Growth hormone receptor antagonist transgenic mice are protected from hyperinsulinemia and glucose intolerance despite obesity when placed on a HF diet.
Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.


Drotrecogin alfa (activated) for nonmenstrual toxic shock syndrome associated with methicillin resistant Staphylococcus aureus infection.
Nonmenstrual toxic shock syndrome (TSS) due to Staphylococcus aureus can lead to significant morbidity and mortality. While drotrecogin alfa (DA) has been employed in patients with Methicillin-resistant Staphylococcus aureus (MRSA) severe sepsis and septic shock, its utility in TSS remains unclear. The authors report a case of severe sepsis in the setting of MRSA-associated TSS that responded to treatment with DA. This case illustrates a potential role for DA in the treatment of toxic shock syndromes and emphasizes the importance of aggressive diagnostic and therapeutic modalities in approaching these conditions.


Can Community Gardens with Workshops Increase Gardening Behavior? A Navajo Wellness Collaboration.
This project evaluated the potential efficacy of a community gardening intervention on the Navajo Nation to increase gardening and healthy eating behaviors, which are potentially important in preventing obesity and related health conditions. Rates of obesity are high among American Indians, including those living on Navajo Nation land. Eating fresh fruits and vegetables is part of healthy eating. However, availability and access to fresh fruits and vegetables are severely limited due to distance and cost. One way to increase both availability and consumption of fresh fruits and vegetables is through community gardening, yet many on the Navajo Nation have limited knowledge and capacity to garden. We used a quasi-experimental pre-post study design to estimate the effect of a community gardening intervention. Primary outcomes of interest were gardening frequency and fruit and vegetable consumption. Community gardens were constructed and planted in two communities on the Navajo Nation. In addition, a series of gardening workshops were held in each community. Community members were recruited to complete surveys at time points before and after the workshops. The time between baseline and follow-up was approximately one year. We surveyed 169 participants at one time point at least, across both communities, and 25 of these participated in the gardening workshops. Within the 169, there was a cohort of 32 participants completing both baseline and follow-up surveys. For this cohort, interest in gardening increased from 78% to 97% (p=0.014), but none of the changes in gardening self-efficacy, knowledge or gardening frequency reached statistical significance. There were no measurable changes in reported fruit and vegetable consumption, self-efficacy or knowledge. Overall, the reported financial barriers to gardening increased from baseline to follow-up from 4.6 to 5.5 (p=0.035). Among those who completed follow-up, those who attended at least one workshop gardened more frequently than those who did not attend any workshops (21 times per month compared to 10 times per month (p=0.065). Despite enthusiasm for the community garden in both the communities studied and the increased interest in gardening, workshop attendance and participant retention in the study were low. These factors limited our ability to evaluate the potential efficacy of the intervention on gardening and healthy eating behaviors. Nonetheless, we found some evidence that participating in gardening workshops may lead to increased gardening frequency. Future studies should augment the intervention to include explicit efforts to reduce barriers to long term engagement and extend intervention reach.


Postpartum nutrient intake and body condition: effect on pituitary function and onset of estrus in beef cattle.
From calving through first estrus, 30 Brangus females were assigned equally to one of three diets to study the effect of postpartum nutrient intake and body condition on the ability of the pituitary to release luteinizing hormone (LH) and on the postpartum interval to estrus (PPI). The postpartum diets were calculated to achieve a 1) low [90% of the National Research Council (NRC) recommendations], 2) maintenance (100% of the NRC recommendations), or 3) high (110% of the NRC recommendations) level of nutrient intake. The females were group-fed within a treatment and calves were allowed to suckle ad libitum. Cow weight, body condition score and calf weight were recorded 24 h aftercalving, d 20 postpartum and at first behavioral estrus. On d 21 postpartum, blood samples were collected via jugular cannulae at 15-min intervals for 4 h, followed by a 100-micrograms im injection of gonadotropin-releasing hormone (GnRH) and continued sampling at 15-min intervals for an additional 6 h to determine serum LH. Although there was a significant decrease in PPI with increasing levels of nutrient intake (low = 57.5 +/- 8.8 d; maintenance = 40.3 +/- 6.6 d; high = 34.7 +/- 5.1 d), there were no differences in any of the observed LH characteristics (or variables) due to treatment. There were, however, marked differences in both the PPI and LH characteristics when data were analyzed on the basis of ability to maintain body condition from calving through 20 d postpartum, regardless of calculated dietary treatments. Cows that maintained body condition (MBC) had a shorter PPI [MBC, 31.7 +/- 2.8 vs lost (LBC) 60.0 +/- 7.5 d; P less than .01], higher basal levels of endogenous LH (MBC, .83 +/- .09 vs LBC, .61 +/- .04 ng/ml; P less than .025), higher GnRH-induced peak LH concentration (MBC, 58.99 +/- 11.15 vs LBC, 38.86 +/- 8.37 ng/ml. P less than .10), higher LH levels throughout the GnRH-induced LH surge (P less than .001), and greater release curve areas for the endogenous (MBC, 124.6 +/- 13.3 vs LBC, 91.7 +/- 5.6 units; P less than .025), GnRH-induced (MBC, 4370.8 +/- 699.5 vs LBC, 3039.7 +/- 683.3 units; P less than .10) and total (MBC, 4510.7 +/- 706.7 vs LBC, 3141.9 +/- 684.7 units; P less than .10) LH release.(ABSTRACT TRUNCATED AT 400 WORDS)


Juvenile onset ankylosing spondylitis (JAS) has less severe spinal disease course than adult onset ankylosing spondylitis (AAS): clinical comparison between JAS and AAS in Korea.
To assess the frequency of juvenile onset ankylosing spondylitis (JAS) in Korean patients with AS and to differentiate the clinical characteristics of JAS from adult onset ankylosing spondylitis (AAS). We studied 98 consecutive patients with AS who visited the rheumatology clinic of a tertiary referral center and compared clinical and radiographic features of JAS (n = 41) with those of AAS (n = 57). Median age at onset in JAS was 14 years (range 7-16) and in AAS 22 years (range 17-38) (p < 0.01). Patients with JAS at presentation showed fewer spinal symptoms and more frequent peripheral joint symptoms than those with AAS (41.5% vs 80.7% and 73.2% vs 36.8%, respectively; p < 0.01). Current cervical spine disease was more frequent in AAS (66.7% vs 43.9%; p = 0.02) and current knee disease in JAS (26.8% vs 8.8%; p = 0.02). Patients with JAS showed a shorter tragus-wall distance (mean +/- SD 10.6 +/- 1.7 vs 13.1 +/- 6.9 cm; p < 0.01), more mobility on the modified Schober test (5.7 +/- 2.0 vs 4.0 +/- 2.6 cm; p < 0.01) and chest expansion (4.4 +/- 1.7 vs 3.2 +/- 1.8 cm; p < 0.01), and a better forced vital capacity (75.1 +/- 14.1% vs 82.1 +/- 16.1% of predicted value; p = 0.03) than those with AAS. Totally ankylosed sacroiliitis and spinal syndesmophyte on radiographs were less frequent in JAS patients than in AAS (19.5% vs 47.4% and 17.1% vs 54.4%, respectively; p < 0.01). The frequency of JAS (41.3%) among Koreans was higher than that reported for Caucasians. General joint involvement pattern at disease onset in JAS was similar to previous reports. Our data suggest that clinically and radiographically JAS has a less severe spinal disease course than AAS.


Application of the anthraquinone drug rhein as an axial ligand in bifunctional Pt(IV) complexes to obtain antiproliferative agents against human glioblastoma cells.
Octahedral Pt(IV) prodrugs are an effective way to combine cisplatin-like moieties and a second drug to obtain selective and stimuli responsive bifunctional antiproliferative compounds. Recently, two bifunctional Pt(IV) complexes have shown interesting in vitro and in vivo effects in glioblastoma, the most aggressive primary brain tumor. An interesting observation indicates that 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (rhein) can inhibit in vivo glioma tumor progression. Furthermore, a prodrug in which cisplatin was combined with two molecules of rhein showed a potency higher than that of cisplatin toward cisplatin-resistant lung carcinoma cells. However, the high lipophilicity of this type of complex affects their solubility and bioavailability. To overcome these limits, in the present work, three Pt(IV) derivatives were obtained by differently linking one molecule of rhein and one acetato ligand at the axial position to a cisplatin core. The complexes proved to be similar to or more potent than the parent cisplatin and rhein, and the reference drug temozolomide on two human glioblastoma cell lines (U87-MG and T98G). They retained their activity under hypoxia and caused a significant reduction in the motility of both cell lines, which can be related to their ability to inhibit MMP2 and MMP9 matrix metalloproteinases. Finally, physicochemical and computational studies indicated that these Pt(IV) derivatives are more prone than rhein to cross the blood-brain barrier.


Seed Rot and Damping-off of Alfalfa in Minnesota Caused by Pythium and Fusarium Species.
Globally, 15 Pythium species have been found to cause damping-off and seed rot of alfalfa, although surveys of species causing disease on alfalfa in the midwestern United States are lacking. Pathogens were isolated by a seedling baiting technique from soil samples of five alfalfa fields in Minnesota with high levels of damping-off. Of the 149 organisms isolated, 93 (62%) were identified as Pythium spp. and 43 (29%) were identified as Fusarium species. Pythium sylvaticum, P. irregulare, and P. ultimum var. ultimum were aggressive pathogens on germinating alfalfa seedlings. Strains of seven Pythium spp. pathogenic on soybean and corn were also pathogenic on alfalfa. The majority of the Fusarium isolates were identified as F. solani and F. oxysporum with a low number of F. redolens and F. incarnatum-equiseti. The F. oxysporum and F. incarnatum-equiseti strains were the most aggressive in causing seed and root rot. Pythium strains were sensitive to Apron XL (mefenoxam) and pyraclostrobin in vitro but efficacy varied when the fungicides were applied as a seed treatment. Seed treatments with Apron XL were more effective than treatments with Stamina against Pythium. The presence of aggressive, broad-host-range pathogens causing seed rot and damping-off suggests that new strategies are needed for managing this disease in alfalfa production systems.


Oxalate retention in chronic renal failure: tubular vs glomerular diseases.
Plasma oxalate concentration was measured using an enzyme/bioluminescent assay in 289 patients (178 males, 111 females) with chronic renal failure (plasma creatinine greater than 200 mumol/l), age (SD) 55.5 (13.8) years. Plasma oxalate ranged between less than 0.8 and 48 mumol/l and showed a positive correlation with plasma creatinine (r = 0.57, p less than 0.0001). The slope of the regression line in 55 patients with glomerulonephritis (GN) was significantly lower than in patients with tubulointerstitial disease (TI); however the intercept was significantly higher in GN than in TI. Analysis of covariance showed no relationship between plasma oxalate concentration and age, duration of renal impairment, or administration of diuretics, vitamin D analogues, or phosphate binders. Longitudinal analysis of plasma oxalate measured 3-monthly in selected patients showed marked variability of oxalate/creatinine and oxalate/urea ratios.


Fluid overload as a major target in management of cardiorenal syndrome: Implications for the practice of peritoneal dialysis.
Congestion is an integral component of cardiorenal syndrome and portends an adverse impact on the outcomes. Recent studies suggest that congestion has the ability of modulating the interactions between the kidney and the heart in this setting. Peritoneal dialysis (PD) is a home-based therapeutic modality that is not only offered to patients with end-stage renal disease to provide solute clearance and ultrafiltration, but it has also been used in patients with refractory heart failure and fluid overload to help optimize volume status. Several uncontrolled studies and case series have so far evaluated the role of PD in management of hypervolemia for patients with heart failure. They have generally reported favorable results in this setting. However, the data on the outcomes of patients with end-stage renal disease and concomitant heart failure is mixed, and the proposed theoretical advantages of PD might not translate into improved clinical endpoints. Congestion is prevalent in this patient population and has a significant effect on their survival. As studies suggest that a significant subset of patients with end-stage renal disease who receive PD therapy are hypervolemic, suboptimal management of congestion could at least in part explain these conflicting results. PD is a highly flexible therapeutic modality and the choice of techniques, regimens, and solutions can affect its ability for optimization of fluid status. This article provides an overview of the currently available data on the role and clinical relevance of congestion in patients with cardiorenal syndrome and reviews potential options to enhance decongestion in these patients.


Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer.
Prostate cancer is the most common type of cancer in men and ranks second only to lung cancer in cancer-related deaths. The management of locally advanced prostate cancer is difficult because the cancer often becomes hormone insensitive and unresponsive to current chemotherapeutic agents. Knowledge about the regulatory molecules involved in the transformation to androgen-independent prostate cancer is essential for the rational design of agents to prevent and treat prostate cancer. Protein kinase Cepsilon (PKCepsilon), a member of the novel PKC subfamily, is linked to the development of androgen-independent prostate cancer. PKCepsilon expression levels, as determined by immunohistochemistry of human prostate cancer tissue microarrays, correlated with the aggressiveness of prostate cancer. The mechanism by which PKCepsilon mediates progression to prostate cancer remains elusive. We present here for the first time that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, including prostate cancer, interacts with PKCepsilon. The interaction of PKCepsilon with Stat3 was observed in human prostate cancer, human prostate cancer cell lines (LNCaP, DU145, PC3, and CW22rv1), and prostate cancer that developed in transgenic adenocarcinoma of mouse prostate mice. In reciprocal immunoprecipitation/blotting experiments, prostatic Stat3 coimmunoprecipitated with PKCepsilon. Localization of PKCepsilon with Stat3 was confirmed by double immunofluorescence staining. The interaction of PKCepsilon with Stat3 was PKCepsilon isoform specific. Inhibition of PKCepsilon protein expression in DU145 cells using specific PKCepsilon small interfering RNA (a) inhibited Stat3Ser727 phosphorylation, (b) decreased both Stat3 DNA-binding and transcriptional activity, and (c) decreased DU145 cell invasion. These results indicate that PKCepsilon activation is essential for constitutive activation of Stat3 and prostate cancer progression.


Spliceosome mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia.
The recently discovered spliceosome mutations represent a group of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDS), chronic myelomonocytoic leukemia (CMML) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype correlations have been observed, including the clustering of ring sideroblasts with SF3B1 mutations in MDS. Spliceosome mutations might result in defective small nuclear ribonucleoprotein complexes assembly on the pre-mRNA, deregulated global and alternative mRNA splicing, nuclear-cytoplasm export, and unpliced mRNA degradation, and thus may alter the expression of multiple genes. In the current review, we discuss the potential role of these mutations in cell transformation and how they could impact the therapeutic approaches.


Cooperative interaction of multiple DNA elements in the human interferon-beta promoter.
Analysis of promoter mutants and hybrids in permanently transformed murine L cells reveals several regulatory DNA sequence elements in the 5' flanking region of the human interferon-beta gene, which together constitute the inducible promoter. The elements consist almost exclusively of purine runs in the region -111 to -1. Deletion of single elements reduces the expression capacity drastically, whereas duplication leads to a synergism of inducible expression. These elements act together in a cooperative way to achieve high inducibility. Natural and mutant promoter fragments containing these elements impose inducibility on a heterologous promoter. However, typical enhancer activity in this system is not observed.


The cGMP-gated channel and related glutamic acid-rich proteins interact with peripherin-2 at the rim region of rod photoreceptor disc membranes.
The rod cGMP-gated channel is localized in the plasma membrane of rod photoreceptor outer segments, where it plays a central role in phototransduction. It consists of alpha- and beta-subunits that assemble into a heterotetrameric protein. Each subunit contains structural features characteristic of nucleotide-gated channels, including a cGMP-binding domain, multiple membrane-spanning segments, and a pore region. In addition, the beta-subunit has a large glutamic acid- and proline-rich region called GARP that is also expressed as two soluble protein variants. Using monoclonal antibodies in conjunction with immunoprecipitation, cross-linking, and electrophoretic techniques, we show that the cGMP-gated channel associates with the Na/Ca-K exchanger in the rod outer segment plasma membrane. This complex and soluble GARP proteins also interact with peripherin-2 oligomers in the rim region of outer segment disc membranes. These results suggest that channel/peripherin protein interactions mediated by the GARP part of the channel beta-subunit play a role in connecting the rim region of discs to the plasma membrane and in anchoring the channel.exchanger complex in the rod outer segment plasma membrane.


Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling.
The mechanisms by which ethanol damages the developing and adult central nervous system (CNS) remain unclear. Activity-dependent neuroprotective protein (ADNP) is a glial protein that protects the CNS against a wide array of insults and is critical for CNS development. NAPVSIPQ (NAP), a potent active fragment of ADNP, potentiated axon outgrowth in cerebellar granule neurons by activating the sequential tyrosine phosphorylation of Fyn kinase and the scaffold protein Crk-associated substrate (Cas). Pharmacological inhibition of Fyn kinase or expression of a Fyn kinase siRNA abolished NAP-mediated axon outgrowth. Concentrations of ethanol attained after social drinking blocked NAP-mediated axon outgrowth (IC(50) = 17 mM) by inhibiting NAP activation of Fyn kinase and Cas. These findings identify a mechanism for ADNP regulation of glial-neuronal interactions in developing cerebellum and a pathogenesis of ethanol neurotoxicity.


Systems Pharmacology Modeling Identifies a Novel Treatment Strategy for Bortezomib-Induced Neuropathic Pain.
Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.


Electronic excitation spectrum of the photosensitizer [Ir(ppy)2(bpy)]+.
The vertical singlet-singlet and singlet-triplet electronic excitation energies of bis(2-phenylpyridinato-)(2,2'-bipyridine)iridium(III) ([Ir(ppy)(2)(bpy)](+)) are calculated on the basis of a comparative quantum chemical study using wave function methods such as CASSCF∕CASPT2 and density functional theory (TDDFT) with local and range-separated functionals. The TDDFT results show a strong dependence of the charge-transfer transition energies on the amount of the exact exchange in the functional. In general, TDDFT with range-separated functionals provides a good agreement with the experimental spectra. As a result a new assignment of the absorption spectrum of the title compound is proposed.


The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders.
The first use of immunoglobulin therapy, historically, was in 1890 when Emil von Behring developed effective antiserum against diphtheria toxin, but only in the early 1970s technological advancements in the fractionation of plasma lead to the production of Ig preparations which could be administered intravenously. Intravenous Ig products are a mainstay for disorders such as: primary immunodeficiency, serious infections, autoimmune and inflammatory disorders. During autoimmune and systemic inflammatory disease IVIg exhibits a number of immune modulatory activities such as: Fc Receptor-mediated effects, modulation of complement, modulation of cytokine production, superantigens neutralization, antibodies neutralization by idiotype network, increased catabolism of IgG, but also biologic effects of other molecules present in IVIg preparations. Recent understanding about IVIg composition and mechanism of action can explain its therapeutic effect in autoimmune and inflammatory disorders. Nevertheless it is important to underline that IVIg is a heterogeneous product and it is difficult to determine the exact mechanism of its activities in every disease. The increased use of IVIg in the treatment of autoimmune disorders outlined the issue of tolerability. Undesiderable effects to IVIg occurs in less than 5% of patients.


Neural correlates of cognitive efficiency.
Since its inception, experimental psychology has sought to account for individual differences in human performance. Some neuroimaging research, involving complex behavioral paradigms, has suggested that faster-performing individuals show greater neural activity than slower performers. Other research has suggested that faster-performing individuals show less neural activity than slower performers. To examine the neural basis of individual performance differences, we had participants perform a simple speeded-processing task during fMRI scanning. In some prefrontal cortical (PFC) brain regions, faster performers showed less cortical activity than slower performers while in other PFC and parietal regions they showed greater activity. Regional-causality analysis indicated that PFC exerted more influence over other brain regions for slower than for faster individuals. These results suggest that a critical determinant of individual performance differences is the efficiency of interactions between brain regions and that slower individuals may require more prefrontal executive control than faster individuals to perform successfully.


Permanent lesion of the lateral femoral cutaneous nerve after low-volume ethanol 96%application on the lumbar sympathetic chain.
Lumbar sympathetic blocks and chemical sympathectomies are used for the pain treatment of peripheral arterial occlusive disease or sympathetically maintained pain syndrome after nerve injury or complex regional pain syndrome (CRPS). A 30-year-old patient was referred to the pain department with all the clinical signs and symptoms of a CRPS of the right foot one and a half years after being surgically treated for rupture of the achilles tendon. An inpatient admission was necessary due to insufficient pain reduction upon the current treatment, strong allodynia in the medial distal right lower leg and decreased load-bearing capacity of the right foot. A computed tomography (CT)-guided lumbar sympathetic block at the right L3 (Bupivacaine 0.5%, 4 mL) led to a skin temperature increase from 21° C before block to > 34° C for about 5 hours after the intervention. The patient experienced significant pain relief, indicating sympathetically maintained pain. Thus, we performed a CT-guided lumbar sympathetic neurolysis at the same level (ethanol 96%, 2 mL) 5 days later, achieving again a significant skin temperature increase of the right foot and a slight reduction of his pain intensity from numeric rating scale (NRS) 7 prior to the intervention to NRS 4 after 8 hours (NRS, 0 = no pain, 10 = strongest pain imaginable). Eight months later a repeated inpatient admission was necessary due to considerable pain relapse and decreased load-bearing capacity of his right foot. A CT-guided lumbar sympathetic neurolysis was repeated at the L4 level on the right side and was successful, inducing a significant skin temperature increase. Despite a temporary irritation of the genitofemoral nerve 8 hours after the intervention, a delayed irritation of the lateral femoral cutaneous nerve occurred. This was a long-lasting lesion of the lateral femoral cutaneous nerve following a CT-guided chemical sympathectomy with a low-volume ethanol 96% application - a complication which has not been described in literature until now. This is probably caused by broad dissemination of the neurolytic agent along the psoas muscle despite a correct needle position and spread of contrast agent. The development of this nerve injury even after injection of a small volume of ethanol (2 mL) may be delayed.


[Morphological and Physiological Properties of the Micromycete Arthrobotrys longa, a Producer of Longolytin, a Proteolytic Complex with a Thrombolytic Effect].
Production of proteinases with plasmin-like and plasminogen-activating activities by a micromycete Arthrobotrys longa 1 was studied. Polycyclic growth of the producer in submerged cultures was observed, with an endogenous rhythm of the periods of intense microconidia formation alternating with the phases of drastic increase in the content of producing mycelium. The highest plasminogen-like and plasminogen-activating activities (up to 1000 and 500 cond. U/mL, respectively) were found to correlate with the polycyclic growth of the producer, coinciding with the stage of microconidia germination. Enhanced secretion of proteinases with plasminogen-like and plasminogen-activating activity was found to be associated with increased specific growth rate of A. longa l.


Composite biomaterials with chemical bonding between hydroxyapatite filler particles and PEG/PBT copolymer matrix.
In an effort to make composites from hydroxyapatite and a PEG/PBT copolymer (Polyactive 70/30), chemical linkages were introduced between the filler particles and polymer matrix using hexamethylene diisocyanate as a coupling agent. Infrared spectra (IR) and thermal gravimetric analysis (TGA) confirmed the presence of Polyactive 70/30 on the surface of HA filler particles. The amount of chemically bound polymer was 4.7 wt.%, as determined by TGA. The mechanical properties of the composites, that is, tensile strength and Young's modulus, were improved significantly by the introduction of a chemical linkage between the filler particles and polymer matrix compared to control composites. This method provides an effective way to introduce chemical linkage between HA filler particles and a polymer matrix. By optimizing the grafting process, a further improvement of the mechanical properties in the composites can be expected.


Trace metals in e-waste lead to serious health risk through consumption of rice growing near an abandoned e-waste recycling site: Comparisons with PBDEs and AHFRs.
Despite the endeavour to eradicate informal e-waste recycling, remediation of polluted sites is not mandatory in many developing countries and thus the hazard of pollutants remaining in soil is often overlooked. It is noteworthy that a majority of previous studies only analysed a few pollutants in e-waste to reflect the impact of informal e-waste recycling. However, the actual impact may have been largely underestimated since e-waste contains various groups of pollutants and the effect of some emerging pollutants in e-waste remains unexplored. Thus, this study examined the contamination of metals, PBDEs and AHFRs in the vicinity of an abandoned e-waste recycling site. The accumulation and translocation of these pollutants in rice plants cultivated at the nearby paddy field were measured to estimate the health risk through rice consumption. We revealed that the former e-waste burning site was still seriously contaminated with some metals (e.g. Sn, Sb and Ag, Igeo > 5), PBDEs (Igeo > 3) and AHFRs (Igeo > 3), which can disperse to the nearby paddy field and stream. The rice plants can effectively absorb some metals (e.g. Mo, Cr and Mn, BCF > 1), but not PBDEs and AHFRs (BCF < 0.15), from soil and translocate them to the leaves. Alarmingly, the health risk through rice consumption was high primarily due to Sb and Sn (HQ > 20), whereas PBDEs and AHFRs had limited contribution (HQ < 0.08). Our results imply that abandoned e-waste recycling sites still act as the pollution source, jeopardising the surrounding environment and human health. Since some trace metals (e.g. Sb and Sn) are seldom monitored, the impact of informal e-waste recycling would be more notorious than previously thought. Remediation work should be conducted promptly in abandoned e-waste recycling sites to protect the environment and human health.


To be(long) or not to be(long): social identification in organizational contexts.
In the past few years, ideas of Social Identity Theory and Self-Categorization Theory have been successfully applied to the organizational domain. In this article, the authors provide an overview of these recent developments and present a concept of social identification in organizational contexts, based on these theories. The assumptions of this framework are that (a) social identification in organizational contexts is a multifaceted concept consisting of different dimensions and foci (or targets), (b) higher levels of identification are related to higher productivity and more positive work-related attitudes, and (c) identification is a very flexible concept that is linked to the situational context. The authors present the results of a series of field and laboratory studies in which the proposed relationships are analyzed and, in the main, confirmed.


Cost-effectiveness of hepatitis A vaccination in Indonesia.
This study aims to assess the cost-effectiveness of hepatitis A immunization in Indonesia, including an explicit comparison between one-dose and two-dose vaccines. An age-structured cohort model based on a decision tree was developed for the 2012 Indonesia birth cohort. Using the model, we made a comparison on the use of two-dose and one-dose vaccines. The model involved a 70-year time horizon with 1-month cycles for children less than 2 years old and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of the hepatitis A vaccination. Vaccination would save US$ 3,795,148 and US$ 2,892,920 from the societal perspective, for the two-dose and one-dose vaccine schedules, respectively, in the context of hepatitis A treatment. It also would save 8917 and 6614 discounted quality-adjusted-life-years (QALYs), respectively. With the vaccine price of US$ 3.21 per dose, the implementation of single dose vaccine would yield an incremental cost-effectiveness ratio (ICER) of US$ 4933 per QALY gained versus no vaccination, whereas the two-dose versus one-dose schedule would cost US$ 14 568 per QALY gained. Considering the 2012 gross-domestic-product (GDP) per capita in Indonesia of US$ 3557, the results indicate that hepatitis A vaccination would be a cost-effective intervention, both for the two-dose and one-dose vaccine schedules in isolation, but two-dose vaccination would no longer be cost-effective if one-dose vaccination is a feasible option. Vaccination would be 100% affordable at budgets of US$ 71,408 000 and US$ 37,690,000 for the implementation of the two-dose and one-dose vaccine schedules, respectively. The implementation of hepatitis A vaccination in Indonesia would be a cost-effective health intervention under the market vaccine price. Given the budget limitations, the use of a one-dose-vaccine schedule would be more realistic to be applied than a two-dose schedule. The vaccine price, mortality rate and discount rate were the most influential parameters impacting the ICERs.


SARS-CoV-2 in the pancreas and the impaired islet function in COVID-19 patients.
Diabetes mellitus (DM) is one of the most common underlying diseases that may aggravates COVID-19. In the present study, we explored islet function, the presence of SARS-CoV-2 and pathological changes in the pancreas of patients with COVID-19. Oral glucose tolerance tests (OGTTs) and the C-peptide release test demonstrated a decrease in glucose-stimulated C-peptide secretory capacity and an increase in HbA1c levels in patients with COVID-19. The prediabetic conditions appeared to be more significant in the severe group than in the moderate group. SARS-CoV-2 receptors (ACE2, CD147, TMPRSS2 and neuropilin-1) were expressed in pancreatic tissue. In addition to SARS-CoV-2 virus spike protein and virus RNA, coronavirus-like particles were present in the autophagolysosomes of pancreatic acinar cells of a patient with COVID-19. Furthermore, the expression and distribution of various proteins in pancreatic islets of patients with COVID-19 were altered. These data suggest that SARS-CoV-2 in the pancreas may directly or indirectly impair islet function.


Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1.
Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knock-out mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.


Bile secretion and liver regeneration in partially hepatectomized rats.
The purpose of this research was to study the correlation between bile secretion and the liver regeneration in the partially hepatectomized rat. Significant alteration in bile formation and secretion is expected in the liver after hepatectomy. There is scant literature, however, about the effects of liver regeneration in bile secretion. The work was done in rats with 50% hepatectomy, 75% hepatectomy, and sham operation as the control. A chronic common bile duct fistula and a duodenal cannula were established for bile collection and the sample analysis on days 1, 3, 5, 7, and 9. With size reduced in the liver after 50% and 75% hepatectomy, the total bile volume decreased 45.9% and 51.5%, bile salt independent flow decreased 59.3% and 64.9%, bile salt secretion rate decreased 36.1% and 43.4%, bile salt basal synthesis rate decreased 52.3% and 56.4%, phospholipid secretion rate decreased 52.6% and 68.0%, and cholesterol secretion rate decreased 54.3% and 72.4% from control on day 1, respectively. All changes returned to the control level in 3 to 9 days with accompanying increasing liver size during regeneration. Alterations of total bile flow, bile salt independent flow, bile salt secretion rate, bile salt basal synthesis rate, and biliary lipid secretion after partial hepatectomy correlate with the liver regeneration rate in rats. Partial hepatectomy reduces the bile salt independent fraction calculated as per 100 g body weight rather than the dependent fraction. The study of bile salt and biliary lipid secretion is a useful method for monitoring synthetic function in liver regeneration in vivo.


A simple and reliable semipreparative high-performance liquid chromatography technique for the isolation of marker-grade hyperforin from Hypericum perforatum L extract.
The present work describes isolation of bioactive lipophilic constituent [namely, hyperforin from St. John's wort (Hypericum perforatum L.)], of approximately 98% purity by semipreparative high-performance liquid chromatography (LC). The extraction, isolation, and analysis of the collected compound is performed without the use of antioxidants and inert gas atmospheres at all the stages. Hyperforin, separated isocratically on a 12microm semiprep column, is obtained in high purity, lyophilized after the removal of the organic phase, and preserved at a low temperature. The purity of the collected marker compound is estimated by the use of LC-mass spectrometry and spectroscopic techniques.


Imaging characterization of myocardial function, fibrosis, and perfusion in a nonhuman primate model with heart failure-like features.
The availability of a human-like chronic heart failure (HF) animal model was critical for affiliating development of novel therapeutic drug treatments. With the close physiology relatedness to humans, the non-human primate (NHP) HF model would be valuable to better understand the pathophysiology and pharmacology of HF. The purpose of this work was to present preliminary cardiac image findings using echocardiography and cardiovascular magnetic resonance (CMR) in a HF-like cynomolgus macaque model. The NHP diet-induced model developed cardiac phenotypes that exhibited diastolic dysfunction with reduced left ventricular ejection fraction (LVEF) or preserved LVEF. Twenty cynomolgus monkeys with cardiac dysfunction were selected by echocardiography and subsequently separated into two groups, LVEF < 65% (termed as HFrEF, n = 10) and LVEF ≥ 65% with diastolic dysfunction (termed as HFpEF, n = 10). Another group of ten healthy monkeys was used as the healthy control. All monkeys underwent a CMR study to measure global longitudinal strain (GLS), myocardial extracellular volume (ECV), and late gadolinium enhancement (LGE). In healthy controls and HFpEF group, quantitative perfusion imaging scans at rest and under dobutamine stress were performed and myocardial perfusion reserve (MPR) was subsequently obtained. No LGE was observed in any monkey. Monkeys with HF-like features were significantly older, compared to the healthy control group. There were significant differences among the three groups in ECV (20.79 ± 3.65% in healthy controls; 27.06 ± 3.37% in HFpEF group, and 31.11 ± 4.50% in HFrEFgroup, p < 0.001), as well as for stress perfusion (2.40 ± 0.34 ml/min/g in healthy controls vs. 1.28 ± 0.24 ml/min/g in HFpEF group, p < 0.01) and corresponding MPR (1.83 ± 0.3 vs. 1.35 ± 0.29, p < 0.01). After adjusting for age, ECV (p = 0.01) and MPR (p = 0.048) still showed significant differences among the three groups. Our preliminary imaging findings demonstrated cardiac dysfunction, elevated ECV, and/or reduced MPR in this HF-like NHP model. This pilot study laid the foundation for further mechanistic research and the development of a drug testing platform for distinct HF pathophysiology.


Probiotics: Potential Novel Therapeutics Against Fungal Infections.
The global infection rate of fungal diseases is increasing year by year, and it has gradually become one of the most serious infectious diseases threatening human health. However, the side effects of antifungal drugs and the fungal resistance to these drugs are gradually increasing. Therefore, the development of new broad-spectrum, safe, and economical alternatives to antibacterial drugs are essential. Probiotics are microorganisms that are beneficial for human health. They boost human immunity, resist pathogen colonization, and reduce pathogen infection. Many investigations have shown their inhibitory activity on a wide range of pathogenic fungi. However, their antibacterial mechanism is still a secret. This article reviews the progress of probiotics as a new method for the treatment of fungal diseases.


Major Histocompatibility Complex Class I Chain-Related A (MICA) Molecules: Relevance in Solid Organ Transplantation.
An ever growing number of reports on graft rejection and/or failure even with good HLA matches have highlighted an important role of non-HLA antigens in influencing allograft immunity. The list of non-HLA antigens that have been implicated in graft rejection in different types of organ transplantation has already grown long. Of these, the Major Histocompatibility Complex class I chain-related molecule A (MICA) is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in the kidney transplantation. Humoral response to MICA antigens has repeatedly been associated with lower graft survival and an increased risk of acute and chronic rejection following kidney and liver transplantation with few studies showing conflicting results. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, a definitive consensus on this relationship has not been arrived yet. Furthermore, only a few studies have dealt with the impact of MICA donor-specific antibodies as compared to those that are not donor specific on graft outcome. In addition to the membrane bound form, a soluble isoform of MICA (sMICA), which has the potential to engage the natural killer cell-activating receptor NKG2D resulting in endocytosis and degradation of receptor-ligand interaction complex leading to suppression of NKG2D-mediated host innate immunity, has been a subject of intense discussion. Most studies on sMICA have been directed toward understanding their influence on tumor growth, with limited literature focusing its role in transplant biology. Furthermore, a unique dimorphism (methionine to valine) at position 129 in the α2 domain categorizes MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor depending on whether they have methionine or valine at this position. Although the implications of MICA 129 dimorphism have been highlighted in hematopoietic stem cell transplantation, its role in solid organ transplantation is yet to be explored. This review summarizes the currently available information on MICA antibodies, soluble MICA, and MICA-129 dimorphism in a setting of solid organ transplantation.


Neutrophil mobilization induced by complement fragments during experimental group B streptococcal (GBS) infection.
Degradation products of the third component of complement have been reported to have the ability to mobilize leukocytes from the marrow and induce leukocytosis. The effect of C3d,g preparations on neutrophil responses in a neonatal rat model of group B streptococcal infection in which neutrophil mobilization from the marrow is inadequate has been evaluated. Dimeric and monomeric fragments of C3d,g were isolated from human serum; the identity of the C3d,g preparations was confirmed by SDS-PAGE, Western blotting, and N-terminal amino acid sequencing. Uninfected neonatal rats responded to intraperitoneal injection of C3d,g with a peripheral blood neutrophilia at 30 minutes and 4 hours after inoculation. C3d,g, which lacks intrinsic chemotactic activity, enhanced the local accumulation of neutrophils in the peritoneal cavity of infected, but not uninfected, neonatal rats. In addition, myeloid cell release from the marrow of isolated femurs of neonatal rats receiving C3d,g was significantly enhanced. Thus, the effect of C3d,g in this model was to mobilize marrow cells and induce peripheral leukocytosis. Chemotactic factors released at the site of infection then resulted in the local accumulation of these inflammatory cells. Complement-derived components capable of releasing marrow myeloid elements may play a major role in determining the outcome of bacterial infection in the immature host.


Alcoholics' and nonalcoholics' attributions of control of future life events.
Alcoholic and nonalcoholic subjects rated the degree of control that they and others possess over future life events. Alcoholics attributed less personal control over events to themselves than nonalcoholics did. Alcoholics also attributed less control to themselves than to others, whereas nonalcoholics attributed more control to themselves than to others. These differences prevailed despite the similar socioeconomic and demographic characteristics, recent life experiences and beliefs concerning the general controllability of events of both alcoholics and nonalcoholics. The attributions of alcoholics were consistent with others' notions of self-handicapping. The attributions of nonalcoholics were consistent with control motivation. Alcoholics who attributed less control to themselves than to others more frequently failed to complete treatment than did alcoholics who attributed more control to themselves.


Optimized Design Method for Pt/SiO2-Al2O3 with High NH3-SCO Activity and Thermal Stability.
Pt/SiO2-Al2O3 catalysts were prepared by the traditional impregnation method (IM) and the strong electrostatic adsorption (SEA) process. Differences in particle size, surface chemical state, Pt adsorption site, ammonia oxidation activity, and thermal stability of Pt species were studied systematically. For the fresh catalyst of Pt/SiO2-Al2O3-IM (Pt/SiO2-Al2O3-IM-fresh), Pt species were dispersed unselectively on SiO2-Al2O3, and the large average size (6.6 nm) of Pt species could be observed in a bimodal distribution (ranges of 5.5-6.5 and 8.5-9.5 nm). After the hydrothermal treatment, the Pt size of the aged catalyst (Pt/SiO2-Al2O3-IM-aged) increased significantly, especially Pt particles on SiO2 showed obvious agglomeration and some even increased to 40 nm. Conversely, for the catalyst prepared through the SEA process, Pt species of Pt/SiO2-Al2O3-SEA-fresh were selectively absorbed on Al2O3, the Pt particle size was in the range of 1.5-6.0 nm, and the average particle size was only 2.7 nm. After hydrothermal aging, Pt species did not show obvious agglomeration (the average particle size was 3.2 nm). Above all, Pt/SiO2-Al2O3-SEA presented better catalytic activity and thermal stability than Pt/SiO2-Al2O3-IM, i.e., the temperatures of 50% NH3 conversion for the fresh and aged Pt/SiO2-Al2O3-SEA catalysts were 216 and 223 °C, respectively, much lower than those for Pt/SiO2-Al2O3-IM-fresh (228 °C) and Pt/SiO2-Al2O3-IM-aged (250 °C).


[Design and Optimization of Surface Plasmon Resonance Sensor Based on Side Polished Single-Mode Fiber].
Fiber-coupling surface Plasmon resonance sensor has attractive advantages of information transmission such as small volume, anti-electric magnetic field interference, and online real-time remote detection. In order to improve the performance of the sensor, the effect of the residual fiber thickness and the silver film thickness to the sensitivity of the sensor and the depth of the resonance peaks and full width ar half maximum (FWHM) are analyzed respectively. The results show that the increasing fiber residual thickness weakens the SPR phenomenon, and that the increasing silver film thickness widens the resonance peak, while the sensitivity of the sensor does not change monotonously. Through the integration of refractive index sensing sensitivity and full width at half maximum, figure of merit is presented and regarded as the optimized objective. The optimal design is achieved in the case of the fiber residual thickness for 66. 5 µm, and the silver film thickness for 50 nm. The optimized design with the figure of merit of 98. 67 is expected to be applied in the bio-chemical sensing and analysis.


Simulation in paediatrics: An educational revolution.
Recent changes in the culture of medical education have highlighted deficiencies in the traditional apprenticeship model of education, and emphasized the need for more experiential modalities of learning. Simulations, which are scenarios or environments designed to closely approximate real-world situations, have recently found their way into the medical training of health care providers. High-fidelity simulators are life-like mannequins connected to computer systems that control the physiological and physical responses of the mannequin. These simulators are able to provide direct feedback to learners in safe, risk-free environments. This technology has been used to teach all aspects of medical care, including medical knowledge, technical skills, and behavioural training or communication skills. The present article provides a general overview of simulation that will hopefully help to generate interest in paediatric simulation across Canada. Several tertiary care paediatric hospitals in Canada are already using simulation to teach health care providers; continued growth and interest is expected in this exciting area of medical education.


Effects of acute heat stress on lipid metabolism of bovine primary adipocytes.
Heat stress (HS) affects numerous physiological processes including nutrient partitioning and lipid metabolism. Objectives of this study were to evaluate how acute HS affects lipid metabolism in subcutaneous adipose tissue of dairy cattle. Adipose tissue biopsies were performed on Holstein cows for bovine primary adipocyte isolation and cultured at either 42°C (HS) or 37°C (thermal neutral, TN). Adipocytes were incubated with increasing isoproterenol (ISO), and with increasing concentrations of insulin in the presence of ISO to evaluate changes in lipolysis. Incorporation of radioactive acetate into lipids was measured as an indicator of lipogenesis. Abundance and phosphorylation of several lipolytic and lipogenic proteins were also measured. Adipocytes exposed to HS had an elevated maximal response to ISO and were more sensitive to lipolytic stimulation by ISO compared with cells cultured at TN. Thermal treatment did not affect the antilipolytic effects of insulin in the presence of ISO. Lipogenesis measured as acetate incorporation was not altered by HS, but a temperature by insulin interaction was observed for the regulation of acetyl CoA carboxylase, such that the presence of insulin resulted in a reduction in phosphorylation of acetyl CoA carboxylase in adipocytes cultured at TN but not HS conditions. Results of this study demonstrate that acute HS has a direct effect on the regulation of lipolysis and the rate-limiting enzyme of lipogenesis in isolated bovine adipocytes.


Limited enzymatic cleavage of pig immunoglobulin G and of specific antibodies. IV. Characteristics of the tFc' fragment obtained from the S-sulpho derivative of non-specific immunoglobulin G.
By tryptic cleavage of the S-sulpho derivative of non-specific pig IgG and subsequent separation by gel chromatography on Sephadex G-100 a fragment with molecular mass 11 900 +/- 500 was obtained. This fragment originates in the Fc part of the molecule because it precipitates with anti-Fc serum. It was therefore designated tFc'. From the pFc' fragment obtained by peptic cleavage it significantly differs in amino acid composition. tFc' fragment was subjected to ion-exchange chromatography on SE-Sephadex at pH 3.0 in a dissociating medium containing 8 M urea. Three major variants of tFc' fragment were purified by rechromatography and characterized by amino acid composition and by peptide maps. Their characteristic features are a high half-cystine content and a low content of arginine, histidine and methionine. The characteristics of all the three variants of tFc' fragment suggest that they most probably originate in the CH2 domain of immunoglobulin G.


Laser-Engineered Microcavity Surfaces with a Nanoscale Superhydrophobic Coating for Extreme Boiling Performance.
Functionalized interfaces enhancing phase-change processes have immense applicability in thermal management. Here, a methodology for fabrication of surfaces enabling extreme boiling heat transfer performance is demonstrated, combining direct nanosecond laser texturing and chemical vapor deposition of a hydrophobic fluorinated silane. Multiple strategies of laser texturing are explored on aluminum with subsequent nanoscale hydrophobization. Both superhydrophilic and superhydrophobic surfaces with laser-engineered microcavities exhibit significant enhancement of the pool boiling heat transfer. Surfaces with superhydrophobic microcavities allow for enhancements of a heat transfer coefficient of over 500%. Larger microcavities with a mean diameter of 4.2 μm, achieved using equidistant laser scanning separation, induce an early transition into the favorable nucleate boiling regime, while smaller microcavities with a mean diameter of 2.8 μm, achieved using variable separation, provide superior performance at high heat fluxes. The enhanced boiling performance confirms that the Wenzel wetting regime is possible during boiling on apparently superhydrophobic surfaces. A notable critical heat flux enhancement is demonstrated on superhydrophobic surfaces with an engineered microstructure showing definitively the importance and concomitant effect of both the surface wettability and topography for enhanced boiling. The fast, low-cost, and repeatable fabrication process has great potential for advanced thermal management applications.


Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite.
Asbestos exposure is strongly associated with the development of malignant mesothelioma, yet the mechanistic basis of this observation has not been resolved. Carcinogenic transformation or tumor progression mediated by asbestos may be related to the generation of free radical species and perturbation of cell signaling and transcription factors. We report here that exposure of human mesothelioma or lung carcinoma cells to nitric oxide (NO) in the presence of crocidolite asbestos resulted in a marked decrease in intracellular nitrosation and diminished NO-induced posttranslational modifications of tumor-associated proteins (hypoxia-inducible factor-1alpha and p53). Crocidolite rapidly scavenged NO with concomitant conversion to nitrite (NO(2)(-)). Crocidolite also catalyzed the nitration of cellular proteins in the presence of NO(2)(-) and hydrogen peroxide. Nitrated protein adducts are a prominent feature of asbestos-induced lung injury. These data highlight the ability of asbestos to induce phenotypic cellular changes through two processes: (a) by directly reducing bioactive NO levels and preventing its subsequent interaction with target molecules and (b) by increasing oxidative damage and protein modifications through NO(2) production and 3-nitrotyrosine formation.


Inhibition of exogenous 3-deoxy-D-manno-octulosonate incorporation into lipid A precursor of toluene-treated Salmonella typhimurium cells.
Analogs of 3-deoxy-D-manno-octulosonate (KDO) were designed to inhibit CTP:CMP-KDO cytidylyltransferase (CMP-KDO synthetase). Since these analogs lacked whole-cell antibacterial activity, a permeabilized-cell method was developed to measure intracellular compound activity directly. The method employed a mutant of Salmonella typhimurium defective in KDO-8-phosphate synthetase (kdsA), which accumulated lipid A precursor at 42 degrees C. Cells permeabilized with 1% toluene were used to evaluate inhibitor effect on [3H]KDO incorporation into preformed lipid A precursor. KDO incorporation proceeded through the enzymes CMP-KDO synthetase and CMP-KDO:lipid A KDO transferase. Optimum KDO incorporation occurred between pH 8 and 9 and required CTP, prior lipid A precursor accumulation, and a functional kdsB gene product, CMP-KDO synthetase. The apparent Km for KDO in this coupled system at pH 7.6 was 1.38 mM. The reaction products isolated and characterized contained 1 and 2 KDO residues per lipid A precursor molecule. Several KDO analogs produced concentration-related reductions of KDO incorporation in toluenized cells with 50% inhibitory concentrations comparable to those obtained in purified CMP-KDO synthetase systems. Two compounds, 8-amino-2-deoxy-KDO (A-60478) and 8-aminomethyl-2-deoxy-KDO (A-60821), competitively inhibited KDO incorporation, displaying Kis of 4.2 microM for A-60478 and 2.5 microM for A-60821. These data indicated that the inactivity of the KDO analogs on intact bacteria was the result of poor permeation into cells rather than intracellular inactivation.


PtrA is required for coordinate regulation of gene expression during phosphate stress in a marine Synechococcus.
Previous microarray analyses have shown a key role for the two-component system PhoBR (SYNW0947, SYNW0948) in the regulation of P transport and metabolism in the marine cyanobacterium Synechococcus sp. WH8102. However, there is some evidence that another regulator, SYNW1019 (PtrA), probably under the control of PhoBR, is involved in the response to P depletion. PtrA is a member of the cAMP receptor protein transcriptional regulator family that shows homology to NtcA, the global nitrogen regulator in cyanobacteria. To define the role of this regulator, we constructed a mutant by insertional inactivation and compared the physiology of wild-type Synechcococcus sp. WH8102 with the ptrA mutant under P-replete and P-stress conditions. In response to P stress the ptrA mutant failed to upregulate phosphatase activity. Microarrays and quantitative RT-PCR indicate that a subset of the Pho regulon is controlled by PtrA, including two phosphatases, a predicted phytase and a gene of unknown function psip1 (SYNW0165), all of which are highly upregulated during P limitation. Electrophoretic mobility shift assays indicate binding of overexpressed PtrA to promoter sequences upstream of the induced genes. This work suggests a two-tiered response to P depletion in this strain, the first being PhoB-dependent induction of high-affinity PO(4) transporters, and the second the PtrA-dependent induction of phosphatases for scavenging organic P. The levels of numerous other transcripts are also directly or indirectly influenced by PtrA, including those involved in cell-surface modification, metal uptake, photosynthesis, stress responses and other metabolic processes, which may indicate a wider role for PtrA in cellular regulation in marine picocyanobacteria.


The role of carrier size in the pharmacodynamics of antisense and siRNA oligonucleotides.
Effective therapeutic utilization of antisense and siRNA oligonucleotides represents a major challenge to drug delivery science. Although many strategies and technologies have been applied to oligonucleotide delivery, a key issue remains the role of molecular or carrier size. In this brief review, we address some of the size-related parameters that regulate the biodistribution of oligonucleotides. We also reprise several recent studies that have examined the inter-relationship of size and shape in influencing delivery.


Rapid and slow maxillary expansion: a posteroanterior cephalometric study.
The purpose of this study was to evaluate and compare the dental and orthopaedic effects of rapid and slow maxillary expansion in a sample of young patients with transversal maxillary deficiency by using a postero-anterior cephalometric analysis. Two groups of patients were considered: 10 patients (3 males, 7 females) with an average age of 8.9 years were treated with a rapid maxillary expansor (RME); 10 patients (7 males, 3 females) with an average age of 12.2 years were treated with a new slow maxillary expansion appliance (ELA). Postero-anterior cephalometric analyses were made at the beginning of the therapy (T0) and at the end of expansion (T1) using a computerised cephalometric programme. Four parameters were measured: Nasal width, maxillary width, mandibular width, upper molars width. Transversal average width increased 5.435 mm (SD 3.31 mm) between the upper molars in the RME group and 5.547 mm (SD 3.49 mm) in the SME group. Maxillary average width increased 4.254 mm in the first group and 2.845 mm in SME group. Discussion An orthopaedic result was reached with both treatments. These results are in agreement with the orthodontic literature. This work confirms the effectiveness, efficiency and usefulness of this new ELA appliance in the correction of transversal deficiency with orthopaedic results, if used in growing patients.


Highly acidic glycans from sea cucumbers. Isolation and fractionation of fucose-rich sulfated polysaccharides from the body wall of Ludwigothurea grisea.
The body wall of the sea cucumber contains high amounts of sulfated glycans, which differ in structure from glycosaminoglycans of animal tissues and also from the fucose-rich sulfated polysaccharides isolated from marine algae and from the jelly coat of sea urchin eggs. In Ludwigothurea grisea, glycans can be separated into three fractions which differ in molecular mass and chemical composition. The fraction containing a high-molecular-mass component has a high proportion of fucose and small amounts of amino sugars, whereas another fraction contains primarily a sulfated fucan. The third fraction, which represents the major portion of the sea cucumber polysaccharides, contains besides fucose, approximately equimolar proportions of glucuronic acid and amino sugars, and has a sulfate content higher than that in the other two fractions. Both D and L-isomers of fucose are found in these polysaccharides, and the sulfate is linked to the O-3 position of the fucose residues. The attachment position of the sulfate groups to the glucuronic acid units and amino sugars is still undetermined. It is possible that these compounds are involved in maintaining the integrity of the sea cucumber's body wall, in analogy with the role of other macromolecules in the vertebrate connective tissue.


Small molecule ligand docking to genotype specific bundle structures of hepatitis C virus (HCV) p7 protein.
The genome of hepatitis C virus encodes for an essential 63 amino acid polytopic protein p7 of most likely two transmembrane domains (TMDs). The protein is identified to self-assemble thereby rendering lipid membranes permeable to ions. A series of small molecules such as adamantanes, imino sugars and guanidinium compounds are known to interact with p7. A set of 9 of these small molecules is docked against hexameric bundles of genotypes 5a (bundle-5a) and 1b (bundle-1b) using LeadIT. Putative sites for bundle-5a are identified within the pore and at pockets on the outside of the bundle. For bundle-1b preferred sites are found at the site of the loops. Binding energies are in favour of the guanidinium compounds. Rescoring of the identified poses with HYDE reveals a dehydration penalty for the guanidinium compounds, leaving the adamantanes and imino sugar in a better position. Binding energies calculated by HYDE and those by LeadIT indicate that all compounds are moderate binders.


Gut-inhabiting bacterium Oxalobacter formigenes: role in calcium oxalate urolithiasis.
Oxalate plays a crucial role in the formation of most renal stones. Oxalate is a common constituent of most diets and a byproduct of metabolism, and if it is not sufficiently degraded, it may accumulate. In humans, gut bacteria degrade 70 to 100 mg of oxalate per day. Oxalobacter formigenes is a gram-negative, obligately anaerobic, rod-shaped bacterium with an absolute requirement for oxalate. Although not present in the gut at birth, it quickly colonizes most children, and there is epidemiologic evidence that its absence is a risk factor in calcium oxalate stone formation. We review the metabolism, genetics, and identification of this organism and its possible therapeutic role in recurrent stone-forming patients.


Leucoagaricus decipiens and La. erythrophaeus, a new species pair in sect. Piloselli.
Leucoagaricus decipiens and La. erythrophaeus, are described as new from Sardinia, Italy, and California, USA, respectively. These sister species show distinct reddening when touched on all parts of the basidiocarps and darken on drying. Their collariate lamellae, broadly cylindrical to utriform cheilocystidia and trichodermal pileus covering distinguish them morphologically from other species in sect. Piloselli, while nrITS and EF1-alpha sequences distinguish them from each other. Leucoagaricus erythrophaeus has been known under the name Lepiota roseifolia, but the type collection of this species does not fit the interpretation.


Foliar pH as a new plant trait: can it explain variation in foliar chemistry and carbon cycling processes among subarctic plant species and types?
Plant traits have become popular as predictors of interspecific variation in important ecosystem properties and processes. Here we introduce foliar pH as a possible new plant trait, and tested whether (1) green leaf pH or leaf litter pH correlates with biochemical and structural foliar traits that are linked to biogeochemical cycling; (2) there is consistent variation in green leaf pH or leaf litter pH among plant types as defined by nutrient uptake mode and higher taxonomy; (3) green leaf pH can predict a significant proportion of variation in leaf digestibility among plant species and types; (4) leaf litter pH can predict a significant proportion of variation in leaf litter decomposability among plant species and types. We found some evidence in support of all four hypotheses for a wide range of species in a subarctic flora, although cryptogams (fern allies and a moss) tended to weaken the patterns by showing relatively poor leaf digestibility or litter decomposability at a given pH. Among seed plant species, green leaf pH itself explained only up to a third of the interspecific variation in leaf digestibility and leaf litter up to a quarter of the interspecific variation in leaf litter decomposability. However, foliar pH substantially improved the power of foliar lignin and/or cellulose concentrations as predictors of these processes when added to regression models as a second variable. When species were aggregated into plant types as defined by higher taxonomy and nutrient uptake mode, green-specific leaf area was a more powerful predictor of digestibility or decomposability than any of the biochemical traits including pH. The usefulness of foliar pH as a new predictive trait, whether or not in combination with other traits, remains to be tested across more plant species, types and biomes, and also in relation to other plant or ecosystem traits and processes.


Trends in cardiovascular risk factors and their treatment among patients discharged from divisions of internal medicine. The FAPOI-1 and FADOI-2 studies.
There is an increasing interest in monitoring cardiovascular risk factor levels and their treatment. Two studies were run in patients discharged from Divisions of Internal Medicine. Two studies, respectively conducted in 1996 and 1999, have collected data on the diagnoses of cardiovascular diseases and cardiovascular risk factor levels and treatment in 6450 and 8133 patients (age > or = 35 years) discharged during 1 week from 235 and 345 Italian Divisions of Internal Medicine. The second survey revealed: a relative increase in heart failure and cerebrovascular disease diagnoses; lower serum levels of total cholesterol and triglycerides, lower systolic and diastolic blood pressure mean levels, and a decreased incidence of the habit of smoking among males. The proportion of treated hypertensives (blood pressure > or = 140/90 mmHg, or the use of antihypertensive drugs) increased slightly (65 to 68% among men and 69 to 71% among women). A reduction in the use of ACE-inhibitors was observed, balanced by an increase in the use of angiotensin II antagonists. The proportion of treated dyslipidemic patients (total cholesterol levels > or = 250 mg/dl, or HDL cholesterol levels < 35 mg/dl or triglyceride levels > or = 200 mg/dl or the use of hypolipidemic drugs) significantly increased from 10 to 25% among males and from 12 to 25% among females, due to a substantial increase in the use of statins. During a 3-year period increasing attention for cardiovascular risk factors and their treatment among patients discharged from Divisions of Internal Medicine has been documented. In particular, there has been a large increase in the use of statins, although large segments of patients may need further attention and drug treatment.


A study on the localization of the sternocleidomastoid and trapezius motoneurons in the rat by means of the HRP method.
The sternocleidomastoid and trapezius muscles of the rat, which are innervated by the spinal accessory nerve (SAN) and cervical spinal nerve (CSN), consist of five smaller muscles: the sternomastoid, cleidomastoid, clavotrapezius, acromiotrapezius, and spinotrapezius. In this study, the location of cell somata of the motoneurons supplying each of these smaller muscles and the peripheral course of their axons have been studied by means of the horseradish peroxidase retrograde axonal transport technique (the HRP method) in combination with cutting of the SAN. The sternocleidomastoid and trapezius motoneurons formed three cell columns, column-M, -L, and -5, in the ipsilateral ventral horn of the cervical spinal cord. Column-M and -L extend longitudinally in the medial nucleus of C1 and C2 and in the ventrolateral nucleus from the middle of C2 to the middle of C6, respectively. These columns consist of the motoneurons whose axons pass through the SAN and they merge in the caudal C2 to constitute the spinal accessory nucleus. Column-5, which consists of the motoneurons passing through the CSN, extends longitudinally from C3 to C5 close to column-L in the ventrolateral nucleus. Motoneurons supplying the sternomastoid, cleidomastoid, clavotrapezius, acromiotrapezius, and spinotrapezius muscles showed a rostrocaudal somatotopic distribution in the spinal accessory nucleus and in column-5 in this order, though the sternomastoid motoneurons were not found in column-5.


Renal and biliary disposition of dapsone in the dog.
Dapsone (4,4'-diaminodiphenylsulfone [DDS]) was administered intravenously to anesthetized dogs; urine was collected, heparinized venous blood was obtained, and bile was collected from some of the dogs. A constant infusion of inulin was maintained, and isosmotic or hypoosmotic fluids were administered. Dogs were studied under conditions of standardized, increased or decreased urine flow, and before and after plasmapheresis. Plasma, urine, and bile samples were analyzed for DDS and DDS conjugates; the degree of binding of DDS by plasma proteins was also determined. The renal clearances of inulin and DDS were calculated. No monoacetyldapsone (MADDS) was detected in the plasma, and only negligible quantities were found in the urine. Small quantities of DDS and DDS conjugates were detected in the bile in 4 h following the dose. Between 10 and 30% of the administered drug could be identified as DDS plus DDS conjugates in the urine in 8 h after the dose. Renal clearance of unbound DDS was proportional to the urine flow rate, and the clearance ratio of DDS to inulin approached the same maximal value as that for urea. Although the rate of urinary excretion of DDS conjugates was the same in the dog as in man, the rates of excretion of DDS and of DDS plus DDS conjugates were greater in the dog than in man, suggesting that the acetylation of DDS to MADDS by man but not by the dog and the greater degree of plasma protein binding of DDS and MADDS by man account for the longer half-time of disappearance of DDS in man compared to that in the dog.


Treatment for meningeal carcinomatosis in breast cancer.
Forty breast cancer patients with meningeal carcinomatosis were treated with a combined program of whole brain irradiation therapy with intrathecal and intraventricular methotrexate and citrovorum factor rescue. Responses were seen in 26 patients (65%); 13 patients (35%) failed to respond. The median survival time for the responding patients was six months, and for the nonresponders, one month. Factors affecting response and survival included pretreatment spinal fluid glucose, protein, and duration of CNS-related symptomatology prior to onset of therapy. In contrast, pretreatment CSF tumor cell count, CEA and initial CNS functional status did not appear to have prognostic significance. The authors conclude that following intensive therapy there can be much improvement in the quality of life and disease-free survival in breast cancer patients with meningeal carcinomatosis.


Interaction of myenteric neurons and extrinsic nerves in the intestinal inhibitory response induced by mesenteric nerve stimulation.
Effects of the mesenteric nerve stimulation (MNS) on the twitch contraction induced by field stimulation were investigated regarding the relationship between myenteric neurons and extrinsic cholinergic nerves in the guinea-pig mesenteric nerve-ileal preparation. The twitch contraction was inhibited after MNS. The inhibition of the twitch contraction after MNS was induced twice, just after MNS (1st inhibition) and 2-3 min later (2nd inhibition) (type I), or once, just after MNS (1st inhibition) (type II), in recovery course of twitch contraction for 6-8 min. The 1st inhibition was slightly decreased by guanethidine and hexamethonium. The inhibitory response (1st inhibition) in both types I and II was recovered to the control level by pretreatment with naloxone (recovered twitch contraction), but the late inhibitory response (2nd inhibition) was markedly observed after 2-3 min in types I and II. Either the 1st or the 2nd inhibition was not altered by capsaicin, desensitization to calcitonin gene-related polypeptide (CGRP), vasoactive intestinal polypeptide (VIP), somatostatin, or galanin. The recovered twitch contraction in types I and II was decreased by CGRP-desensitization, or capsaicin. These results suggest that the first inhibitory response was induced by enteric opioid neurons connected with extrinsic cholinergic nerves, but the 2nd inhibition was induced by unknown substances other than CGRP, VIP, somatostatin, and galanin. The twitch contraction may partly be induced by endogenous neurokinin-like substances. And, some CGRP containing neurons, which connect with extrinsic cholinergic nerves, probably activate the intrinsic excitatory neurons.


Unveiling the Interplay between the TLR4/MD2 Complex and HSP70 in the Human Cardiovascular System: A Computational Approach.
While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully understood, previous studies suggest that the innate immune system, through Toll-like receptor 4 (TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay with endogenous molecules. The Heat-shock protein 70 family (HSP70-70kDa) is of particular interest in cardiovascular tissues as it may have dual effects when interacting with TLR4 pathways. Although the hypothesis of the HSP70 family members acting as TLR4 ligands is becoming widely accepted, to date no co-crystal structure of this complex is available and it is still unknown whether this process requires the co-adaptor MD2. In this study, we aimed at investigating the interplay between the TLR4/MD2 complex and HSP70 family members in the human cardiovascular system through transcriptomic data analysis and at proposing a putative interaction model between these proteins. We report compelling evidence of correlated expression levels between TLR4 and MD2 with HSP70 cognate family members, especially in heart tissue. In our molecular docking simulations, we found that HSP70 in the ATP-bound state presents a better docking score towards the TLR4/MD2 complex compared to the ADP-bound state (-22.60 vs. -10.29 kcal/mol, respectively). Additionally, we show via a proximity ligation assay for HSP70 and TLR4, that cells stimulated with ATP have higher formation of fluorescent spots and that MD2 might be required for the complexation of these proteins. The insights provided by our computational approach are potential scaffolds for future in vivo studies investigating the interplay between the TLR4/MD2 complex and HSP70 family members in the cardiovascular system.


Interspinous ligament steroid injections for the management of Baastrup's disease: a case report.
Mitra R, Ghazi U, Kirpalani D, Cheng I. Interspinous ligament steroid injections for the management of Baastrup's disease: a case report. Baastrup's disease has been identified as a source of axial low back pain. There has been debate as to the etiology of pain in patients with Baastrup's disease. It has been theorized that the pain may originate from degenerative disk disease and spinal stenosis associated with the disease, whereas some have identified the neoarthrosis between joints and accompanying reactive eburnation as the source of pain. We present a simple case report of an 89-year-old woman with symptomatic Baastrup's disease. The patient underwent a fluoroscopically guided interspinous process injection of 20mg of triamcinolone acetate with local anesthetic. The patient remained pain free for 3 months. The neoarthrosis in Baastrup's disease may be the primary pain generator in cases of Baastrup's disease without significant central canal stenosis.


Informativeness of Early Huntington Disease Signs about Gene Status.
The cohort-level risk of Huntington disease (HD) is related to the age and symptom level of the cohort, but this relationship has not been made precise. To predict the evolving likelihood of carrying the Huntington disease (HD) gene for at-risk adults using age and sign level. Using data from adults with early signs and symptoms of HD linked to information on genetic status, we use Bayes' theorem to calculate the probability that an undiagnosed individual of a certain age and sign level has an expanded CAG repeat. Both age and sign levels have substantial influence on the likelihood of HD onset, and the probability of eventual diagnosis changes as those at risk age and exhibit (or fail to exhibit) symptoms. For example, our data suggest that in a cohort of individuals age 26 with a Unified Huntington's Disease Rating Scale (UHDRS) motor score of 7-10 70% of them will carry the HD mutation. For individuals age 56, the same motor score suggests only a 40% chance of carrying the mutation. Early motor signs of HD, overall and the chorea subscore, were highly predictive of disease onset at any age. However, body mass index (BMI) and cognitive performance scores were not as highly predictive. These results suggest that if researchers or clinicians are looking for early clues of HD, it may be more foretelling to look at motor rather than cognitive signs. Application of similar approaches could be used with other adult-onset genetic conditions.


[Primary research on indoor air concentration of particulate matter in residential house and its relationship with ambient pollution level].
To investigate the indoor air concentration of particulate matter in residential house and its relationship with ambient pollution level. Indoor and outdoor air level of PM2.5 and PM10 were monitored in 10 residential houses in downtown area. In the non-heating period, the indoor air level of PM2.5 and PM10 were 27.0 - 272.9 microg/m3 and 42.9 - 309.6 microg/m3, respectively. In the heating period, PM2.5 and PM10 were 20.7 - 251.4 microg/m3 and 34.0 - 283.9 microg/m3, respectively. There were good correlation between the indoor air concentrations of PM2.5 and PM10. The relationships between the indoor and outdoor air concentrations of PM2.5 and PM10, however, were not clear. Our results showed that there were serious indoor air pollution of particulate matter in residential house. Further research will be needed to clarify the characteristics of indoor air particulate matter pollution and its influence on resident.


Comparative in vitro study of the proliferation and growth of ovine osteoblast-like cells on various alloplastic biomaterials manufactured for augmentation and reconstruction of tissue or bone defects.
In this in vitro study ovine osteoblast-like cells were cultured on seven different alloplastic biomaterials used for augmentation and for reconstruction of bone defects in dental and craniomaxillofacial surgery. The aim of this study was to examine the growth behaviour (viability, cell density and morphology) of ovine osteoblast-like cells on the investigated biomaterials to get knowledge which biomaterial is qualified to act as a cell carrier system in further in vivo experiments. The biomaterials were either synthetically manufactured or of natural origin. As synthetically manufactured biomaterials Ethisorb, MakroSorb, PalacosR, and PDS film were used. As biomaterials of natural origin BeriplastP, Bio-Oss and Titanmesh were investigated. The cell proliferation and cell colonization were analyzed by a proliferation assay and scanning electron microscopy. Osteoblast-like cells proliferated and attached on all biomaterials, except on Beriplast. On Ethisorb the highest cell proliferation rate was measured followed by PalacosR. Both biomaterials offer suitable growth and proliferation conditions for ovine osteoblast-like cells. The proliferation rates of Bio-Oss, MakroSorb, PDS-film and Titanmesh were low and SEM examinations of these materials showed less spread osteoblast-like cells. The results showed that ovine osteoblast-like cells appear to be sensitive to substrate composition and topography. This in vitro study provides the basis for further in vivo studies using the sheep model to examine the biocompatibility and the long-term interaction between the test material and tissue (bone regeneration).


Glial Sphingosine-Mediated Epigenetic Regulation Stabilizes Synaptic Function in Drosophila Models of Alzheimer's Disease.
Destabilization of neural activity caused by failures of homeostatic regulation has been hypothesized to drive the progression of Alzheimer's Disease (AD). However, the underpinning mechanisms that connect synaptic homeostasis and the disease etiology are yet to be fully understood. Here, we demonstrated that neuronal overexpression of amyloid β (Aβ) causes abnormal histone acetylation in peripheral glia and completely blocks presynaptic homeostatic potentiation (PHP) at the neuromuscular junction in Drosophila The synaptic deficits caused by Aβ overexpression in motoneurons are associated with motor function impairment at the adult stage. Moreover, we found that a sphingosine analog drug, Fingolimod, ameliorates synaptic homeostatic plasticity impairment, abnormal glial histone acetylation, and motor behavior defects in the Aβ models. We further demonstrated that perineurial glial sphingosine kinase 2 (Sk2) is not only required for PHP, but also plays a beneficial role in modulating PHP in the Aβ models. Glial overexpression of Sk2 rescues PHP, glial histone acetylation, and motor function deficits that are associated with Aβ in Drosophila Finally, we showed that glial overexpression of Sk2 restores PHP and glial histone acetylation in a genetic loss-of-function mutant of the Spt-Ada-Gcn5 Acetyltransferase complex, strongly suggesting that Sk2 modulates PHP through epigenetic regulation. Both male and female animals were used in the experiments and analyses in this study. Collectively, we provided genetic evidence demonstrating that abnormal glial epigenetic alterations in Aβ models in Drosophila are associated with the impairment of PHP and that the sphingosine signaling pathway displays protective activities in stabilizing synaptic physiology.SIGNIFICANCE STATEMENT Fingolimod, an oral drug to treat multiple sclerosis, is phosphorylated by sphingosine kinases to generate its active form. It is known that Fingolimod enhances the cognitive function in mouse models of Alzheimer's disease (AD), but the role of sphingosine kinases in AD is not clear. We bridge this knowledge gap by demonstrating the relationship between impaired homeostatic plasticity and AD. We show that sphingosine kinase 2 (Sk2) in glial cells is necessary for homeostatic plasticity and that glial Sk2-mediated epigenetic signaling has a protective role in synapse stabilization. Our findings demonstrate the potential of the glial sphingosine signaling as a key player in glia-neuron interactions during homeostatic plasticity, suggesting it could be a promising target for sustaining synaptic function in AD.


The relationship between scholastic progress and nutritional status. Part II. A one-year follow-up study.
A 1-year follow-up study was conducted on a group of Indian children who were initially identified as being grossly anthropometrically stunted, and who had severe problems in reading after having attended school for 1 year. It was found that after an additional year's schooling virtually no improvement, either in the ability to read or in anthropometric status, had occurred. It is suggested that as a matter of urgency educationists, sociologists and physiologists should confer to take cognizance of the recent, extremely important findings pertaining to permanent intellectual stunting resulting from chronic malnutrition of infants up to their 4th postnatal year.


The human pregnancy-specific glycoprotein genes are tightly linked on the long arm of chromosome 19 and are coordinately expressed.
The pregnancy-specific glycoprotein (PSG) genes encode a group of proteins which are found in large amounts in placenta and maternal serum. In situ hybridization analyses of metaphase chromosomes reveal that all the human pregnancy-specific glycoprotein (PSG) genes are located on the long arm of chromosome 19 (19q13.2-13.3), overlapping the region containing the closely-related carcinoembryonic antigen (CEA) gene subgroup. Higher resolution analyses indicate that the PSG genes are closely linked within an 800kb SacII restriction endonuclease fragment. This has been confirmed through restriction endonuclease mapping and DNA sequence analyses of isolated genomic clones, which show that at least some of these genes are located in very close proximity. Further, these studies have helped to identify a new member of the PSG gene subfamily (PSG7). DNA/RNA hybridization analyses, using gene-specific oligonucleotide probes based on published sequences, showed that five from six PSG genes tested are coordinately transcribed in the placenta. Due to the close proximity of these genes and their coordinated expression pattern, common transcriptional regulatory elements may exist.


Satisfaction and well-being of primary care providers in managed care.
We compared perceptions about the practice environment and the job satisfaction of physician assistants (PAs), nurse practitioners (NPs), and primary care physicians in a large group-model HMO. The data source was a self-administered mail survey (average response rate = 79%). PA/NPs and primary care physicians reported that professional autonomy was not a problem and were satisfied with most aspects of practice in this setting. Common areas of dissatisfaction included patient load and amount of time with patients. PA/NPs were more likely than the physicians to experience stress on a daily basis, however, and were less likely to report that they would choose the practice setting again. They also were significantly less satisfied than the physicians with their incomes and fringe benefits. Our findings suggest that more attention should be given to practice conditions and compensation of PAs and NPs in managed care.


Phagocytosis: Our Current Understanding of a Universal Biological Process.
Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 μm in diameter, including microorganisms, foreign substances, and apoptotic cells. Phagocytosis is found in many types of cells and it is, in consequence an essential process for tissue homeostasis. However, only specialized cells termed professional phagocytes accomplish phagocytosis with high efficiency. Macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts are among these dedicated cells. These professional phagocytes express several phagocytic receptors that activate signaling pathways resulting in phagocytosis. The process of phagocytosis involves several phases: i) detection of the particle to be ingested, ii) activation of the internalization process, iii) formation of a specialized vacuole called phagosome, and iv) maturation of the phagosome to transform it into a phagolysosome. In this review, we present a general view of our current understanding on cells, phagocytic receptors and phases involved in phagocytosis.


'False positive' MRI of the knee: a literature review study.
A retrospective literature review study was performed because our group has seen an increasing number of patients with a "positive MRI" for torn meniscus being referred for arthroscopic surgery yet their clinical signs and symptoms do not fit that of a "torn meniscus." Fifteen literature articles from 1989 through 1999 were evaluated for MRI studies on asymptomatic volunteers. Starting in the third decade, there is "age-dependent degeneration" of the meniscus with increasing MRI signals in the meniscus in asymptomatic patients. By the fourth and fifth decades, significant MRI changes are present, especially in the medial meniscus, yet these patients were asymptomatic. Studies in the literature urge that "clinicians match clinical signs and symptoms with magnetic resonance imaging before instituting surgical treatment." The authors of this paper encourage the MRI report to use the term "signal change--1, 2, 3" rather than describing them as "tears." A "tear" is a clinical-pathological diagnosis.


Subcutaneous enoxaparin for outpatient anticoagulation therapy in a patient with an aortic valve replacement.
Low-molecular-weight heparins have been administered for a variety of clinical conditions. A patient with a mechanical aortic valve replacement patient underwent elective transurethral prostatectomy. Anticoagulation was managed with unfractionated heparin immediately preoperatively and postoperatively. Warfarin was begun on postoperative day 1. The patient had a prolonged hospitalization due to subtherapeutic international normalized ratios (INR) despite warfarin administration. Because he intended to leave the hospital against medical advice before therapeutic INR was achieved, enoxaparin 1 mg/kg subcutaneously every 12 hours was prescribed to provide anticoagulation, facilitating discharge and improving the patient's quality of life. Enoxaparin was associated with an approximate saving of $4500 over warfarin. The only adverse event reported was bruising at the injection site.


Endoscopic Recurrence 6 Months After Ileocecal Resection in Children With Crohn Disease Treated With Azathioprine.
Intestinal surgery is an important part of Crohn disease (CD) treatment in children. The aim of the present study was to compare the rate of endoscopic recurrence at the sixth month after ileocecal resection (ICR) in children with CD treated with azathioprine between patients who received prior antitumor necrosis factor alpha (anti-TNF-α) therapy and those who were not administered this therapy. Moreover, we tried to identify the potential risk factors for disease recurrence and describe the schedule of long-term follow-up after surgery. We prospectively collected data from pediatric patients with CD, who underwent ICR between October 2011 and June 2015 at our hospital and were treated with azathioprine monotherapy after ICR. We evaluated the endoscopic recurrence (Rutgeerts score) at the sixth month after ICR in all included patients. Among 21 included patients, 13 achieved endoscopic remission (Rutgeerts score < i2) at the sixth month after ICR. No difference was found between patients who received prior anti-TNF-α therapy and those who did not. We did not find any clinically relevant factors associated with endoscopic recurrence rate at the sixth month. Prior anti-TNF-α therapy does not seem to be a strong risk factor for endoscopic recurrence within 6 months after ICR. Further studies on large sample of patients are needed to identify potential predictors of disease recurrence.


Molecular Engineering of Robustness and Resilience in Enzymatic Reaction Networks.
Living systems rely on complex networks of chemical reactions to control the concentrations of molecules in space and time. Despite the enormous complexity in biological networks, it is possible to identify network motifs that lead to functional outputs such as bistability or oscillations. One of the greatest challenges in chemistry is the creation of such functionality from chemical reactions. A key limitation is our lack of understanding of how molecular structure impacts on the dynamics of chemical reaction networks, preventing the design of networks that are robust (i.e., function in a large parameter space) and resilient (i.e., reach their out-of-equilibrium function rapidly). Here we demonstrate that reaction rates of individual reactions in the network can control the dynamics by which the system reaches limit cycle oscillations, thereby gaining information on the key parameters that govern the dynamics of these networks. We envision that these principles will be incorporated into the design of network motifs, enabling chemists to develop "molecular software" to create functional behavior in chemical systems.


Factors in Gestational Diabetes Mellitus Predicting the Needs for Insulin Therapy.
Objective. To identify factors predicting the need for insulin therapy in pregnancies complicated by gestational diabetes mellitus (GDM). Methods. A total of 1352 patients with GDM diagnosed by the 75-g/2-h oral glucose tolerance test (OGTT) were enrolled in this study. Univariate and multivariate analysis were performed; receiver operating characteristics (ROC) were also drawn. Results. There was a significant difference in factors such as maternal age, pregestational BMI, first visit SBP, first visit DBP, FBG of first visit, FBG at time of OGTT, 75-g OGTT glucose value (fasting, after 1 h and 2 h), and serum HbA1c level at diagnosis between patients with insulin therapy and patients with medical nutrition therapy (MNT) alone. Multivariate analysis showed that higher FBG at time of OGTT, first 75 g OGTT 2 h plasma glucose, and HbA1c concentration at diagnosis lead to more likely need of insulin therapy. Conclusion. The probability of insulin therapy can be estimated in pregnant women with GDM based on fasting and 2 h glucose values during OGTT and HbA1c value at diagnosis of GDM.