Brain network dynamics in the human articulatory loop

Objective

The articulatory loop is a fundamental component of language function, involved in the short-term buffer of auditory information followed by its vocal reproduction. We characterized the network dynamics of the human articulatory loop, using invasive recording and stimulation.

Time trends in <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> bacteremia, 1988–2010, in a tertiary center with high methicillin resistance rates

Introduction

Changes in the epidemiology of Staphylococcus aureus bacteremia (SAB) have been described in recent decades. Decreased mortality has been reported over time, mostly from countries with low methicillin resistance rates. We aimed to describe time trends in SAB in a tertiary center with high methicillin resistance rates.

Methods

We retrospectively analyzed 1692 patients with SAB, and compared between three time periods: 1988–1994 (342 patients), 1998–2004 (597 patients) and 2005–2010 (753 patients).

Results

In our cohort, 30 days mortality increased significantly with time, reaching 42.9 % during 2005–2010. The latter period was characterized by higher rates of older patients (35.1 % aged 80 years and older), with lower functional capacity (46.5 % bedridden) and higher rates of comorbidities (33.6 % renal disease, 24.8 % heart failure, 19.0 % dementia). These patients were more likely to be ventilated (18.7 %) and carry a urinary catheter at presentation (46.6 %); present with septic shock (15.9 %) and have pneumonia (20.5 %) or endocarditis (7.2 %) as source. Similar characteristics were found among patients younger than 50 years and with independent functional status. No significant increase in methicillin resistant Staph aureus (MRSA) rates or inappropriate empirical therapy was demonstrated during 2005–2010.

Conclusions

In our cohort, increased mortality in recent years in patients with SAB can be explained by baseline condition of patients. MRSA or inappropriate empiric therapy did not explain the increase in mortality. The patients afflicted with SAB changed over time. Epidemiology and outcomes of SAB vary with time and according to geographical location. External validity of studies should be taken into consideration.

     

Effects of D-003 on Lipopolysaccharides-induced Osteonecrosis in Rabbits

D-003, a mixture of high molecular weight acids, inhibits cholesterol synthesis prior to mevalonate and prevents osteoporosis induced by ovariectomy in rats, and both osteoporosis and osteonecrosis induced by corticoids in rats. The aim of this study was to investigate effects of D-003 on lipopolysaccharides-induced osteonecrosis in rabbits. Animals were randomized into 5 groups: a sham and four groups injected with lipopolysaccharides: one treated orally with vehicle and three with D-003 (5, 25 and 200 mg/kg, respectively) during four weeks. We assessed the effects of treatments on the incidence of osteonecrosis (number of animals with osteonecrosis lesions/animals per group), the mean numbers and areas of osteonecrosis per animal and on the mean sizes of the bone marrow fat cells. The incidence of osteonecrosis in the groups of D-003 25 and 200 mg/kg was significantly lower than in the positive controls. The reduction of osteonecrosis increased with the doses, but significant dose-dependence relationship was not achieved. D-003 significantly and dose-dependently decreased the number of osteonecrosis lesions per animal as compared to the positive controls. Likewise, the mean osteonecrosis areas in the proximal femoral and humeral bones were significantly decreased by D-003. The injection of lipopolysaccharides significantly increased the average size of bone marrow fat cells as compared to the negative controls, and such increase was significantly and markedly reduced with D-003. It is concluded that D-003 reduced the incidence, number and percent areas of osteonecrosis lesions, and the size of bone marrow fat cells, a marker of adipogenesis, in rabbits with lipopolysaccharides-induced ostenonecrosis.     

Evaluating the effective shear modulus of the cytoplasm in cultured myoblasts subjected to compression using an inverse finite element method

In the present study, we employ our recently developed confocal microscopy-based cell-specific finite element (FE) modeling method, which is suitable for large deformation analyses, to conduct inverse FE analyses aimed at determining the shear modulus of the cytoplasm of cultured skeletal myoblasts, G_cp, and its variation across a number of cells. We calibrate these cell-specific models against experimental data describing the force–deformation behavior of the same cell type, which were published by Peeters et al. (2005b) [J. Biomech.]. The G_cp calculated for five different myoblasts were contained in the range of 0.8–2.4 kPa, with the median value being 1 kPa, the mean being 1.4 kPa, and the standard deviation being 0.7 kPa. The normalized sum of squared errors resulting from the fit between experimental and calculated force–deformation curves ranged between 0.12–0.73%, and Pearson correlations for all fits were greater than 0.99. Determining the mechanical properties of the cytoplasm through cell-specific FE will now allow calculation of cell stresses using cell-specific FE under various cell loading configurations, in support of experimental work in cellular mechanics.     

Is C-reactive protein level a marker of advanced motor and neuropsychiatric complications in Parkinson’s disease?

C-reactive protein (CRP) is a plasma protein involved in inflammation. While its levels have been associated with stroke, cognitive impairment and depression, the association with clinical characteristics of Parkinson’s disease (PD) is unknown. A total of 73 consecutive patients with PD (46 males, age 68.8 ± 11.5 years) were evaluated regarding motor as well as cognitive and psychiatric features of PD. Plasma CRP levels were determined and tests for associations with disease parameters were performed. The average level of CRP was 3.9 ± 4.1 μmol/L, and 45.2% of the patients (n = 33) had a level above 3.0 μmol/L. Patients in the high CRP group tended to be older (71.4 ± 9.2 vs. 66.7 ± 12.9 years; p = 0.08) and coronary artery disease (CAD) was more common (36 vs. 10%, p < 0.05) in the high CRP group, but no differences were found between the groups regarding gender, disease duration, levodopa dose, motor scores or most of the neuropsychiatric complications such as severity of depression, psychosis, dementia, cognitive decline or frontal lobe dysfunction. Reported depression (at present or in the past) was more common in the high CRP group (54.5 vs. 25%, p = 0.01). CRP levels in patients with PD are associated with a higher prevalence of CAD, but are not associated with PD duration or severity, or with neuropsychiatric complications other than reported depression.     

Inferior vena cava diameter pulse waveforms in the human fetus: relationship with flow velocity waveform

Our purpose was to evaluate the hemodynamic significance of fetal inferior vena cava (IVC) flow velocity waveform indices during fetal development in relation to the diameter pulse waveform. Doppler ultrasound and a phase locked loop echo tracking system were used to measure flow velocity waveform and diameter pulse waveform, respectively. Twenty-seven normal singleton pregnancies were examined from 20 weeks until term at 4-week intervals. The diameter pulse waveform consisted of four waves (A, X, V, and Y waves). The A value (end-diastolic diameter) was associated with the end-diastolic pressure, which causes reverse flow during right atrial contraction. In normal fetuses, a weight-related lower end-diastolic diameter suggested that the end-diastolic pressure was decreased. Except for a positive correlation between the percent reverse flow during atrial contraction and the A value per unit fetal weight, no correlations were found between diameter waveform indices and blood flow velocity waveform indices. The peak velocity index of the velocity waveform significantly correlated with the umbilical artery flow velocity waveform systolic/diastolic ratio. The fetal IVC velocity waveform indices did not yield unequivocal information as to changes in central venous pressure, for which purpose the diameter pulse waveform analysis would seem to be the only available method.     

p62-containing,proteolytically active nuclear condensates,increase the efficiency of the ubiquitin–proteasome system

Degradation of a protein by the ubiquitin–proteasome system (UPS) is a multistep process catalyzed by sequential reactions. Initially, ubiquitin is conjugated to the substrate in a process mediated by concerted activity of three enzymes; the last of them—a ubiquitin ligase (E3)—belongs to a family of several hundred members, each recognizing a few specific substrates. This is followed by repeated addition of ubiquitin moieties to the previously conjugated one to generate a ubiquitin chain that serves as a recognition element for the proteasome, which then degrades the substrate. Ubiquitin is recycled via the activity of deubiquitinating enzymes (DUBs). It stands to reason that efficiency of such a complex process would depend on colocalization of the different components in an assembly that allows the reactions to be carried out sequentially and processively. Here we describe nuclear condensates that are dynamic in their composition. They contain p62 as an essential component. These assemblies are generated by liquid–liquid phase separation (LLPS) and also contain ubiquitinated targets, 26S proteasome, the three conjugating enzymes, and DUBs. Under basal conditions, they serve as efficient centers for proteolysis of nuclear proteins (e.g., c-Myc) and unassembled subunits of the proteasome, suggesting they are involved in cellular protein quality control. Supporting this notion is the finding that such foci are also involved in degradation of misfolded proteins induced by heat and oxidative stresses, following recruitment of heat shock proteins and their associated ubiquitin ligase CHIP.

An important, yet unsolved question is how cells recruit the appropriate reactants involved in biochemical reactions, to a defined location at a specific time to increase the reaction efficiency and processivity. This is particularly relevant for sequential transformations along cascades that are catalyzed by different enzymes and complexes, such as degradation of a protein by the ubiquitin–proteasome system (UPS). Separation of the interior milieu of membrane-bound organelles (e.g., nucleus, Golgi apparatus, endoplasmic reticulum, mitochondria, and lysosomes) from the surrounding environment enables the cells to control the spatial distribution of specific reactions and their components. However, this compartmentalization makes it difficult to allow exchange of components necessary for providing high specificity, for example. In addition, cells contain supramolecular assemblies that are not bound by surrounding membranes and can be found both in the cytoplasm (such as the centriole, P bodies, and stress granules) and the nucleus (such as nucleoli, promyelocytic leukemia [PML] bodies, Cajal bodies, and nuclear speckles) (1, 2).Emerging evidence shows that many membraneless biomolecular condensates are formed by liquid–liquid phase separation (LLPS) (3). These condensates provide a different environment from the surrounding cytoplasm or nucleoplasm and probably have an important role in the concentration of biomolecules, thus allowing efficient multistep processes to occur. In addition, it allows for rapid exchange of specific components—such as ubiquitin ligases—to occur and thus allowing accommodation to changing pathophysiological conditions and the requirement for high specificity of different processes. Recently, it was shown that p62, also known as Sequestosome-1 (SQSTM-1), forms spherical liquid-like condensates (bodies) both in the cytosol and in a cell-free system (4). Formation of these condensates is mediated by the ability of the protein to oligomerize into helical filaments through its N-terminal PB1 (Phox and Bem1) domain, and to bind ubiquitin (Ub) chains attached to target substrates via its C-terminal UBA (ubiquitin-associated) domain (5). The efficiency of p62 condensate formation was shown to be strongly dependent on the length of the Ub chains attached to the substrates (6).Cytosolic p62 condensates play an important role in maintaining protein homeostasis and quality control by their ability to sequester ubiquitinated proteins and shuttle them for degradation by the autophagy–lysosome system. This is mediated via direct interaction of the p62’s LIR motif with the autophagosome-incorporated LC3 (7). In addition to its role in autophagy, p62 was shown to deliver cytosolic ubiquitinated substrates to the proteasome, by direct interaction of its PB1 domain with the 19S Rpn1 and Rpn10 proteasomal subunits (8).p62 is widely distributed in the cell, and its nucleocytoplasmic shuttling is mediated by two nuclear localization signals (NLS1 and NLS2) and one nuclear export signal (NES) (9). In addition to its cytosolic functions, p62 forms nuclear bodies that exist both as separate and as hybrid structures by interacting with PML or Cajal bodies (10). Since autophagy occurs exclusively in the cytosol, the role and biological significance of nuclear p62 have remained elusive.In the present study we show that p62 is involved in the formation of nuclear LLP-separated foci, which recruit components of the UPS and protein substrates, resulting in their efficient degradation under both basal and stressed conditions.     

Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors

Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients.     

Morphologic changes of the nasopalatine canal related to dental implantation: a radiologic study in different degrees of absorbed maxillae

Background: Implant rehabilitation of the edentulous anterior maxilla remains a complex restorative challenge. Intricate preexisting anatomy dictates meticulous and accurate osteotomy planning. With progressive bone loss, the alveolar crest may approach anatomic structures. The nasopalatine nerve and vessels may ultimately emerge from the ridge crest. The radiologic changes of the nasopalatine canal were evaluated in different resorption phases of the premaxilla alveolus with regard to dental implantation. Methods: The study consisted of 207 subjects who had maxillary computed tomography scans before dental implantation. The Lekholm and Zarb classification was used to divide images according to the residual bony ridge: Class A (control group) and classes B to E (study group). Anatomic mapping of the nasopalatine canal structure was carried out in both groups. Results: The canal diameter was wider along the degree of ridge resorption from classes A to E in all dimensions, mainly in the palatal opening (P <0.01), middle area (P <0.001), and nasal area. The mean diameter of the enlargement was 1.8 mm, which reached 5.5 +/- 1.08 mm (P <0.01) in type E bone. In the severely resorbed ridges (classes C through E), when the palatal opening was situated on the ridge, it occupied a mean of 35.6% (13% to 58%) of the area devoted to implant placement. Tooth loss was the main reason for ridge resorption (P <0.01). Conclusions: Canal diameter enlargement was greater anteriorly to the ridge and posteriorly to the palatal bone, mainly because of tooth extraction. The atrophy of disuse may influence surrounding structures, similar to the maxillary sinus tendency to expand into surrounding bone mainly after tooth loss.