aortic compliance using magnetic resonance pulse wave velocity measurement.
A method for compliance estimation employing magnetic resonance pulse wave velocity measurement is presented. Time-resolved flow waves are recorded at several positions along the vessel using a phase contrast sequence, and pulse wave velocity is calculated from the delay of the wave onsets. Using retrospective cardiac gating in combination with an optically decoupled electrocardiogram acquisition, a high temporal resolution of 3 ms can be achieved. A phantom set-up for the simulation of pulsatile flow in a compliant vessel is described. In the phantom, relative errors of pulse wave velocity estimation were found to be about 15%, whereas in a volunteer, larger errors were found that might be caused by vessel branches. Results of pulse wave velocity estimation agree with direct aortic distension measurements which rely on a peripheral estimate of aortic pressure and are therefore less accurate. Studies in 12 volunteers show values of pulse wave velocity consistent with the literature; in particular the well-known increase in pulse wave velocity with age was observed. Preliminary results show that the method can be applied to aortic aneurysms.


Three-dimensional mathematical model for deformation of human fasciae in manual therapy.
Although mathematical models have been developed for the bony movement occurring during chiropractic manipulation, such models are not available for soft tissue motion. To develop a three-dimensional mathematical model for exploring the relationship between mechanical forces and deformation of human fasciae in manual therapy using a finite deformation theory. The predicted stresses required to produce plastic deformation were evaluated for a volunteer subject's fascia lata, plantar fascia, and superficial nasal fascia. These stresses were then compared with previous experimental findings for plastic deformation in dense connective tissues. Using the three-dimensional mathematical model, the authors determined the changing amounts of compression and shear produced in fascial tissue during 20 seconds of manual therapy. The three-dimensional model's equations revealed that very large forces, outside the normal physiologic range, are required to produce even 1% compression and 1% shear in fascia lata and plantar fascia. Such large forces are not required to produce substantial compression and shear in superficial nasal fascia, however. The palpable sensations of tissue release that are often reported by osteopathic physicians and other manual therapists cannot be due to deformations produced in the firm tissues of plantar fascia and fascia lata. However, palpable tissue release could result from deformation in softer tissues, such as superficial nasal fascia.


Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma.
The aim of the present study was to determine whether modifying the local bone environment with osteoprotegerin (OPG), the soluble decoy receptor for receptor activator of nuclear factor-kappaB (RANK) ligand, could affect tumor burden and survival in the 5T33MM murine model of multiple myeloma. Treatment of mice, injected with 5T33MM cells, with recombinant OPG (Fc-OPG) caused a significant decrease in serum paraprotein and tumor burden and a significant increase in time to morbidity. This was associated with a decrease in osteoclast number in vivo but had no effect on apoptosis and proliferation of 5T33MM cells in vitro. These data indicate that targeting the bone microenvironment by inhibiting the interaction between RANK ligand and RANK with Fc-OPG not only inhibits the development of myeloma bone disease but also decreases tumor growth and increases survival.


Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity.
Mutations in the gene encoding transforming growth factor-beta receptor type II (TGFBR2) have been described in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). Here, we present a comprehensive and quantitative analysis of TGFBR2 expression, turnover and TGF-β-induced Smad and ERK signaling activity for nine mutations identified in patients with LDS, MFS2 and TAAD. The mutations had different effects on protein stability, internalization and signaling. A dominant-negative effect was demonstrated for mutations associated with LDS and MFS2. No mutation showed evidence of an immediate cell-autonomous paradoxical activation of TGF-β signaling. There were no cell biological differences between mutations described in patients with LDS and MFS2. By contrast, R460C, which has been found in familial TAAD but not in MFS2 or LDS, showed a less-severe dominant-negative effect and retained residual Smad phosphorylation and transcriptional activity. TAAD is characterized primarily by thoracic aortic aneurysms or dissections. By contrast, MFS2 is characterized by numerous skeletal abnormalities, and patients with LDS additionally can display craniofacial and other abnormalities. Therefore, our findings suggest that the balance between defects in Smad and ERK signaling might be an important determinant of phenotypic severity in disorders related to mutations in TGFBR2.