Regulation of sphingomyelin metabolism.
Sphingolipids (SFs) represent a large class of lipids playing diverse functions in a vast number of physiological and pathological processes. Sphingomyelin (SM) is the most abundant SF in the cell, with ubiquitous distribution within mammalian tissues, and particularly high levels in the Central Nervous System (CNS). SM is an essential element of plasma membrane (PM) and its levels are crucial for the cell function. SM content in a cell is strictly regulated by the enzymes of SM metabolic pathways, which activities create a balance between SM synthesis and degradation. The de novo synthesis via SM synthases (SMSs) in the last step of the multi-stage process is the most important pathway of SM formation in a cell. The SM hydrolysis by sphingomyelinases (SMases) increases the concentration of ceramide (Cer), a bioactive molecule, which is involved in cellular proliferation, growth and apoptosis. By controlling the levels of SM and Cer, SMSs and SMases maintain cellular homeostasis. Enzymes of SM cycle exhibit unique properties and diverse tissue distribution. Disturbances in their activities were observed in many CNS pathologies. This review characterizes the physiological roles of SM and enzymes controlling SM levels as well as their involvement in selected pathologies of the Central Nervous System, such as ischemia/hypoxia, Alzheimer disease (AD), Parkinson disease (PD), depression, schizophrenia and Niemann Pick disease (NPD).


Effect of phytic acid on colonic epithelial cell proliferation.
Cell proliferation was studied in descending, transverse and ascending colonic crypts of rats fed either 0%, 0.6%, 1.2% or 2.0% phytic acid (PA). Significant effects of phytic acid were seen only in the descending colon. No changes in crypt height were observed. Both the 1.2 and 2.0% phytic acid groups exhibited significantly lower uppermost labelled cells than the control group. Animals given 1.2% and 2.0% phytic acid also showed significantly reduced DNA synthetic cells, as indicated by lower labelling indices.


Effects of relative low-frequency bilateral globus pallidus internus stimulation for treatment of cervical dystonia.
To assess the effect of relative lower amplitude and frequency for globus pallidus internus (GPi) deep brain stimulation (DBS) of cervical dystonia (CD). Between February 2005 and October 2008, 14 patients diagnosed with CD underwent bilateral GPi DBS and all the patients received low-frequency stimulation and were followed for more than 2 years. We activated the implantable pulse generator 3-4 days postoperatively and initial amplitude, pulse width, and frequency were set at 1.5 V, 120 μs, and 70 Hz. The Toronto Western Spasmodic Torticolis Rating Scale (TWSTRS) was applied preoperatively and at 1, 6, 12 and 24 months postoperatively. The overall TWSTRS scores improved 71.2% 2 years postoperatively (p = 0.001). The mean improvement was 78.4% in severity subscores, 68.4% in disability, and 66.8% in pain scores for the 2-year follow-up period. The TWSTRS scores were significantly reduced (p < 0.05), suggesting that the most significant improvement of the TWSTRS scores occurred within 1 month. The final amplitude was 2.9/2.7 V with the pulse width of 147.9/147.9 μs and the frequency of 101.1/100 Hz. According to our results, the initial settings of low amplitude and especially relatively low frequency are safe and effective for treatment of CD.


9-(7-Fluoro-4-oxo-4H-chromen-3-yl)-3,3,6,6-tetra-methyl-2,3,4,5,6,7,8,9-octa-hydro-1H-xanthene-1,8-dione.
In the title compound, C(26)H(25)FO(5), the terminal cyclo-hexane rings of the xanthene ring system adopt half-boat conformations. The 4H-chromene ring make a dihedral angle of 87.94 (5)° with the xanthene ring system and its carbonyl O atom lies above the xanthene O atom. In the crystal, mol-ecules are linked into ribbons propagating along the a-axis direction by C-H⋯O hydrogen bonds. Aromatic π-π stacking inter-actions [centroid-centroid distance = 3.7367 (12) Å] also occur.


Spatial Stress and Strain Distributions of Viscoelastic Layers in Oscillatory Shear.
One of the standard experimental probes of a viscoelastic material is to measure the response of a layer trapped between parallel surfaces, imposing either periodic stress or strain at one boundary and measuring the other. The relative phase between stress and strain yields solid-like and liquid-like properties, called the storage and loss moduli, respectively, which are then captured over a range of imposed frequencies. Rarely are the full spatial distributions of shear and normal stresses considered, primarily because they cannot be measured except at boundaries and the information was not deemed of particular interest in theoretical studies. Likewise, strain distributions throughout the layer were traditionally ignored except in a classical protocol of Ferry, Adler and Sawyer, based on snapshots of standing shear waves. Recent investigations of thin lung mucus layers exposed to oscillatory stress (breathing) and strain (coordinated cilia), however, suggest that the wide range of healthy conditions and environmental or disease assaults lead to conditions that are quite disparate from the "surface loading" and "gap loading" conditions that characterize classical rheometers. In this article, we extend our previous linear and nonlinear models of boundary stresses in controlled oscillatory strain to the entire layer. To illustrate non-intuitive heterogeneous responses, we characterize experimental conditions and material parameter ranges where the maximum stresses migrate into the channel interior.


Pleiotropic effects of pufX gene deletion on the structure and function of the photosynthetic apparatus of Rhodobacter capsulatus.
By deletion of the pufX gene of Rhodobacter capsulatus from a plasmid carrying the puf operon and complementation of a chromosomal puf operon deletion, we created pufX mutants and used them to characterize possible functions of the pufX gene product. The pufX mutants were incapable of photosynthetic growth in a minimal medium, or in a rich medium at low light intensities, although second-site mutations suppressed this phenotype. Measurements made in vitro with intact and solubilized chromatophore preparations indicated that the individual complexes of the photosynthetic unit seemed to function normally, but electron transfer from the reaction center to the cytochrome b/c1 complex was impaired. The structures of the photosynthetic apparatus of pseudo-wild type and mutant strains were evaluated using absorption spectroscopy and electron microscopy. The pufX mutants had intracytoplasmic membrane invaginations about 50% larger in diameter than those of the pseudo-wild type and higher levels of B870 light-harvesting complex. It is concluded that the PufX protein plays an important role in the structure of the functional photosynthetic unit, and its absence results in loss of efficient electron transfer from the QB site of the reaction center to the Qz site of the cytochrome b/c1 complex.


TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.
PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria by autophagy. Other than translocase of the outer mitochondrial membrane complexes, members of PINK1-containing protein complexes remain obscure. By mass spectrometric analysis of PINK1 co-immunoprecipitates, we identify the inner membrane protein TIM23 as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and significantly delays autophosphorylation, indicating that TIM23 promotes PINK1 accumulation in response to depolarization. Moreover, inactivation of the mitochondrial protease OMA1 not only enhances PINK1 accumulation but also represses the reduction in PINK1 levels induced by TIM23 downregulation, suggesting that TIM23 facilitates PINK1 activation by safeguarding against degradation by OMA1. Indeed, deficiencies of pathogenic PINK1 mutants that fail to interact with TIM23 are partially restored by OMA1 inactivation. These findings indicate that TIM23 plays a distinct role in activating mitochondrial autophagy by protecting PINK1.


Slow subcutaneous immunoglobulin therapy in a patient with reactions to intramuscular immunoglobulin.
A 35-year-old man with common variable hypogammaglobulinemia had repeated anaphylactic reactions to intramuscular human immune serum globulin (HISG), preventing him from receiving the injections. He was able to tolerate slow subcutaneous HISG infusions without local or systemic side effects at a dose of 12 ml/week given at a rate of 2 ml/hr. He has been maintained on these infusions for 2 years in an infection-free state.


MnTnBuOE-2-PyP treatment protects from radioactive iodine (I-131) treatment-related side effects in thyroid cancer.
Treatment of differentiated thyroid cancer often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. However, there is morbidity associated with I-131 therapy, which can result in both acute and chronic complications. Currently, there are no approved radioprotectors that can be used in conjunction with I-131 to reduce complications in thyroid cancer therapy. It is well known that the damaging effects of ionizing radiation are mediated, in part, by the formation of reactive oxygen species (ROS). A potent scavenger of ROS, Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP), has radioprotective and anti-tumor effects in various cancer models including head and neck, prostate, and brain tumors exposed to external beam radiation therapy. Female C57BL/6 mice were administered I-131 orally at doses of 0.0085-0.01 mCi/g (3.145 × 105 to 3.7 × 105 Bq) of body weight with or without MnTnBuOE-2-PyP. We measured acute external inflammation, blood cell counts, and collected thyroid tissue and salivary glands for histological examination. We found oral administration of I-131 caused an acute decrease in platelets and white blood cells, caused facial swelling, and loss of thyroid and salivary tissues. However, when MnTnBuOE-2-PyP was given during and after I-131 administration, blood cell counts remained in the normal range, less facial inflammation was observed, and the salivary glands were protected from radiation-induced killing. These data indicate that MnTnBuOE-2-PyP may be a potent radioprotector of salivary glands in thyroid cancer patients receiving I-131 therapy.


Sevoflurane-remifentanil vs isoflurane-remifentanil for the surgical correction of craniosynostosis in infants.
The aim of the present study was to compare the efficacy of isoflurane-remifentanil and sevoflurane-remifentanil combinations during neurosurgical correction craniosynostosis. Twenty-two infants with craniosynostosis received a slow bolus of remifentanil followed by continuous infusion. The infants were randomly divided into two groups: remifentanil followed by sevoflurane (the 'sevoflurane group'), and remifentanil followed by isoflurane (the 'isoflurane group'). We monitored electrocardiogram (ECG), heart rate (HR), invasive arterial blood pressure (IABP), pulse oximetry saturation (SpO(2)), endtidal CO(2) (P(ECO(2))), inspired fraction of oxygen (FiO(2)) and endtidal volatile agent (PE volatile agent) at 12 time points, from the beginning of surgery (T0) until the cessation of drugs (T11). The volatile agent was stopped prior to skin suture and the remifentanil infusion after skin closure. Subsequently, we evaluated recovery time of spontaneous breathing and spontaneous eye opening and time of extubation at 5, 10, and 15 min after extubation, the Steward Recovery Score (SRS) was assessed. Patients were then transferred to the Pediatric Intensive Care Unit (PICU). During the surgical procedure the hemodynamic parameters between the two groups did not show statistically significant differences. There were also no significant differences in terms of awakening time or SRS. The rapid recovery of the children (confirmed by their high values of SRS) makes it possible to reliably assess the patient's neurological condition immediately after surgery.


The Golgi localization of phosphatidylinositol transfer protein beta requires the protein kinase C-dependent phosphorylation of serine 262 and is essential for maintaining plasma membrane sphingomyelin levels.
Recombinant mouse phosphatidylinositol transfer protein (PI-TP)beta is a substrate for protein kinase C (PKC)-dependent phosphorylation in vitro. Based on site-directed mutagenesis and two-dimensional tryptic peptide mapping, Ser(262) was identified as the major site of phosphorylation and Ser(165) as a minor phosphorylation site. The phospholipid transfer activities of wild-type PI-TP beta and PI-TP beta(S262A) were identical, whereas PI-TP beta(S165A) was completely inactive. PKC-dependent phosphorylation of Ser(262) also had no effect on the transfer activity of PI-TP beta. To investigate the role of Ser(262) in the functioning of PI-TP beta, wtPI-TP beta and PI-TP beta(S262A) were overexpressed in NIH3T3 fibroblast cells. Two-dimensional PAGE analysis of cell lysates was used to separate PI-TP beta from its phosphorylated form. After Western blotting, wtPI-TP beta was found to be 85% phosphorylated, whereas PI-TP beta(S262A) was not phosphorylated. In the presence of the PKC inhibitor GF 109203X, the phosphorylated form of wtPI-TP beta was strongly reduced. Immunolocalization showed that wtPI-TP beta was predominantly associated with the Golgi membranes. In the presence of the PKC inhibitor, wtPI-TP beta was distributed throughout the cell similar to what was observed for PI-TP beta(S262A). In contrast to wtPI-TP beta overexpressors, cells overexpressing PI-TP beta(S262A) were unable to rapidly replenish sphingomyelin in the plasma membrane upon degradation by sphingomyelinase. This implies that PKC-dependent association with the Golgi complex is a prerequisite for PI-TP beta to express its effect on sphingomyelin metabolism.


Velocity of linear crystallization of ice in macromolecular systems.
The velocity of ice crystallization in gelled systems was compared with that in solutions of similar macromolecular materials. Neither the constituting material nor the dimensions of the tubes in which the measurements were made influenced the results. The velocity of linear crystallization of ice was slowed in macromolecular solutions and gels, and this decrease was not associated with changes in dynamic or thermodynamic properties of water. It was probably the consequence of a mechanical effect of the macromolecules directly on ice crystal growth.


Asymmetric cell division in skin development: a new look at an old observation.
During skin development, the single-layered surface ectoderm covering the mouse embryo must initiate stratification and terminal differentiation to develop a functional epidermis. A recent article by Lechler and Fuchs in Nature (Lechler and Fuchs, 2005) suggests that these events are triggered by asymmetric cell division.


Thinning Faster? Age-Related Cortical Thickness Differences in Adults with Autism Spectrum Disorder.
Over the course of the last 30 years, autism spectrum disorder (ASD) diagnoses have increased, thus identifying a large group of aging individuals with ASD. Currently, little is known regarding how aging will affect these individual's neuroanatomy, compared to the neurotypical (NT) population. Because of the anatomical overlap of ASD-related cortical pathology and age-related cortical thinning, both following an anterior-to-posterior severity gradient, we hypothesize adults with ASD will show larger age-related cortical thinning than NT adults. We analyzed cortical measurements using available data from the multi-site Autism Brain Imaging Data Exchange I (ABIDE I; n=282) and our own cohort of middle-age to older adults with and without ASD (n=47) mostly available in ABIDE II (n=35). We compared correlations between cortical measures and age in right-handed adults with ASD (n=157) and similar NT adults (n = 172), controlling for IQ and site. Participants were 18 to 64 years of age (mean=29.8 years; median=26 years). We found significant differences between diagnosis groups in the relationship between age and cortical thickness for areas of left frontal lobe (pars opercularis), temporal lobe (inferior gyrus, middle gyrus, banks of the superior temporal sulcus, and entorhinal cortex), parietal lobe (inferior gyrus), and lateral occipital lobe. For all areas, adults with ASD showed a greater negative correlation between age and cortical thickness than NT adults. As hypothesized, adults with ASD demonstrated exacerbated age-related cortical thinning, compared to NT adults. These differences were the largest and most extensive in the left temporal lobe. Future longitudinal work is warranted to investigate whether differences in brain age trajectories will translate to unique behavioral needs in older adults with ASD.


Isolongifolene mitigates rotenone-induced dopamine depletion and motor deficits through anti-oxidative and anti-apoptotic effects in a rat model of Parkinson's disease.
Isolongifolene (ILF), a novel tricyclic sesquiterpene compound isolated from the Indian herb Murraya koenigii (M. koenigii), has been previously demonstrated to have a neuroprotective effect against rotenone-induced oxidative stress, mitochondrial dysfunction, and apoptosis in in vitro model. However, these neuroprotective and anti-apoptotic effects of ILF are not well understood and must be further investigated to elucidate the underlying molecular mechanism of ILF in animal experiments. The objective of this study was to evaluate the neuroprotective effect of ILF on motor impediments, neurochemical variables, anti-oxidative indices, and apoptotic protein expression in a rotenone-induced rat model of Parkinson's disease (PD). PD was induced in male albino Wistar rats via injection of 2.5 mg/kg rotenone for 4 weeks. Rotenone produces PD-like effects by promoting mitochondrial complex I inhibition and microglial activation properties. The protective effect of three different doses of ILF 5, 10 and 20 mg/kg were evaluated for spontaneous locomotion, rotarod performance, and striatal dopamine (DA) content. The results showed that ILF dose-dependently ameliorated the rotenone-induced striatal DA loss and motor impairment from 10 mg/kg. Therefore, we selected 10 mg/kg as the ILF dose for further investigation. Chronic administration of rotenone caused PD-related pathological processes like oxidative stress, and produced a significant decrease in tyrosine hydroxylase (TH), DA transporter (DAT), Vesicular monoamine transporter 2 (VMAT2), and a significant upregulated in α-synuclein and apoptotic protein expression of Bax, Cyt-C and caspases -3, -8 and -9 as well as by decreasing Bcl2 expression. Treatment with ILF 10 mg/kg mitigated oxidative stress in rotenone-treated rats. Furthermore, ILF dramatically alleviated rotenone-induced toxicity and cell death by increasing TH, DAT and VMAT2 expression and reducing the upregulation of α-synuclein, Bax, Cyt-C, caspases -3, -8 and -9. Together, our results confirm that ILF's protective effect against rotenone-induced PD is mediated through anti-oxidant and anti-apoptotic properties. However, further in-depth investigations on ILF's anti-inflammatory and mitochondrial protective abilities are needed to establish ILF as a potential drug candidate for the treatment of Parkinson's disease.


Design, synthesis and biological evaluation of 4-aryl-5-aminoalkyl-thiazole-2-amines derivatives as ROCK II inhibitors.
A series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized, and their inhibitory activity on ROCK II was screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives had certain ROCK II inhibitory activities. Compound 10l showed ROCK II inhibitory activity with IC50 value of 20 nM.


Versatile chip-based nanoscopy becomes ready for histopathology assessment.
Nanoscopy is a mature technology used routinely in life science to obtain images well below the optical diffraction limit. But the use of nanoscopy in histopathology assessment is very limited mostly due to the low throughput of traditional nanoscopic techniques. So far, Chip-nanoscopy, nanoscopy in which sample illumination is performed by an integrated photonic chip instead of bulk optics, has been shown to provide an enhanced field of view and throughput for cell biology. Now, a new development shows that chip-nanoscopy also offers interesting progress for the study of histological samples offering a complementary technique to electron microscopy for histopathology assessment.


Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia.
A Native American-Indian female presenting with anemia and thrombocytosis was diagnosed with myelodysplastic syndrome (MDS, refractory anemia). Over the course of 5 years she developed cytopenias and periods of leukocytosis with normal bone marrow (BM) blast counts, features of an unclassifiable MDS/MPS syndrome. The patient ultimately progressed to acute myelogenous leukemia (AML, FAB M2) and had a normal karyotype throughout her course. The episodes of leukocytosis were associated with infectious complications. Transformation to AML was characterized by a BM blast percentage of 49%. Peripheral blood and BM samples were obtained for serum protein analysis and gene expression profiling (GEP) to elucidate her disease process. An ELISA assay of the serum analyzed approximately 80 cytokines, which demonstrated that hepatocyte growth factor/scatter factor and insulin-like growth factor binding protein 1 were markedly elevated compared to normal. GEP demonstrated a unique "tumor molecular profile," which included overexpression of oncogenes (HOXA9, N-MYC, KOC1), proliferative genes (PAWR, DLG5, AKR1C3), invasion/metastatic genes (FN1, N-CAM-1, ITGB5), pro-angiogenesis genes (c-Kit), and down regulation of tumor suppressor genes (SUI1, BARD1) and anti-apoptotic genes (PGLYRP, SERPINB2, MPO). Hence, a biomics approach has provided insight into elucidating disease mechanisms, molecular prognostic factors, and discovery of novel targets for therapeutic intervention.


Synthesis of docosahexaenoyl-, arachidonoyl- and palmitoyl-coenzyme A in ocular tissues.
The synthesis of long-chain acyl coenzyme A (CoA) was studied in the cornea, lens, vitreous, retina and pigment epithelium (PE) in the rat using [14C]-labeled palmitic, arachidonic and docosahexaenoic acids as substrates. Except for retina and PE, the ocular tissues studied showed relatively little enzyme activity with the fatty acid substrates. In addition, the enzyme activities were studied in homogenates and microsomal fractions from retina, pigment epithelial cells and choroid of frog, bovine and human eyes. Long-chain acyl CoA synthetase from the microsomal fraction exhibited three- to fivefold greater activity than homogenates in retina and PE. The enzyme activity was highest with palmitic acid, followed by arachidonic acid and docosahexaenoic acid. There were significant differences in enzyme activity between the species. The apparent Km (microM) and Vmax [nmol min-1 (mg protein)-1] values for the enzyme in bovine retinal microsomes were 7.91 +/- 0.39 (S.E.) and 21.6 +/- 1.04, respectively, for palmitic acid substrate and 5.88 +/- 0.25 and 4.58 +/- 0.21, respectively, for docosahexaenoic acid substrate. These values for bovine pigment epithelial microsomes were 13.0 +/- 0.27 and 36.9 +/- 1.18, respectively, for palmitic acid and 15.8 +/- 0.40 and 13.2 +/- 0.56, respectively, for docosahexaenoic acid. The synthesis of acyl CoA may play a central role in controlling the availability of free arachidonic acid for eicosanoid formation and in the retention of polyunsaturated fatty acid families (18:2, n-6 and 18:3, n-3) within cells of ocular tissues, particularly retina and retinal PE.


Chronic desipramine treatment influences D1 stimulation and D2 inhibition (dual control) of adenylate cyclase by dopamine in rat striatum.
The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)- or saline-treated rats. DMI (15 mg/kg) or saline was injected i.p. once a day for 3 weeks. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity; peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. On the other hand, peak levels moved to the right in the GTP dose response curve in DMI-treated membranes. Therefore, D2 inhibition might be attenuated, while the D2 specific agonist, PPHT, was not observed to cause inhibition of adenylate cyclase. Furthermore, D1 stimulation of adenylate cyclase via D1 specific agonist SKF was attenuated in DMI-treated membranes. It seems, therefore, that chronic treatment of rat striatum with DMI exerts a dual influence, that is, a lessening of both D1 stimulation and D2 inhibition of adenylate cyclase, and alters specifically the overall process of the adenylate cyclase system.


Endophytic Fusarium species, a unique bioresource for disaggregator of misfolded alpha-synuclein.
Aggregation of α-synuclein into toxic oligomeric structures has been implicated in the pathogenesis of Parkinson's disease via several key stages of fibrillation, oligomerization, and aggregation. Disaggregation or prevention of aggregation has garnered a lot of attention as a therapeutic strategy to prevent or delay the progression of Parkinson's disease. It has been recently established that certain polyphenolic compounds and catechins present in plants and tea extracts exhibit the potential to inhibit the α-synuclein aggregation. However, their copious supply for therapeutic development is still unsolved. Herein, we report for the first time the disaggregation potential of α-synuclein by an endophytic fungus residing in tea leaves (Camellia sinensis). Briefly, a recombinant yeast expressing α-synuclein was used for pre-screening of 53 endophytic fungi isolated from tea using anti-oxidant activity as a marker for the disaggregation of the protein. One isolate #59CSLEAS exhibited 92.4% reduction in production of the superoxide ions, which were similar to the already established α-synuclein disaggregator, Piceatannol exhibiting 92.8% reduction. Thioflavin T assay further established that #59CSLEAS decreased the oligomerization of α-synuclein by 1.63-fold. Subsequently Dichloro-dihydro-fluorescein diacetate-based fluorescence assay exhibited a reduction in total oxidative stress in the recombinant yeast in the presence of fungal extract, thereby indicating the prevention of oligomerization. Oligomer disaggregation potential of the selected fungal extract was found to be 56.5% as assessed by sandwich ELISA assay. Using morphological as well as molecular methods, the endophytic isolate #59CSLEAS was identified as Fusarium sp. The sequence was submitted in the Genbank with accession number ON226971.1.


Oncocytic mucoepidermoid carcinoma (OMEC) of the parotid gland in a 12-year-old patient: A diagnostic challenge on cytology.
Mucoepidermoid carcinoma is the most common malignant salivary gland neoplasm comprising approximately 10% of all tumours of the major salivary gland. Owing to a plethora of morphological variations, it poses a diagnostic challenge on fine-needle aspiration cytology. Oncocytic variant of mucoepidermoid carcinoma is a rare subtype seen in the age group of 20-80 years. It is crucial to make the correct diagnosis on cytology as it has therapeutic implications. Oncocytes can be present in a wide range of salivary gland lesions ranging from non-neoplastic conditions to benign and malignant lesions. We report a case of oncocytic mucoepidermoid carcinoma of the parotid gland in a 12-year-old boy which is the youngest age reported for the same. On cytology, this case was initially diagnosed as Warthin's tumour and was supported by radiology. However, histomorphological findings clinched the diagnosis of an oncocytic variant of mucoepidermoid carcinoma with the aid of immunohistochemistry.


Limited analgesic efficacy of nitrous oxide for painful procedures in children.
Nitrous oxide (N(2)O) is an attractive agent for procedural analgesia and sedation of children in the emergency department (ED). Despite increasing use, efficacy data for painful procedures are limited. This study aimed to determine pain scores during ED procedural sedation with N(2)O in the ED setting. Prospective observational study of N(2)O use as a sole agent for procedural analgesia at a tertiary children's hospital ED. Pain scores were obtained from patients and parents using visual analogue or faces scales, as appropriate. Parent and staff satisfaction with sedation and analgesia were assessed. 124 children aged 1-17 years (mean 8.1) underwent procedural analgesia with N(2)O for 131 procedures. Most procedures were orthopaedic (44%) or laceration repair (30%). In 51% of patients (95% CI 42% to 60 to 23%) pain scores remained unchanged and in 34% (95% CI 26% to 43%) pain scores increased. Overall, 34% (95% CI 26% to 43%) patients had intraprocedural scores of 50 mm or greater and 21% (95% CI 14% to 29%) had pain scores of 70 mm or greater. Some procedures such as fracture reduction had a larger proportion of patients with high pain scores or 50 mm or greater (45%) and 70 mm or greater (29%). Staff rated both sedation and analgesia as "adequate" in 92%. Parents contacted in follow-up were satisfied or very satisfied with procedures in 96% and sedations in 93%. Data indicate that parents and staff are generally satisfied with N(2)O for procedural use in the ED. The efficacy of N(2)O as a sole agent in very painful procedures is limited.


Predictors of Treatment Failure for Hip and Knee Prosthetic Joint Infections in the Setting of 1- and 2-Stage Exchange Arthroplasty: A Multicenter Retrospective Cohort.
Prosthetic hip and knee joint infections (PJIs) are challenging to eradicate despite prosthesis removal and antibiotic therapy. There is a need to understand risk factors for PJI treatment failure in the setting of prosthesis removal. A retrospective cohort of individuals who underwent prosthesis removal for a PJI at 5 hospitals in Toronto, Canada, from 2010 to 2014 was created. Treatment failure was defined as recurrent PJI, amputation, death, or chronic antibiotic suppression. Potential risk factors for treatment failure were abstracted by chart review and assessed using a Cox proportional hazards model. A total of 533 individuals with prosthesis removal were followed for a median (interquartile range) of 814 (235-1530) days. A 1-stage exchange was performed in 19% (103/533), whereas a 2-stage procedure was completed in 88% (377/430). Treatment failure occurred in 24.8% (132/533) at 2 years; 53% (56/105) of recurrent PJIs were caused by a different bacterial species. At 4 years, treatment failure occurred in 36% of 1-stage and 32% of 2-stage procedures (P = .06). Characteristics associated with treatment failure included liver disease (adjusted hazard ratio [aHR], 3.12; 95% confidence interval [CI], 2.09-4.66), the presence of a sinus tract (aHR, 1.53; 95% CI, 1.12-2.10), preceding debridement with prosthesis retention (aHR, 1.68; 95% CI, 1.13-2.51), a 1-stage procedure (aHR, 1.72; 95% CI, 1.28-2.32), and infection due to Gram-negative bacilli (aHR, 1.35; 95% CI, 1.04-1.76). Failure of PJI therapy is common, and risk factors are not easily modified. Improvements in treatment paradigms are needed, along with efforts to reduce orthopedic surgical site infections.


Multifaceted role of polyphenols in the treatment and management of neurodegenerative diseases.
Neurodegenerative diseases (NDDs) are conditions that cause neuron structure and/or function to deteriorate over time. Genetic alterations may be responsible for several NDDs. However, a multitude of physiological systems can trigger neurodegeneration. Several NDDs, such as Huntington's, Parkinson's, and Alzheimer's, are assigned to oxidative stress (OS). Low concentrations of reactive oxygen and nitrogen species are crucial for maintaining normal brain activities, as their increasing concentrations can promote neural apoptosis. OS-mediated neurodegeneration has been linked to several factors, including notable dysfunction of mitochondria, excitotoxicity, and Ca2+ stress. However, synthetic drugs are commonly utilized to treat most NDDs, and these treatments have been known to have side effects during treatment. According to providing empirical evidence, studies have discovered many occurring natural components in plants used to treat NDDs. Polyphenols are often safer and have lesser side effects. As, epigallocatechin-3-gallate, resveratrol, curcumin, quercetin, celastrol, berberine, genistein, and luteolin have p-values less than 0.05, so they are typically considered to be statistically significant. These polyphenols could be a choice of interest as therapeutics for NDDs. This review highlighted to discusses the putative effectiveness of polyphenols against the most prevalent NDDs.


Characterisation of a mutant from Escherichia coli lacking protein L15 and localisation of protein L15 by immuno-electron microscopy.
Two mutants lacking protein L15 from the ribosome as determined by two dimensional gels were investigated using a number of different immunological methods. One strain was found to possess several protein L15 moieties which differed in net charge and in size. The other showed no evidence of L15 cross-reacting material (CRM) on the ribosome or in the supernatant. Ribosomes of this strain were used as a control in the process of the localisation of protein L15 on the surface of the large subunit of Escherichia coli ribosomes. Antigenic determinants mapped in the angle between the central protuberance and the L1 protuberance. Protein L15 has been assigned a central role in the large subunit in vitro assembly map, in peptidyltransferase activity and in the binding of erythromycin, so the significance of a mutant lacking this protein is discussed.


Imperatorin reduces the inflammatory response of atherosclerosis by regulating MAPKs signaling pathway in vivo and in vitro.
Inflammation plays an important role in the process of atherosclerosis (AS). Inhibition of inflammation is an effective way to prevent AS. Imperatorin (IMP) is a kind of furan coumarin with various activities. In this study, the anti-inflammatory effect of IMP was explored in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs and high fat diet (HFD)-induced ApoE-/- mice. The results showed that IMP attenuated the elevation of TNF-α, IL-6, MCP-1 and NO induced by ox-LDL in supernatant of VSMCs. IMP has normalized the levels of serum lipids (TC, TG, LDL-C and HDL-C) and attenuated inflammatory cytokines in serum. IMP also improved pathological changes and lipid accumulation in aorta. Matrix metalloproteinase-2 (MMP-2) expression in aorta was down-regulated by IMP. IMP could inhibit the phosphorylation of MAPKs pathway in the aorta and VSMCs, resulting in a significant decrease in the contents of p-ERK 1/2, p-JNK and p-P38. Overall, IMP could exert anti-inflammatory effects in vivo and in vitro to interfere with AS.


Chronic stress in old age: Psychometric properties of the Trier Inventory of Chronic Stress (TICS), based on a general population sample aged 60 and over.
Chronic stress results from an imbalance of personal traits, resources and the demands placed upon an individual by social and occupational situations. This chronic stress can be measured using the Trier Inventory for Chronic Stress (TICS). The aims of the present study are to test the factorial structure of the TICS in a sample of elderly people, report its psychometric properties, and give norm values for elderly individuals. The TICS was answered by N = 790 healthy participants aged 60 to 99 years. The sample was selected by random-route sampling. Confirmatory factor analyses applying Robust Maximum Likelihood estimations (MLM) tested model fit and factorial structure. Reliability estimations and norm values are reported. Confirmatory factor analyses replicate the reported nine-factor as well as the higher-order two-factor solution. Additionally, a general one-factor model was identified. All models provide acceptable model fit, with model comparison fit statistics corroborating the superiority of the nine-factor model. Reliability coefficients were good to very good. The TICS can now also be used reliably in samples with elderly people. Its proposed nine-factor structure could be factorially validated and results in good scale reliability. Norm values for an elderly sample are now available.


Psychological distress and health-related quality of life among women with breast cancer: a descriptive cross-sectional study.
Breast cancer is the most common type of cancer found in women in Sweden and worldwide. Treatment leads to increased survival of patients, but they are at risk to experience psychological distress, including anxiety and depressive symptoms, and decreased health-related quality of life (HRQoL). This study investigated the relationship between psychological distress and HRQoL and related factors among women with breast cancer in Sweden. This descriptive cross-sectional study was conducted in Sweden. A total of 481 women with breast cancer answered voluntarily a questionnaire about sociodemographic and support factors, psychological distress, and HRQoL. Data were subjected to Pearson's correlation and linear regression analyses. Psychological distress was related to HRQoL in terms of body image, future perspective, side effects of systemic therapy, breast symptoms, arm symptoms, and hair loss. Women with lower age were associated with increased symptoms of anxiety, while those having undergone breast reconstruction were associated with increased symptoms of depression. Breast reconstruction and chemotherapy worsened body image, low support from partner decreased sexual functioning and enjoyment, and low support from physicians and nurses worsened future perspective, side effects of systemic therapy, breast symptoms, and indignation about hair loss. Psychological distress was correlated with the HRQoL. Increased support from physicians, nurses, and husband/partner may increase the HRQoL among women with breast cancer. Breast cancer treatments such as breast reconstruction and chemotherapy were factors that decreased the psychological distress and increased the HRQoL.


[Determination of the expression phase of chb(V40) gene in the cell cycle of Drosophila melanogaster].
Using autoradiography, we have determined cell cycle parameters in neuroblasts of III-rd instar larvae of D. melanogaster. The overall duration of the cell cycle is 9 h, tG1 = 4 h, tS = 3.5 h, tG2 = 1 h, and tM = = 0.5 h. Using histochemical staining for beta-galactosidase activity, we have determined the stage of expression of the reporter gene of P[1ArB] element inserted into chb gene. The chb gene, which codes for a centrosomal protein, is expressed during the last third of S phase. This result illustrates the feasibility of using the enhancer trap P[1ArB] to study differential expression of cell cycle genes.


Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.
Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge.


Copper-Catalyzed Enantioselective Reductive Aldol Reaction of α,β-Unsaturated Carboxylic Acids to Alkyl Aryl Ketones: Silanes as Activator and Transient Protecting Group.
The first enantioselective reductive aldol reaction of unprotected α,β-unsaturated carboxylic acids was developed by employing a copper/bisphosphine catalyst. The reaction features in situ protection and activation of an α,β-unsaturated carboxylic acid by a hydrosilane. The copper enolate formed in situ reacts with an alkyl aryl ketone to afford the β-hydroxy carboxylic acid with excellent enantioselectivity (up to 99 % ee). The corresponding gram-scale reaction with a low catalyst loading and the derivatization of the β-hydroxy carboxylic acids highlight the practicality of this transformation.


Halogen bonding at the active sites of human cathepsin L and MEK1 kinase: efficient interactions in different environments.
In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.


Polycyclic aromatic hydrocarbon exposure and wheeze in a cohort of children with asthma in Fresno, CA.
Polycyclic aromatic hydrocarbons (PAHs) are found widely in the ambient air and result from combustion of various fuels and industrial processes. PAHs have been associated with adverse human health effects such as cognitive development, childhood IQ, and respiratory health. The Fresno Asthmatic Children's Environment Study enrolled 315 children aged 6-11 years with asthma in Fresno, CA and followed the cohort from 2000 to 2008. Subjects were evaluated for asthma symptoms in up to three 14-day panels per year. Detailed ambient pollutant concentrations were collected from a central site and outdoor pollutants were measured at 83 homes for at least one 5-day period. Measurements of particle-bound PAHs were used with land-use regression models to estimate individual exposures to PAHs with 4-, 5-, or 6-member rings (PAH456) and phenanthrene for the cohort (approximately 22,000 individual daily estimates). We used a cross-validation-based algorithm for model fitting and a generalized estimated equation approach to account for repeated measures. Multiple lags and moving averages of PAH exposure were associated with increased wheeze for each of the three types of PAH exposure estimates. The odds ratios for asthmatics exposed to PAHs (ng/m(3)) ranged from 1.01 (95% CI, 1.00-1.02) to 1.10 (95% CI, 1.04-1.17). This trend for increased wheeze persisted among all PAHs measured. Phenanthrene was found to have a higher relative impact on wheeze. These data provide further evidence that PAHs contribute to asthma morbidity.


Osteoarthritis pain mechanisms: basic studies in animal models.
Osteoarthritis (OA) is a complex and painful disease of the whole joint. At present there are no satisfying agents for treating OA. To promote OA research and improved treatment, this review summarizes current preclinical evidence on the development of OA. Preclinical OA research was searched and key findings are summarized and commented. Mechanisms of OA-associated pain have been studied in rodent knee OA models produced by intra-knee injection of the chondrocyte glycolytic inhibitor mono-iodoacetate (MIA), surgery, or spontaneous development in some species. These models are clinically relevant in terms of histological damage and functional changes, and are used to study mechanisms underlying mechanical, thermal, ambulatory, body weight supporting-evoked, and ongoing OA pain. Recent peripheral, spinal, and supraspinal biochemical and electrophysiological studies in these models suggest that peripheral pro-inflammatory mediators and neuropeptides sensitize knee nociceptors. Spinal cytokines and neuropeptides promote OA pain, and peripheral and spinal cannabinoids inhibit OA pain respectively through cannabinoid-1 (CB1) and CB1/CB2 receptors. TRPV1 and metalloproteinases contribute and supraspinal descending facilitation of 5-hydroxytryptamine (5-HT)/5-HT 3 receptors may also contribute to OA pain. Conditioned place preference tests demonstrate that OA pain induces aversive behaviors, suggesting the involvement of brain. During OA, brain functional connectivity is enhanced, but at present it is unclear how this change is related to OA pain. Animal studies demonstrate that peripheral and central sensitization contributes to OA pain, involving inflammatory cytokines, neuropeptides, and a variety of chemical mediators. Interestingly, brainstem descending facilitation of 5-HT/5-HT3 receptors plays a role OA pain.


Cytokeratin 7-negative mammary Paget's disease: A diagnostic pitfall.
Pathologists should be aware of the existence of a rare CK7-negative variant of breast carcinoma in general, and of Paget's disease in particular. Cytokeratin 7-negative Paget's disease and CK7-negative ductal intraepithelial neoplasia (ductal carcinoma in situ) present a major diagnostic challenge for pathologists since there is limited awareness of their existence. When there is classic Paget's morphology on H&E sections, GATA3 positivity should resolve any doubts about the diagnosis in the setting of a CK7-negative neoplastic cell population.


Sexual Dysfunction in Patients with Chronic Hepatitis B: Prevalence and Risk Factors.
Sexual dysfunction (SD) is an increasingly serious global problem that has adverse effects on the physical and mental health of patients. This study aimed to investigate the prevalence of SD and its related factors in patients with chronic hepatitis B (CHB). A total of 673 outpatients with CHB from October 2019 to December 2020 were included in the analysis. Demographic and clinical information was collected at enrolment. The Arizona Sexual Experiences Scale was used to evaluate SD. The primary outcome measure was the prevalence of SD in CHB patients and its associated factors. Secondary outcomes were the corresponding scores in five domains of ASEX: drive, arousal, lubrication and/or erection, orgasm and satisfaction from orgasm. The average age of patients was 47.0 years, with 85.6% male and 88.1% with cirrhosis. The SD prevalence was 25.4% and was increased with the decrease in liver function reserve (Child-Pugh A vs Child-Pugh B: 24.6% vs 44.8%, P = .016), the progression of liver fibrosis (FIB-4 < 1.45, 1.45-3.25, and > 3.25: 21.3%, 26.5%, and 34.4%, respectively; P < .001), and the aggravation of depression (without, mild, and moderate to severe: 18.1%, 33.6%, and 34.2%, respectively; P < .001). In multivariate analysis, SD was independently correlated with female sex (OR: 5.627, 95% CI: 3.501 - 9.044, P < .001), liver fibrosis (OR: 1.730, 95% CI: 1.054 - 2.842, P = .030), depression (OR: 2.290, 95% CI: 1.564 - 3.354, P < .001), and frequent diarrhea and/or upper respiratory tract infection/urinary system infection (OR: 2.162, 95% CI: 1.313-3.560, P = .002). This study revealed the current situation of SD in CHB patients in China, and appealed to clinicians to pay attention to the physical and mental health of the CHB patients. This study has a large sample size and detailed demographic and clinical data. It evaluated the relationship between SD and liver function reserve and liver fibrosis degree, and compared gender differences of SD. However, this study is a cross-sectional study design and does not include healthy controls. The effects of conflicts between the couple, SD in a partner, antidepressants and hormone changes on SD were not analyzed. SD in CHB patients was highly prevalent, and its prevalence increased significantly with the deterioration of liver function reserve, liver fibrosis and depression. Additional longitudinal studies are needed to further explore its causality. Xingmei L, Siru Z, Junhua Y, et al. Sexual Dysfunction in Patients with Chronic Hepatitis B: Prevalence and Risk Factors. J Sex Med 2022;19:207-215.


Thrombopoietin: basic biology, clinical promise.
Cytokines which regulate thrombopoiesis have been the subject of intense study and debate over the past 35 years. Recently, based on recognition of the orphan cytokine receptor c-mpl, thrombopoietin (Tpo), the primary regulator of platelet production has been cloned. Its biological properties form the basis of this review. Tpo promotes both the proliferation of megakaryocytic progenitor cells and their maturation into platelet-producing megakaryocytes. It acts to expand megakaryocyte size and ploidy, and increases the expression of platelet-specific membrane glycoproteins. In vivo, Tpo greatly augments marrow and splenic megakaryocytic progenitor cells and large megakaryocytes, and leads to profound increases in platelet production. In addition, the hormone hastens the recovery or platelet counts following cytoreductive therapies, and has been associated with improved survival in certain murine models. Clearly, our growing understanding of the biology or Tpo will lead to important new insights into megakaryopoiesis, and to clinical improvements in the therapy of both natural and acquired states of marrow failure.


Ischaemic brain damage in fatal non-missile head injuries.
The incidence and distribution of ischaemic brain damage in a consecutive series of 151 patients who died as a result of a non-missile head injury in the Institute of Neurological Sciences was determined on the basis of a comprehensive neuropathological and neurohistological examination. Ischaemic damage was identified in 138 cases (91%) even after excluding cases who only had necrosis and infarction related to contusions or fat embolism, and infarction in the brain stem of the type conventionally associated with raised intracranial pressure. The ischaemic damage was assessed as severe in 37 (27%), moderately severe in 59 (43%) and mild in 42 (30%), and in the 138 cases with ischaemic brain damage it was found more frequently in the hippocampus (122 cases; 81%), and in the basal ganglia (119 cases; 79%) than in the cerebral cortex (70 cases; 46%) and in the cerebellum (67 cases; 44%). There were statistically significant correlations between ischaemic brain damage and either an episode of hypoxia or of raised intracranial pressure. From the nature of the brain damage it seems likely that much of it was due to a reduction in the cerebral perfusion pressure. This study has shown that ischaemic brain damage is common after head injury, that at least a proportion of it is probably avoidable, and that it is more important as a cause of mortality and morbidity after head injury than has been hitherto realised.


[Principles in stenosing surgical disease: multiple-staged surgery (author's transl)].
Colonic surgery today is usually performed in a one-stage procedure. Multiple resection is indicated only for bowel obstruction or severe inflammation. There is some discussion about the necessity of colostomy in left colon resection, mainly in cases of anterior resection. We strongly suggest a double loop transverse colostomy, since anastomotic leaks are frequent even with subtile techniques, and increasingly old high-risk patients have to be operated upon. Also, the fact that younger residents operate is no justification for forsaking this safety measure. According to the literature, most surgeons feel this way.


A complication of pacemaker lead extraction: paradoxical embolism of a lead fragment in a leg artery.
Extraction of three chronically implanted pacemaker leads was performed via the implant vein in a 71-year-old man. One of the leads broke in the subclavian scar tissue. The lead fragment migrated into the left peroneotibial trunk artery. Transesophageal echocardiography showed patent foramen ovale associated with right-to-left atrial shunt. This complication of lead extraction is discussed along with the role of echocardiography prior to lead removal.


Nitric oxide synthase and tyrosine nitration in idiopathic asthenozoospermia: an immunohistochemical study.
To characterize the expression pattern of constitutive and inducible nitric oxide synthase (NOS) in spermatozoa isolated from normospermic fertile donors and asthenozoospermic infertile patients, by means of immunohistochemistry. Also to evaluate the immunohistochemical expression of citrulline, a marker of NOS activity, and nitrotyrosine, which indicates the formation of peroxynitrite, which may affect sperm functionality through its cytotoxic action. Prospective study. Academic male infertility center. Twenty-nine infertile patients affected by idiopathic asthenozoospermia and 26 age-matched normospermic fertile donors. Sperm parameters were evaluated, and immunohistochemical analysis was performed in isolated spermatozoa. Semen analyses, to ascertain volume, sperm count, motility, and morphology. Immunohistochemical expression of NOS isoforms, citrulline, and nitrotyrosine. Constitutive NOS expression was greater in spermatozoa isolated from normospermic fertile donors. In contrast, the immunohistochemical expression of inducible NOS and nitrotyrosine was higher in asthenozoospermic samples. Our data concerning citrulline indicated enhanced NOS activity in sperm from idiopathic asthenozoospermic patients. Our results support the hypothesis that increased NOS activity and an excess of tyrosine nitration may affect the functional characteristics of spermatozoa in idiopathic asthenozoospermia.


Water and sodium retention in edematous disorders: role of vasopressin and aldosterone.
This article discusses the pathophysiology of sodium and water retention in edematous disorders with a particular focus on cardiac failure, cirrhosis, and pregnancy. The body fluid volume hypothesis, which emphasizes the dominant role of arterial baroreceptors in renal sodium and water excretion, is reviewed. With arterial underfilling, either due to a decrease in cardiac output or peripheral arterial vasodilation, the normal central inhibition of the sympathetic nervous system activity and baroreceptor-mediated, nonosmotic arginine vasopressin (AVP) release is attenuated. The resultant increase in renal adrenergic activity stimulates the renin-angiotensin-aldosterone system. Although the resultant increase in systemic vascular resistance compensates for the primary arterial underfilling, this activation of the neurohumoral axis results in diminished sodium and water delivery to the renal collecting duct sites of aldosterone, AVP, and natriuretic peptide action. This diminished distal sodium and water delivery will be discussed as an important factor in the failure to escape from the sodium-retaining effects of aldosterone, the resistance to the natriuretic and diuretic effects of natriuretic peptides, and the diminished maximal solute-free water excretion in patients with edema. The role of the nonosmotic AVP release in water retention and hypo-osmolality/hyponatremia has been demonstrated in patients and experimental animals by administering nonpeptide, orally active vasopressin V2 receptor antagonists. These agents have been found to increase solute-free water excretion in patients with water-retaining, hyponatremic edema as well as in experimental animals.


The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women.
The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.


[Effect of vitamin K on lipid peroxidation in E-avitaminosis].
Content of malonic dialdehyde was increased 2-fold in liver homogenates of E-avitaminous animals and 5-fold in muscle homogenates. In animals, maintained at E-avitaminous diet but treated with vitamin K, content of malonic dialdehyde in liver homogenates was similar to its content in controls; it increased only 2-fold in muscle homogenates.


A retrospective quality improvement study of ketorolac use following spinal fusion in pediatric patients.
There are studies and literature that support the claim that ketorolac use after spinal fusion in the adult population can increase the risk of pseudarthrosis, instrumentation failure, and/or nonunion. There is limited research when using ketorolac in the pediatric population, especially short-term use. Chart review of 46 pediatric patients who had prior spinal fusions for scoliosis between July 2003 and August 2005. Twenty-five of the patients received ketorolac and 21 did not. The lengths of stay, incidence of curve progression, and/or incidence of nonunion or instrumentation failure were compared in the 2 groups. At the 1-year follow-up, 95% of the patients returned and at the 3-year follow-up, 52% of the patients returned and there was no clinical or radiographic evidence of curve progression, nonunion, or instrumentation failure. This is a retrospective study looking at results of 2 patient groups. This is a level III study.


Effects of the Nature of the Metal Ion, Protein and Substrate on the Catalytic Center in Matrix Metalloproteinase-1: Insights from Multilevel MD, QM/MM and QM Studies.
Matrix metalloproteinase-1 (MMP-1) is a Zn(II) dependent endopeptidase involved in the degradation of collagen, the most abundant structural protein in the extracellular matrix of connective tissues and the human body. Herein we performed a multilevel computational analysis including molecular dynamics (MD), combined quantum mechanics/molecular mechanics (QM/MM), and quantum mechanics (QM) calculations to characterize the structure and geometry of the catalytic Zn(II) within the MMP-1 protein environment in comparison to crystallographic and spectroscopic data. The substrate's removal fine-tuned impact on the conformational dynamics and geometry of the catalytic Zn(II) center was also explored. Finally, the study examined the effect of substituting catalytic Zn(II) by Co(II) on the overall structure and dynamics of the MMP-1 THP complex and specifically on the geometry of the catalytic metal center. Overall our QM/MM and QM studies were in good agreement with the MM description of the Zn(II) centers in the MD simulations.


Docosahexaenoic acid attenuates breast cancer cell metabolism and the Warburg phenotype by targeting bioenergetic function.
Docosahexaenoic acid (DHA; C22:6n-3) depresses mammary carcinoma proliferation and growth in cell culture and in animal models. The current study explored the role of interrupting bioenergetic pathways in BT-474 and MDA-MB-231 breast cancer cell lines representing respiratory and glycolytic phenotypes, respectively and comparing the impacts of DHA with a non-transformed cell line, MCF-10A. Metabolic investigation revealed that DHA supplementation significantly diminished the bioenergetic profile of the malignant cell lines in a dose-dependent manner. DHA enrichment also resulted in decreases in hypoxia-inducible factor (HIF-1α) total protein level and transcriptional activity in the malignant cell lines but not in the non-transformed cell line. Downstream targets of HIF-1α, including glucose transporter 1 (GLUT 1) and lactate dehydrogenase (LDH), were decreased by DHA treatment in the BT-474 cell line, as well as decreases in LDH protein level in the MDA-MB-231 cell line. Glucose uptake, total glucose oxidation, glycolytic metabolism, and lactate production were significantly decreased in response to DHA supplementation; thereby enhancing metabolic injury and decreasing oxidative metabolism. The DHA-induced metabolic changes led to a marked decrease of intracellular ATP levels by 50% in both cancer cell lines, which mediated phosphorylation of metabolic stress marker, AMPK, at Thr172. These findings show that DHA contributes to impaired cancer cell growth and survival by altering cancer cell metabolism, increasing metabolic stress and altering HIF-1α-associated metabolism, while not affecting non-transformed MCF-10A cells. This study provides rationale for enhancement of current cancer prevention models and current therapies by combining them with dietary sources, like DHA.


Does a pay-for-performance program for primary care physicians alleviate health inequity in childhood vaccination rates?
Childhood vaccination rates in Manitoba populations with low socioeconomic status (SES) fall significantly below the provincial average. This study examined the impact of a pay-for-performance (P4P) program called the Physician Integrated Network (PIN) on health inequity in childhood vaccination rates. The study used administrative data housed at the Manitoba Centre for Health Policy. We included all children born in Manitoba between 2003 and 2010 who were patients at PIN clinics receiving P4P funding matched with controls at non-participating clinics. We examined the rate of completion of the childhood primary vaccination series by age 2 across income quintiles (Q1-Q5). We estimated the distribution of income using the Gini coefficient, and calculated concentration indices for vaccination to determine whether the P4P program altered SES-related differences in vaccination completion. We compared these measures between study cohorts before and after implementation of the P4P program, and over the course of the P4P program in each cohort. The PIN cohort included 6,185 children. Rates of vaccination completion at baseline were between 0.53 (Q1) and 0.69 (Q5). Inequality in income distribution was present at baseline and at study end in PIN and control cohorts. SES-related inequity in vaccination completion worsened in non-PIN clinics (difference in concentration index 0.037; 95 % CI 0.013, 0.060), but remained constant in P4P-funded clinics (difference in concentration index 0.006; 95 % CI 0.008, 0.021). The P4P program had a limited impact on vaccination rates and did not address health inequity.


Air Breathing in an Exceptionally Preserved 340-Million-Year-Old Sea Scorpion.
Arachnids are the second most successful terrestrial animal group after insects [1] and were one of the first arthropod clades to successfully invade land [2]. Fossil evidence for this transition is limited, with the majority of arachnid clades first appearing in the terrestrial fossil record. Furthermore, molecular clock dating has suggested a Cambrian-Ordovician terrestrialization event for arachnids [3], some 60 Ma before their first fossils in the Silurian, although these estimates assume that arachnids evolved from a fully aquatic ancestor. Eurypterids, the sister clade to terrestrial arachnids [4-6], are known to have undergone major macroecological shifts in transitioning from marine to freshwater environments during the Devonian [7, 8]. Discoveries of apparently subaerial eurypterid trackways [9, 10] have led to the suggestion that eurypterids were even able to venture on land and possibly breathe air [11]. However, modern horseshoe crabs undertake amphibious excursions onto land to reproduce [12], rendering trace fossil evidence alone inconclusive. Here, we present details of the respiratory organs of Adelophthalmus pyrrhae sp. nov. from the Carboniferous of Montagne Noire, France [13], revealed through micro computed tomography (μ-CT) imaging. Pillar-like trabeculae on the dorsal surface of each gill lamella indicate eurypterids were capable of subaerial breathing, suggesting that book gills are the direct precursors to book lungs while vascular ancillary respiratory structures known as Kiemenplatten represent novel air-breathing structures. The discovery of air-breathing structures in eurypterids indicates that characters permitting terrestrialization accrued in the arachnid stem lineage and suggests the Cambrian-Ordovician ancestor of arachnids would also have been semi-terrestrial.


Nontraumatic tibial polyethylene insert cone fracture in mobile-bearing posterior-stabilized total knee arthroplasty.
A 72-year-old male patient underwent mobile-bearing posterior-stabilized total knee arthroplasty for osteoarthritis. He experienced a nontraumatic polyethylene tibial insert cone fracture 27 months after surgery. Scanning electron microscopy of the fracture surface of the tibial insert cone suggested progress of ductile breaking from the posterior toward the anterior of the cone due to repeated longitudinal bending stress, leading to fatigue breaking at the anterior side of the cone, followed by the tibial insert cone fracture at the anterior side of the cone, resulting in fracture at the base of the cone. This analysis shows the risk of tibial insert cone fracture due to longitudinal stress in mobile-bearing posterior-stabilized total knee arthroplasty in which an insert is designed to highly conform to the femoral component.


Is there a final common path in malignancies?
We found that malignant cells and tumors contain very little low molecular weight (MW) peptides and amino acids compared to normal cells and tissues. However, the low molecular weight (MW) peptides that inhibit mitosis, cell growth and cause differentiation were recovered from cell growth medium or ascites. We therefore hypothesize that out transport and, or diffusion of the low MW compounds is possibly central to carcinogenesis, since the controlling low MW signals are lost from the cell. Without inhibitors mitosis should not or would not stop. Loss of low MW peptides and amino acids may be a common trait in carcinogenesis. It would entail that normal cell regulation such as growth, mitosis inhibition and differentiation would probably be lost, especially as we recover the missing compounds (chalones) from the incubation fluid or ascites. The chalones and deprimerones seem to induce differentiation of cells when inhibiting mitosis, and when lost from the cells may explain the de-differentiation typical of malignant cells. Such a mechanism would make room for membrane damaging mechanical, inflammatory and chemical as well as viral aetiologies in carcinogenesis. Faster than normal growth also increases the probability of geneic malfunction.


Possible role of Akt to improve vascular endothelial dysfunction in diabetic and hyperhomocysteinemic rats.
The study has been designed to investigate the effect of demethylasterroquinone B1 (DAQ B1), an activator of Akt, in diabetes mellitus (DM) and hyperhomocysteinemia (HHcy)-induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of messenger RNA for p22phox and eNOS was assessed by reverse transcription-polymerase chain reaction. Serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion were estimated to assess oxidative stress. DAQ B1 (5 mg kg(-1), p.o.) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. DAQ B1 or atorvastatin markedly improved acetylcholine-induced endothelium-dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of DAQ B1 has been prevented by L-NAME (25 mg kg(-1), i.p.), an inhibitor of eNOS. Therefore, it may be concluded that DAQ B1-induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction.


The novel left atrial appendage strain parameters are associated with thrombosis risk in patients with non-valvular atrial fibrillation.
We sought to explore a novel left atrial appendage (LAA) strain parameter which could represent the cumulative adverse impact of chronic Atrial fibrillation (AF) on the LAA function, and the relationship between the LAA strain parameter and thrombosis risk in patients with non-valvular AF. We enrolled 268 patients with non-valvular AF and 58 sinus rhythm subjects who underwent transesophageal echocardiography in the study. LAA longitudinal strain amplitude (LAA LSA) was defined as the sum of the value of the maximum positive peak strain (LAA PLS) and the absolute value of the minimum negative peak strain (LAA NLS). Dense spontaneous echo contrast (SEC) was defined as grade 3 or 4 SEC. Compared to sinus rhythm group, the global LAA strain parameters were significantly lower in paroxysmal AF (n = 148), and the lowest of them were found in persistent AF (n = 120), which suggested that the global LAA strain parameters could evaluate LAA function in sinus rhythm, paroxysmal AF and persistent AF. Compared with patients in AF without SEC/thrombus (n = 113), the regional and global LAA strain parameters were significantly depressed in AF with SEC/thrombus (n = 155). Multivariate logistic regression analyses showed that LAA global LSA (OR 0.768; 95% CI:0.569, 0.970; p = 0.027) was an independent predicter of the SEC/thrombus. Compared with patients in AF without dense SEC or thrombus (n = 210), the regional and global LAA strain parameters were significantly impaired in the patients with dense SEC/thrombus(n = 58). LAA global LSA (AUC 0.884) had the best predictable accuracy for dense SEC or thrombus, and outperformed LAA PLS, LAA NLS, CHA2DS2-VASc score and conventional LAA functional parameters that have been used in the evaluation blood flow stasis in LAA. LAA LSA showed excellent interobserver and intra-observer agreement beyond LAA PLS and LAA NLS. The novel LAA strain parameters, which were feasible and reproducible parameters for evaluation LAA mechanic function, had good predictive accuracy for blood flow stasis in LAA beyond conventional LAA functional parameters.


Foraging by Passerine birds and Anolis lizards on St. Eustatius (Neth. Antilles): implications for interclass competition, and predation.
Observations of foraging and diet for eight Passerine bird, two Anolis lizard, and one Ameiva lizard species in dry sclerophyll scrub on St. Eustatius (Neth. Antilles) show that none of the bird species competes as much with either anole as does the other anole, or the Ameiva. Anoles feed on insects, primarily on the ground and in low vegetation; on St. Eustatius no mainly insectivorous bird species feeds primarily in these places. Instead, the main presentday interaction between birds and anoles is predation. The abundant pearly-eyed thrasher (Margarops fuscatus) and the sparrow hawk (Falco sparverius) are the major predators on anoles. This predation has little effect on the niche relations of the anoles, according to a model for the coevolution of competing species.


BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes.
Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.


Lack of a hypotensive effect with rapid administration of a new aqueous formulation of intravenous amiodarone.
Hypotension is the most frequent adverse event reported with intravenous amiodarone. Hypotension has been attributed to the vasoactive solvents of the standard formulation (Cordarone IV) and is not dose related, but related to the rate of infusion. Drug labeling calls for intravenous amiodarone to be administered over 10 minutes. A new aqueous formulation of amiodarone (Amio-Aqueous) does not contain vasoactive excipients and may be administered safely by rapid administration without hypotension. This hypothesis was tested using combined data of 4 clinical trials; each assessed the development of hypotension prospectively. Hypotension was defined as a 25% decrease in systolic blood pressure (BP), with the development of a systolic BP of <90 mm Hg or a systolic BP that decreased to <80 mm Hg. In all, 358 Amio-Aqueous and 225 lidocaine boluses were administered to 278 patients; 246 had ventricular tachycardia (VT) during drug administration. Hypotension developed in 11% of patients on Amio-Aqueous versus 19% on lidocaine (p = NS), all during VT; most resolved spontaneously with VT termination. With both drugs, hypotension persisted after VT termination in 1% of patients; the incidence of drug-related hypotension occurred in 2% of patients (1% had hypotension requiring treatment). The Amio-Aqueous was discontinued in 1% of patients, and lidocaine was discontinued in 2% of patients because of hypotension. We conclude that Amio-Aqueous is at least as safe as lidocaine in terms of causing hypotension when administered rapidly. This is a significant advantage over the standard amiodarone formulation, because Cordarone cannot be administered by rapid bolus owing to excipient-related hypotension.


Diaphragm and intercostal surface EMG and muscle performance after acute inspiratory muscle loading.
We examined the effect of an acute bout of submaximal non-fatiguing inspiratory loading (IL) on maximal inspiratory pressure (MIP), and on the activation of the diaphragm (DI) and intercostals (IC) using surface electromyography (sEMG). After baseline measurements, 12 healthy subjects performed two sets of 30 inspiratory efforts at a load equivalent to 40% of their initial MIP. MIP and maximal DI and IC sEMG activity were recorded after the first and second set of IL, and 15 min after task cessation. After IL, MIP reached (+/-S.E.M.) 111+/-4% (P=0.032) of baseline values, and during MIP, DI and IC root mean square (RMS) sEMG amplitude increased significantly above baseline (143+/-21%, P=0.039 and 137+/-33%, P=0.016, respectively). The significant increase in MIP and RMS amplitude after IL suggests that MIP efforts were initially submaximal, and that prior loading enabled full activation. The changes in DI and IC RMS amplitude may also reflect an improvement in the synergy between them during these maximal efforts.


Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor.
In rheumatoid and osteoarthritis, degradation of articular cartilage is mediated by the matrix metalloproteinases collagenase, stromelysin and gelatinase. The key event in this process is the cleavage of triple helical collagen by collagenase. We have determined the crystal structure of the catalytic domain of human recombinant fibroblast collagenase complexed with a synthetic inhibitor at 2.2 A resolution. The protein fold is similar to the amino termini of the zinc endopeptidases astacin thermolysin and elastase despite a lack of primary sequence homology. The conformation of the bound inhibitor provides a molecular basis for the design of inhibitors of collagenase and other matrix metalloproteinases. Such inhibitors should be useful in the treatment of a variety of diseases including arthritis and cancer.


Octreotide for resuscitation of cardiac arrest due to carcinoid crisis precipitated by novel peptide receptor radionuclide therapy (PRRT): A case report.
Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic carcinoid tumours but can precipitate a carcinoid crisis through release of stored bioamines. Cardiac arrest is an uncommon manifestation of carcinoid crisis and has never been reported as a complication of PRRT. We report a case of a 58-year old female who suffered from cardiac arrest following PRRT for metastatic carcinoid tumour. She was successfully resuscitated using intravenous octreotide following 22 min of failure to resuscitate with a standard advanced cardiac life support protocol. Following resuscitation, severe carcinoid heart disease was diagnosed, and the patient subsequently underwent successful surgical valve replacement. Although there is no trial evidence, considering pharmacological rationale and successful outcome in this case, we suggest early administration of intravenous octreotide during resuscitation of patients suffering cardiac arrest post PRRT for carcinoid disease and recommend preventive strategies.


The relationship between negative workplace gossip and thriving at work among Chinese kindergarten teachers: the roles of psychological contract breach and bianzhi.
Exploring the influencing factors and functioning mechanisms of thriving at work is of practical significance both for teachers and kindergartens. Based on the socially embedded model of thriving at work, this study aimed to examine the association between negative workplace gossip and thriving at work. The mediating role of psychological contract breach and the moderating role of bianzhi were also examined. A total of 1105 Chinese kindergarten teachers were chosen to complete a questionnaire on negative workplace gossip, psychological contract breach, and thriving at work. The results demonstrated that negative workplace gossip was positively associated with psychological contract breach and negatively associated with thriving at work. In addition, psychological contract breach was negatively associated with thriving at work. According to the mediation model test, psychological contract breach was a mediating factor between negative workplace gossip and thriving at work. The impact of psychological contract breach on thriving at work could be further moderated by bianzhi. This study complements knowledge systems about the influential factors and functional mechanisms of thriving at work. In practical terms, this study offers a fresh and innovative perspective for kindergartens seeking to enhance teachers' thriving at work.


Transglutaminase 2 on the surface of dendritic cells is proposed to be involved in dendritic cell-T cell interaction.
Transglutaminase 2 (TG2) is a ubiquitous enzyme involved in diverse biological processes. Recently, its function in adaptive immune responses has begun to emerge. Its presence and functions in B cells and T cells, for example, have been reported. However, those in dendritic cells (DCs), the principal antigen-presenting cells, are as yet unexplored in murine system. In this study, we first investigated the expression of TG2 in murine bone marrow-derived DCs, and then compared the functioning of these cells in the presence or absence of this enzyme using wild-type (WT) and TG2(-/-) mice. We found that the WT DCs expressed TG2 both in the cytoplasm and on the cell surface, both of which were elevated after LPS stimulation. Unexpectedly, between WT and TG2(-/-) DCs, there were no remarkable differences in cytokine secretion, IL-10 and IL-12, and neither in the expression of surface molecules CD80, CD86, and MHC II, excepting a moderate decrease of CD40 expression on the TG2(-/-) DCs. However, when T cells were stimulated with TG2(-/-) DCs, they showed decreased levels of proliferation, CD69 and CD25 expression, and IFN-γ secretion. The addition of anti-TG2 antibody to the WT DC-T cell co-culture resulted in decreased T cell activation. By immunofluorescence staining, TG2 was observed at DC-T cell interface (contact point). Taken together, we propose that TG2 on the surface of DCs modulates the DC-T cell interaction.


Optimization of a two-step desolvation method for preparing gelatin nanoparticles and cell uptake studies in 143B osteosarcoma cancer cells.
To establish a matrix of parameters to synthesize nanoparticles of different sizes and to investigate the cellular uptake of these nanoparticles by osteosarcoma cancer cells in order to investigate their potential as therapeutic drugdelivery carriers. Gelatin A and B were used to synthesize nanoparticles by a two-step desolvation process. Different parameters were investigated, including temperature, pH, concentration of glutaraldehyde, type of desolvating agent and nature of gelatin. For cell uptake studies, Texas Red labeled nanoparticles were incubated with 143B osteosarcoma cells and then evaluated using confocal laser scanning microscopy (CLSM). The systematic investigation of the synthesis parameters showed that it is possible to prepare gelatin-based nanoparticles with different particle sizes and a narrow size distribution. Temperature and nature of the gelatin were the most important synthesis factors. Bioimaging using CLSM showed uptake of the nanoparticles by 143B osteosarcoma cancer cells. Osteosarcoma cancer cells take up gelatin nanoparticles. This might improve the clinical effectiveness of anti-cancer treatments if nanoparticles are used as a drug delivery system and has important implications for future cancer treatment strategies.


Fluoxetine in the treatment of obsessive compulsive disorder.
In a 9-week open-label study, 7 outpatients with obsessive compulsive disorder were treated with fluoxetine, a selective inhibitor of neuronal reuptake of serotonin. A significant improvement was found in the symptomatology of patients as measured on the obsessive compulsive subscale of the Comprehensive Psychopathological Rating Scale (p less than 0.001) and the Clinical Global Impression of severity of illness (p less than 0.01). These findings support the hypothesis that serotoninergic antidepressants may be useful in the treatment of obsessive compulsive disorder.


Use of immuno-dominant epitope derived from genotype 4 as a diagnostic reagent for detecting the antibodies against Hepatitis E Virus.
Despite the genotype 4 has become the dominant cause of hepatitis E disease in China, none antigen derived from genotype 4 of hepatitis E virus (HEV) was used in current commercial anti-HEV immunoassay, and the serological reactivity of antigen derive from genotype 4 is not well-charactered. We expressed and purified the 4 main immuno-dominant epitopes derived from genotype 1 and 4 including ORF2 (410-621aa) of genotype 4, ORF3 (47-114aa) of genotype 4, ORF2 (396-606aa) of genotype 1 and ORF3 (56-123aa) of genotype 4. The ORF2 of genotype 4 displayed good diagnostics performance according to ROC analysis using in-house panel, and the immunoassays based the ORF2 of genotype 4 was then developed to detect the anti-HEV IgG antibodies and evaluated further in 530 anti-HEV IgG positive specimens and 380 negative specimens. The sensitivity and the specificity is 98.1% (520/530) and 94.7% (360/380) for immunoassay based on ORF2 of genotype 4, 96.6% (512/530) and 92.6% (352/380) for commercial immunoassay based on genotype 1. It is noted that all of the positive samples will be detected by combing two assays together. The anti-HEV immunoassays based on genotype 4 are in accordance with Chinese anti-HEV national standard,and show an good agreement of 95.8% with commercial assay (kappa=0.913, P=0.014). The immunoassay based on ORF2G4 displays good performance, and combining assay based on genotype 1 together with genotype 4 will benefit the HEV diagnosis in large scale samples.


Detection and Quantification of Botanical Impurities in Commercial Oregano (Origanum vulgare) Using Metabarcoding and Digital PCR.
DNA technology for food authentication is already well established, and with the advent of Next Generation Sequencing (NGS) and, more specifically, metabarcoding, compositional analysis of food at the molecular level has rapidly gained popularity. This has led to several reports in the media about the presence of foreign, non-declared species in several food commodities. As herbs and spices are attractive targets for fraudulent manipulation, a combination of digital PCR and metabarcoding by NGS was employed to check the purity of 285 oregano samples taken from the European market. By using novel primers and analytical approaches, it was possible to detect and quantify both adulterants and contaminants in these samples. The results highlight the high potential of NGS for compositional analysis, although its quantitative information (read count percentages) is unreliable, and other techniques are therefore needed to complement the sequencing information for assessing authenticity ('true to the name') of food ingredients.


Palliative Care for Idiopathic Pulmonary Fibrosis Patients: Pulmonary Physicians' View.
Although idiopathic pulmonary fibrosis (IPF) has worse outcomes compared with most malignancies, patients with IPF receive poor access to optimal palliative care. This study aimed to characterize the practice of pulmonologists regarding palliative care and end-of-life communication for patients with IPF and identify perceived difficulties and barriers thereto. Self-administered questionnaires were sent by mail to representative pulmonologists from Shizuoka prefecture, Japan. Physician-reported practice, difficulties, timing of end-of-life communication, and barriers related to palliative care were investigated. Among the 135 participants, 130 (96%) completed the questionnaire. Most of the participants reported that patients with IPF complained of dyspnea and cough. However, less morphine was prescribed for IPF than for lung cancer. The participants experienced greater difficulty in providing palliative care for IPF than for lung cancer. Moreover, actual end-of-life discussions in patients with IPF were conducted later than the physician-perceived ideal timing. Among the barriers identified, few established treatment and difficulty in predicting prognosis (odds ratio [OR] 2.0; P = 0.04), discrepancies in understanding and care goals among patients, family, and medical staff (OR 2.2; P = 0.03), and inadequate communication about goal of care (OR 2.3; P = 0.003) were significantly associated with the physician-perceived difficulties in providing palliative care for patients with IPF. Pulmonologists experienced greater difficulty in providing palliative care to patients with IPF than to those with lung cancer. Clinical studies on the optimal palliative care for patients with IPF are urgently required.


Recovery of agricultural nutrients from biorefineries.
This review lays the foundation for why nutrient recovery must be a key consideration in design and operation of biorefineries and comprehensively reviews technologies that can be used to recover an array of nitrogen, phosphorus, and/or potassium-rich products of relevance to agricultural applications. Recovery of these products using combinations of physical, chemical, and biological operations will promote sustainability at biorefineries by converting low-value biomass (particularly waste material) into a portfolio of higher-value products. These products can include a natural partnering of traditional biorefinery outputs such as biofuels and chemicals together with nutrient-rich fertilizers. Nutrient recovery not only adds an additional marketable biorefinery product, but also avoids the negative consequences of eutrophication, and helps to close anthropogenic nutrient cycles, thereby providing an alternative to current unsustainable approaches to fertilizer production, which are energy-intensive and reliant on nonrenewable natural resource extraction.


Oxidized low-density lipoprotein acts synergistically with beta-glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells.
Previous studies have localized osteoblast specific markers to sites of calcified atherosclerotic lesions. We therefore decided to use an established in vitro model of vascular calcification in order to confirm earlier reports of oxidized low-density lipoprotein (oxLDL) promoting the osteogenic differentiation of vascular smooth muscle cells. Treatment of primary bovine aortic smooth muscle cells (BASMCs) with beta-glycerophosphate was found to induce a time-dependent increase in osteoblast differentiation. In contrast, no effect was seen when BASMCs were cultured in the presence of oxLDL alone. However, when the BASMCs were cultured in the presence of both beta-glycerophosphate and oxLDL, beta-glycerophosphate's ability to induce osteoblast differentiation was significantly enhanced. In an attempt to resolve the mechanism by which this effect was occurring, we examined the effect of beta-glycerophosphate and oxLDL on several pathways known to be critical to the differentiation of osteoblasts. Surprisingly, beta-glycerophosphate alone was found to enhance Osterix (Osx) expression by inducing both Smad 1/5/8 activation and Runx2 expression. In contrast, oxLDL did not affect either Smad 1/5/8 activation or Runx2 activation but rather, it enhanced both beta-glycerophosphate-induced Osx expression and osteoblast differentiation in an extracellular signal-regulated kinase 1 and 2 (Erk 1 and 2) -dependent manner. When taken together, these findings suggest a plausible mechanism by which oxLDL may promote osteogenic differentiation and vascular calcification in vivo. J. Cell. Biochem. 105: 185-193, 2008. (c) 2008 Wiley-Liss, Inc.


Effectiveness of anger treatments for specific anger problems: a meta-analytic review.
This meta-analytic review analyzed the effects of anger treatment on various aspects of anger with 65% of studies not previously reviewed. To improve on past reviews, this review included only noninstitutionalized adults with demonstrable anger as determined by standardized measures. The studies were compiled from a computer search of published and unpublished anger treatment studies conducted between January 1980 and August 2002. The search resulted in 23 studies containing one or more treatment groups and a control group, with effect sizes derived for each anger problem within each treatment category. The meta-analysis resulted in medium to large effect sizes across therapies. Further analyses of effect sizes within treatment groups by the kind of anger reported support the implementation of cognitive therapies for driving anger, anger suppression, and trait anger. In contrast, relaxation is recommended in cases of state anger. Other implications for treatment and future research directions are discussed, including a special need for research with treatment-seeking individuals and clinical populations.


Musculoskeletal disorders of the upper extremities: the use of epidemiologic approaches in industrial settings.
This article illustrates the use of a simple questionnaire in identifying those sections of a work force at risk for musculoskeletal disorders and chronic discomfort of the upper extremities. Two research studies are described. The first, conducted in a chicken-processing factory, illustrates the use of self-administered questionnaires in the assessment of the musculoskeletal health of the work force and in the identification of groups of workers who may be at increased risk and for whom ergonomic reappraisal of the tasks performed may be beneficial. A second study of retail trade staff suggests that chronic musculoskeletal discomfort is widespread. The article further considers the importance of such data for those persons concerned with the allocation of health care. The need to consider the broader spectrum of musculoskeletal health from discomfort to clinical disorder is stressed.


Building a community-based maternity program.
The MotherCare Project has as its goal the reduction of maternal and neonatal mortality and related morbidities, and the promotion of the health of women and newborns. To achieve these goals, maternal and family planning programs were strengthened in both rural and urban settings through three intervention strategies--policy reform, affecting behaviors and improving services. The fundamental premise in each project was to strengthen the weakest part of the maternity care pyramid, ensuring linkages among all levels of service--from community through to the referral hospital level. In rural Andean populations of Bolivia, knowledge of danger signs and women's response to them improved, increasing in use of prenatal and family planning services through a participatory problem-solving and community-based strategy. In West Java, Indonesia, bringing professional midwifery services and facilities closer to women together has resulted in a positive response to their use. Augmenting this intervention with a transport and intercommunication system together with improved hospital practice through perinatal mortality meetings and in-service training for doctors and midwives has reduced the maternal and perinatal mortality over a four year period. Hospital practice has improved in Uganda and in two states of Nigeria, maternal mortality and morbidity have been reduced in the training facility where seminars for physicians, training of midwives in life saving midwifery and interpersonal communication skills have taken place, and equipment and supplies have been improved. Furthermore, in rural Guatemala, implementation of norms and protocols, expert supervision and sensitization of hospital staff to the needs of the community has increased referral by traditional birth attendants (TBAs) to the hospital and reduced perinatal mortality.