The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young ( Analysis of cerebral arterial blood flow and its coupling with cerebrospinal fluid (CSF) dynamics can be of significant value for the diagnosis of pathologies such as hydrocephalus, provided that appropriate physiological reference standards exist. Age-related changes in cerebral and cerebrovascular physiology necessitate different reference standards for different age groups. In the present study on phase-contrast magnetic resonance imaging (MRI) derived data from twenty-two age and sex matched healthy subjects we show that age significantly influences various components of cerebral arterial blood flow and CSF dynamics. The novelty of the work at hand derives from a balanced study population, high temporal resolution MR imaging and a multi-tier data analysis which, in combination, allowed for the detection of significant differences in flow frequencies between the age groups that have, to our knowledge, not been published to date.Various studies thus far have evaluated phase-contrast MRI flow measurements to assess arterial and venous blood flow, CSF flow in the aqueduct and subarachnoid space, and their mechanical coupling. Aging effects of CSF flow only in the aqueduct of healthy volunteers were studied by Feature points of the arterial waveforms, such as flow at aortic valve closure or maximum systolic flow of internal carotid and vertebral arteries of young healthy volunteers were evaluated in Several studies have compared generally elderly normal pressure hydrocephalus (NPH), asymptomatic ventricular dilation (VD), or Alzheimer's disease (AD) patients to healthy subjects of various age groups. CSF flow in the aqueduct was analyzed with regard to frequency components The study at hand quantifies age and sex related differences in physiological arterial blood flow and in cervical spinal and aqueductal CSF flows in a well-balanced population of volunteers. In contrast to previous studies, it addresses the pitfalls of flow signal processing and demonstrates the importance of data normalization for the purpose of meaningful comparison.The investigations described herein were approved by the ethics committee of the Canton of Zurich and conducted according to the principles expressed in the Declaration of Helsinki. All subjects gave written informed consent.Two categories of healthy subjects were included in the study: Eleven young volunteers , mainly students, were found via an online search portal. Eleven elderly volunteers  answered an advertisement to retired employees of ETH Zurich. Thus, retired ETH Zurich employees of various professions, their relatives or acquaintances participated. The young group's subjects' age ranged from 21 to 29 years and the elderly group's from 64 to 81 years . All parAll subjects were scanned in supine position on a 3T Philips Achieva MRI system . Velocity measurements of blood flow in the common carotid and vertebral arteries, and of CSF flow in the cervical spinal canal and in the aqueduct were acquired using 2D cine phase-contrast gradient echo sequences.A 3D time-of-flight angiography was used to plan the imaging slice of the arterial blood velocity measurement, which was acquired through-plane, 2 cm below the right carotid bifurcation. This imaging plane was additionally aligned perpendicular to the cervical spinal cord and covered the entire cervix. The signal was acquired using two small circular surface coil elements with a diameter of 7.5 cm placed next to the left and right carotid arteries, respectively. Imaging parameters for the velocity measurements in the common carotid and vertebral arteries were set to an in-plane acquisition resolution of 0.8×0.7 mmCSF velocity in the cervical spinal canal was acquired between the third (C3) and fourth (C4) cervical spinal vertebrae orthogonal to the spinal cord. The transversal imaging slice was positioned on a sagittal survey view. Imaging parameters were identical to those described for arterial flow measurements, except for the encoding velocity, which was set to 12 cm/s (15 cm/s for one subject). The resulting TR/TE were 9.4/5 ms, yielding a minimal temporal resolution of 18.8 ms (36 to 64 heart phases).To acquire the aqueductal CSF velocity data, a sagittal, balanced gradient echo scan was used to plan the imaging slice. CSF flow was acquired through-plane in the central part of the aqueduct, using an eight-element head coil. The imaging parameters were in-plane resolution of 0.4×0.4 mmAll data processing was performed semi-automatically in MATLAB R2009a . Aliased pixels were detected with a jump tolerance of Otsu's method The background phase error correction was initiated by choosing a preferably large rectangular area in the closest possible proximity of the ROI (e.g. the carotid arteries or the aqueduct) while avoiding overlap with it. The velocity content of the rectangular region was then checked manually for remaining velocity fractions. The background phase error was corrected by subtracting the mean velocity of this reference area. This procedure worked well for the arterial and aqueductal background phase correction. However, for the cervical spinal area, no rectangular area in vicinity of the spinal canal showed non-negligible velocity fractions. Instead, a one-voxel wide contour adjacent to the spinal canal was chosen and fulfilled the requirement that only minor velocity fractions were contained. The mean offset value was subsequently calculated and subtracted from the respective velocity data in the ROI Finally, the volumetric flow rate was obtained by summation of the products of area and respective velocity of all pixels included in the segmentation mask.Spinal and aqueductal CSF flows were normalized by the average flow rate of the corresponding CC. The average flow rate (1) is defined as the average of the absolute flow rates in caudocranial and craniocaudal direction within one cardiac cycle It does not correspond to the net flow rate as a result of CSF production.Arterial blood flow was normalized by the average flow rate of the systolic phase only. This approach was chosen as the arterial systole has a relatively constant duration, while the diastolic phase is dependent on heart rate Based on the various CC durations of the participants, the spacing of the frequency components is non-uniform and, therefore, the evaluated frequencies would not match . AccordiA nominal CC length of 1 s was chosen for the following reason: All but one CC in the study had a length of less than or equal to 1 s  of the detected points were analyzed with respect to amplitude and timing of each age and sex group. Subsequently, the curves were fitted with a piecewise cubic Hermite interpolating polynomial The normalized data were analyzed by discrete Fourier transformation Transfer functions (TF) were evaluated by a time-invariant black-box system identification approach Temporal relationships of the pulse transmission from the arterial inflow to both CSF flows were analyzed by cross-correlations Non-normally distributed data were logarithmically transformed before analysis. Characteristic waveforms, frequencies, transfer functions, and cross-correlations of the young and elderly age groups were evaluated using repeated measures analysis of variance (ANOVA) with Greenhouse-Geisser correction to compensate for non-sphericity. The ANOVA was performed within both age groups and between the data of the young and elderly participants. Feature points of the waveforms, individual frequency components and delays were compared with a nonparametric Mann-Whitney test. Correlations were calculated with Spearman's rho. All data were analyzed using SPSS Statistics 17.0 . Differences were considered significant at PThe Mann-Whitney test of the female and the male volunteers' stroke volume and average flow in the aqueduct  show a sThe body height of all female participants is below the average of 173 cm and that of all but one male participant above 173 cm. Height correlates with age  and temporal locations , Transmission latencies from the arterial input to the spinal and the aqueductal CSF compartments were determined via cross-correlation. The maximum caudal cervical spinal CSF flow latency shows a significant difference (P = 0.0004) between the elderly subjects with a delay of 34Our results demonstrate that age significantly influences various characteristics of arterial blood flow into the brain and its coupling with the dynamics of the cerebrospinal fluid. Concretely, transfer functions of arterial input to both cervical spinal and aqueductal CSF output distinctly characterize the here studied young and elderly age groups. Corresponding differences in phase lag are confirmed by cross-correlation of the arterial input and the respective output. We further show that significant differences exist between the male and female subgroups in arterial flow waveforms, which indicate that reference standards for diagnostic purposes should not only be age, but also sex specific. In the paragraphs below, we first outline limitations of our study, and then discuss individual aspects of our results in comparison to data reported in the literature.This study has three main limitations. First, the number of studied subjects is comparably small. It is conceivable that a larger study population may reveal further significant differences that could not be recognized with the current population size. Second, the type of beverage consumed by the participants to reach comparable hydration levels was not controlled for. Caffeine, for example, is known to affect cerebral blood flow Frequency analyses of cervical spinal and aqueductal flows allow for the identification of age effects that cannot be observed in the time domain. For instance, the elderly group's aqueductal flows resemble sinusoidal waves with gentle slopes, whereas the curves of the young group show distinct inflection points. Most magnitudes of the frequency components in all three compartments differ considerably between the two age groups and thus accentuate the various characteristics of the age groups' waveforms.In either age group and for all subjects, arterial inflow to both the spinal and the aqueductal flow transfer functions show low-pass characteristics. Above 0.5 Hz, the two mean transmissions of the elderly group lead in phase those of the young group. De Marco et al We confirmed phase differences obtained through the investigation of transfer functions by analysis of corresponding cross-correlations of arterial input and respective cerebrospinal fluid flow output, which is a data-driven, phenomenological approach free of assumptions. The delays observed in the elderly group are significantly shorter in both transmissions to the aqueduct and the spinal canal. We interpret these shorter delays as a result of the faster wave propagations in elderly subjects due to their stiffer arterial walls 14 healthy volunteers in our study, 10 of which male subjects, have stroke volumes in the aqueduct greater than 42 Various research groups have analyzed arterial, cervical spinal, and aqueductal CSF volumetric flow rates. Some assessed flow as a percentage of one CC Our data show that the arterial waveform shapes of the elderly group differ significantly from those of the young group. The maximum volumetric flow rate of the young and the late systolic peak of the elderly group are distinctively higher than in the respective other group. The observed high late systolic peak of the elderly subjects can be explained by their stiffer arterial walls that cause higher pulsation amplitudes than in the softer arteries of younger subjects and faster pressure wave reflections from distal boundaries, such as capillaries, where impedance changes markedly In the young group, the pulse of the cervical spinal flow is narrower, i.e. the duration of the caudal cervical spinal CSF flow is shorter. Stoquart-ElSankari et al (2007) described a comparable finding as “a loss of sharpness in the cervical CSF curve peaks in the elderly group.” The wider cervical spinal CSF waveforms of our elderly group can be explained by the proximity of the respective anatomic structures to the arterial input and the corresponding wider arterial waveforms due to their earlier pulse wave reflections. The spinal waveforms of our young subjects show distinct local maxima due to aortic valve closure, which is also noticeable, though to a lesser degree, in their aqueductal flow. Balédent et al The normalized maximum cranial aqueductal flows of our elderly subjects are significantly lower than the youngs' and their waveforms are in the style of a sinusoidal wave. Softening of the elderly brain parenchyma as shown by multifrequency magnetic resonance elastography In contrast to Sack and co-workers Vascular changes as discussed and brain atrophy are the most intuitive potential causes for the here observed differences between the young and elderly groups. According to Enzinger et al We hypothesize that the observed sex dependence of aqueductal CSF stroke volume and average flow is a result of the probable size difference between the male and female volunteers' brains. While brain size was not measured in this study, it is well documented that the male brain is in average larger than the female brain Cerebral arterial inflow and cerebrospinal fluid dynamics, as well as their coupling, show significant age-dependence that can be discerned by frequency analysis of phase-contrast MRI data with sufficiently high temporal resolution and after proper temporal normalization. This suggests, together with the observed sex-dependence of the combined carotid and vertebral arterial waveform, that respective reference standards for the evaluation of cerebral pathologies such as hydrocephalus should be both age- and sex-specific.Appendix S1Details on nominal cardiac cycle length and transfer function identification.(PDF)Click here for additional data file.


Aging is accompanied by reduced regenerative capacity of all tissues and organs and dysfunction of adult stem cells. Notably, these age-related alterations contribute to distinct pathophysiological characteristics depending on the tissue of origin and function and thus require special attention in a type by type manner. In this paper, we review the current understanding of the mechanisms leading to tissue-specific adult stem cell dysfunction and reduced regenerative capacity with age. A comprehensive investigation of the hematopoietic, the neural, the mesenchymal, and the skeletal stem cells in age-related research highlights that distinct mechanisms are associated with the different types of tissue stem cells. The link between age-related stem cell dysfunction and human pathologies is discussed along with the challenges and the future perspectives in stem cell-based therapies in age-related diseases. These properties provide stem cells the ability to sustain their population during life, and to maintain tissue remodeling and repair  is vital.Here, we present a comprehensive overview of recent achievements and debates about the dysregulation of four types of tissue stem cells in the elderly , highlighting that distinct age-related effects are associated with the different types of tissue stem cells. We analyze how the dysfunction of the tissue stem cells and the decrease in regeneration potential are associated with age and ARDs Table . Last buHematopoietic stem cells (HSCs), first identified in the 1960s  and the interactions between the HSCs and their microenvironment are also altered with age -beta levels   was able to functionally rejuvenate old murine HSCs. Cdc42 is a small RhoGTP-ase that by regulating the cytoskeletal organization is involved in several signalling pathways and epigenetic processes, including genome markings by histones  provides an alternative approach for the treatment of age-related hematological malignancies. In HSCT, cells are collected from mobilized blood, bone marrow or umbilical cord blood and intravenously injected in the preconditioned recipient  lining the lateral ventricles and the subgranular layer (SGL) of the hippocampal dentate gyrus  display adult neurogenesis both in the SGL and SVZ, and aging is associated with the decrease of DCX-positive neuroblasts  were connected in different combinations via their circulation, demonstrated that factors present in the blood can affect neurogenesis, synaptic plasticity and spatial learning  , Huntington’s disease (HD) and Parkinson’s disease (PD). The main features of these pathologies involve aberrant protein aggregation, selective neuronal loss, and subsequent physical and mental decline. There are several genetic rodent models established to investigate the pathogenesis of the devastating diseases [e.g.  the altered processing of the transmembrane amyloid precursor protein (APP) resulting in the accumulation of extracellular amyloid-beta deposits (senile plaques), and (ii) the hyperphosphorylation of the microtubule-associated protein tau that aggregates in the cell to neurofibrillary tangles. The most affected brain regions/cell types in AD are the basal forebrain cholinergic neurons, hippocampus and cortex.In AD model systems, NSCs of different transgenic animals respond differently depending on the type of transgene [reviewed in , however, other non-motor phenotypes appear, as well .Animal and human studies of Parkinson’s disease gave more or less clear-cut evidence for impaired SVZ and SGL neurogenesis [reviewed in . One way to replace the lost cells in the brain is to transplant neurally committed cells to the damaged area. This procedure, however, raises serious concerns about the fate of the injected cells, the extent of regeneration and its relevance in the above mentioned diseases, since the pathological phenotype of the diseased endogenous cells may affect the graft tissue, as well. Another therapeutic avenue, which seems less invasive, is to activate the endogenous stem cells located in the nervous system to replace the eliminated neurons and glial cells. Nevertheless, the limited availability of adult NSCs may interfere with this approach to cure devastating diseases. Further studies in the field will hopefully shed more light on the process of adult neurogenesis and will enable the development of promising and effective strategies to cure at least some age-related neurodegenerative diseases.Mesenchymal stem cells (MSCs) were identified almost forty years ago by the work of Friedenstein et al. . They deSince MSCs may provide a major source of cells for therapeutic purposes, age-related alterations with respect to their pool size and function have been extensively addressed.Reports about the effect of aging on isolated human MSC proliferation are conflicting. In a number of studies, no significant changes in cultured MSC doubling time or proliferation capacity have been observed in young versus elderly people  Will satellite cells derived from young animals or humans result in higher therapeutic success? (2) Will the age of the host influence the functionality and thus the success rates of the transplantation? Further investigation of the regulators that are at work during aging will likely allow increasing the success rates of cell-based therapies and thus improving the life quality of muscular disease patients.The association between adult stem cells dysfunction and aging has been subjected to extensive research. Here, we emphasize that aging manifests differently in adult stem cells depending on their tissue of origin Table . For exaAdvancing current knowledge in age-related alterations in adult stem cell contributes to our understanding of not only the pathophysiological alterations occurring in ARDs, but also of the use of stem cells in regeneration medicine. As discussed herein, aging tissue stem cells are involved in the initiation or progression of diseases in the elderly, such as in the cases of HSCs in leukemias, NSCs in neurodegenerative diseases and MSCs in osteoarthritis. Further studies characterizing the involvement of stem cells and their complex interactions with the microenvironment in the disease are vital. Such studies are expected to provide new insights into how to modulate the age-related processes in stem cells and may allow inhibiting or delaying the disease progression. Last but not least, special care needs to be taken when considering adult stem cells for regenerative therapies since stem cell function highly depends on the microenvironment, and the aging or imbalanced niche negatively affects stem cell performance (Larsen et al.


Iatrogenic perforation of the furcation area in multi-rooted molars during preparation of the access cavity can potentially lead to tooth extraction. The present case report describes the nonsurgical endodontic management of an extensive pulp chamber floor perforation in a first mandibular molar with calcium enriched mixture (CEM) cement. The perforation was chemically cleaned and then physically sealed with CEM cement. Root canal therapy was completed and the tooth was then restored with amalgam. A one-year follow-up revealed the absence of symptoms of infection/inflammation as well as clinical and radiographic signs/symptoms and therefore, can be interpreted as a favorable treatment outcome. Iatrogenic perforation of pulp chamber floor is an undesirable complication in dental practice that can have a negative impact on the treatment prognosis , 2. The The ideal (bio)material for perforation repair should be antibacterial , radiopaCEM cement is a water-based tooth-colored biomaterial with variable applications in endodontics . SeveralThis article represents a case of an unusual extensive perforation of the pulp chamber floor in a first mandibular left molar and its subsequent repair with CEM cement.A healthy Caucasian 28-year old female was referred to our dental clinic with a continuous dull pain in the left mandibular region, which had started after initiation of root canal treatment on the first molar by her general dentist about two weeks before. Upon clinical examination, a localized inflammation overlying the buccal mucosa in furcal region of the tooth #36 became evident which was tender on palpation. The tooth had no tenderness on percussion and no mobility. Careful periodontal probing showed a pocket depth within the normal range (<3 mm). Radiographic examination revealed overextended endodontic access cavity preparation and extensive destruction of pulp-chamber floor .In the radiography a small piece of amalgam was evident in the apical extend of the perforation which is believed to have separated from the previous amalgam restoration of the tooth. The location of this small piece was an indicator of wide destruction of the interradicular bone during the preparation of the access cavity . The possible treatment options, including tooth extraction with/without replacement, tooth hemisection and non-surgical perforation repair with subsequent continuing of the root canal therapy (RCT) and coronal restoration were explained for the patient. The patient preferred the option of saving the tooth via a non-surgical endodontic treatment and furcal perforation repair with CEM cement. She also read and signed an informed consent.Before the start of the treatment, mouth rinse with 0.2% chlorhexidine rinse  was carried out in order to control the oral microbial flora. After administering local anesthesia  and proper tooth isolation, the temporary restorative material was removed with a slight correction in the outlines of access cavity and then all canal orifices were located. The cavity and perforation site were copiously irrigated with full concentration of sodium hypochlorite and then normal saline. All canal orifices were preflared with #2 and 3 Gates-Glidden drills. Then the canals were blocked with appropriate-sized gutta-percha points to avoid obstruction with perforation repair material. CEM cement  was prepared according to manufacturer's instruction and was placed into the cavity. In order to obtain a good marginal adaptation, the bulk of biomaterial was gently packed with a dry cotton pellet. After a few minutes required for initial setting of CEM, the gutta-percha points were removed and the biomaterial was covered with a moistened cotton pellet. After application of temporary restoration , the patThe second visit was a week later during which the patient was clinically evaluated. All the sign/symptoms had subsided and the tooth underwent conventional non-surgical root canal treatment. The working length was established and all four canals  were mechanically shaped using modified step-back technique and chemically cleaned by means of copious irrigation with 5.25% sodium hypochlorite and then normal saline. The root canals were filled with gutta-percha points  and Roth root canal sealer  using lateral condensation technique; the tooth was then restored with amalgam in the very same session. After taking the postoperative radiography , the patDuring the one year follow-up, the tooth remained functional and asymptomatic. Clinical examination showed that the tooth had no tenderness to percussion/palpation and the probing depth remained within normal level. Radiographic examination demonstrated adequate filling and sealing of the perforation site with normal periodontal apparatus .The present article reported the non-surgical repair of an extensive perforation in the pulp chamber floor of a mandibular molar with notable bone destruction, using CEM biomaterial. Many issues can affect the prognosis of furcation perforations, including the level and location of the lesion, size of the perforated area, as well as the time elapsed between the accident and its repair , 15. WhiA tightly sealed repair in the perforation site is the key to successful treatment as it disrupts path of microbial contamination and guards the periodontium apparatus for optimal healing , 15. It In cases of extensive furcal perforations, an internal matrix (barrier) technique has been suggested; albeit the defect should be directly accessible for the successful use of this technique. The matrix should be sterile and non-irritant and easily manipulated . Hydroxyin vitro and in vivo biocompatibility of CEM [The desirable chemical and physical characteristics of CEM make it an optimal biomaterial for repairing the furcal perforations . Studiesy of CEM , 25, revy of CEM , 11, buty of CEM  and cemey of CEM . The raty of CEM , 11.In the presented case no radiographic and clinical sign/symptoms of disease in the bifurcation area was evident after a one-year follow-up; accordingly, CEM cement may be a suitable endodontic biomaterial for the non-surgical repair of extensive furcal perforations.The favorable treatment outcomes of this case confirms that CEM cement is a cementogenic and osteogenic biomaterial with good biocompatible sealing properties, and is ideal for use as a barrier and repair material in cases of teeth with extensive furcal perforation.


Diabetes mellitus is a progressive disease. Most investigators have focused on glomerular changes in diabetic kidney and non-glomerular alterations have been less attended. The present study has been conducted to find early non-glomerular histological changes in diabetic renal tissue. Twenty male Wistar rats weighting 200-250 g were used for the diabetic group. Diabetes mellitus was induced by single injection of Alloxan. After 8 weeks, paraffin embedded blocks of kidneys were prepared for evaluating the histological changes due to diabetes. Histological study showed the deposit of eosinophilic materials in the intermediate substantial of medulla and thickening of renal arterial wall in the kidney of 70% of diabetic rats. The average weight of kidneys increased when compared to non diabetic animals. Furthermore, the amount of blood flow in arteries of all diabetic kidneys has been enhanced. The present study demonstrates some early renal histological changes in diabetes mellitus which were earlier compared to those reported previously. Diabetic nephropathy is a progressive disease and renal care design can help better prognosis achievement. Diabetes mellitus is the most common cause of chronic renal disorders and end stage kidney disease in developed countries. It is the major cause of dialysis and transplantation. The development of diabetic nephropathy is associated to several factors such as genetic susceptibility, hemodynamic and biochemical changes . All sizMost investigations have shown that the earliest detectable changes in the course of diabetic nephropathy in human will be seen 10 years after diabetes mellitus initiation. However, morpho-metric studies showed that the signs can be diagnosed 18 months after diabetes initiation . DiabetiA wide range of alterations in the renal tissue have been described in diabetes. Renal tubular function has been changed and consequently there are tubular proteinuria, sodium and glucose transport disorders -8.In our previous researches, we had shown an increase of lipofuscin pigments in the renal tubular cells and increased glomerular mesangium at an earlier time in the kidney of a diabetic rat -10. ThisBased on an experimental study, 20 male Wistar rats (weight 200 - 250 g) were considered as experimental group. Weight and time-matched rats were used as control animals. The animals were housed in a standard laboratory condition, 12 hours light/darkness cycle, constant temperature, 50-55% moisture and easy access to food and water. Animal care was performed in accordance with the Ethics Committee of Babol University of Medical Sciences. Diabetes mellitus was induced by a single subcutaneous injection (120 mg/kg) of freshly prepared solution of alloxan monohydrate  dissolved in PBS subcutaneously . The indHistological study showed a deposit of eosinophilic materials in the intermediate substantial of medulla in the kidney of 73% (11 rats) of diabetic animals . VacuolaThe amount of blood flow in arteries of all diabetic kidneys especially in vasa recta have been enhanced .Compared to matched renal arterial lumen diameter of control group, the increase of thickness in the intrarenal arterial walls has been observed in all diabetic rats . This study has been conducted to find earlier possible histological changes in the kidney of diabetic rats. Eight weeks after the initiation of diabetes mellitus, the histological study of kidney demonstrated the presence of abnormal cells in the wall of renal tubules which could lead to cell damages. The cytoplasm resolution of abnormal cells changed and vacuolar modifications occurred. According to the association between cell shape and cell function, these changes may correspond to an adaptation of cells to a new situation such as increased load. This is in agreement with an increase of lipofuscin pigments in the renal tubular cells which has been reported previously . The incGlycation is a nonenzymatic reaction between sugars and the free amino groups of materials in a hyperglycemic situation such as diabetes mellitus. The glycation of materials induces a wide range of chemical, cellular and tissue effects and leads to nephropathy development. Sabbatini et al. showed that the early glycation products (EGPs) induce glomerular hyperfiltration even in normal rats . The glyRenal investigations have demonstrated that hyperfiltration is associated to vasodilatation and the consequent increase in blood flow and glomerular capillary pressure -16. The The kidney weight increased when compared to control animals. This result indicates that the onset of renal enlargement can be a characteristic feature of diabetic kidney. It has manifested that the kidney enlargement is caused by certain factors like glucose over-administration, glycogen accu-mulation, lipogenesis and protein synthesis in the diabetic kidney -19. ActuVascular hypertrophy is presented in this study. The thickening of renal arterial wall during 8 weeks diabetes needs more attention. The result is in agreement with those, have been reported previously -22. It iIn conclusion, there are many early nonglomerular structural changes in the diabetic kidney which need more attention for patient care. Furthermore, the diagnosis of affected kidney in diabetes is possible before prominent functional disorders occur.


Chlamydia trachomatis occupy one of three specific tissue niches. Genomic analyses indicate that the serovars have a phylogeny congruent with their pathobiology and have an average substitution rate of less than one nucleotide per kilobase. In contrast, the gene that determines serovar specificity, ompA, has a phylogenetic association that is not congruent with tissue tropism and has a degree of nucleotide variability much higher than other genomic loci. The ompA gene encodes the major surface-exposed antigenic determinant, and the observed nucleotide diversity at the ompA locus is thought to be due to recombination and host immune selection pressure. The possible contribution of a localized increase in mutation rate, however, has not been investigated.Serovars of the human pathogen ompA gene, as well as several loci surrounding ompA, were examined for each serovar. The loci flanking the ompA gene demonstrated that nucleotide diversity increased monotonically as ompA is approached and that their gene trees are not congruent with either ompA or tissue tropism. The variable domains of the ompA gene had a very high level of non-synonymous change, which is expected as these regions encode the surface-exposed epitopes and are under positive selection. However, the synonymous changes are clustered in the variable regions compared to the constant domains; if hitchhiking were to account for the increase in synonymous changes, these substitutions should be more evenly distributed across the gene. Recombination also cannot entirely account for this increase as the phylogenetic relationships of the constant and variable domains are congruent with each other.Nucleotide diversity and phylogenetic relationships of the five constant and four variable domains of the ompA appears to be due to an increased mutation rate within this region of the genome, whereas the increase in nucleotide substitution rate and the lack of phylogenetic congruence in the regions flanking ompA are characteristic motifs of gene conversion. Together, the increased mutation rate in the ompA gene, in conjunction with gene conversion and positive selection, results in a high degree of variability that promotes host immune evasion.The high number of synonymous substitutions observed within the variable domains of  Chlamydia trachomatis is an obligate intracellular bacterium that is the most frequently reported bacterial sexually transmitted disease in the United States  . Orthologous regions from the Mouse Pneumonitis (MoPn) biovar of Chlamydia muridarum strain Nigg were retrieved from the genome sequence [GenBank: AE002160] [The Q064299] . PrimersE002160] .http://www.mbio.ncsu.edu/BioEdit/bioedit.html. For coding regions, nucleotide sequences were translated to their amino acid sequences, aligned, and then translated back to their nucleotide sequences within the alignment. The software package MEGA4 [C. trachomatis: the number of variable nucleotide sites in each locus; the number of non-synonymous substitutions per non-synonymous site (dN) and the number of synonymous substitutions per synonymous site (dS) using the Nei-Gojobori method and Jukes and Cantor correction with pairwise deletions for alignment gaps; and the ratio of transitions to transversions using pairwise deletion of alignment gaps (ts/tv). MEGA4 was also used to construct phylogenetic trees using the Maximum Composite Likelihood neighbor-joining method and pairwise deletions for alignment gaps. The only exception was the two trees built from either the synonymous or non-synonymous sites of ompA; for these analyses, the Nei-Gojobori neighbor-joining method was employed with the Jukes and Cantor correction and pairwise deletions for alignment gaps. All trees were supported by 1000 bootstrap replicates. The software package DnaSP v5 [C. trachomatis and the MoPn isolate: non-synonymous substitutions per non-synonymous site (KA), synonymous substitutions per synonymous site (KS), and average number of substitutions per nucleotide site between populations (DXY).The nucleotide sequences for each locus were aligned using ClustalX  employedge MEGA4  was usedDnaSP v5  was usedThe authors declare that they have no competing interests.BWB and GFS designed the study, BWB performed experiments, and BWB and GFS analyzed data and wrote the manuscript. Both authors read and approved the final manuscript.Figure S1. Phylogenetic analyses of the C. trachomatis ompA gene flanking regions.Click here for fileFigure S2. Phylogenetic analyses of the synonymous and non-synonymous sites of the ompA gene.Click here for file


Gingival adenoid cystic carcinoma (ACC) is a rare malignancy. We describe the diagnosis and treatment of a 43 year-old woman who presented with a persistent oral ulcer for approximately 1 year, and subsequent pain in the left posterior maxillary region. Clinical examination revealed an ulcer in the left upper molar gingiva, with swelling in the region from the second premolar to the third molar. X-ray images demonstrated the involvement of the maxillary alveolar bone. The histopathological and immunohistochemical features were diagnostic of ACC. ACC is often presented as a gingival lesion; thus, it may easily be neglected by patients. The identification of this tumor using specific pathological analyses prevents misdiagnosis and enables clinicians to determine the appropriate treatment. In this case, no recurrence or distant metastasis was observed after 2 years of follow-up. Adenoid cystic carcinoma (ACC) is an uncommon malignant neoplasm that develops within secretory glands. ACC commonly occurs in the major and minor salivary glands of the head and neck. Other sites include the lungs, breasts, lacrimal glands, and skin,ACC is known to have long benign periods followed by instances of malignancy, but it may behave aggressively in some patientsA 43 year-old woman complained of an oral ulcer that persisted for almost 1 year as well as pain in the left posterior maxillary region for 1 month. Clinical examination revealed an ulcer on the left upper molar gingiva, with swelling from the second premolar to the third molar in the same region. X-ray images showed the involvement of the maxillary alveolar bone (Upon admission, malignant mesenchymal or odontogenic neoplasia was suspected. An incisional biopsy was then performed under local anesthesia. The histopathological and immunohistochemical features were diagnostic of ACC. Microscopic examination showed prominent solid, microcystic, and focally tubular glandular patterns of growth, as well as numerous cells with myoepithelial characteristics and a few luminal cells. The histopathological features were similar to those of the solid subtype of salivary gland ACC (The patient underwent left total maxillectomy, followed by buccal fat pad flap reconstruction. Histopathological analysis of the resected specimen showed similar features with those of the incisional biopsy. The surgical margins revealed no residual carcinomas.Extensive clinico-radiological investigations were performed to identify potential metastasis. Chest radiography, as well as computerized tomography of the head and neck regions, was conducted. No metastatic lesions or other primary neoplasms were detected. The patient remained in good health after 25 months of follow-up, with no evidence of local recurrence.Carcinomas of the maxillary gingiva are relatively common but easily neglected by patients. Such tumors differ from those that originate from the maxillary sinus and have secondary extensions to the gingiva. Radiography of the paranasal sinuses aids differential diagnosis and allows for the careful evaluation of the extent of bone involvement. Gingival carcinomas in the maxilla usually invade the maxillary sinus. These carcinomas may extend onto the palate or the tonsillar pillar.,ACC is one of the most common tumors in the salivary glands; it mainly involves the palate but rarely affects the gingivaMost, if not all, patients with long-term ACC eventually develop distant metastases, mainly in the lungs and bone, despite the local control of the tumor. The occurrence of bone metastasis usually corresponds to rapid tumor dissemination and death of the patient, whereas lung metastases demonstrate a less aggressive clinical course-In this case, the central salivary gland tumors should be included in the differential diagnosis. These tumors develop within the mandible or maxilla and can extend to the more usual locations. Most central salivary gland tumors of the jaw involve the mandible, which account for approximately 65% of intraosseous ACC


We present a case of florid cemento-osseous dysplasia occurring in a 20-year-old Indian woman. The subject presented with three lesions involving the maxillary right quadrant, maxillary left quadrant and mandibular left quadrant. The mandibular left quadrant also demonstrated a cyst.The diagnosis was made by correlating the clinical presentation with that of the radiological and histopathological findings. This is a rare entity because of an unusual combination of Asian race along with the association of dentigerous cyst. Agazi anet al.36 The FCet al.3 In a syset al.3 The FCODet al.3The pathogenesis of the FCOD has been bestowed on periodontal ligament by most authorities. However, few authors suggest remnants of cementum left in the bone after extraction7 or expo8A 20-year-old female patient reported to our institute with a swelling on the zygomatic area on the right side of the face. The swelling was noticed 10 years ago, which remained asymptomatic and had gradually increased to the present size of 6 cm in diameter causing asymmetry of the face . AnotherThe intraoral examination in relation to the maxillary right quadrant revealed a bony hard swelling involving the buccal  and palaThe orthopantomograph of the maxillary right quadrant revealed mixed, radiopaque [The maxillary left quadrant revealed an impacted second premolar [On the basis of clinical and radiological findings, dentigerous cyst was suspected involving the impacted 35. Incisional biopsy was performed on the maxillary right quadrant and provisional diagnosis of cemento-ossifying fibroma was given. Surgery was planned and performed for all three quadrants under general anesthesia.The surgical specimen received showed multiple bits of tissue that were white in color with a gritty surface. It was hard in consistency in relation to the maxillary right quadrant , maxillaMicroscopic features in relation to the maxillary right quadrant exhibited trabeculae of immature bone and irregular basophilic cemental masses in a moderately cellular fibrous connective tissue stroma . The perThe decalcified tissue section in relation to the maxillary left quadrant showed trabeculae of immature bone and irregular basophilic cemental masses in a highly cellular fibrous connective tissue stroma exhibiting whorling around the cemental masses and the immature bone . The immThe mandibular left quadrant showed a cyst-like area with irregular basophilic cemental masses in a background of less-cellular fibrous connective tissue . The cysThe cement-osseous dysplasia is considered as a non-neoplastic fibro-osseous lesion wherein bone is replaced by fibrous connective tissue along with the cemental masses and is categorized into three different entities, such as periapical, focal and florid. However, now the COD term has been replaced as osseous dysplasia in the recent WHO classification and is believed that the three entities represent a spectrum of lesions appearing to be reactive in nature and have differences only in clinical and radiological presentation. Histologically, it appears to affect the tooth-bearing areas probably derived from the periodontal ligament and from the cementum or cemental-like tissues.The periapical osseous dysplasia appears as a radiolucent area at the apices of the anterior teeth and with time, the mineralization becomes radiopaque and rare2Although histopathology will remain similar for all the types, as this represents a spectrum of lesion rather than an entity, the earlThe diagnosis of COD is a challenge, especially when it shows the cortical plate enlargement along with mixed radiopacities, as seen in the present case, in relation to the maxillary right quadrant Figures  and 4 an1The present case showed connective tissue fibers as filling material between the trabeculae, which may resemble chronic sclerosing osteomyelitis.12 SequesThe histopathology of COD most commonly resembles cemento-ossifying fibroma.27 Cement21Because this case demonstrated impaction of permanent premolars in the maxillary left and mandibular left quadrants, the possibility of Gardner’s syndrome has to be questioned as earlier reports suggested misdiagnosing Gardner’s syndrome as COD. However,The mandibular left quadrant showed radiopacity in relation to the apex of the root surface of the retained deciduous molar. However, the received specimen did not show any attachment to the apex of the root, a feature of cementoblastoma. The presIn addition, the mandibular left quadrant also showed unilocular radiolucency that resembled a dentigerous cyst in histopathological findings. However, earlier reports suggested FCOD in association with simple bone cyst, which exWe conclude this case as an unusual manifestation of FCOD in association with dentigerous cyst in a 20-year-old woman of Asian race. There was no relationship between dentigerous cyst and FCOD. This could be considered as the first case of dentigerous cyst co-existing with FCOD. Most often, the cases of FCOD should not be surgically treated, as it may result in secondary osteomyelitis. But in the present case, surgery was performed as it caused asymmetry of the face. In such a situation, close monitoring of the patient is necessary to prevent secondary complications of osteomyelitis.


This paper investigates the dependence of synchronization transitions of bursting oscillations on the information transmission delay over scale-free neuronal networks with attractive and repulsive coupling. It is shown that for both types of coupling, the delay always plays a subtle role in either promoting or impairing synchronization. In particular, depending on the inherent oscillation period of individual neurons, regions of irregular and regular propagating excitatory fronts appear intermittently as the delay increases. These delay-induced synchronization transitions are manifested as well-expressed minima in the measure for spatiotemporal synchrony. For attractive coupling, the minima appear at every integer multiple of the average oscillation period, while for the repulsive coupling, they appear at every odd multiple of the half of the average oscillation period. The obtained results are robust to the variations of the dynamics of individual neurons, the system size, and the neuronal firing type. Hence, they can be used to characterize attractively or repulsively coupled scale-free neuronal networks with delays. ExperimPrevious research highlighted that information transmission delays are inherent to the nervous system because of the finite speed at which action potentials propagate across neuron axons, as well as due to time lapses occurring by both dendritic and synaptic processing Both phase-attractive (which can be related to excitatory synapses) and phase-repulsive (which can be related to inhibitory synapses) coupling exists in realistic neuronal systems. Hence, it is important to take this explicitly into account in theoretical studies. Effects of phase-repulsive coupling on neuronal dynamics have also been investigated in the past Here, we aim to extend the scope of research by studying the dependence of synchronization transitions on the information transmission delay over scale-free neuronal networks with attractive or repulsive coupling, respectively. Since a power law distribution of the degree of neurons has been found applicable for the coherence among activated voxels using functional magnetic resonance imaging Firstly, we present in In order to investigate the impact of different values of Performing the same analysis for repulsive coupling reveals several similarities, but also significant differences. Results presented in It is next of interest to explore and determine the mechanisms behind these observations. We will do this by means of the duration of bursting periods of individual neurons constituting the scale-free network. The top three panels of i.e. minimal Upon connecting the values of Merging these observation into an overall insight about delay-induced synchronization transition on scale-free networks with attractive and repulsive coupling, we show in In what follows, in order to test the generality of the above results, we investigate the impact of different system sizes Lastly, we construct a square lattice occupying We have studied delay-induced synchronization transitions on attractively and repulsively coupled scale-free neuronal networks that were locally modeled by the Rulkov map. We have shown that, irrespective of the type of couplings, information transmission delays play a pivotal role in ensuring synchronized neuronal activity. By attractive and repulsive couplings, the synchronization of bursting oscillations was found undulating intermittently as the delay was increased. However, while for attractive coupling the regions of high synchronization appeared every integer multiple of the average oscillation period, for the repulsive coupling they appeared every odd multiple of the half of the average oscillation period. Aiming to explain these observation, we have argued that by attractive coupling the intermittent outlay of synchronized regions emerges due to the locking between the delay length and the average oscillation period of bursting oscillations of individual neurons constituting the scale-free network. Conversely, by repulsive coupling the emergence of antiphase synchronization indicates locking between the delay and odd multiples of one half of the average oscillation period. Our results indicate that information transmission delays can either promote or impair synchrony among neurons and can thus effectively supplement other mechanisms of synchronization The map proposed by Rulkov As the interaction network between neurons we use the scale-free network generated via growth and preferential attachment as proposed by Barabási and Albert e.g.In order to study synchronization transitions quantitatively, we introduce, by means of the standard deviation, a synchronization parameter see e.g., which cIn particular, The full Hodgkin-Huxley model is given by the following equations The membrane capacity The dynamics of the type I Morris-Lecar neuron is described by the following equations The potassium current activation amplitude and activation rate are:


In cariously exposed immature permanent teeth, the treatment choice is controversial in pediatric dentistry. Radical root canal treatment usually appears to be the solution for these teeth. Even partial pulpotomy is a vital treatment for traumatically exposed immature permanent teeth; extending the borders of indication towards cariously exposed immature permanent teeth with reversible pulpitis may abolish the necessity of pulpectomy. This article describes the partial pulpotomy of a cariously affected immature permanent teeth and the follow-up for 1 year. A healthy 11-year-old male patient was referred to Gazi University Faculty of Dentistry Department of Pediatric Dentistry. The patient had reversible pulpitis symptoms on teeth numbered 45. At radiographic examination, immature apex and deep caries lesion were observed and partial pulpotomy was performed by using calcium hydroxide to maintain vitality of the pulp and allow continued development of root dentin expecting the root will attain full maturity. Clinical and radiographic follow-up demonstrated a vital pulp besides not only closure of the apex (apexogenesis), but also physiologic root development (maturogenesis) after 1 year. Partial pulpotomy is an optional treatment for cariously exposed immature permanent teeth for preserving vitality and physiological root development. The treatment of cariously exposed permanent teeth should maintain an arrestment of carious process and vital pulp free of inflammation . The aimDifferent factors such as trauma or caries can affect immature permanent teeth's root development and maturation. If the damage occurs including the pulp of the immature permanent teeth, the treatment becomes a challenge. It has been stated that pulpectomy is the best treatment choice to prevent and/or heal apical periodontitis . It has The overall success of vital pulp therapy mainly depends on which technique is performed, the inflammatory status of the teeth, the type of the agent which is used, the success criteria, and the period of follow-up . As Cvek described in 1978 , partialCalcium hydroxide, has been the material of choice to stimulate dentin formation after a carious exposure of immature permanent teeth for many years . Cvek haNot only calcium hydroxide but also mineral trioxide aggregate (MTA) has been suggested as a suitable material to be used in vital pulp therapy . It has 2 partial pulpotomy allowing the physiological root development.The term “maturogenesis” has been used for the continued physiologic root development which is not restricted to the apical segment . In thisAn 11-year-old Turkish boy consulted to the Gazi University Faculty of Dentistry Department of Pediatric dentistry clinic  with sensitivity to cold and sweets. No spontaneous pain was reported by the patient. The medical history was noncontributory. In the clinical examination gross occlusodistal caries was observed on his mandibular right second premolar (number 45) without signs of extraoral or intraoral swelling or sinus tract formation . The lowAs a result of clinical and radiographic assessments, the pulpal status of the lower right second premolar was determined as vital with reversible pulpitis due to caries. The treatment plan included the removal of the carious lesion and clinical evaluation of the pulp exposure. Vital pulp therapy including partial pulpotomy with calcium hydroxide was planned and an informed consent was obtained from patient's father. After local anesthesia, the tooth was cleaned with pumice and isolated with a rubber dam. Caries removal was performed with a sterile high-speed 801-016 ML diamond round bur with copious irrigation which was continued with steel round bur and exposure of pulp horns with moderate bleeding was observed. The amputation of the 2-3 mm damaged pulp was executed. The cavity was rinsed with saline and a sterile cotton pellet moistened with saline was used to apply moderate pressure to the exposed pulp for 5 min. After the homeostasis was achieved, calcium hydroxide was gently placed on the exposed pulp. A glass ionomer cement  was used as base material and the tooth was restored with amalgam . The patient was scheduled for 1 month follow-up in order to assess root developmentvitality and examine any signs or symptoms. The parents were informed to call the dental clinic if the patient reported any pain or discomfort. At the 1-month follow-up, the clinical examination showed an intact restoration and absence of any abnormal signs or symptoms. The patient reported no pain or discomfort. The tooth tested positive to the electrical pulp test and radiographic examination showed continued development of root and maturation of the root .At 3 and 6 months, no abnormal findings were observed, and the clinical examination revealed no changes from the previous visit. The pulp continued to respond positive to the electrical pulp test. Root maturation was observed as a significant progression when compared with the preoperative radiographs Figures  and 6. The patient was reexamined 12 months after treatment began, and reported as asymptomatic. The pulp tests repeated and the tooth responded normally to the tests. A periapical radiographical assessment showed continued root development and apical closure . Root maRecently, vital pulp therapy and regeneration of infected pulps have become an alternative treatment procedure for immature permanent teeth , 26. TheWhile deciding the treatment options of an exposed teeth, the main consideration should be the degree of infection and inflammation in the pulp, instead of the size or duration of pulp exposure . In cont2  is still a well-accepted material to stimulate dentin formation after a carious exposure of immature permanent teeth [Although many new agents were introduced to the market, Ca(OH)nt teeth . In the nt teeth , 17, 28.Clinical and radiographical evaluations at 1, 3, 6, and 12 months showed pulpal vitality maintenance. Current vitality tests are still based on neurological inducement, and this is still a contradictory in immature teeth [In spite of the fact that histological success cannot be evaluated, clinical success can be assessed by the absence of any clinical or radiographic signs of failure and the substantiation of the development of the root dentin and apex closure. Thus, the patient should be recalled and reexamined periodically against any failure even if absence of visible symptoms. The optimal choice of treatment is, to maintain vitality of an exposed pulp rather than replacing it with a root filling material. However, the technique, the type of the agent which is used, the inflammatory status of the teeth is variable and a challenge to the dentists.In the light of the literature and this case, for cariously exposed immature permanent teeth, partial pulpotomy is an optional treatment for preserving vitality and physiological root development. In this manner, as well as a vital pulp, not only closure of the apex (apexogenesis) but also physiologic root development (maturogenesis) occurs.


Antipsychotic treatment has been repeatedly found to be associated with an increased risk for venous thromboembolism in schizophrenia. The extent to which the propensity for venous thromboembolism is linked to antipsychotic medication alone or psychosis itself is unclear. The objective of this study was to determine whether markers of thrombogenesis are increased in psychotic patients who have not yet been treated with antipsychotic medication.We investigated the plasma levels of markers indicating activation of coagulation (D-dimers and Factor VIII) and platelets  in an antipsychotic-naive group of fourteen men and eleven women with acute psychosis , and twenty-five healthy volunteers were matched for age, gender and body mass index.D-dimers  and sP-selectin  plasma levels were significantly increased in the group of patients with acute psychosis as compared with healthy volunteers. We found a trend  of increased plasma levels of factor VIII in psychotic patients as compared with healthy volunteers.The results suggest that at least a part of venous thromboembolic events in patients with acute psychosis may be induced by pathogenic mechanisms related to psychosis rather than by antipsychotic treatment. Finding an exact cause for venous thromboembolism in psychotic patients is necessary for its effective treatment and prevention. Schizophrenia is a chronic mental disorder that affects about 1% of people worldwide. The disease tends to begin when patients are young and results in a shortened life span. Indeed, the life span among patients with schizophrenia is 20% shorter than that of the general population . Approximately 40% of mortality in schizophrenia is due to "unnatural causes", such as suicide or accidents. Somatic disorders represent the remaining 60% of "natural causes" [Patients with schizophrenia have higher rates of somatic morbidity and mortality when compared with the general population . This isThe risk for cardiovascular mortality among those with schizophrenia is increased twofold as compared with patients without schizophrenia . Of the Venous thromboembolism (VTE), which is clinically manifest as a deep vein thrombosis (DVT) or a pulmonary embolism (PE), is a multifactorial disease. The primary symptom of DVT is asymmetrical oedema of the limb, while chest pain, breathlessness, haemoptysis, syncope or tachycardia are the most important signs for pulmonary embolism . The incAntipsychotic medication is associated with an increased risk for VTE . This haThe primary aim of the study was to determine whether markers of thrombogenesis  and thrombocyte activation (sP-selectin) were activated in unmedicated patients with acute psychosis as compared with matched healthy volunteers.The patients were recruited for the study at the Dept. of Psychiatry, University Hospital in Hradec Králové. Inclusion criteria were as follows: hospitalised patients with acute psychosis , age beHealthy volunteers were recruited from the staff at the University Hospital in Hradec Králové. Healthy volunteers without any mental or serious somatic disorder were matched to the sample with respect to age, gender, weight, and body mass index (BMI). The possibility of mental illness among the volunteers was excluded by using a psychiatric examination. All participants voluntarily signed the "informed consent" form.Venous blood from both the patients and healthy volunteers was taken between 7 and 9 AM after twelve hours of fasting. Laboratory examinations for markers of thrombogenesis and platelet activation are described in Table We compared values of descriptive statistics  between the patients and healthy controls using the Student's t-test. As for laboratory assessments in patients versus healthy volunteers, we used the Mann-Whitney U Test and Student's t-test.All aspects of the present study were approved by the Ethical Committee of the University Hospital in Hradec Králové. Even if patients signed the written "Informed Consent" in a state of acute psychosis, all also agreed to continue in the study in remission later on.Twenty-five (women N = 11) patients with acute psychosis  were included in the study. The control subjects were matched to the patients with respect to age, gender, weight, and body mass index. We did not find any significant demographic difference between the patients and healthy volunteers . Demographic data on patients and healthy volunteers are shown in Table Plasma levels of D-dimer and sP-selectin were significantly higher in the patients as compared with the healthy volunteers . The plasma level of D-dimer was pathologically increased (> 0.5 mg/l) in ten patients and in only two healthy controls. We found a trend  towards increased levels of factor VIII in patients with psychosis as compared with healthy volunteers. Laboratory data in patients and healthy volunteers are presented in Table Venous thromboembolism may not always be adequately recognised in people with a severe mental disorder. Asymptomatic VTE, decreased interest in the maintenance of good health care by either patients or their physicians, a lack of collaboration between the patient and his physicians, the patient's distrust of other medical specialists who are not psychiatrists, and finally psychiatrists' limited knowledge concerning VTE diagnostics are factors that may contribute to the underdiagnosis of VTE in patients with mental illness. At the same time, the life of the patient may be at risk, especially in the case of pulmonary embolism .Data in the literature concerning markers of thrombogenesis in unmedicated schizophrenic patients is limited. Iwata et al.  found inIn a study by Walsh et al. , patientMorioka et al.  reportedOur findings suggest that acute psychosis may reflect a pro-coagulatory state. D-dimers are fragments of insoluble fibrin detectable in plasma after fibrin coagulum has been cleaved by plasmin. Increased plasma level of D-dimer results from pathological activation of blood clotting and occurs following fibrinolysis. Assessment of the D-dimer plasma level is important in clinical practice to exclude the diagnosis of deep vein thrombosis or pulmonary embolism, especially in the outpatient setting . The speThe finding of elevated sP-selectin plasma levels as a marker of inflammation and increased thrombogenesis in our patients is consistent with the process described above. Thrombocytes are involved in atherogenesis if endothelial dysfunction is also present. The membrane pro-coagulatory protein sP-selectin is produced by activated thrombocytes . sP-seleThe median level of factor VIII coagulatory activity showed a trend towards being higher in patients than in healthy volunteers . The difference was statistically significant in the subgroups of women . Twelve patients in contrast to six healthy volunteers had factor VIII coagulatory activity that was abnormally high (above 150%). Increased blood levels of factors II, V, and VIII are associated with an increased risk of venous thromboembolism according to the current literature . IndividThe authors are aware of limitations of the results. The study sample is small, so the results may only be considered as preliminary at this moment. The generalisibility of the findings may also be limited by the disease heterogeneity in psychosis.Since the 1950s, when the first antipsychotic medications were developed, there have been reports of an increased prevalence of venous thromboembolism in patients treated with antipsychotics. In the last decade, this topic has received increased attention within the scientific literature. The diagnoses of schizophrenia or bipolar affective disorder themselves as well as hospitalisation or stress-induced increases in sympathetic activation and catecholamine blood levels are also pro-thrombogenic factors. In our sample of unmedicated patients with acute psychosis, we found an increased level of blood markers of the pathological activation of blood clotting and fibrinolysis, as well as activation of thrombocytes when compared with matched healthy volunteers. Prospective studies are needed to elucidate the biological mechanisms involved in the relationship between venous thromboembolism and antipsychotic medication versus the mental disorder itself.The authors declare that they have no competing interests.JM, RM and LH conceived of the study, participated in its design, collected data and drafted the manuscript. CA carried out the immunoassays and made substantial contributions to the analysis and interpretations of the data. MV helped draft the manuscript and participated in data collection. JB provided statistical analysis and made substantial contributions to the analysis and interpretation of the data. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/11/2/prepub


Well-performing automated protein function recognition approaches usually comprise several complementary techniques. Beside constructing better consensus, their predictive power can be improved by either adding or refining independent modules that explore orthogonal features of proteins. In this work, we demonstrated how the exploration of global atomic distributions can be used to indicate functionally important residues.http://www.bioinformatics.org/surpresi.Using a set of carefully selected globular proteins, we parametrized continuous probability density functions describing preferred central distances of individual protein atoms. Relative preferred burials were estimated using mixture models of radial density functions dependent on the amino acid composition of a protein under consideration. The unexpectedness of extraordinary locations of atoms was evaluated in the information-theoretic manner and used directly for the identification of key amino acids. In the validation study, we tested capabilities of a tool built upon our approach, called SurpResi, by searching for binding sites interacting with ligands. The tool indicated multiple candidate sites achieving success rates comparable to several geometric methods. We also showed that the unexpectedness is a property of regions involved in protein-protein interactions, and thus can be used for the ranking of protein docking predictions. The computational approach implemented in this work is freely available via a Web interface at Probabilistic analysis of atomic central distances in globular proteins is capable of capturing distinct orientational preferences of amino acids as resulting from different sizes, charges and hydrophobic characters of their side chains. When idealized spatial preferences can be inferred from the sole amino acid composition of a protein, residues located in hydrophobically unfavorable environments can be easily detected. Such residues turn out to be often directly involved in binding ligands or interfacing with other proteins. The integration of knowledge of the locations of binding sites with ligand screening or docking protocols improves initial stages of the rational drug design  over all protein atoms. In the header section, the file contains detailed information about clustering and ranking of clusters. The web server and source code are freely available at The presented approach quantifies polar and directional propensities of amino acids using the partition in the knowledge-based continuous gradient of hydrophobicity generated by the protein itself. It yields a middle level of description of hydrophobic preferences between (coarse-grained) scales of hydrophobicity and (fine-grained) residue-residue contact matrices, where more specific local effects such as homophilic, counterion or phenyl rings interactions can be expressed explicitly . It has The adopted view concentrates on the characterization of proteins not assuming any specific chemical properties of ligands. Although based on a statistical model parametrized assuming spherical shapes of proteins , the method works well for moderately aspherical macromolecules, allowing for not only descriptive but also predictive applications. We do not incorporate into the identification method any additional features, such as the solvent accessible area or evolutionary conservation; the direct distance to the centroid was used only for the ranking in order to enable fair comparison with the FOD method; our measure is assigned homogeneously and isotropically in the whole protein volume, thus allowing for the examination of the predictive potential of the sole unexpectedness.Favorable outcomes of our approach, especially when applied to enzymatic active sites, can be explained by analyzing the consequences of the requirement of the precise and resolute positioning of a ligand , which can be best fulfilled by the creation of a binding pocket . The burThe most unexpected atoms are usually found in the deep-set parts of the pockets. The atomic depth has been found to be correlated with residue conservation ,79  atoms but does not enumerate explicitly all possible interactions between them.The approach is useful for the construction of a generic method that quantifies the unexpectedness of occurrences of individual atoms in a given distance from the geometric center of a protein. It turns out that the characteristics can be applied to the recognition of binding sites of both small ligands (enzymatic active sites) and other proteins (protein-protein interfaces).MK conceived of the study, implemented the method, carried out computations, analyzed results and wrote the manuscript.Protein chains in the learning set.Click here for fileGeometric characteristics of the learning set and their dependencies.Click here for fileThe plot of the probability density function used in this work.Click here for fileParameters of atomic distributions.Click here for fileα and distal side chain atoms of 20 amino acidsProbability densities of C.Click here for fileα and distal side chain atoms of CysProbability densities of C.Click here for file48 test setDetails on the efficiency of the SurpResi applied to the LB.Click here for file


Current human resources planning models in nursing are unreliable and ineffective as they consider volumes, but ignore effects on quality in patient care. The project RN4CAST aims innovative forecasting methods by addressing not only volumes, but quality of nursing staff as well as quality of patient care.A multi-country, multilevel cross-sectional design is used to obtain important unmeasured factors in forecasting models including how features of hospital work environments impact on nurse recruitment, retention and patient outcomes. In each of the 12 participating European countries, at least 30 general acute hospitals were sampled. Data are gathered via four data sources . All staff nurses of a random selection of medical and surgical units  were surveyed. The nurse survey has the purpose to measure the experiences of nurses on their job  as well as to allow the creation of aggregated hospital level measures of staffing and working conditions. The patient survey is organized in a sub-sample of countries and hospitals using a one-day census approach to measure the patient experiences with medical and nursing care. In addition to conducting a patient survey, hospital discharge abstract datasets will be used to calculate additional patient outcomes like in-hospital mortality and failure-to-rescue. Via the organizational survey, information about the organizational profile  is collected to control the analyses for institutional differences.This information will be linked via common identifiers and the relationships between different aspects of the nursing work environment and patient and nurse outcomes will be studied by using multilevel regression type analyses. These results will be used to simulate the impact of changing different aspects of the nursing work environment on quality of care and satisfaction of the nursing workforce.RN4CAST is one of the largest nurse workforce studies ever conducted in Europe, will add to accuracy of forecasting models and generate new approaches to more effective management of nursing resources in Europe. All countries, rich and poor, have numeric, skill, and geographic imbalances in their healthcare and nursing workforce  and are To our knowledge none of these models take into account the dynamics between nurse-to-patient ratios, skill mix, nurses' education level, the nursing work environment on one hand and nurse outcomes  and patient outcomes on the other hand. Evidence, nonetheless, confirms that effective nursing workforce strategies enhance the performance of health care organizations and health systems -16. It wThe main aim of the RN4CAST-study is to expand and refine typical forecasting models with factors that take into account how features of work environments and qualifications of the nurse workforce impact on nurse retention, burnout among nurses and patient outcomes. The RN4CAST-study aims to simulate scenarios to illustrate what happens to the quality of patient care and nursing outcomes when different aspects of the nursing workforce  are changed.This 3-year project involves two major phases. The first phase is focused on instrument development and data gathering (January 2009-June 2010), whereas the second study phase is focused on data analysis and policy synthesis (July 2010-December 2011).A common international protocol was written to standardize data collection procedures, instruments, and training of staff and to enable comparability of measures across sites and to facilitate cross-country analyses. At the same time, the study protocol integrates flexibility to allow for differences in the health system structures and nature of the nursing workforces in each country. All differences included in the national study protocols had to be reported by each collaborating team to and approved by the coordinating center.This study makes use of a cross-sectional multilevel design with data collected at the hospital, nursing unit, individual nurse and patient level via four different data sources. A first data source is a survey of the general hospital management about general hospital-wide characteristics like bed size, teaching status and technology level. A second data source is a survey of nurses. Nurses serve as informants about organizational characteristics (e.g. nursing work environment) situated at the nursing unit or hospital level. In addition nurses are also surveyed about individual nurse outcomes like job satisfaction, intention to leave the hospital and burnout. A third data source is routinely collected administrative databases, used to derive patient level data on mortality and other patient outcomes. From the start, it was anticipated that in some countries the availability of routinely collected patient level data is limited, of poor quality or the process to acquire data access could be time consuming hampering to meet the project deadlines. Therefore, in a sub-sample of countries and hospitals a patient survey was conducted to ensure that patient level data can be included in the analysis within the time limits of the project. The different data sources can be linked on the level of the nursing unit/hospital by means of common identifiers.Twelve European countries  were selected on the basis of research expertise, availability of patient discharge data from hospitals, geographic distribution, and duration of membership in the European Union. There are many similarities in healthcare in these selected countries, but also some striking differences, particularly in the size and structure of their healthcare workforces, the percentage of Gross Domestic Product spent on health care and the average length of acute hospital care stays . The theThe setting for the RN4CAST-study focused on general acute hospitals (with at least 100 beds) that either have mixed age clienteles or treat adults only. This setting was chosen since general acute hospitals are the largest employers of nurses  and thusWithin each hospital a minimum of 2 nursing units  were randomly selected from a master list of nursing units. The study sample included only adult medical-surgical care nursing units since the science of linking different elements of nursing practice environment (including nurse staffing) to patient safety and clinical outcomes is best documented within this area ,15,16,19In each country all staff nurses  providing direct care to patients on the selected nursing units were included in the nurse survey. 'Nurses' are defined in each country as those meeting the European Union definition of trained and licensed nurses according to directive 2005/36/EC. In Sweden a different sampling design was used. Nurses were not approached through hospitals but via the Swedish Nursing Association . Via the member register all registered nurses employed in hospitals and working in medical and surgical departments were selected. Nurses were asked to identify the hospital in which they work. This method has proved to be effective in previous research .In five countries  all the selected hospitals were included in the patient survey. Whilst in other countries the patient survey was only conducted in a selection  or none of the hospitals . A one-day census approach was used to select patients of the selected nursing units. All eligible patients (i.e. able to speak and understand the language of the questionnaire and to respond to the questions), present on the selected nursing units on the day of the census, were included in the study sample.Drawing on previous experience of the 'International Hospital Outcome Study', wherever possible, existing instruments were used .The study team in each country collected information about each hospital in their study, including variables about the organizational profile , as well as detailed information on staffing for all categories of hospital workers  and the organization and management of nursing work within the hospital . Standard definitions of all of these variables were prepared based on previous experience and expert discussion within the RN4CAST-consortium. Each study team enquired if these data could be drawn from existing databases maintained by governmental or quasi-governmental agencies or if the general management of the selected hospitals had to be questioned to obtain these data. These data will be used to control the analyses for institutional differences.Each team conducted surveys of hospital nurses based on a core battery of well-known and extensively validated instruments and questions developed and tested in prior research ,11. The Practice Environment Scale of the Nursing Work Index or PES-NWI [The  PES-NWI , was use PES-NWI . The sub PES-NWI ,25. The  PES-NWI .Maslach Burnout Inventory or MBI [Burnout, found in front-line human services workers, has important deleterious effects on job satisfaction, nurse turnover, patient satisfaction . The levy or MBI . MBI incy or MBI .job satisfaction was employed because of the overlap of existing longer measures with the PES-NWI. Published reliability coefficients for single-item overall job satisfaction are in the range of 0.70-0.80 [Rather than using multi-item, comprehensive measures  about jo.70-0.80 . In addiNurse ratings of quality of nursing care provide related yet distinct information about patient outcomes when compared with statistics derived from hospital discharge databases [atabases . The folatabases  were incmeasures of the numbers of nurses working in hospitals within and across hospitals from administrative or regulatory databases led researchers [Difficulties in obtaining consistent earchers  to develearchers ,13,34,35demographics section of the questionnaire, specific demographic characteristics of the respondents were gathered for descriptive purposes and these will also be used as explanatory covariates in our modeling including age and sex. Questions were asked regarding the country where each nurse received their basic nursing education, years since first licensure as a nurse, years working in the current country, hospital, and position, and highest achieved level of education in nursing. In research by Aiken et al. [In the n et al.  and repln et al. , educatihospital discharge abstract datasets in particular, will be used to calculate patient outcomes. Hospital discharge data summarize key information about each hospital stay over a specific time period and contain useful details that can be used to gauge the quality of care being delivered across facilities. Records in these data files include a facility identifier indicating where the hospitalization occurred, patient demographics, characteristics of the admission, principal and secondary International Classification of Diseases (ICD) diagnosis and procedure codes, payer, length of stay, discharge status  and destination, and Diagnosis Related Groups (DRG) assignment. While all participating countries, except Greece, have some type of hospital discharge dataset in use, the specific nomenclatures  and DRG-schemes vary somewhat from country to country as does the history of use and extent to which data have been validated [Routinely collected administrative databases, alidated . Despitealidated -15.Recent research illustrated that higher nurse-to-patient ratios ,38 and aThe English core battery of survey instruments was translated into the 10 primary language(s)  using translation-back translation method. No changes to the template  of the core questionnaire were allowed. In each country the quality of the translated instruments were assessed by a panel of 7 to 11 bilingual experts to obtain Content validity indexes for each item separately (I-CVI) and for the entire scale (S-CVI) .In all of the countries (except Sweden) a field manager was identified in each hospital as key contact with the national RN4CAST team throughout the conduct of the study. In six countries  the field manager was responsible to distribute questionnaires to the nurses and patients (if applicable) within their hospital whereas in four countries  the field manager accommodated visits of the research team to the selected nursing units. In the latter group of countries the research team explained the context of the study and distributed the questionnaires. In Finland nurses and patients received the questionnaires via e-mail and the local field manager, respectively. In Sweden nurses received questionnaire packets by mail at their home address. Nurses were asked to return their questionnaires in sealed envelopes in a secured box on the unit , via pre-paid envelopes  or online (Finland) within 2-3 weeks. Patients were asked to return the questionnaires by pre-paid envelopes  or to hand them to the nurses who can return the questionnaires in sealed envelopes in a secured box on the unit . Various approaches were used  to maximize response rates.The collection of the patient discharge data depends on the nature of the database and the laws and regulations surrounding access of researchers to their use in each country. Different procedures were followed at each site to acquire patient level data about adult hospitalized medical and surgical patients.Preliminary analyses of the raw country-specific datasets including descriptive work to identify out-of-range values for variables, conflicting results, missing values and possible data entry errors will be performed. A cleaned version of the different data sources will be organized in an interrelated multilevel meta-database. This multi-country database contains information at the hospital level , the individual nurse level (data resulting from the nurse survey) and the patient level . The cross-country patient outcomes database will not contain all the original data but rather a selection of original variables  and deduced variables . Patient outcomes and co-morbidities will be based on published work like that of Aiken et al. ,34, the Two major types of analyses will be done using the multi-country survey and outcomes data. The first will involve descriptive and comparative analyses of variables reflecting commonalities and differences, policy implications and the strengths and weaknesses of the nurse workforce across countries. In these analyses individual level nurse data will be used and aggregated at the country level.The second type of analysis involves the modeling of relationships between core independent and dependent hospital variables within and across countries. Independent measures will include staffing and work environment variables. Dependent measures will be both indicators of experiences of nurses  on the job and patient outcomes variables. Regression models that estimate average differences in continuous outcome variables or differences in the odds of various negative events for nurses and patients will be fitted. The clustering of nurses and patients within hospitals  will require the use of multilevel modeling strategies . A five Whenever missing data are present, statistical imputation methods will be used to provide alternative analyses  to the approaches where cases with missing data are omitted.An extensive literature review was undertaken to gather information allowing the team to evaluate and appraise the current nurse workforce projection models and forecasts. In addition to searching the traditional databases like CINAHL, Embase and Medline, teams in each country contacted institutions and stakeholders in each country to obtain published and unpublished data and reports about forecasting models. Based on the results of the literature review, the researchers will appraise and evaluate the currently employed forecasting and planning models.A policy synthesis will combine the literature review on nurse forecasting models with the results of the data analysis about the impact of different aspects of the nursing work environment on patient outcomes and nurses' job experiences. The likely impact of a range of policy instruments  on patient outcomes and nurse retention and ultimately staffing levels and patient outcomes, will, for instance, be estimated from country-specific data. Sensitivity analyses considering the impact of altering the underlying assumptions in various ways will be used to frame the estimates generated. This will result in several types of country-specific scenarios for the nurse workforce in each country in the coming decades including the simulation of what happens when different conditions in the nursing workforce are changed. A synthesis document will be created and indicating how similar or different the conclusions of the data analyses are across countries, whether or not it is possible to identify clear Europe-wide conclusions from the work in RN4CAST.The project has been granted financial support from the European Commission. Depending on national legislation, the study protocol was approved by either central ethical committees (e.g. nation or university) or local ethical committees . Proof of the ethical approvals has been submitted to the editorial board of this journal for verification. The consortium has developed strict criteria  regarding the sampling of nurses and patients, the storage, flows and access of the data to safeguard the security, privacy and confidentiality.Human workforce planning in healthcare and patient safety are high on the priority list of international policy organizations. Linking both workforce planning in nursing and patient safety would give a major support to these actions. Nursing is numerically the largest health profession providing direct care. Given their impact on patient outcomes and safety and the costs involved, workforce planning for nursing has significant impacts at a public and policy level .The study will make a strong significant scientific contribution by shifting the main focus of nursing workforce planning from rather simple projections in demand and supply of labour to impact on patient safety and quality. The innovative nature of the RN4CAST project is the consideration of new factors in workforce planning such as the work environment recruiting and retention of nurses within the profession and the link between nursing adequacy and patient safety and quality. The study will generate the necessary scientific basis to underpin informed policy decisions on health systems and more effective and efficient strategies of nursing workforce planning. The studies of Needleman et al.  and RothAlso in Europe, it is illustrated that the potential quality gain in acute hospitals can be substantial. It was shown, for example, that if Belgian acute hospitals would manage to shift the prevalence of "failure-to-rescue" (deaths of patients with complications), to the performance level of the current 20th percentile, the overall in-hospital mortality in Belgian hospitals would decrease with 3.95% in the group of medical patients and with 6.50% in the group of surgical patients . SimilarThe study will allow countries to learn from the experience of other health systems and their sustainability, taking into account the importance of national contexts and population characteristics. Focus will be on how nurse staffing and organizational aspects of health systems impact on patient outcomes. The study can serve as an evaluative lens on the nurse workforce impacts of recent national policy initiatives in health care, such as the recent adoption of prospective payment and Diagnostic Related Groups in Germany and the slowing of investments in the National Health Service in England.Simultaneously to the research activities, the project entails dissemination and stakeholder activities toward achieving the study objectives. An impact assessment preceded the establishment of a stakeholder panel representing patient, nursing and healthcare organizations at the European level. The main role of the international panel is to raise awareness of the project and to support the research team in formulating policy recommendations based on the scientific results. Next to the international stakeholder panel, in each partnering country national stakeholder committees are formed to further gain support for the project.Next to the large-scale European part of the RN4CAST project, three International Cooperating Partner Countries of the European Union  participate in the project consortium. All three countries will at least perform a pilot study to provide a broader international perspective on the study results.th edition; ICD-10: International Classification of Diseases, 10th edition; I-CVI: Item Content Validity Index; MBI: Maslach Burnout Inventory; PES-NWI: Practice Environment Scale of the Nursing Work Index; S-CVI: Scale Content Validity Index.AHRQ: Agency for Healthcare Research and Quality; CAHPS: Consumer Assessment of Healthcare Providers and Systems; DRG: Diagnosis Related Groups; ICD-9: International Classification of Diseases, 9The authors declare that they have no competing interests.WS is the principal researcher of the study, LA is co-principal researcher, KV is the day-to-day project and scientific manager. WS, LA and KV equally contributed to developing the research question and study design. WS, LA, KV, AR, PG, MM, RB, RL, AS, LB, TB, JK, MS, LS, DZ equally contributed to implementation of the study protocol. KV drafted the overall manuscript. All those listed as authors were responsible for reading, commenting upon, and approving the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6955/10/6/prepub