Evaluation of bone thickness in the anterior hard palate relative to midsagittal orthodontic implants.
The Straumann Orthosystem (Institut Straumann, Waldenburg, Switzerland) describes a technique that involves placement of titanium implants (4 or 6 mm long and 3.3 mm in diameter) into the midsagittal hard palate for orthodontic anchorage. The aim of this study was to determine the quantity of bone in the midline of the anterior hard palate, and specifically the thickness inferior to the incisive canal. Twenty-five dry skulls were radiographed with a standardized cephalometric technique. The vertical thickness of the midsagittal palate was then measured to the nearest tenth of a millimeter. Next, gutta-percha was injected into the incisive canal, and the radiograph was repeated. The bone thicknesses were then measured from the inferior hard palate to the most Inferior part of the radiopaque canal. This is defined as the actual bone available for the implant without violating the canal. The measurements have shown that an average of 8.6 +/- 1.3 mm of bone is theoretically available for the implant. However, considering the canal (where only bone thickness inferior to it is utilized and measured), only 4.3 +/- 1.6 mm of bone exists. The canal itself averaged 2.5 +/- 0.6 mm in diameter. Prior studies have overestimated the amount of bone available for implants in the median hard palate. The main reason for this is that the incisive canal is not well visualized on cephalometric radiographs of live patients. This study supports the continued use of implants, as approximately 50% of skulls still had the requisite minimum 4 mm of bone inferior to the incisive canal for maximum osseointegration with the 4-mm implants. However, 6-mm implants should be used with caution.


Organization of cytoskeleton elements during herpes simplex virus type 1 infection of human fibroblasts: an immunofluorescence study.
Cultured human fibroblasts showed a typical fibrillar organization of microtubules in immunofluorescence, including the vimentin type of intermediate filament as well as actin-containing microfilaments. During infection with herpes simplex virus type 1 (HSV-1), the vimentin organization was maintained whereas actin, myosin and tubulin showed a progressive association with the viral glycoproteins within juxtanuclear structures. These structures could also be revealed with fluorochrome-coupled wheat germ agglutinin. Disruption of the microtubules by demecolcine treatment or their stabilization by taxol treatment did not prevent the aggregation of viral proteins in the cytoplasm. Taxol stabilization of the microtubules allowed the juxtanuclear accumulation of the glycoproteins in HSV-infected cells whereas treatment with demecolcine led to an accumulation of the glycoproteins either in small vesicles in the cytoplasm or in the focal adhesion areas of the cells. Production of infectious intracellular virus particles was reduced in cells treated with demecolcine or with taxol before and during infection. The results of this study indicate that the normal intracellular transport and distribution of the HSV glycoproteins and the formation of infectious virus are dependent on the presence of intact microtubules.


A High Polyphenol Diet Improves Psychological Well-Being: The Polyphenol Intervention Trial (PPhIT).
Mental ill health is currently one of the leading causes of disease burden worldwide. A growing body of data has emerged supporting the role of diet, especially polyphenols, which have anxiolytic and antidepressant-like properties. The aim of the present study was to assess the effect of a high polyphenol diet (HPD) compared to a low polyphenol diet (LPD) on aspects of psychological well-being in the Polyphenol Intervention Trial (PPhIT). Ninety-nine mildly hypertensive participants aged 40-65 years were enrolled in a four-week LPD washout period and then randomised to either an LPD or an HPD for eight weeks. Both at baseline and the end of intervention, participants' lifestyle and psychological well-being were assessed. The participants in the HPD group reported a decrease in depressive symptoms, as assessed by the Beck Depression Inventory-II, and an improvement in physical component and mental health component scores as assessed with 36-Item Short Form Survey. No differences in anxiety, stress, self-esteem or body image perception were observed. In summary, the study findings suggest that the adoption of a polyphenol-rich diet could potentially lead to beneficial effects including a reduction in depressive symptoms and improvements in general mental health status and physical health in hypertensive participants.


Assessing and treating insulin resistance in women with polycystic ovarian syndrome.
Polycystic ovarian syndrome (PCOS) is a highly prevalent hormonal and metabolic disorder among reproductive aged women worldwide. Women with PCOS have widely varying phenotypes and seek medical care for differing reasons. In addition to concern for menstrual cycle function, ovulation, hirsutism and acne, many PCOS women have abnormal glucose metabolism. While diabetes mellitus and impaired glucose tolerance are easily diagnosed, the diagnosis of and concern for insulin resistance as a precursor disorder is underappreciated. Insulin resistance may be the first important marker of metabolic disease in PCOS women at risk for metabolic syndrome and coronary artery disease.


Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing.
GPR88 is an orphan G-protein coupled receptor originally characterized as a striatal-enriched transcript and is a potential target for neuropsychiatric disorders. At present, gene knockout studies in the mouse have essentially focused on striatal-related functions and a comprehensive knowledge of GPR88 protein distribution and function in the brain is still lacking. Here, we first created Gpr88-Venus knock-in mice expressing a functional fluorescent receptor to fine-map GPR88 localization in the brain. The receptor protein was detected in neuronal soma, fibers and primary cilia depending on the brain region, and remarkably, whole-brain mapping revealed a yet unreported layer-4 cortical lamination pattern specifically in sensory processing areas. The unique GPR88 barrel pattern in L4 of the somatosensory cortex appeared 3 days after birth and persisted into adulthood, suggesting a potential function for GPR88 in sensory integration. We next examined Gpr88 knockout mice for cortical structure and behavioral responses in sensory tasks. Magnetic resonance imaging of live mice revealed abnormally high fractional anisotropy, predominant in somatosensory cortex and caudate putamen, indicating significant microstructural alterations in these GPR88-enriched areas. Further, behavioral analysis showed delayed responses in somatosensory-, visual- and olfactory-dependent tasks, demonstrating a role for GPR88 in the integration rather than perception of sensory stimuli. In conclusion, our data show for the first time a prominent role for GPR88 in multisensory processing. Because sensory integration is disrupted in many psychiatric diseases, our study definitely positions GPR88 as a target to treat mental disorders perhaps via activity on cortical sensory networks.


Under-utilisation of reproducible, child appropriate or patient reported outcome measures in childhood uveitis interventional research.
Childhood uveitis is a collection of chronic rare inflammatory eye disorders which result in visual loss in at least one eye of one fifth of affected children. Despite the introduction of novel systemic immunochemotherapies, it remains a blinding disease. We have undertaken a systematic review of outcome measures used in interventional trials of children with, or at risk of uveitis, in order to investigate metric quality and heterogeneity, as possible barriers to the translation of clinical research into improved outcomes. Systematic review of trials registered within databases approved by the International Committee of Medical Journal Editors (ICMJE). Eligible trials for were those which involved participants aged under 18 years with or at risk of non-infectious uveitis. Data on date of study commencement, uveitis site, inclusion age criteria, and outcome measure characteristics including type, dimension and quality were extracted independently by two authors. Quality was determined using the reproducibility, validity and age-appropriateness of the metric. Of 917 identified trials, 57 were eligible for inclusion. Twenty different domains across five dimensions were used as primary outcome measures. The structure most commonly used was multiple separate outcome measures. In a quarter of studies, outcomes were assessed less than 3 months following the intervention. Disease activity was the most commonly assessed dimension, with only 30 studies (60%) using reproducible methodologies to assess activity. Only 2/12 (18%) studies on intermediate or posterior uveitis used reproducible activity grading schemes. Of 18 studies involving children aged under 6 years old which used outcome measures related to visual function, only 8/18 (44%) described the use of age-appropriate acuity assessment measures. None of the studies used a vision related quality of life metrics which had been validated for use in childhood. This review of outcome measures in childhood uveitis interventional trials has identified under-utilisation of reproducible or child appropriate measures, and considerable heterogeneity in metric type, and structure. Clinicians and researchers interested in improving outcomes for affected children must identify a patient and family centred core outcome set, and work to validate both objective and patient (or proxy) reported disease age appropriate outcome measures.


Ganoderma lucidum reduces kainic acid-induced hippocampal neuronal damage via inflammatory cytokines and glial fibrillary acid protein expression.
Ganoderma lucidum, a traditional Chinese medicine, has been shown to target the Central Nervous System. In this work we analyze whether G. lucidum, collected in Mexico, has a protective effect in the hippocampus of rats treated with kainic acid, a neurotoxin that causes seizures and neuronal loss. The aqueous extract of G. lucidum (10 mg/Kg, i.p.) was administered to rats 30 min before kainic acid injection (5 mg/Kg, i.p.). Animals that had received prior treatment with G. lucidum showed no tonic-clonic seizure activity. Histopathological analysis showed a significant decrease in neuronal loss and cellular alterations in the hippocampal CA3 region. Immunohistochemical analysis shows that when using G. lucidum in rats, there is less immunoreactivity for GFAP as well as TNF-alpha and IL-1beta in the CA3 region when compared with rats treated with kainic acid. Our results demonstrate that G. lucidum protects against kainic acid-induced alterations of hippocampal cells and expression of immunological markers in this model of excitotoxicity.


Pattern Recognition of Cells via Multiplexed Imaging with Monosaccharide-Imprinted Quantum Dots.
Recognition of cancer cells is essential for many important areas such as targeted cancer therapy. Multimonosaccharide-based recognition could be a useful strategy to improve the recognition specificity, but such a possibility has not been explored yet. Herein we report pattern recognition of cells via multiplexed imaging with monosaccharide-imprinted quantum dots (QDs). Imprinted with sialic acid, fucose, and mannose as the template, respectively, the QDs exhibited good specificity toward the template monosaccharides. Multiplexed imaging of cells simultaneously stained with these monosaccharide-imprinted QDs revealed the relative expression levels of the monosaccharides on the cells. Pattern recognition constructed using the intensities of multiplexed imaging unveiled the similarities and differences of different cell lines, allowing for the recognition of not only cancer cells from normal cells but also cancer cells of different cell lines. Thus, this study paved a solid ground for the design and preparation of novel cancer-cell targeting reagents and nanoprobes.


Acclimation process of the chlorophyll d-bearing cyanobacterium Acaryochloris marina to an orange light environment revealed by transcriptomic analysis and electron microscopic observation.
The cyanobacterium Acaryochloris marina MBIC 11017 (A. marina 11017) possesses chlorophyll d (Chl. d) peaking at 698 nm as photosystem reaction center pigments, instead of chlorophyll a (Chl. a) peaking at 665 nm. About 95% of the total chlorophylls is Chl. d in A. marina 11017. In addition, A. marina 11017 possesses phycobilisome (PBS) supercomplex to harvest orange light and to transfer the absorbing energy to the photosystems. In this context, A. marina 11017 utilizes both far-red and orange light as the photosynthetic energy source. In the present study, we incubated A. marina 11017 cells under monochromatic orange and far-red light conditions and performed transcriptional and morphological studies by RNA-seq analysis and electron microscopy. Cellular absorption spectra, transcriptomic profiles, and microscopic observations demonstrated that PBS was highly accumulated under an orange light condition relative to a far-red light condition. Notably, transcription of one cpcBA operon encoding the phycobiliprotein of the phycocyanin was up-regulated under the orange light condition, but another operon was constitutively expressed under both conditions, indicating functional diversification of these two operons for light harvesting. Taking the other observations into consideration, we could illustrate the photoacclimation processes of A. marina 11017 in response to orange and far-red light conditions in detail.


Survival and Injury of Listeria monocytogenes , Listeria innocua and Listeria ivanovii in Ground Pork Following Electron Beam Irradiation †.
The sensitivity of five strains of Listeria to electron beam irradiation in ground pork as well as the extent of sublethal radiation injury exhibited by each were investigated. Ground pork was inoculated with one of five strains of Listeria and irradiated with from 0 to 1.25 kGy at 0.25 kGy intervals. Listeria innocua NADC 2841 was more radiation-resistant (D10 = 0.638 kGy) than L. monocytogenes NADC 2045 Scott A (D10 = 0.447 kGy), L. monocytogenes NADC 2783 (a hamburger isolate) (D10 = 0.424 kGy), L. monocytogenes ATCC 15313 (D10 = 0.445 kGy), and L. ivanovii NADC 3518 (D10 = 0.372 kGy), when recovered on tryptic soy agar supplemented with 0.6% yeast extract. D10 values for L. innocua , L. ivanovii , and L. monocytogenes ATCC 15313 were lower when cells were recovered on modified Oxford medium. These three strains were susceptible to radiation-induced sublethal injury, with the numbers of injured organisms increasing with irradiation dose. The two pathogenic strains of L. monocytogenes were not injured significantly at the dose levels used. The results show that the dose range currently being considered by the Food and Drug Administration for the irradiation of beef and pork (1.5 to 4.5 kGy) is adequate for the elimination of L. monocytogenes from pork.


Nucleic acid detection systems for enteroviruses.
The enteroviruses comprise nearly 70 human pathogens responsible for a wide array of diseases including poliomyelitis, meningitis, myocarditis, and neonatal sepsis. Current diagnostic tests for the enteroviruses are limited in their use by the slow growth, or failure to grow, of certain serotypes in culture, the antigenic diversity among the serotypes, and the low titer of virus in certain clinical specimens. Within the past 6 years, applications of molecular cloning techniques, in vitro transcription vectors, automated nucleic acid synthesis, and the polymerase chain reaction have resulted in significant progress toward nucleic acid-based detection systems for the enteroviruses that take advantage of conserved genomic sequences across many, if not all, serotypes. Similar approaches to the study of enteroviral pathogenesis have already produced dramatic advances in our understanding of how these important viruses cause their diverse clinical spectra.


Sbp1 modulates the translation of Pab1 mRNA in a poly(A)- and RGG-dependent manner.
RNA-binding protein Sbp1 facilitates the decapping pathway in mRNA metabolism and inhibits global mRNA translation by an unclear mechanism. Here we report molecular interactions responsible for Sbp1-mediated translation inhibition of mRNA encoding the polyadenosine-binding protein (Pab1), an essential translation factor that stimulates mRNA translation and inhibits mRNA decapping in eukaryotic cells. We demonstrate that the two distal RRMs of Sbp1 bind to the poly(A) sequence in the 5'UTR of the Pab1 mRNA specifically and cooperatively while the central RGG domain of the protein interacts directly with Pab1. Furthermore, methylation of arginines in the RGG domain abolishes the protein-protein interaction and the inhibitory effect of Sbp1 on translation initiation of Pab1 mRNA. Based on these results, the underlying mechanism for Sbp1-specific translational regulation is proposed. The functional differences of Sbp1 and RGG repeats alone on transcript-specific translation were observed, and a comparison of the results suggests the importance of remodeling the 5'UTR by RNA-binding proteins in mRNA translation.


Antigen loading of MHC class I molecules in the endocytic tract.
Major histocompatibility complex (MHC) class I molecules bind antigenic peptides that are translocated from the cytosol into the endoplasmic reticulum by the transporter associated with antigen processing. MHC class I loading independent of this transporter also exists and involves peptides derived from exogenously acquired antigens. Thus far, a detailed characterization of the intracellular compartments involved in this pathway is lacking. In the present study, we have used the model system in which peptides derived from measles virus protein F are presented to cytotoxic T cells by B-lymphoblastoid cells that lack the peptide transporter. Inhibition of T cell activation by the lysosomotropic drug ammoniumchloride indicated that endocytic compartments were involved in the class I presentation of this antigen. Using immunoelectron microscopy, we demonstrate that class I molecules and virus protein F co-localized in multivesicular endosomes and lysosomes. Surprisingly, these compartments expressed high levels of class II molecules, and further characterization identified them as MHC class II compartments. In addition, we show that class I molecules co-localized with class II molecules on purified exosomes, the internal vesicles of multivesicular endosomes that are secreted upon fusion of these endosomes with the plasma membrane. Finally, dendritic cells, crucial for the induction of primary immune responses, also displayed class I in endosomes and on exosomes.


EDC/NHS cross-linked collagen foams as scaffolds for artificial corneal stroma.
In this study, a highly porous collagen-based biodegradable scaffold was developed as an alternative to synthetic, non-degradable corneal implants. The developed method involved lyophilization and subsequent stabilization through N-ethyl-N'-[3-dimethylaminopropyl] carbodiimide/N-hydroxy succinimide (EDC/NHS) cross-linking to yield longer lasting, porous scaffolds with a thickness similar to that of native cornea (500 microm). For collagen-based scaffolds, cross-linking is essential; however, it has direct effects on physical characteristics crucial for optimum cell behavior. Hence, the effect of cross-linking was studied by examining the influence of cross-linking on pore size distribution, bulk porosity and average pore size. After seeding the foam with human corneal keratocytes, cell proliferation, cell penetration into the scaffold and ECM production within the scaffold were studied. After a month of culture microscopical and immunohistochemical examinations showed that the foam structure did not undergo any significant loss of integrity, and the human corneal keratocytes populated the scaffold with cells migrating both longitudinally and laterally, and secreted some of the main constituents of the corneal ECM, namely collagen types I, V and VI. The foams had a layer of lower porosity (skin layer) both at the top and the bottom. Foams had an optimal porosity (93.6%), average pore size (67.7 microm), and chemistry for cell attachment and proliferation. They also had a sufficiently rapid degradation rate (73.6+/-1.1% in 4 weeks) and could be produced at a thickness close to that of the natural corneal stroma. Cells were seeded at the top surface of the foams and their numbers there was higher than the rest, basically due to the presence of the skin layer. This is considered to be an advantage when epithelial cells need to be seeded for the construction of hemi or full thickness cornea.


Long-term monitoring of feral genetically modified herbicide-tolerant Brassica napus populations around unloading Japanese ports.
Genetically modified, herbicide-tolerant (GMHT) Brassica napus plants originating from seed spill have recently been found along roadsides leading from Japanese ports that unload oilseed rape. Such introductions have potential biodiversity effects (as defined by the Cartagena Protocol): these include replacement of native elements in the biota through competitive suppression or hybridization. We conducted surveys in the period 2006-2011 to assess such threats. We examined shifts in the population distribution and occurrence of GMHT plants in 1,029 volunteer introduced assemblages of B. napus, 1,169 of B. juncea, and 184 of B. rapa around 12 ports. GMHT B. napus was found around 10 of 12 ports, but its proportion in the populations varied greatly by year and location. Over the survey period, the distributions of a pure non-GMHT population around Tobata and a pure GMHT population around Hakata increased significantly. However, there was no common trend of population expansion or contraction around the 12 ports. Furthermore, we found no herbicide tolerant B. juncea and B. rapa plants derived from crosses with GMHT B. napus. Therefore, GMHT B. napus is not invading native vegetation surrounding its populations and not likely to cross with congeners in Japanese environment.


Juvenile hormone analogs: detrimental effects on the development of an endoparasitoid.
A high incidence of mortality of the endoparasitoid Aphidius nigripes was observed when its host. Macrosiphum euphorbiae, was treated with juvenile hormone analogs. Larval and pupal stages of the parasitoid were susceptible. Off-target effects on natural enemies may seriously limit the use of juvenile hormone analogs, especially in integrated control programs.


Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats.
Our aim was to test the hypothesis that angiotensin II receptor blockade combined with exercise training after myocardial infarction (MI) could attenuate post-MI left ventricular remodelling and preserve cardiac function. Sprague-Dawley rats underwent ligation of the left descending coronary artery, resulting in MI, or a sham operation. Losartan treatment and exercise training were initiated 1 week after infarction and continued for 8 weeks, either as a single intervention or combined. Collagen volume fraction in the sedentary MI (MISed) group was significantly higher than other MI groups treated with exercise training and/or losartan. Compared with MISed group, hearts of rats receiving exercise and/or losartan treatment had lower tissue inhibitor of matrix metalloproteinase (TIMP) 1. Matrix metalloproteinase (MMP) 2 or MMP-9 did not differ among all groups. Additionally, the level of angiotensin II receptor type 1 (AT1) protein significantly decreased in response to exercise training. Furthermore, angiotensin converting enzyme (ACE) binding was markedly lower in hearts receiving exercise training than in the MISed hearts. Cardiac function was preserved in rats receiving exercise training, and the beneficial effect was further improved by exercise combined with losartan treatment in comparison to the MISed group. Our results suggest that post-MI exercise training and/or AngII receptor blockade reduces TIMP-1 expression and mitigates the expressions of ACE and AT1 receptor. These improvements, in turn, attenuate myocardial fibrosis and preserve post-MI cardiac function.


[The effect of tissue preparations on the development of anaphylaxis].
The paper analyses results of experimental studies conducted in 60 guinea pigs with the purpose to determine the influence of preparations of a group of distillate (torfot, FiBS) and protein preparations of vegetable (aloe extract) and animal (extract of placenta) origin on the development of a reaction of hypersensitivity of a delayed type. It was found that tissue preparations both in doses adequate to those used in clinic (0.03 ml) and in doses biologically active in pharmacologic tests (0.3 ml) don't stimulate the development of anaphylactic shock and the usage of FiBS leads to a remarkable reduction of its manifestations in experimental animals. The results obtained speak about the difference between immunomodulating influence of the preparation of a group of distillates and protein preparations on the development of anaphylaxis and allow to show, for the first time, a desensitizing action of a bioregulator of medicinal peloids (FiBS).


NT-pro-BNP: not the prognostic all-rounder in elderly patients undergoing allogeneic stem cell transplantation.
Allogeneic hematopoietic cell transplantation (HCT) is a curative approach for several diseases predominantly affecting elderly patients. Overall survival is compromised by treatment-related mortality (TRM), GvHD, and relapse. Pretransplant clinical risk indicators in elderly patients qualifying for HCT are highly desirable. Pro-BNP is known as a predictor of death in patients with an increasing variety of clinical conditions and frequently used as a routine parameter for organ complications in the allogeneic transplant setting without well-established scientific evidence. Our hypothesis was that pre-HCT NT-pro-BNP could aid in identifying elderly patients at risk for early mortality. We retrospectively evaluated NT-pro-BNP values in 177 consecutive patients of ≥60 years HCT (2005-2010). In 29.4 % of cases, NT-pro-BNP values were within our institute's normal range (<125 pg/ml). Analysis of different NT-pro-BNP cutoff points by receiver operating characteristics curve for mortality at day +100 revealed no single cutoff value with satisfying specificity and sensitivity. The individual outcome of patients with extremely high NT-pro-BNP values was not associated with an increase in mortality or cardiovascular morbidity. NT-pro-BNP values of patients succumbing to TRM did not differ significantly from those alive or having died of relapse-median 276 vs. 217 pg/ml. In conclusion, pre-HCT NT-pro-BNP was of no convincing prognostic relevance for day 100 mortality.


[Effect of fentanyl and morphine on local blood flow and tissue oxygen tension in cortical frontal-parietal area and nucleus accumbens in albino rats].
The aim of this study was to examine effects of i.p. injected Fentanyl (0.005 mg/kg) and Morphine (1 mg/kg) on local cerebral blood flow (ICBF) and tissue pO2 level in frontal-parietal area of the cortex and nucleus accumbens of the rat's brain. Either fentanyl or morphine injection resulted in significant increase of local blood flow in the n.accumbens and its decrease in frontal-parietal area of cortex. Measurement of oxygen partial pressure revealed the opposite (to ICBF) changes: a decrease in n.accumbens and its increase in cortical area of the brain. Analysis of this data and electrical activity recorded from both said structures allow to conclude that they are conditioned by respective changes in functional-metabolic activity induced by intraperitoneal injection either fentanyl or morphine: its suppression in frontal-parietal area of the cortex and development of seizure-like activity in the n.accumbens.


Pathophysiology of hypertension in blacks.
The pathophysiology of hypertension in the black population differs to some extent from that of the nonblack population. Although black hypertensives exhibit enhanced sodium retention, expanded plasma volume, lower plasma renin activity, and a greater increase in blood pressure in response to high levels of Na+ intake compared with nonblack hypertensives, there is considerable heterogeneity in these studies. Alterations in ion transport mechanisms, such as a decrease in Na+K(+)-ATPase activity and Na+K+ cotransport, have been demonstrated in the black hypertensive population. Those features provide the physiologic basis for the differential response to monotherapy with diuretics and, perhaps, with calcium channel blockers, that is observed in black hypertensives, particularly when compared with responses to beta-blockers or angiotensin converting enzyme inhibitors.


Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses.
Accumulation and propagation of hyperphosphorylated Tau (p-Tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating Tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-Tau pathology after injection into mouse brain. To gain an understanding of the mTau exosome cargo involved in Tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in 1) proteins uniquely present only in mTau, and not control exosomes, 2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and 3) shared proteins which were significantly upregulated or downregulated in mTau compared with control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-Tau. Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes. Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or downregulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-Tau neuropathology in mouse brain.


Conservation of DNA methylation in dipteran insects.
DNA methylation is a central mechanism of epigenetic regulation. Whereas vertebrate DNA methylation requires at least four different DNA methyltransferases, Drosophila melanogaster only utilizes a single, Dnmt2-like enzyme. This profound difference has raised the question of the evolutionary significance of the Drosophila methylation system. We have now identified Dnmt2-like open reading frames in the genome sequences of Drosophila pseudoobscura and Anopheles gambiae. These genes represent the only candidate DNA methyltransferases in their respective genomes. Consistent with a catalytic activity of Dnmt2 proteins, we could also demonstrate low but significant levels of DNA methylation in genomic DNA from these species. Lastly, we were also able to detect highly conserved Dnmt2-like open reading frames and concomitant DNA methylation in several additional Drosophila species, which suggests that Dnmt2-mediated DNA methylation has been conserved over a considerable evolutionary distance.


Delirium superimposed on dementia versus delirium in the absence of dementia: phenomenological differences.
To examine differences in the phenomenological characteristics of delirium superimposed on dementia compared to those observed in delirious patients without dementia, based on the rating items of the Memorial Delirium Assessment Scale (MDAS). We conducted an analysis of a prospectively collected clinical delirium database utilized to record and monitor the care of delirious patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC). Sociodemographic, medical variables, and MDAS total score and individual item ratings were analyzed in respect to differences between delirium in the demented (DD) versus delirium in the nondemented (ND). We were able to examine data collected on 100 delirious patients: 82 ND patients and 18 DD patients. Patients in the DD group, compared to the ND group, had significantly greater levels of disturbance of consciousness and impairments in all cognitive domains (i.e., orientation, short term memory, concentration, organization of thought process). Severe symptoms were more common in the DD group compared to the ND group on all the MDAS cognitive items as well as in disturbance of consciousness. There were no significant differences between the DD and ND groups in terms of presence or severity of hallucinations, delusions, psychomotor behavior, and sleep-wake cycle disturbance. Delirium superimposed on dementia has phenomenological differences compared to delirium in the absence of dementia. There are no significant differences in the severity of hallucinations, delusions, psychomotor behavior, or sleep-wake cycle disturbances. However, level of disturbance in consciousness (arousal and awareness) and impairments in multiple cognitive domains are significantly more severe in patients with delirium superimposed on dementia.


Randomized, double-blind comparison of indocyanine green with or without albumin premixing for near-infrared fluorescence imaging of sentinel lymph nodes in breast cancer patients.
Near-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available fluorophore that can be used for SLN mapping. Preclinically, ICG adsorbed to human serum albumin (ICG:HSA) improves its performance as a lymphatic tracer in some anatomical sites. The benefit of ICG:HSA for SLN mapping of breast cancer has not yet been assessed in a clinical trial. We performed a double-blind, randomized study to determine if ICG:HSA has advantages over ICG alone. The primary endpoint was the fluorescence brightness, defined as the signal-to-background ratio (SBR), of identified SLNs. Clinical trial subjects were 18 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using (99m)Technetium-nanocolloid and patent blue. Patients were randomly assigned to receive 1.6 ml of 500 μM ICG:HSA or ICG that was injected periareolarly directly after patent blue. The Mini-Fluorescence-Assisted Resection and Exploration (Mini-FLARE) imaging system was used for NIR fluorescence detection and quantitation. SLN mapping was successful in all patients. Patient, tumor, and treatment characteristics were equally distributed over the treatment groups. No significant difference was found in SBR between the ICG:HSA group and the ICG alone group (8.4 vs. 11.3, respectively, P = 0.18). In both groups, the average number of detected SLNs was 1.4 ± 0.5 SLNs per patient (P = 0.74). This study shows that there is no direct benefit of premixing ICG with HSA prior to injection for SLN mapping in breast cancer patients, thereby reducing the cost and complexity of the procedure. With these optimized parameters that eliminate the necessity of HSA, larger trials can now be performed to determine patient benefit.


Optimal management of prostate cancer with lethal biology--state-of-the-art local therapy.
Defining prostate cancer with lethal biology based upon clinical criteria is challenging. Locally advanced/High-Grade prostate cancer can be downstaged or even downgraded with cure in up to 60% of patients with primary therapy. However, what is known is that high-grade prostate cancers have a greater potential for recurrence and progression to metastatic disease, which can ultimately result in a patient's death. Patients with clinical features of "high-risk" prostate cancer (cT2c, PSA >20, ≥ Gl 8 on biopsy) are more likely to harbor more aggressive pathologic findings. The optimal management of high-risk prostate cancer is not known as there are not prospective studies comparing surgery to radiation therapy (RT). Retrospective and population-based studies are subject to many biases and attempts to compare surgery and radiation have demonstrated mixed results. Some show equivalent survival outcomes while others showing an advantage of surgery over RT. Local therapy for high-risk disease does appear to be beneficial. Improved outcomes realized with local therapy have been clearly demonstrated by several prospective studies evaluating androgen deprivation therapy (ADT) alone versus ADT plus RT. The combination of local with systemic treatment showed improved disease-specific and overall survival outcomes. Unfortunately, primary ADT for N0M0 prostate cancer is still inappropriately applied in general practice. While the surgical literature is largely retrospective, it too demonstrates that surgery in the setting of high-risk prostate cancer is effective in providing durable disease-specific and overall survivals. [


Robot-assisted general surgery in Aotearoa New Zealand.
Robot-assisted surgery refers to a surgeon controlling a robotic device that performs an operation. This viewpoint explores the current state of robot-assisted surgery in Aotearoa New Zealand using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, California, United States), the only currently available robotic surgical system for general surgery in the country. We describe the contemporary progress in Aotearoa New Zealand compared to Australia and globally, and present emerging high-level evidence from randomised controlled trials regarding the utility of the robot-assisted approach for general surgery procedures. From the available evidence, we suggest that the value of robot-assisted general surgery in the public healthcare system arises from its emerging clinical benefits for complex procedures and its potential to engender equitable access and outcomes, particularly for Māori and Pacific peoples, improve education and training and contribute towards quality assurance and workforce development. Therefore, its implementation aligns with the New Zealand Health Strategy's long-term goals and priority areas to achieve pae ora, healthy futures for all.


Comparative evaluation of chelating agents on the mobilization of cadmium: a mechanistic approach.
A comparative evaluation of chelating agents, namely, diethyl dithiocarbamate (DDC), dimethyl dithiocarbamate (DMDC), 1,4,8,11-tetraazacyclotetradecane (CYCLAM), 1,4,8,12-tetraazacyclopentadecane (TACPD), 2,3-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propane sulfonate (DMPS) was conducted to assess their efficacy against acute cadmium (Cd) toxicity. DMSA and DMPS appeared to be most effective in reducing mortality as well as Cd burden of liver, kidneys, and brain in cadmium intoxicated mice. DMDC reduced Cd levels only in liver and kidneys, while DDC significantly enhanced its level in brain. CYCLAM and TACPD significantly increased the Cd level in liver and kidneys and were ineffective in brain. The therapeutic index as well as therapeutic efficacy was highest for DMSA followed by DMPS and DMDC. A fair degree of correlation was found to exist between (1) stability constant of Cd chelates and percent survival (r = .438, (2) stability constant and percent transport (r = .479), and (3) percent survival and percent transport (r =.447). However, the lipophilicity did not show any appreciable correlation with percent survival and stability constant of Cd chelates.


Treatment of diabetic nephropathy in its early stages.
Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.


Challenges Faced by Latino Caregivers in Transportation of Children with Medical Complexity.
BACKGROUND Transportation challenges affect access to health care. Our objective was to describe transportation challenges faced by Latino children with medical complexity and identify strategies that could address these challenges.METHODS This is a qualitative study. Seventy Latino children with medical complexity who were enrolled in a complex care program of a tertiary care children's hospital were followed for a median duration of 18 months. Qualitative data were care coordination notes for each child obtained from care coordinators' encounter logs and reported experiences. Using thematic content analysis and an iterative process, we identified recurrent themes related to transportation challenges.RESULTS Caregivers of Latino children with medical complexity face many challenges transporting their children to medical appointments. These include lack of vehicle, inability to drive, lack of driver's license due to immigration status, and lack of resources to maintain a vehicle. As a result, Latino children with medical complexity often need non-emergency medical transportation, but caregivers find these systems difficult to use, in part because of language difficulties. Thus, they rely on care coordinators to access non-emergency medical transportation. Transportation problems can lead to missed medical appointments for the child and lost work for the caregiver. We identified interrelated factors that contributed to transportation issues for Latino children with medical complexity and potential strategies to address them.LIMITATIONS The extent of transportation challenges cannot be discerned because this is a qualitative study.CONCLUSIONS Transportation is difficult for Latino children with medical complexity, who rely on non-emergency medical transportation to access medical services. Care coordinators play a major role in addressing transportation problems for Latino children with medical complexity and their caregivers.


[Evaluation of the quality of life of cardiovascular disease patients].
A questionnaire was prepared for the evaluation of the quality of life directed at assessment of the patient's attitude to changes that had taken place in his life due to his illness. Results of observations of 124 patients (94 with myocardial infarction and 30 with arterial hypertension) show the validity of the questionnaire and its discriminant possibility. Difference in the indices of quality of life has been established between the infarction and the hypertensive patients. In persons who retained working capacity and in patients used to physical exercise the overall index of quality of life was higher than invalids or patients who were not used to physical training. In persons with low overall index of quality of life MMPI, according to 1, 2, 7 and 8 scales, were statistically significantly higher than in persons with high overall index of quality of life. The method permits one not only to give a quantitative assessment of the quality of life as a whole, but also to take into consideration concrete reasons for its deterioration.


"Should I Inhale?"-Perceptions, Barriers, and Drivers for Medicinal Cannabis Use amongst Australian Women with Primary Dysmenorrhoea: A Qualitative Study.
This study sought to investigate the perceptions, barriers, and drivers associated with medicinal cannabis use among Australian women with primary dysmenorrhea. A qualitative study via virtual focus groups involving 26 women experiencing regular, moderate, or greater menstrual pain explored categories including cost, associated stigma, current drug driving laws, community and workplace ethics, and geographical isolation within the context of patient access under current Australian laws and regulations. A qualitative descriptive analysis identified that dissatisfaction with current management strategies such as over-the-counter analgesic usage was the key driver for wanting to use medicinal cannabis. A number of significant barriers to use were identified including patient access to medical prescribers, medical practitioner bias, current drug driving laws, geographic location, and cost. Community and cultural factors such as the history of cannabis as an illicit drug and the resulting stigma, even when prescribed by a medical doctor, still existed and was of concern to our participants. Whilst medicinal cannabis is legal in all states and territories within Australia, several barriers to access exist that require government regulatory attention to assist in increasing patient adoption, including possible subsidisation of cost. The high cost of legal, medicinal cannabis was a key factor in women's choice to use illicit cannabis. Overall, the concerns raised by our participants are consistent with the broader findings of a recent Australian Senate inquiry report into barriers to patient access to medicinal cannabis in Australia, suggesting many of the issues are systematic rather than disease-specific. Given the interest in use of medicinal cannabis amongst women with primary dysmenorrhea, clinical trials in this area are urgently needed.


Eliminating accidental deviations to minimize generalization error and maximize replicability: Applications in connectomics and genomics.
Replicability, the ability to replicate scientific findings, is a prerequisite for scientific discovery and clinical utility. Troublingly, we are in the midst of a replicability crisis. A key to replicability is that multiple measurements of the same item (e.g., experimental sample or clinical participant) under fixed experimental constraints are relatively similar to one another. Thus, statistics that quantify the relative contributions of accidental deviations-such as measurement error-as compared to systematic deviations-such as individual differences-are critical. We demonstrate that existing replicability statistics, such as intra-class correlation coefficient and fingerprinting, fail to adequately differentiate between accidental and systematic deviations in very simple settings. We therefore propose a novel statistic, discriminability, which quantifies the degree to which an individual's samples are relatively similar to one another, without restricting the data to be univariate, Gaussian, or even Euclidean. Using this statistic, we introduce the possibility of optimizing experimental design via increasing discriminability and prove that optimizing discriminability improves performance bounds in subsequent inference tasks. In extensive simulated and real datasets (focusing on brain imaging and demonstrating on genomics), only optimizing data discriminability improves performance on all subsequent inference tasks for each dataset. We therefore suggest that designing experiments and analyses to optimize discriminability may be a crucial step in solving the replicability crisis, and more generally, mitigating accidental measurement error.


Micro-Pillar Integrated Dissolving Microneedles for Enhanced Transdermal Drug Delivery.
The dissolving microneedle (DMN) patch is a transdermal delivery system, containing arrays of micro-sized polymeric needles capable of encapsulating therapeutic drugs within their matrix and releasing them into the skin. However, the elastic properties of the skin prevent DMNs from complete insertion and accurate delivery of encapsulated compounds into the skin. Moreover, the adhesive materials used in patches may cause skin irritation, inflammation, and redness. Therefore, we developed a patchless, micro-pillar integrated DMN (P-DMN) that is simple to fabricate and enhances transdermal drug delivery compared with traditional DMN patches. The micro-pillars were made of polymethyl methacrylate at a height of 300 μm and a base diameter of 500 μm. To fabricate P-DMNs, we employed hyaluronic acid, which is a widely used derma filler and plays a role in tissue re-epithelialization. We demonstrate that utilizing P-DMNs significantly improves the delivery efficiency of an encapsulated drug surrogate (91.83% ± 7.75%) compared with traditional DMNs (64.86% ± 8.17%). Interestingly, P-DMNs remarkably increase the skin penetration accuracy rate of encapsulated drugs, up to 97.78% ± 2.22%, compared with 44.44% ± 7.85% in traditional DMNs. Our findings suggest that P-DMNs could serve as a highly accurate and efficient platform for transdermal delivery of various types of micro- and macro-biomolecules.


Neighborhood Characteristics at Birth and Positive and Negative Psychotic Symptoms in Adolescence: Findings From the ALSPAC Birth Cohort.
Urban birth is associated with risk of non-affective psychoses, but the association with subclinical positive and negative symptoms is less clear, despite emerging evidence. Further the extent to which these findings are confounded by polygenic risk scores (PRS) for schizophrenia is also unknown. Using data from the Avon Longitudinal Study of Parents and Children, linked to census geographical indicators, we examined whether various indices of urbanicity at birth were associated with negative and positive psychotic symptoms at age 16 and 18 years, respectively. We used logistic regression models, controlling for child's ethnicity, maternal age, education, marital status, social class, depressive symptoms, other neighborhood exposures, and, in a subsample of children of white ethnicity (N = 10 283), PRS for schizophrenia. Amongst 11 879 adolescents, those born in the most densely populated tertile had greater odds of reporting positive psychotic experiences, after multivariable adjustment (odds ratio [OR]: 1.57, 95% confidence intervals (CIs): 1.14-2.17). Adolescents born in the most socially fragmented neighborhoods had greater odds of negative symptoms, after multivariable adjustment (OR: 1.43, 95% CI: 1.06-1.85). Although we found that greater schizophrenia PRS were associated with an increased risk of being born in more deprived and fragmented (bot not more densely populated areas), these associations were not confounded by PRS. Birth into more densely populated and socially fragmented environments increased risk of positive and negative psychotic phenomena in adolescence, respectively, suggesting that different forms of neighborhood social adversity may impinge on different psychopathophysiologies associated with the clinical expression of psychosis.


Infective endocarditis in children.
The clinical manifestations, infective microorganisms, underlying diseases, complications and prognosis of infective endocarditis (IE) were studied in 17 current patients. Data were compared with 101 previous cases reported in Japan. Most patients with IE (110/118 = 93.2%) had underlying heart diseases. IE was noted most often in patients with ventricular septal defect (VSD) and tetralogy of Fallot. The incidence of post operative endocarditis was high (29.4% in the present series and 9.0% in the overall series), too. Streptococcus viridans, Staphylococcus aureus and GNB were the most common etiologic agents with incidences of 28.8% (34/118), 25.4% (30/118) and 9.3% (11/118), respectively. Almost half of the deaths from IE were caused by s. aureus. The mortality was 11.9% (14/118) in both series. The death rate from candida albicans was 100%, from s. aureus 33.3% (10/30) and from str. viridans 5.9% (2/34) in both series. Culture negative patients accounted for 11.9% (14/118) in both series. Complications which did not involve the valves were noted in one patient with cerebral emboli and in two patients with pulmonary infarction in the present series. Cerebral emboli phenomena were seen 8 cases of the overall series, 4 of whom died.


Lifestyle precision medicine: the next generation in type 2 diabetes prevention?
The driving force behind the current global type 2 diabetes epidemic is insulin resistance in overweight and obese individuals. Dietary factors, physical inactivity, and sedentary behaviors are the major modifiable risk factors for obesity. Nevertheless, many overweight/obese people do not develop diabetes and lifestyle interventions focused on weight loss and diabetes prevention are often ineffective. Traditionally, chronically elevated blood glucose concentrations have been the hallmark of diabetes; however, many individuals will either remain 'prediabetic' or regress to normoglycemia. Thus, there is a growing need for innovative strategies to tackle diabetes at scale. The emergence of biomarker technologies has allowed more targeted therapeutic strategies for diabetes prevention (precision medicine), though largely confined to pharmacotherapy. Unlike most drugs, lifestyle interventions often have systemic health-enhancing effects. Thus, the pursuance of lifestyle precision medicine in diabetes seems rational. Herein, we review the literature on lifestyle interventions and diabetes prevention, describing the biological systems that can be characterized at scale in human populations, linking them to lifestyle in diabetes, and consider some of the challenges impeding the clinical translation of lifestyle precision medicine.


Socioeconomic Differentials Between HIV Caregivers and Noncaregivers: Is There a Selection Effect? A Case of Older People Living in Nairobi City Slums.
This article seeks to investigate the association between caregiving to someone with an HIV-related illness and the socioeconomic status of the caregiver using a population-based survey of 1,587 older people living in Nairobi slums. Findings indicate significant differences in living arrangements, wealth, income, and expenditure between HIV caregivers and noncaregivers. HIV caregivers lived in larger households and were also more likely to live in households with a large number of children younger than the age of 15 years. Whereas a high proportion of HIV caregivers were ranked highly in terms of wealth status, differences in per capita income and expenditure were not significant when household size and other confounders were accounted for. The financial costs associated with caring for someone with a chronic illness and the reliance on family members with financial ability for material support, a common feature of African extended family systems, may account for the relative economic advantage of HIV caregivers.


Ozonation-based decolorization of food dyes for recovery of fruit leather wastes.
Commercial manufacture of fruit leathers (FL) usually results in a portion of the product that is out of specification. The disposition of this material poses special challenges in the food industry. Because the material remains edible and contains valuable ingredients (fruit pulp, sugars, acidulates, etc.), an ideal solution would be to recover this material for product rework. A key practical obstacle to such recovery is that compositing of differently colored wastes results in an unsalable gray product. Therefore, a safe and scalable method for decolorization of FL prior to product rework is needed. This research introduces a novel approach utilizing ozonation for color removal. To explore the use of ozonation as a decolorization step, we first applied it to simple solutions of the commonly used food colorants 2-naphthalenesulfonic acid (Red 40), tartrazine (Yellow 5), and erioglaucine (Blue 1). Decolorization was measured by UV/vis spectrometry at visible wavelengths and with a Hunter colorimeter. Volatile and semivolatile byproducts from ozone-based colorant decomposition were identified and quantified with solid phase microextraction coupled with gas chromatography-mass spectrometry (SPME-GC-MS). Removal of Yellow 5, Red 40 and Blue 1 of about 65%, 80%, and 90%, respectively, was accomplished with 70 g of ozone applied per 1 kg of redissolved and resuspended FL. Carbonyl compounds were identified as major byproducts from ozone-induced decomposition of the food colorants. A conservative risk assessment based on quantification results and published toxicity information of potentially toxic byproducts, determined that ozone-based decolorization of FL before recycling is acceptable from a safety standpoint. A preliminary cost estimate based on recycling of 1000 tons of FL annually suggests a potential of $275,000 annual profit from this practice at one production facility alone.


Design and fabrication of a magnetic propulsion system for self-propelled capsule endoscope.
This paper investigates design, modeling, simulation, and control issues related to self-propelled endoscopic capsule navigated inside the human body through external magnetic fields. A novel magnetic propulsion system is proposed and fabricated, which has great potential of being used in the field of noninvasive gastrointestinal endoscopy. Magnetic-analysis model is established and finite-element simulations as well as orthogonal design are performed for obtaining optimized mechanical and control parameters for generating appropriate external magnetic field. Simulated intestinal tract experiments are conducted, demonstrating controllable movement of the capsule under the developed magnetic propulsion system.


Symptomatic and Radiographic Manifestations of Kidney Stone Recurrence and Their Prediction by Risk Factors: A Prospective Cohort Study.
Meaningful interpretation of changes in radiographic kidney stone burden requires understanding how radiographic recurrence relates to symptomatic recurrence and how established risk factors predict these different manifestations of recurrence. We recruited first-time symptomatic stone formers from the general community in Minnesota and Florida. Baseline and 5-year follow-up study visits included computed tomography scans, surveys, and medical record review. We noted symptomatic recurrence detected by clinical care (through chart review) or self-report, and radiographic recurrence of any new stone, stone growth, or stone passage (comparing baseline and follow-up scans). To assess the prediction of different manifestations of recurrence, we used the Recurrence of Kidney Stone (ROKS) score, which sums multiple baseline risk factors. Among 175 stone formers, 19% had symptomatic recurrence detected by clinical care and 25% detected by self-report; radiographic recurrence manifested as a new stone in 35%, stone growth in 24%, and stone passage in 27%. Among those with a baseline asymptomatic stone (54%), at 5 years, 51% had radiographic evidence of stone passage (accompanied by symptoms in only 52%). Imaging evidence of a new stone or stone passage more strongly associated with symptomatic recurrence detected by clinical care than by self-report. The ROKS score weakly predicted one manifestation-symptomatic recurrence resulting in clinical care (c-statistic, 0.63; 95% confidence interval, 0.52 to 0.73)-but strongly predicted any manifestation of symptomatic or radiographic recurrence (5-year rate, 67%; c-statistic, 0.79; 95% confidence interval, 0.72 to 0.86). Recurrence after the first stone episode is both more common and more predictable when all manifestations of recurrence (symptomatic and radiographic) are considered.


Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways.
Following acute brain injury, albumin may gain access to the brain parenchyma. Clinical studies indicate a protective role for albumin in stroke but an increase in mortality associated with albumin administration following traumatic brain injury. We investigated the effects of albumin on astrocyte and microglial activation, and the role of mitogen-activated protein kinases (MAPK) in these responses. Albumin activated ERK1/2, p38 MAPK and JNK signaling pathways in astrocytes, and induced the production of interleukin (IL)-1beta, inducible nitric oxide (NO) synthase, the NO metabolite nitrite, and the chemokine CX3CL1 while reducing the level of S100B. The release of inflammatory markers by astrocytes was partially dependent on p38 MAPK and ERK1/2 pathways, but not JNK. In microglia, albumin exposure activated all three MAPK pathways and produced an increase in IL-1beta and nitrite. Inhibition of p38 MAPK in microglia leads to an increased level of IL1beta, while inhibition of all three MAPKs suppressed the release of nitrite. These results suggest that albumin activates astrocytes and microglia, inducing inflammatory responses involved both in the mechanisms of cellular injury and repair via activation of MAPK pathways, and thereby implicate glial activation in the clinical responses to administration of albumin.


Boosting ethanol production rates from carbon dioxide in MES cells under optimal solventogenic conditions.
Microbial Electrosynthesis (MES) has been widely applied for acetic acid (HA) production from CO2 and electricity. Ethanol (EtOH) has a higher market value than HA, and wide application in industry and as a biofuel. However, it has only been obtained sporadically and at low concentrations, probably due to sub-optimal operating conditions. This study aimed at enhancing EtOH productivity in MES cells by jointly optimising key operation parameters, including pH, H2 and CO2 partial pressure (pH2 and pCO2), and HA concentration, to promote solventogenesis. Two H-type cells were operated in fed-batch mode at -0.8 V vs. SHE with CO2 as the sole carbon source. A mixed culture, enriched with Clostridium ljungdahlii was used as the biocatalyst. The combination of low pH (<4.5) and pCO2 (<0.3 atm), along with high HA concentration (about 6 g L-1) and pH2 (>3 atm), were mandatory conditions for maintaining an efficient solventogenic culture, dominated by Clostridium sp., capable of high-rate EtOH production. The maximum EtOH production rate was 10.95 g m-2 d-1, and a concentration of 5.28 g L-1 was achieved. Up to 30 % of the electrons and 15.2 % of the carbon provided were directed towards EtOH production, and 28.1 kWh were required for the synthesis of 1 kg of EtOH from CO2. These results highlight that strict conditions are required for a continuous, reliable, EtOH production in MES cells. Future investigation should focus on improving cell configuration to achieve EtOH production at higher current densities while minimizing the electric energy input.


Mitochondrial DNA haplogroup analysis in patients with bipolar disorder.
Several lines of evidence support mitochondrial dysfunction in bipolar disorder. Elevated calcium level in platelets is reported in this disease. To verify mitochondrial DNA (mtDNA) haplogroups characteristic to bipolar disorder, we sequenced mtDNA of seven regions and performed haplogroup analysis in 195 patients with bipolar disorder and 255 controls. They belonged to 16 major mtDNA haplogroups, A, B4, B5, C, D4, D5, F, G, M7, M8, M9, M10-12, N9a, N9b, Y, and Z. The logistic regression analysis revealed that the haplogroup N9a was over-represented in bipolar disorder. We also performed a case-control study for two functional mtDNA polymorphisms, mtDNA5460G > A and 12358A > G, that altered intracellular calcium dynamics. While the mtDNA5460G > A polymorphism was not associated with bipolar disorder, the mtDNA12358A > G polymorphism was associated with bipolar disorder in 199 patients with bipolar disorder and 260 controls. However, this association was not replicated in an independent sample set. Possible significances of these findings are discussed.


Synthesis of 1,3,4-oxadiazoles with 4-methoxynaphthalene ring: discovering new compounds with antimicrobial activity.
Background: Paracoccidioidomycosis (PCM) is a systemic infection caused by Paracoccidioides spp. (Pb). PCM can be associated or clinically confused with tuberculosis (TB), another pulmonary infection, caused by Mycobacterium tuberculosis (Mtb). Futhermore, the long treatment time of TB and PCM and the cases of TB drug resistance impose difficulties for the cure of these diseases. Results: New 1,3,4-oxadiazoles containing the 4-methoxynaphthalene ring were synthesized and their antimicrobial activity was evaluated against Pb and Mtb. The derivative 6n (with 2-hydroxy-5-nitrophenyl subunit) is the most promising of the series. Conclusion: The 1,3,4-oxadiazole 6n can be used as a prototype drug candidate, with anti-Pb and anti-MTb activities, showing a broad-spectrum profile for the treatment of both pulmonary infections.


Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives.
Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.


The effect of exogenous phytase supplementation on nutrient digestibility, ruminal fermentation and phosphorous bioavailability in Rambouillet sheep.
The effect of phytase supplementation with respect to a high sorghum grain diet on sheep voluntary feed intake, apparent nutrient digestibility, ruminal fermentation, phosphorus (P) excretion and blood serum P concentration was evaluated. Phytase supplementation significantly decreased fecal P excretion (P = 0.003), resulting in a 26% decrease in relation to the phytase free diet. Dry matter intake, nutrient digestibility, ruminal butyrate and serum P were not (P > 0.10) affected by the phytase level. Neutral detergent digestibility showed a tendency to increase linearly (P = 0.10) with increasing phytase levels. Ruminal pH was lower for phytase supplemented sheep, with a significant decrease (P = 0.007) at 9 h post feeding, whereas ruminal ammonia-N at 3 h post feeding was lower (P = 0.004) for the phytase treatment groups, resulting in a decreasing linear response (P = 0.001) with an increasing phytase dose. Duodenal pH was significantly reduced at 6 h post feeding. Propionate tended (P = 0.051) to be increased linearly as the phytase supplementation level increased. Exogenous phytase supplementation of high sorghum grain diets significantly decreased fecal P excretion in Rambouillet rams. Phytase supplementation appears to affect neutral detergent fiber digestibility, duodenal and ruminal pH, ammonia and propionate. © 2018 Society of Chemical Industry.


[Sociomedical factors of survival in first detected patients with caseous pneumonia].
To provide evidence for the association of survival in patients with caseous pneumonia with sociomedical factors, a group of 116 patients aged 18 to 65 years with this new-onset disease from the Samara Region was examined. The results of the study were statistically processed by the SPSS program version 10.0. It has been established that there are critical periods in the life of patients with caseous pneumonia. The critical period is an early period (month 1 of the onset of the disease) for alcohol abusers and, in addition to the early period, a later period (from 1 to 1.5 years) in non-abusers. Young persons with the preserved social status have better chances of surviving early in the disease. Passion for alcohol decreases a survival chance in patients with caseous pneumonia by 1.9 times.


Some computational analyses of the PBK test: effects of frequency and lexical density on spoken word recognition.
The Phonetically Balanced Kindergarten (PBK) Test (Haskins, Reference Note 2) has been used for almost 50 yr to assess spoken word recognition performance in children with hearing impairments. The test originally consisted of four lists of 50 words, but only three of the lists (lists 1, 3, and 4) were considered "equivalent" enough to be used clinically with children. Our goal was to determine if the lexical properties of the different PBK lists could explain any differences between the three "equivalent" lists and the fourth PBK list (List 2) that has not been used in clinical testing. Word frequency and lexical neighborhood frequency and density measures were obtained from a computerized database for all of the words on the four lists from the PBK Test as well as the words from a single PB-50 (Egan, 1948) word list. The words in the "easy" PBK list (List 2) were of higher frequency than the words in the three "equivalent" lists. Moreover, the lexical neighborhoods of the words on the "easy" list contained fewer phonetically similar words than the neighborhoods of the words on the other three "equivalent" lists. It is important for researchers to consider word frequency and lexical neighborhood frequency and density when constructing word lists for testing speech perception. The results of this computational analysis of the PBK Test provide additional support for the proposal that spoken words are recognized "relationally" in the context of other phonetically similar words in the lexicon. Implications of using open-set word recognition tests with children with hearing impairments are discussed with regard to the specific vocabulary and information processing demands of the PBK Test.


Antcins, triterpenoids from Antrodia cinnamomea, as new agonists for peroxisome proliferator-activated receptor α.
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that transcriptionally regulates lipid metabolism and inflammation; therefore, PPARα agonists are promising agents to treat dyslipidemia and metabolic disorders. PPARα full agonists, such as fibrates, are effective anti-hypertriglyceride agents, but their use is limited by adverse side effects. Hence, the aim of this study was to identify small molecules that can activate PPARα while minimizing the adverse effects. Antrodia cinnamomea, a rare medical mushroom, has been used widely in Asian countries for the treatment of various diseases, including liver diseases. Antcin B, H and K (antcins) and ergostatrien-3β-ol (EK100) are bioactive compounds isolated from A. cinnamomea with anti-inflammatory actions. Antcins, ergostane-type triterpenoids, contain the polar head with carboxylate group and the sterol-based body. Here, we showed at the first time that sterol-based compounds, antcins, but not EK100, activate PPARα in a cell-based transactivation study. The in silico docking studies presented several significant molecular interactions of antcins, including Tyr314, and His440 in the ligand-binding domain of PPARα, and these interactions are required for helix 12 (H12) stabilization. We propose that PPARα activation activity of antcins is related to their binding mode which requires conventional H12 stabilization, and that antcins can be developed as safe selective PPARα modulators.


[Monoamine oxidase and adenylate deaminase activity of mitochondrial fractions of the rat liver in alcoholic intoxication].
Decrease in monoamine oxidase and increase in diamine oxidase and adenylate deaminating activities were found in rat liver mitochondrial fractions after repeated injections of ethanol. A monoamine oxidase inhibitor pargyline and an inhibitor of phosphodiesterase theophylline prevented the increase in adenylate deaminating activity in a subfraction of mitochondrial membranes in the ethanol intoxicated rats. In a subfraction of soluble mitochondrial proteins pargyline did not affect but theophylline prevented completely the increase in adenylate deaminating activity. The stimulation of adenylate deaminating activity in mitochondrial fractions of rat liver in ethanol intoxication might be caused by: 1) transformation of mitochondrial monoamine oxidases (in the subfraction of mitochondrial membranes) and 2) activation (or increased biosynthesis) of the adenylate deaminase in the subfraction of soluble mitochondrial proteins. The adenylate cyclase system is probably involved in the latter process.


Cognitive processes in dissociation: an analysis of core theoretical assumptions.
Dissociation is typically defined as the lack of normal integration of thoughts, feelings, and experiences into consciousness and memory. The present article critically evaluates the research literature on cognitive processes in dissociation. The authors' review indicates that dissociation is characterized by subtle deficits in neuropsychological performance (e.g., heightened distractibility). Some of the cognitive phenomena (e.g., weakened cognitive inhibition) associated with dissociation appear to be dependent on the emotional or attentional context. Contrary to a widespread assumption in the clinical literature, dissociation does not appear to be related to avoidant information processing. Rather, it is associated with an enhanced propensity toward pseudo-memories, possibly mediated by heightened levels of interrogative suggestibility, fantasy proneness, and cognitive failures. Evidence for a link between dissociation and either memory fragmentation or early trauma based on objective measures is conspicuously lacking. The authors identify a variety of methodological issues and discrepancies that make it difficult to articulate a comprehensive framework for cognitive mechanisms in dissociation. The authors conclude with a discussion of research domains (e.g., sleep-related experiences, drug-related dissociation) that promise to advance our understanding of cognition and dissociation.


Relative contributions of BRCA1 and BRCA2 mutations to "triple-negative" breast cancer in Ashkenazi Women.
Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry a founder mutation in BRCA1 or BRCA2. There is an association between BRCA1 mutations and "triple-negative" breast cancer (TNBC) [estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative]. We sought to determine the predictive value of the TNBC phenotype for the presence of a BRCA mutation in AJ women ascertained without respect to family history. DNA samples were collected between 8/2000 and 6/2004 from a prevalent cohort of unselected AJ women with breast cancer (median age at diagnosis 56 years). Samples (n = 451) were genotyped for AJ founder mutations. 352 (78.0%) cancers were ER positive, 254 (56.3%) PR positive, and 91 (20.2%) ER negative/PR negative. 63 (14.0%) cancers were HER2 positive (immunohistochemistry 3+ or FISH >2.2). TNBC was observed in 64 patients (14.2%). Founder mutations were detected in 48 samples (10.6%) including 25/64 TNBC (39.1%; 19 BRCA1, 6 BRCA2). Among TNBC patients with family history (FH) information, 6/15 (40%) mutations were found in women without breast or ovarian cancer in a close relative. The positive predictive value of TNBC for a BRCA1 mutation was 30% overall, 50% in women diagnosed<50 years, and 14% in women diagnosed ≥50. TNBC was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TNBC. The prevalence of BRCA founder mutations exceeds 50% in subsets of AJ women with TNBC. FH is an imperfect predictor of mutation status in this group. A significant number of mutation-associated TNBC are due to BRCA2.


Baby-MONITOR: a composite indicator of NICU quality.
NICUs vary in the quality of care delivered to very low birth weight (VLBW) infants. NICU performance on 1 measure of quality only modestly predicts performance on others. Composite measurement of quality of care delivery may provide a more comprehensive assessment of quality. The objective of our study was to develop a robust composite indicator of quality of NICU care provided to VLBW infants that accurately discriminates performance among NICUs. We developed a composite indicator, Baby-MONITOR, based on 9 measures of quality chosen by a panel of experts. Measures were standardized, equally weighted, and averaged. We used the California Perinatal Quality Care Collaborative database to perform across-sectional analysis of care given to VLBW infants between 2004 and 2010. Performance on the Baby-MONITOR is not an absolute marker of quality but indicates overall performance relative to that of the other NICUs. We used sensitivity analyses to assess the robustness of the composite indicator, by varying assumptions and methods. Our sample included 9023 VLBW infants in 22 California regional NICUs. We found significant variations within and between NICUs on measured components of the Baby-MONITOR. Risk-adjusted composite scores discriminated performance among this sample of NICUs. Sensitivity analysis that included different approaches to normalization, weighting, and aggregation of individual measures showed the Baby-MONITOR to be robust (r = 0.89-0.99). The Baby-MONITOR may be a useful tool to comprehensively assess the quality of care delivered by NICUs.


Surgical management of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumour-related and hepatic function-related considerations. As such, HCC is currently managed largely through non-surgical means as the criteria, in relation to the above considerations, for surgical management is still largely restrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes (5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.


A new murine IgG1 anti-Tn monoclonal antibody with in vivo anti-tumor activity.
The Tn antigen (GalNAc α-O-Ser/Thr) is heterogeneously synthesized by a variety of tumors and contains an epitope defined by lectins and antibodies as a cluster of αGalNAc carbohydrates synthesized within a peptide sequence, which is rich in serine and/or threonine. The Tn antigen has been utilized as a target in vaccine experiments and also used as a biomarker for prognosis of different cancer forms. In this paper, we present a new monoclonal antibody, GOD3-2C4, with the clear hallmarks of an anti-Tn antibody. It was generated through somatic cell hybridization after immunization of a mouse with a tumor cell line and a Tn carrying mucin. The antibody recognizes synthetic Tn antigen and binds breast, colon, lung, ovarian and pancreas cancer. The GOD3-2C4 antibody has antibody-dependent cellular cytotoxicity activity against Jurkat cells in vitro, and for the first time, it can be shown that an anti-Tn antibody has a significant in vivo effect on a human cancer cell line grown as a xenograft in severe combined immunodeficiency mice.


Testing criteria for spinal implants: recommendations for the standardization of in vitro stability testing of spinal implants.
New implants and new surgical approaches should be tested in vitro for primary stability in standardized laboratory tests in order to decide the most appropriate approach before being accepted for clinical use. Due to the complex and still unknown loading of the spine in vivo a variety of different test loading conditions have been used, making comparison of the results from different groups almost impossible. This recommendation was developed in a series of workshops with research scientists, orthopedic and trauma surgeons, and research and development executives from spinal implant companies. The purpose was to agree on in vitro testing conditions that would allow results from various research groups to be compared. This paper describes the recommended loading methods, specimen conditions, and analysis parameters resulting from these workshops.


[Choledochotomy and its results].
Of 21 patient to whom after choledochotomy the external drainage of common bile duct was conducted, the suture insufficiency have occurred in 3, 2 patients died. After choledochoduodenostomy conduction the suture insufficiency was observed in 3 of 17 patients, 2 patients died. After papilloshincteroplasty conduction the complications were revealed in 5 of 23 patients, 3 patients died. Of 4 patients, in whom the twin internal drainage was conducted, 3 died.


Seismic anisotropy reveals crustal flow driven by mantle vertical loading in the Pacific NW.
Buoyancy anomalies within Earth's mantle create large convective currents that are thought to control the evolution of the lithosphere. While tectonic plate motions provide evidence for this relation, the mechanism by which mantle processes influence near-surface tectonics remains elusive. Here, we present an azimuthal anisotropy model for the Pacific Northwest crust that strongly correlates with high-velocity structures in the underlying mantle but shows no association with the regional mantle flow field. We suggest that the crustal anisotropy is decoupled from horizontal basal tractions and, instead, created by upper mantle vertical loading, which generates pressure gradients that drive channelized flow in the mid-lower crust. We then demonstrate the interplay between mantle heterogeneities and lithosphere dynamics by predicting the viscous crustal flow that is driven by local buoyancy sources within the upper mantle. Our findings reveal how mantle vertical load distribution can actively control crustal deformation on a scale of several hundred kilometers.


Point-source localization in blurred images by a frequency-domain eigenvector-based method.
We address the problem of resolving and localizing blurred point sources in intensity images. Telescopic star-field images blurred by atmospheric turbulence or optical aberrations are typical examples of this class of images, a new approach to image restoration is introduced, which is a generalization of 2-D sensor array processing techniques originating from the field of direction of arrival estimation (DOA). It is shown that in the frequency domain, blurred point source images can be modeled with a structure analogous to the response of linear sensor arrays to coherent signal sources. Thus, the problem may be cast into the form of DOA estimation, and eigenvector based subspace decomposition algorithms, such as MUSIC, may be adapted to search for these point sources. For deterministic point images the signal subspace is degenerate, with rank one, so rank enhancement techniques are required before MUSIC or related algorithms may be used. The presence of blur prohibits the use of existing rank enhancement methods. A generalized array smoothing method is introduced for rank enhancement in the presence of blur, and to regularize the ill posed nature of the image restoration. The new algorithm achieves inter-pixel super-resolution and is computationally efficient. Examples of star image deblurring using the algorithm are presented.


[The role of immunological changes in diseases in regions contaminated by radionuclides after the accident at the Chernobyl Atomic Electric Power Station].
Autoimmune deviations, both humoral and cellular, related to antigens of thyroid gland, microsomes and thyroglobulin, were observed in residents of controlled districts of Bryansk and Tula regions of Russia. The importance of these deviations at hyperplasia of thyroid gland was demonstrated. In formation of cataracts under chronic influence of low doses of ionizing radiation the humoral autoimmune mechanisms are active but not the cellular ones. The increased content of antibodies against the antigens of crystalline lens found in the residents of the controlled regions shows the possibility to develop initial manifestations of cataract under the effect of low radiation doses.


Peak capacity optimization in comprehensive two dimensional liquid chromatography: a practical approach.
In this work we develop a practical approach to optimization in comprehensive two dimensional liquid chromatography (LC x LC) which incorporates the important under-sampling correction and is based on the previously developed gradient implementation of the Poppe approach to optimizing peak capacity. The Poppe method allows the determination of the column length, flow rate as well as initial and final eluent compositions that maximize the peak capacity at a given gradient time. It was assumed that gradient elution is applied in both dimensions and that various practical constraints are imposed on both the initial and final mobile phase composition in the first dimension separation. It was convenient to consider four different classes of solute sets differing in their retention properties. The major finding of this study is that the under-sampling effect is very important and causes some unexpected results including the important counter-intuitive observation that under certain conditions the optimum effective LC x LC peak capacity is obtained when the first dimension is deliberately run under sub-optimal conditions. In addition, we found that the optimum sampling rate in this study is rather slower than reported in previous studies and that it increases with longer first dimension gradient times.


Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino)propane/butane: Synthesis, structure, antiproliferative activity and mechanism of action.
[M(sac)2(dppp)] (1 and 2), [M(dppp)2](sac)2 (3 and 4) and [M(sac)2(dppb)] (5 and 6) complexes, where M = PdII (1, 3 and 5) and PtII (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage.


Factors affecting cerebral oxygenation in hemodialysis patients: cerebral oxygenation associates with pH, hemodialysis duration, serum albumin concentration, and diabetes mellitus.
Patients undergoing hemodialysis (HD) often develop cerebral disease complications. Furthermore, cerebral regional saturation of oxygen (rSO2) was previously reported to be significantly lower in HD patients than in healthy subjects. We aimed to identify the factors affecting the cerebral rSO2 in HD patients. Fifty-four HD patients (38 men and 16 women; mean age, 67.7 ± 1.2 years, HD duration, 6.5 ± 1.9 years) were recruited. Cerebral rSO2 was monitored at the forehead before HD using an INVOS 5100C (Covidien Japan, Tokyo, Japan). The rSO2 levels were significantly lower in HD patients compared with healthy controls (49.5 ± 1.7% vs. 68.9 ± 1.6%, p <0.001). Multiple regression analysis showed that cerebral rSO2 independently associated with pH (standardized coefficient: -0.35), HD duration (standardized coefficient: -0.33), and serum albumin concentration (standardized coefficient: 0.28). Furthermore, the rSO2 was significantly lower in HD patients with diabetes mellitus (DM), compared with patients without DM (46.8 ± 1.7% vs. 52.1 ± 1.8%, p <0.05). In HD patients, cerebral rSO2 was affected by multiple factors, including pH, HD duration, and serum albumin concentration. Furthermore, this is the first report describing significantly lower levels of rSO2 in HD patients with DM than in those without DM.


Accurately identifying low-allelic fraction variants in single samples with next-generation sequencing: applications in tumor subclone resolution.
Current methods for resolving genetically distinct subclones in tumor samples require somatic mutations to be clustered by allelic frequencies, which are determined by applying a variant calling program to next-generation sequencing data. Such programs were developed to accurately distinguish true polymorphisms and somatic mutations from the artifactual nonreference alleles introduced during library preparation and sequencing. However, numerous variant callers exist with no clear indication of the best performer for subclonal analysis, in which the accuracy of the assigned variant frequency is as important as correctly indicating whether the variant is present or not. Furthermore, sequencing depth (the number of times that a genomic position is sequenced) affects the ability to detect low-allelic fraction variants and accurately assign their allele frequencies. We created two synthetic sequencing datasets, and sequenced real KRAS amplicons, with variants spiked in at specific ratios, to assess which caller performs best in terms of both variant detection and assignment of allelic frequencies. We also assessed the sequencing depths required to detect low-allelic fraction variants. We found that VarScan2 performed best overall with sequencing depths of 100×, 250×, 500×, and 1,000× required to accurately identify variants present at 10%, 5%, 2.5%, and 1%, respectively.


Rhes suppression enhances disease phenotypes in Huntington's disease mice.
In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.


A new food-composition database for 437 polyphenols in 19,899 raw and prepared foods used to estimate polyphenol intakes in adults from 10 European countries.
Accurate assessment of polyphenol intakes is needed in epidemiologic research in order to study their health effects, and this can be particularly challenging in international study settings. The purpose of this work is to describe the procedures to prepare a comprehensive polyphenol food-composition database that was used to calculate standardized polyphenol intakes from 24-h diet recalls (24HDRs) and dietary questionnaires (DQs) in the European Prospective Investigation into Cancer and Nutrition (EPIC). With the use of the comparable food classification and facet-descriptor system of the computerized 24HDR program EPIC-Soft (renamed GloboDiet), foods reported in the 24HDR (n = 74,626) were first aggregated following a stepwise process. Multi-ingredient and generic foods were broken down into ingredients or more-specific foods with consideration of regional consumption habits before matching to foods in the Phenol-Explorer database. Food-composition data were adjusted by using selected retention factors curated in Phenol-Explorer. DQ foods (n = 13,946) were matched to a generated EPIC 24HDR polyphenol-composition database before calculation of daily intakes from the 24HDR and DQ. Food matching yielded 2.0% and 2.7% of foods with missing polyphenol content in the 24HDR and DQ food data sets, respectively. Process-specific retention factors for 42 different polyphenol compounds were applied to adjust the polyphenol content in 35 prioritized Phenol-Explorer foods, thereby adjusting the polyphenol content in 70% of all of the prepared 24 food occurrences. A detailed food-composition database was finally generated for 437 polyphenols in 19,899 aggregated raw and prepared foods reported by 10 EPIC countries in the 24HDR. An efficient procedure was developed to build the most-comprehensive food-composition database for polyphenols, thereby standardizing the calculations of dietary polyphenol intakes obtained from different dietary assessment methods and European populations. The whole database is accessible online. This procedure could equally be used for other food constituents and in other cohorts.


Enhanced antigen retrieval of amyloid β immunohistochemistry: re-evaluation of amyloid β pathology in Alzheimer disease and its mouse model.
Senile plaques, extracellular deposits of amyloid β peptide (Aβ), are one of the pathological hallmarks of Alzheimer disease (AD). As the standard immunohistochemical detection method for Aβ deposits, anti-Aβ immunohistochemistry combined with antigen retrieval (AR) by formic acid (FA) has been generally used. Here, we present a more efficient AR for Aβ antigen. On brain sections of AD and its mouse model, a double combination of either autoclave heating in EDTA buffer or digestion with proteinase K plus FA treatment reinforced Aβ immunoreactivity. A further triple combination of digestion with proteinase K (P), autoclave heating in EDTA buffer (A), and FA treatment (F), when employed in this order, gave a more enhanced immunoreactivity. Our PAF method prominently visualized various forms of Aβ deposits in AD that have not been clearly detected previously and revealed numerous minute-sized plaques both in AD and the mouse model. Quantification of Aβ loads showed that the AR effect by the PAF method was 1.86-fold (in the aged human brain) and 4.64-fold (in the mouse brain) higher than that by the FA method. Thus, the PAF method could have the potential to be the most sensitive tool so far to study Aβ pathology in AD and its mouse model.


Selected determinants of fertility in Vietnam: age at marriage, marriage to first birth interval and age at first birth.
Data from the 4172 women aged 15-49 interviewed in the 1988 Vietnamese Demographic and Health Survey were used to examine age at marriage, marriage to first birth intervals and age at first birth. Differences between urban and rural areas, northern and southern provinces and by education of the women were analysed. The majority of the women had their first birth before age 20, but women with secondary education had a significantly higher age at first birth than those with little or no education, and women from the north had a significantly higher age at first birth than women from the south. Rural women and those with little or no education married at significantly younger ages than urban women and those with secondary education; these education effects were confirmed in a rural subsample of women. Women from rural areas and from the north had significantly shorter marriage to first birth intervals than urban women and those from the south, but there were no significant effects related to education.