Dantrolene downregulates the gene expression and activity of the ubiquitin-proteasome proteolytic pathway in septic skeletal muscle.
In previous studies, dantrolene prevented sepsis-induced muscle proteolysis, but the influence of dantrolene on the expression and activity of the ubiquitin-proteasome proteolytic pathway is not known. In addition, the role of glucocorticoids in the anabolic effect of dantrolene is not well understood. Sepsis was induced in rats by cecal ligation and puncture (CLP). Other rats underwent sham-operation. Groups of rats were treated with dantrolene (10 mg/kg) administered 2 h before and 8 h after sham-operation or CLP. Sixteen hours after sham-operation or CLP, mRNA levels for ubiquitin, the ubiquitin ligase E3alpha, and the 20S proteasome subunit C3 were determined by dot-blot analysis. In additional experiments, the effect of dantrolene on protein degradation was tested in L6 myotubes cultured in the absence or presence of dexamethasone. Treatment of rats with dantrolene prevented the sepsis-induced increase in mRNA levels for ubiquitin, the ubiquitin ligase E3alpha, and the 20S proteasome subunit C3. In additional experiments, treatment of cultured myotubes with dantrolene reduced protein degradation in both the absence and the presence of dexamethasone. The results suggest that dantrolene can prevent sepsis-induced activation of the ubiquitin-proteasome proteolytic pathway in skeletal muscle and that dantrolene reduces muscle protein degradation independent of glucocorticoids.


[Molecular evolution and correlation of HN and P gene among the field Newcastle disease viruses].
The goal of this study is to research the genetic characteristics and relationship between HN and P genes of NDV. The nucleotide sequence and deduced amino acid sequence were analyzed for the Hemagglutinin-neuramindase (HN) and Phosphoprotein (P) gene of twelve field isolates of Newcastle disease virus (NDV) during 1997-2005 in China. The HN and P gene sequences of fifteen NDV reference strains from GenBank were also used in this study. The molecular evolution distance of nucleotides and amino acids were calculated by MEGA 4.0 software, and analysis of variance and correlations were analyzed by SPSS11.0 software among different length sequences of the HN gene or P gene. The nucleotide and amino acids correlation of HN and P gene were analyzed respectively. The correlation of evolution distance and isolation year were also calculated. The results indicated that there were difference and good correlation of nucleotide and amino acid among different length sequences of the HN gene or P gene. These results revealed that the HN and P gene of NDV have the different response to selective pressure to adopt to landscape and closely relationship on heredity mutations. Nucleotide variations of HN and P gene have relationship with isolation year of strains.


MiR-744 increases tumorigenicity of pancreatic cancer by activating Wnt/β-catenin pathway.
The Wnt/β-catenin signaling pathway, commonly hyperactivated in pancreatic cancer, has been reported to play an important role in the maintenance of stemness of cancer stem cells (CSCs), which is closely related to the progression of pancreatic cancer. Therefore, exploring the regulatory mechanism in Wnt/β-catenin signaling may provide valuable clinical targets for cancer therapy. In the current study, we demonstrated that upregulation of miR-744 in pancreatic cancer promoted Wnt/β-catenin signaling by directly targeting secreted frizzled-related protein 1 (SFRP1), glycogen synthase kinase 3β (GSK3β), and transducin-like enhancer of split 3 (TLE3), important negative modulators of Wnt/β-catenin signaling. Expression of miR-744 was markedly upregulated in pancreatic cancer and positively correlated with poor patient survival. Furthermore, we found that overexpressing miR-744 enhanced, while inhibiting miR-744 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. Importantly, in vivo model of human-derived pancreatic xenografts showed that miR-744 upregulation enhanced the tumorigenicity of pancreatic cancer cells. These findings suggest that miR-744 plays a vital role in promoting the stem cell-like phenotype of pancreatic cancer cells, and may represent a novel prognostic biomarker and therapeutic target.


[Level investigation on coptidis rhizoma processing methods and product specifications].
The existing processing methods, commercial specification and grades, and the marketing of Coptidis Rhizoma were systematical researched, referring to ancient, modern and contemporary medical literatures with the combination of our fieldwork on main origins of Coptidis Rhizoma and some herbs markets. Results showed that Coptidis Rhizoma processing methods mainly included sun-dried method and baked method anciently. For now, the processing methods become various, including thin paper-covering under the sun drying, direct drying, oven drying and microflame-fry drying. In the literatures, the main chemical constituent berberine was determined of its content to analyze the processing methods, finding that the sun drying and baked drying affect the berberine content, so the temperature must be controlled when drying. The thin paper-covering drying method is so cumbersome for large quantities of medicinal herbs and in wind conditions that it has been eliminated. Eventually, direct drying, oven drying and microflame-fry drying are chosen to the large-scale socialized production for their convenient and simple operation, making up the current main processing methods. Coptidis Rhizoma products have 3 specifications of Weilian, Yalian, Yunlian, of each specification there are 2 levels, but in fact the market of Weilian commodities overtakes the Yunlian, which only sold in parts of Yunnan, and the no-sale Yalian. The mainstream commercial Weilian are often sold in general way, gradeless and uniformly-priced. There are regional differences of the processing methods on Coptidis Rhizoma, which needs unified research and development of relevant standard operating procedures to ensure the quality of medicine, urgently. Coptidis Rhizoma product specifications and the intrinsic quality-grade correlation need to be further improved, which could provide a more reliable standard for quality at competitive prices, and it is recommended that "medicinal commercial specification and grade standard" content be increased into the Herbs part of Chinese Pharmacopoeia.


Sendai Virus, a Strong Inducer of Anti-Lentiviral State in Ovine Cells.
Small ruminant lentiviruses (SRLVs) are widely spread in the ovine and caprine populations, causing an incurable disease affecting animal health and production. Vaccine development is hindered owing to the high genetic heterogeneity of lentiviruses and the selection of T-cell and antibody escape mutants, requiring antigen delivery optimization. Sendai virus (SeV) is a respiratory paramyxovirus in mice that has been recognized as a potent inducer of innate immune responses in several species, including mouse and human. The aim of this study was to stimulate an innate antiviral response in ovine cells and evaluate the potential inhibitory effect upon small ruminant lentivirus (SRLV) infections. Ovine alveolar macrophages (AMs), blood-derived macrophages (BDMs), and skin fibroblasts (OSFs) were stimulated through infection with SeV encoding green fluorescent protein (GFP). SeV efficiently infected ovine cells, inducing an antiviral state in AM from SRLV naturally-infected animals, as well as in in vitro SRLV-infected BDM and OSF from non-infected animals. Supernatants from SeV-infected AM induced an antiviral state when transferred to fresh cells challenged with SRLV. Similar to SRLV, infectivity of an HIV-1-GFP lentiviral vector was also restricted in ovine cells infected with SeV. In myeloid cells, an M1-like proinflammatory polarization was observed together with an APOBEC3Z1 induction, among other lentiviral restriction factors. Our observations may boost new approximations in ameliorating the SRLV burden by stimulation of the innate immune response using SeV-based vaccine vectors.


[Incidence and classification diagnosis of coronary artery fistula at dual-source CT coronary angiography].
To evaluate the incidence, types and clinical significance of coronary artery fistula (CAF) on CT coronary angiography (CTCA). A total of 48 533 consecutive patients undergoing CTCA at 4 Chinese hospitals were retrospectively analyzed. The incidence, types and clinical significance of CAF were retrospectively summarized. One hundred and two patients had CAF with the incidence of 0.21% (102/48 533). Among them, coronary to pulmonary artery fistulas were seen in 92 patients (90.2%, 92/102), coronary to right atrium fistula in 4 (3.9%, 4/102), coronary to right ventricular fistula in 2 (2.0%, 2/102), coronary to right ventricular fistula in 2 (2.0%, 2/102), coronary to left atrium fistula in 1 (1.0%, 1/102) and coronary to small cardiac vein in 1 (1.0%, 1/102). Among 92 coronary to pulmonary artery fistulas, fistulas originated from both coronary arteries in 46 patients (50.0%, 46/92), from left coronary artery in 28 (30.4%, 28/92) and right coronary artery in 11 (12.0%, 11/92) and the remaining 7 (7.6%, 7/92) coronary to pulmonary artery fistulas were associated with extracardiac communications. The incidence of CAF is 0.21% with a predominance of coronary to pulmonary artery fistulas (90.2%). The most common type of CAF is coronary to pulmonary artery fistulas from both coronary arteries (50.0%). Dual source CTCA can clearly visualize types and abnormal vessels so that it plays an important role in the diagnosis and preoperative evaluation of CAF.


Function of the conserved S1 and KH domains in polynucleotide phosphorylase.
We have examined the roles of the conserved S1 and KH RNA binding motifs in the widely dispersed prokaryotic exoribonuclease polynucleotide phosphorylase (PNPase). These domains can be released from the enzyme by mild proteolysis or by truncation of the gene. Using purified recombinant enzymes, we have assessed the effects of specific deletions on RNA binding, on activity against a synthetic substrate under multiple-turnover conditions, and on the ability of truncated forms of PNPase to form a minimal RNA degradosome with RNase E and RhlB. Deletion of the S1 domain reduces the apparent activity of the enzyme by almost 70-fold under low-ionic-strength conditions and limits the enzyme to digest a single substrate molecule. Activity and product release are substantially regained at higher ionic strengths. This deletion also reduces the affinity of the enzyme for RNA, without affecting the enzyme's ability to bind to RNase E. Deletion of the KH domain produces similar, but less severe, effects, while deletion of both the S1 and KH domains accentuates the loss of activity, product release, and RNA binding but has no effect on binding to RNase E. We propose that the S1 domain, possibly arrayed with the KH domain, forms an RNA binding surface that facilitates substrate recognition and thus indirectly potentiates product release. The present data as well as prior observations can be rationalized by a two-step model for substrate binding.


[Analysis of constituents in urushi wax, a natural food additive].
Urushi wax is a natural gum base used as a food additive. In order to evaluate the quality of urushi wax as a food additive and to obtain information useful for setting official standards, we investigated the constituents and their concentrations in urushi wax, using the same sample as scheduled for toxicity testing. After methanolysis of urushi wax, the composition of fatty acids was analyzed by GC/MS. The results indicated that the main fatty acids were palmitic acid, oleic acid and stearic acid. LC/MS analysis of urushi wax provided molecular-related ions of the main constituents. The main constituents were identified as triglycerides, namely glyceryl tripalmitate (30.7%), glyceryl dipalmitate monooleate (21.2%), glyceryl dioleate monopalmitate (2.1%), glyceryl monooleate monopalmitate monostearate (2.6%), glyceryl dipalmitate monostearate (5.6%), glyceryl distearate monopalmitate (1.4%). Glyceryl dipalmitate monooleate isomers differing in the binding sites of each constituent fatty acid could be separately determined by LC/MS/MS.


Treatment of comminuted distal radius fractures with pins and plaster.
Based on this review, it is evident that the anatomic results obtained by the use of pins and plaster for the treatment of comminuted distal radial fractures is insufficient to yield a high percentage of satisfactory functional end results. In addition, the high complication and reoperation rate noted in our series makes us question whether the technique of pins and plaster should remain a treatment option for these difficult fractures. Perhaps a combination of internal fixation with bone grafting combined with external fixation will provide a solution to this fracture, particularly in young, active patients.


Ultralow thermal sensitivity of phase and propagation delay in hollow core optical fibres.
Propagation time through an optical fibre changes with the environment, e.g., a change in temperature alters the fibre length and its refractive index. These changes have negligible impact in many key fibre applications, e.g., telecommunications, however, they can be detrimental in many others. Examples are fibre-based interferometry (e.g., for precise measurement and sensing) and fibre-based transfer and distribution of accurate time and frequency. Here we show through two independent experiments that hollow-core photonic bandgap fibres have a significantly smaller sensitivity to temperature variations than traditional solid-core fibres. The 18 times improvement observed, over 3 times larger than previously reported, makes them the most environmentally insensitive fibre technology available and a promising candidate for many next-generation fibre systems applications that are sensitive to drifts in optical phase or absolute propagation delay.


Constrained liner in neurologic or cognitively impaired patients undergoing primary THA.
THA performed in patients with cognitive deficits or neuromuscular diseases has been associated with a high postoperative dislocation rate. The constrained liner reportedly provides stability in patients with recurrent dislocation. However, achieving stability could be offset by early loosening when used in patients with neurologic diseases. We therefore asked whether constrained liners had a higher risk of loosening when used in primary THA for patients with neurologic diseases. We retrospectively reviewed a 144 patients (164 hips) with neuromuscular disease who had a constrained polyethylene insert from 1999 to 2004 and compared them to another 120 patients (132 hips) with neuromuscular disease operated on immediately before this period (from 1994 to 1998) who had a conventional polyethylene insert. Thirty-three (25%) of the 132 hips without a constrained liner were known to have had at least one dislocation and 21 had revision for recurrent dislocation. Ten other hips had revision for loosening of the cup. The survival rate was 82% at 5 years and 77% at 10 years with revision due to recurrent dislocation or loosening of the cup as the endpoint. With a constrained liner, at minimum 5-year followup (mean, 7 years; range, 5-10 years), the incidence of complications, particularly dislocation, was decreased (three dislocations among 164 hips; 2%), with one revision for recurrent dislocation and one revision for loosening. This constrained acetabular component provides durable protection against dislocation without substantial increased loosening at midterm followup.


Dissociated human foreskin mast cells degranulate in response to anti-IgE and substance P.
Human skin mast cells release histamine in response to both immunologic stimulation mediated by anti-IgE and IgE-independent mechanisms of which substance P is a prototypical secretagogue. We compared the ultrastructural changes produced in dissociated foreskin mast cells by these two stimuli with histamine release. Mast cells were isolated and pooled from the foreskins of 2- to 7-year-old boys in four separate experiments and comprised 25 to 60% of the total dissociated cells. The secretory granules in resting mast cells comprised 47.5% of the extranuclear cell volume and contained crystalline structures, namely, scrolls, gratings, and lattices, in an electron-dense matrix. Stimulation with either anti-IgE or substance P resulted in a net histamine release of 10.2 +/- 1.7% or 21.4 +/- 4.0%, respectively. After either secretagogue, about 75% of the cells underwent compound exocytosis, with fusion of the granule membranes with one another and with the plasma membrane to produce large degranulation channels that opened to the extracellular space. The granules lost their crystalline structure and electron density during secretion but retained the round shape of the original granule as a core that subsequently formed a fibrillar residue. Degranulation channels occupied 30 to 60% of the cytoplasmic volume after substance P stimulation and 10 to 40% after anti-IgE, which compared well with the greater histamine release measured after substance P. The rapid increase in the volume of the degranulation channels after substance P was accompanied by a decrease in cytoplasmic volume, suggesting water moved from the cytoplasm into the granules after stimulation. This study shows that secretion produced in dissociated human foreskin mast cells by two different stimuli, anti-IgE and substance P, which act through different membrane receptors and have distinct secretory characteristics, is similar morphologically.


Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene.
We report the molecular findings in two independent patients presenting with progressive generalized dystonia and bilateral striatal necrosis in whom we have identified a mutation (T14487C) in the mitochondrial ND6 gene. The mutation is heteroplasmic in all samples analyzed, and it fulfills all accepted criteria of pathogenicity. Transmitochondrial cell lines harboring 100% mutant mitochondrial DNA showed a marked decrease in the activity of complex I of the respiratory chain supporting the pathogenic role of T14487C.


[Component activity of the isoenzyme spectra of Saccharomyces cerevisiae, Saccharomyces carlsbergensis and their hybrids].
The object of this work was to study the activity and the isozyme spectra of hexokinase (the triggering enzyme of glycolysis), glucose-6-phosphate dehydrogenase (the key enzyme of the pentose-phosphate shunt), malate dehydrogenase and isocitrate dehydrogenase (the enzymes of the citric acid cycle) and alcohol dehydrogenase (the enzyme involved in the first steps of ethanol oxidation) in Saccharomyces cerevisiae, race Ya, S. carlsbergensis, race 4228, and their hybrid 67. The parent organisms and their hybrid were shown to differ from one another in the qualitative composition and the activity of the isozyme spectra of the above enzymes.


Acute neonatal glucocorticoid exposure produces selective and rapid cerebellar neural progenitor cell apoptotic death.
There has been a growing controversy regarding the continued use of glucocorticoid therapy to treat respiratory dysfunction associated with prematurity, as mounting clinical evidence has shown neonatal exposure produces permanent neuromotor and cognitive deficits. Here we report that, during a selective neonatal window of vulnerability, a single glucocorticoid injection in the mouse produces rapid and selective apoptotic cell death of the proliferating neural progenitor cells in the cerebellar external granule layer and permanent reductions in neuronal cell counts of their progeny, the cerebellar internal granule layer neurons. Our estimates suggest that this mouse window of vulnerability would correspond in the human to a period extending from approximately 20 weeks gestation to 6.5 weeks after birth. This death pathway is critically regulated by the proapoptotic Bcl-2 family member Puma and is independent of p53 expression. These rodent data indicate that there exists a previously unknown window of vulnerability during which a single glucocorticoid exposure at clinically relevant doses can produce neural progenitor cell apoptosis and permanent cerebellar pathology that may be responsible for some of the iatrogenically induced neurodevelopmental abnormalities seen in children exposed to this drug. This vulnerability may be related to the physiological role of glucocorticoids in regulating programmed cell death in the mammalian cerebellum.


Renal primitive neuroectodermal tumor: a morphologic, cytogenetic, and molecular analysis with the establishment of two cultured cell lines.
We report two patients with renal primitive neuroectodermal tumor (PNET) in whom the diagnosis was established by both a cytogenetic and a molecular analysis. Histologically, both renal tumors were composed of uniform immature round cells with a positive immunoreactivity for O13 (p30/32 MIC2). The cytogenetic analysis with in situ hybridization (chromosome painting) demonstrated reciprocal translocation t(11;22)(q24;q12) specific to PNET in the cultured cells derived from each tumor. The reverse transcriptase-polymerase chain reaction (RT-PCR) in both tumors demonstrated EWS/ FLI-1 fusion transcripts, representing the molecular equivalent of t(11;22). A Southern blot analysis also confirmed EWS gene rearrangement in both renal tumors. In addition, the authors also established two new cell lines (designated as FU-RPNT-1 and FU-RPNT-2) from renal PNETs. When transplanted into athymic mice, FU-RPNT-1 and FU-RPNT-2 reproduced and maintained the morphologic and molecular characteristics of the original tumors. In conclusion, the detection of t(11;22) and EWS/FLI-1 fusion transcripts is considered to provide a novel adjunctive method for diagnosing renal PNET. These newly established cell lines thus may be used to investigate the biologic behavior related to renal PNETs.


Formation of a new solo-LTR of the human endogenous retrovirus H family in human chromosome 21.
Human endogenous retroviruses (HERVs) contribute to various kinds of genomic instability via rearrangement and retrotransposition events. In the present study the formation of a new human-specific solo-LTR belonging to the HERV-H family (AP001667; chromosome 21q21) was detected by a comparative analysis of human chromosome 21 and chimpanzee chromosome 22. The solo-LTR was formed as a result of an equal homologous recombination excision event. Several evolutionary processes have occurred at this locus during primate evolution, indicating that mammalian-wide interspersed repeat (MIR) and full-length HERV-H elements integrated into hominoid genomes after the divergence of Old World monkeys and hominoids, and that the solo-LTR element was created by recombination excision of the HERV-H only in the human genome.


[Pseudotumor of the ureter manifesting periarteritis nodosa].
The authors report a case of anuria. The existence of an isolated pseudotumor of the pelvic ureter revealed a case of periarteritis nodosa. A segmental resection and a psoic bladder provided satisfactory functional recovery.


Cranial nerve syndrome in thrombosis of the transverse/sigmoid sinuses.
Cerebral venous thrombosis (CVT) is a cerebrovascular disease associated with a wide variety of clinical signs and symptoms, which may often delay appropriate diagnosis. Single or multiple cranial nerve palsies (III-VIII) without evidence of other signs and symptoms have not, so far, been considered a relevant syndrome of CVT. This event turned out to be a characteristic finding in five patients with thrombosis of the ipsilateral transverse/sigmoid sinus, who were recruited prospectively over a 14-month period. The diagnosis was supported by non-invasive MRI with the application of a newly developed subtraction technique. In view of the considerable mimics of the syndrome, and the long-standing need for conventional angiography to confirm the disease, it is likely to have been underestimated in the past; since appropriate treatment seems possible the diagnosis and utility of early MR venography should be considered in patients with single or multiple cranial nerve lesions of uncertain aetiology.


Arson: a growing inferno.
In a series of 34 arsonists, our survey compares the changing trends in arson to an earlier study carried out ten years ago in the same region in the UK by Rix (1994). The survey is based on pre-trial court reports done by the second author only. Fire-setting offending was predominantly seen in the young male (18-32). Fire-setting started as early as age seven and was seen as late as 63 years of age. More than half of the subjects received some form of family support. At least one third had an ICD-10 (WHO, 1992) diagnosable mental disorder and more than half were diagnosed with a psychiatric disorder during the time of reporting. A third of the subjects had a personality disorder diagnosis prior to reporting and another third had disordered personality traits established during the time of reporting. More than half had a psychological motive. Eleven per cent started a fire for excitement with only one for revenge. A third of the subjects were first time arsonists. Sixty-five per cent of arson involved building damage and all the 34 subjects were under the influence of alcohol prior to and during the act of arson. Additionally, there was cannabis use in nearly half of the subjects. Opioids and poly substance abuse were seen in a third of subjects. With the extent of financial and social burden along with risks, attention should be focused on accessing these individuals early to preventing recidivism. More research needs to be undertaken to identify the psychological motives behind fire-setting and to look into the drugs and alcohol problems amongst the younger age groups.


Recognition of operator DNA by Tet repressor.
The recognition of operator DNA by Tet repressor was analyzed by fluorescence stopped flow measurements. The main part of the fluorescence change observed for the reaction of the repressor with operator DNA reflects a second-order binding reaction including the expected concentration dependence. Global fitting of transients measured at different concentrations reveal at least one intramolecular step in addition to the bimolecular step. The rate constant for the bimolecular step is strongly salt dependent approaching the limit of diffusion control 2×10(8) M(-1) s(-1) at 50 mM NaCl and decreasing to 5×10(4) M(-1) s(-1) at 600 mM NaCl. These data are consistent with initial formation of a pre-equilibrium complex; electrostatic steering resulting from the high dipole moment of the repressor may contribute to the strong salt dependence. The rate constants of the intramolecular step are in the range of ~0.1 s(-1). Fluorescence quenching is salt dependent; the overall binding constant to operator O1 at 150 mM NaCl is 5×10(8) M(-1); binding constants at different salt concentrations indicate ~5 ion contacts for the specific complex of the Tet repressor dimer. The binding constant to operator O2 is higher than to O1 by a factor of ~2 at 400 mM NaCl.


Molecular dynamics simulations of the structure and single-particle dynamics of mixtures of divalent salts and ionic liquids.
We report a molecular dynamics study of the structure and single-particle dynamics of mixtures of a protic (ethylammonium nitrate) and an aprotic (1-butyl-3-methylimidazolium hexaflurophosphate [BMIM][PF6]) room-temperature ionic liquids doped with magnesium and calcium salts with a common anion at 298.15 K and 1 atm. The solvation of these divalent cations in dense ionic environments is analyzed by means of apparent molar volumes of the mixtures, radial distribution functions, and coordination numbers. For the protic mixtures, the effect of salt concentration on the network of hydrogen bonds is also considered. Moreover, single-particle dynamics of the salt cations is studied by means of their velocity autocorrelation functions and vibrational densities of states, explicitly analyzing the influence of salt concentration, and cation charge and mass on these magnitudes. The effect of the valency of the salt cation on these properties is considered comparing the results with those for the corresponding mixtures with lithium salts. We found that the main structural and dynamic features of the local solvation of divalent cations in ionic liquids are similar to those of monovalent salts, with cations being localized in the polar nanoregions of the bulk mixture coordinated in monodentate and bidentate coordination modes by the [NO3](-) and [PF6](-) anions. However, stronger electrostatic correlations of these polar nanoregions than in mixtures with salts with monovalent cations are found. The vibrational modes of the ionic liquid (IL) are seen to be scarcely affected by the addition of the salt, and the effect of mass and charge on the vibrational densities of states of the dissolved cations is reported. Cation mass is seen to exert a deeper influence than charge on the low-frequency vibrational spectra, giving a red shift of the vibrational modes and a virtual suppression of the higher energy vibrational modes for the heavier Ca(2+) cations. No qualitative difference with monovalent cations was found in what solvation is concerned, which suggests that no enhanced reduction of the mobility of these cations and their complexes in ILs respective to those of monovalent cations is to be expected.


Parasitism rate, parasitoid community composition and host specificity on exposed and semi-concealed caterpillars from a tropical rainforest.
The processes maintaining the enormous diversity of herbivore-parasitoid food webs depend on parasitism rate and parasitoid host specificity. The two parameters have to be evaluated in concert to make conclusions about the importance of parasitoids as natural enemies and guide biological control. We document parasitism rate and host specificity in a highly diverse caterpillar-parasitoid food web encompassing 266 species of lepidopteran hosts and 172 species of hymenopteran or dipteran parasitoids from a lowland tropical forest in Papua New Guinea. We found that semi-concealed hosts (leaf rollers and leaf tiers) represented 84% of all caterpillars, suffered a higher parasitism rate than exposed caterpillars (12 vs. 5%) and their parasitoids were also more host specific. Semi-concealed hosts may therefore be generally more amenable to biological control by parasitoids than exposed ones. Parasitoid host specificity was highest in Braconidae, lower in Diptera: Tachinidae, and, unexpectedly, the lowest in Ichneumonidae. This result challenges the long-standing view of low host specificity in caterpillar-attacking Tachinidae and suggests higher suitability of Braconidae and lower suitability of Ichneumonidae for biological control of caterpillars. Semi-concealed hosts and their parasitoids are the largest, yet understudied component of caterpillar-parasitoid food webs. However, they still remain much closer in parasitism patterns to exposed hosts than to what literature reports on fully concealed leaf miners. Specifically, semi-concealed hosts keep an equally low share of idiobionts (2%) as exposed caterpillars.


[Hepatocyte transplantation].
Transplantation of hepatocytes is considered a promising technology for the cell therapy of liver diseases. Cells are isolated from donor livers, which are not allocated for organ transplantation and transplanted into the liver of a suitable recipient. Ideally, the transplanted cells functionally replace the hepatocytes of the diseased organ and restore its metabolic capacity either permanently or for a period of bridging to organ transplantation. Although about 50 cases of clinical hepatocyte transplantation have been documented, therapeutic benefit is doubtful, and the reasons for this are largely unknown. Minor quality of the transplanted cells isolated from marginal donor livers may be a major cause. Therefore, animal models have been established, which enable scientists to develop novel procedures of hepatocyte transplantation and to specifically study the mechanisms of hepatocyte integration in the host liver. Hopefully, results generated in animal models will set the basis for the design of novel procedures of hepatocyte transplantation individualized to the underlying disease in order to provide a growth advantage for donor over host cells. The plasticity of stem cells and their proliferative potential is the basis for current efforts to generate stem cell-derived hepatocytes of transplantation quality for the treatment of liver diseases.


Energetics and structure of nicotinic acid (niacin).
The standard molar enthalpies of formation and sublimation of crystalline (monoclinic, space group P2(1)/c) nicotinic acid (NA), at 298.15 K, were determined as Delta(f)H(m)(o)(NA, cr) = -344.7 +/- 1.2 kJ x mol(-1) and Delta(sub)H(m)(o)(NA) = 112.1 +/- 0.5 kJ x mol(-1) by using combustion calorimetry, drop-sublimation Calvet microcalorimetry, and the Knudsen effusion method. The experimental determinations were all based on a sample of NIST Standard Reference Material 2151, which was characterized in terms of chemical purity, phase purity, and morphology. From the above results, Delta(f)H(m)(o)(NA, g) = -232.6 +/- 1.3 kJ x mol(-1) could be derived. On the basis of this value and on published experimental data, the enthalpy of the isodesmic reaction nicotinic acid(g) + benzene(g) --> benzoic acid(g) + pyridine(g) was calculated as -3.6 +/- 2.7 kJ x mol(-1) and compared with the corresponding predictions by the B3LYP/cc-pVTZ (-3.6 kJ x mol(-1)), B3LYP/aug-cc-pVTZ (-3.7 kJ x mol(-1)), B3LYP/6-311++G(d,p) (-4.2 kJ x mol(-1)), G3MP2 (-4.3 kJ x mol(-1)), and CBS-QB3 (-4.0 kJ x mol(-1)) quantum chemistry models. The excellent agreement between the experimental and theoretical results supports the reliability of the Delta(f)H(m)(o) (NA, cr), Delta(sub)H(m)(o)(NA), and Delta(f)H(m)(o)(NA, g) recommended in this work. These data can therefore be used as benchmarks for discussing the energetics of nicotinic acid in the gaseous and crystalline states and, in particular, to evaluate differences imparted to solid forms by the production and processing methods. Such differences are perhaps at the root of the significant inconsistencies found between the published enthalpies of sublimation of this important active pharmaceutical ingredient and thermochemical standard. The molecular packing in the crystalline phase studied in this work was also discussed and its influence on the molecular structure of nicotinic acid was analyzed by comparing bond distances and angles published for the solid state with those predicted by the B3LYP/cc-pVTZ method. No advantage in terms of accuracy of the structural predictions was found by the use of the larger aug-cc-pVTZ or 6-311++G(d,p) basis sets.


Safety of standardized Macleaya cordata extract in an eighty-four-day dietary study in dairy cows.
The objective of this study was to evaluate the safety of a standardized Macleaya cordata Extract Product (MCEP) containing the quaternary benzophenanthridine alkaloids, sanguinarine and chelerythrine, when fed to dairy cows. Thirty-six dairy cows were randomized into three groups with twelve cows/treatment in two replica pens for each treatment group: control (C) without MCEP added to feed, treatment 1 (SANG-1000) with MCEP added to feed at 1,000 mg/animal/day (1.5 mg/kg bw/day) and treatment 2 (SANG-10000) with MCEP added to feed at 10,000 mg/animal/day (15.5 mg MCEP/kg bw/day). After two weeks of acclimation, animals were observed for an 84-day experimental period, with body weight, feed intake and milk production measured daily. Milk composition was analysed every two weeks. Haematological analyses were performed on Day 0 and Day 84, and clinical chemistry analyses were performed on Day 84 of the study. There was no statistically significant difference (p > .10) among the three groups on body condition score, milk production or milk composition over the study period. There were no significant differences in body weight gain or feed consumption among the three groups. Animals in the SANG-10000 group had significantly higher mean corpuscular volume (MCV) than the C group (p < .1) and lower mean corpuscular haemoglobin concentration (MCHC) than the SANG-1000 group (p < .1). Concentrations of sanguinarine and chelerythrine in milk samples collected on Day 84 were below the detection limit (LOD) as measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). In conclusion, this study presents compelling data supporting the hypothesis that the test product MCEP, when included in the TMR at up to 10,000 mg/animal/day (15.5 mg MCEP/kg bw/day), is well tolerated by dairy cows.


Low uptake of HIV testing and no HIV positivity in stable serodiscordant heterosexual partners of long-term treated HIV-infected Thais.
The objective of this study was to characterize HIV-serodiscordant heterosexual couples and to evaluate acceptance for HIV testing and HIV prevalence in nonindex partners. We conducted a cross-sectional study with quantitative and qualitative components. Two cohorts of 1767 HIV-positive people were screened to identify heterosexual HIV-serodiscordant couples. HIV-positive partners (index) were administered a questionnaire; CD4, viral load (VL), and antiretroviral therapy (ART) history were gathered from clinical records. HIV-negative/unknown status partners (nonindex) were invited for a similar questionnaire and HIV testing. In-depth interviews with three HIV-serodiscordant couples were conducted. Two hundred and ninety-seven index partners agreed to enroll in this study. The median duration of the relationship was 10 years, and 81% were sexually active. All but two index partners were on ART, and 98% had VL < 1000 copies/mL. Only 111 (37%) nonindex partners came for HIV testing, and all of them tested HIV-negative. In addition, only 41% of nonindex partners had HIV testing in the last one year. The main reasons for the nonindex partners not to come for HIV testing were "no interest" (n = 117, 63%) and "nondisclosure of HIV status" (n = 46, 25%). The latter was substantiated and explained by the qualitative outcome of this study, suggesting relation to stigma against HIV-positive people. Our results support the WHO recommendation for starting ART for treatment and prevention in HIV-serodiscordant couples at any CD4 count. Furthermore, we recommend the dissemination of data showing that no HIV transmission in heterosexual couples through sex practice has been observed provided VL is suppressed. This could be a powerful tool for effective fight against stigma and self-stigma in people living with HIV.


Case-control study of metabolic syndrome and ovarian cancer in Chinese population.
Recent studies have proved metabolic syndrome (MetS) was linked to cancer risks. However, few data has examined the relationship between MetS and epithelial ovarian cancer (EOC). We conducted a population-based case-control study in Tianjin Medical University Cancer Institute and Hospital, China (2010-2015) that enrolled 573 EOC patients and 1146 matched controls. Data were collected through in-person interviews, anthropometric measurement, and 8-h fasting bloods drawn. MetS was estimated by Chinese Diabetes Society (CDS) definition requiring presence of ≥3 of the following risk factors: 1) body mass index (BMI) ≥25.0 kg/m2,2) fasting plasma glucose ≥6.1 mmol/L or 2-h plasma glucose ≥ 7.8 mmol/L, 3) systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, 4) triglyceride (TG) ≥1.70 mmol/L or high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol/L. Statistics were completed using chi-square tests and logistic regression analysis. The survival analysis was conducted by the Kaplan-Meier method and Cox proportional hazard regression models. MetS was significantly more prevalent among EOC (25.13%) than controls (6.89%). A statistically significant increase risk for EOC was observed for MetS (multivariable-adjusted OR = 3.187; 95% CI: 2.135-4.756). MetS was significantly associated with histological grade (P < 0.001), FIGO stage (P = 0.003), and lymph node (LN) status (P = 0.002) of EOC. In binary logistic regression analysis, the presence of MetS predicts the risk of advanced FIGO stage (OR = 2.155, 95% CI: 1.327-3.498, P = 0.002), lower differentiation (OR = 2.472, 95% CI: 1.164-5.250, P = 0.019), and LN metastasis (OR = 2.590, 95% CI: 1.089-6.160, P = 0.031) of EOC. Moreover, MetS is the independent factor for the evaluation of PFS and OS of EOC patients (both of them P < 0.001) in Cox proportional hazard model. MetS is obviously related to increased EOC risk. EOC patients with MetS in Chinese population were found to have statistically significant tumor advanced stage, low differentiation, LN metastasis and poor prognosis.


Epidermal growth factor receptor expression status in lung cancer correlates with its mutation.
The molecular mechanisms for frequent epidermal growth factor receptor (EGFR, a tyrosine kinase [TK]) and HER2 (the preferred coreceptor of EGFR) overexpression in lung cancer are poorly understood. Recent studies have shown the mutations of the TK domain in EGFR and HER2 to be present in lung cancer. The purpose of this study was to investigate the relationship between mutation status and expression of EGFR and HER2 in lung cancer. Immunostaining took place for EGFR and HER2, and mutational analyses for EGFR, HER2, and KRAS (a signaling protein) were conducted using 130 resected lung cancer specimens. Thirty-seven EGFR mutations (28%) and 8 HER2 mutations (6%), both of the TK domains, and 5 KRAS (4%) mutations were found, whereas 73 (56%) EGFR and 47 (36%) HER2 overexpressions were found. EGFR overexpression was seen more frequently in tumors with EGFR mutation (28/37, 76%) than in tumors without EGFR mutations (45/93, 48%; P = .0059). No correlation was found between HER2 mutation and HER2 expression. Multivariate regression revealed that EGFR mutation, adenocarcinoma histology, and HER2 expression were associated with EGFR expression, whereas female sex, EGFR mutation, and EGFR expression were associated with HER2 expression. In conclusion, EGFR and HER2 overexpression is frequent in lung cancer, and EGFR overexpression correlates with the EGFR TK domain mutations.


A Retrospective Chart Review of Antidepressant Use, Effectiveness, and Adverse Effects in Adults Age 70 and Older.
The authors assessed the use, side effects, and outcomes of various antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), in adults 70 years of age and older by means of a retrospective study of outpatient records. Of these patients (N = 70), 26% improved or recovered. Patients were more likely to improve or recover if they took the antidepressant for at least 3 months. Those on TCAs were as likely to improve or recover and no more likely to discontinue because of side effects than those prescribed SSRIs. Approximately one-third of patients discontinued because of side effects, and SSRI gastrointestinal side effects were more common in patients concomitantly taking nonsteroidal anti-inflammatory drugs. Many older patients who undergo antidepressant therapy discontinue because of side effects; however patients are likely to improve or recover with sustained therapy.


Ascites and hydrothorax in association with struma ovarii.
A case is presented of ascites and hydrothorax in association with struma ovarii. Nine previously reported cases are reviewed and the possible causes of the ascites and hydrothorax discussed.


[Antigenic determinants within immune complexes: similar and heterogeneous distribution in cutaneous vasculitis (author's transl)].
Twenty-one patients with various cutaneous vasculitis (8 with leukocytoclastic lesions, 5 with lymphocytic infiltration, 4 with anaphylactoid purpura, 2 with essential mixed cryoglobulinemia and 2 other cases) were studied for the presence and the characterization of circulating immune comlexes. Thirteen patients had circulating immune complexes evidenced by 2 p. 100 polyethylene glycol precipitation. A solid phase cross reaction applied to isolated complexes showed common antigenic determinants and/or antibody specificity in patients with different histopathological and clinical features. On the other hand, patients suffering from identical vasculitis possessed different determinants in their immune complexes. These findings are interpreted to indicate that the distribution of the complexed antigens does not square with a clinical classification.


Usage of personal-protection measures against mosquitoes and the low prevalences of Wuchereria bancrofti microfilaraemia in the Indian city of Chennai.
The usage of personal-protection measures against mosquitoes and the prevalence of Wuchereria bancrofti microfilaraemia were assessed in different areas of the city of Chennai, a large urban area in southern India. Most of the households investigated (75% to 92%, depending on socio-economic status) used some form of personal protection (such as mosquito coils, vaporizing mats and liquids and mosquito nets). The study households spent a mean (S.D.) of 109.45 (141.65) Indian rupees/month on personal protection, such expenditure increasing significantly with increasing household income (F=2.95; P=0.03). Over the last three decades the prevalence of W. bancrofti microfilaraemia has been slowly declining in Chennai. Most of the 'moderate-income' areas of the city investigated in the present study appeared free of such microfilaraemia, and the prevalences recorded in about half of the low- and very-low-income study areas did not exceed 1.0%. The mean prevalences recorded in the moderate-, low- and very-low-income areas were 0.51%, 1.15% and 1.30%, respectively. Given their very low prevalences of microfilaraemia, relatively good housing, sanitation and health care and extensive use of personal-protection measures, the 100 million Indians living in (mostly urban) moderate- and high-income areas may not require active mass drug administrations (MDA) against lymphatic filariasis. The need to develop simple methods to stratify urban areas, into those that require and those that do not require active MDA, remains. If lymphatic filariasis is to be eliminated from India in a reasonable time-frame, at least as a public-health problem, MDA should now be focused on the poorer localities.


Role of iron in neurodegenerative disorders.
Although the pathophysiology underlying a number of neurodegenerative diseases is complex and, in many aspects, only partly understood, increased iron levels in pathologically relevant brain areas and iron-mediated oxidative stress seem to play a central role in many of them. Much has been learned from monogenetically caused disturbances of brain iron metabolism including pantothenate kinase-associated neurodegeneration type 2, hereditary ferritinopathies affecting the basal ganglia, and aceruloplasminemia that may well be applied to the most common neurodegenerative disorders associated with brain iron accumulation including Parkinson disease and Alzheimer disease. Iron-mediated oxidative stress in neurodegenerative diseases caused by other genetic pathways like Huntington disease and Friedreich ataxia underscore the complex interaction of this trace metal and genetic variations. Therapeutical strategies derived from application of iron chelators in monogenetically caused disturbances of brain iron metabolism and new iron and oxidative stress diminishing substances in animal models of Parkinson disease are promising and warrant further investigational effort.


[Symptoms of depression in children and adolescents in relation to psychiatric comorbidities].
The lifetime prevalence of MDD before adolescence is 4-5%, while the symptoms concern 13-20% of the adolescents. In the development of suicidal behaviour the most important risk factors are the use of psychoactive drugs and smoking. Psychiatric comorbidities are aggravating significantly the major depression. The comorbidities are high among major depression, anxiety and disruptive disorders. We examined 649 children being in a depressive episode diagnosed by ISCA-D semi-structured interview, 45,9% of them were girls, and 54,1% were boys, the mean age was 11,7 years ( SD=2,00). The participants were enrolled into three groups according to their comorbidities: group with only depression without comorbidities, group with anxiety comorbidity, and group with disruptive comorbidity. We compared the three groups according to the frequency of their depressive symptoms. Anxiety comorbidities increase the incidence of depressive symptoms. Among the criteria symptoms irritability where the most frequent symptom independently from the comorbidities, the depressed mood is the most frequent within the anxiety group, while anhedonia occurred with a moderate frequency in each groups. In the anxiety group the vegetative symptoms, while in the disruptive group the psychomotor agitation and the feeling of worthlessness are the most frequent symptoms. Comorbidities are increasing the incidence of the suicide symptoms. The incidence of impaired decision making was high in each group, the comorbidities didn't influence it's frequency. Among depressed boys irritability and feelings of worthlessness (low self-esteem) increase the presence of externalisation comorbidity. Among depressed girls guilt was significantly more frequent in the anxiety comorbidity group, and concentration problems are the most typical symptoms in the clear MDD group, without comorbidities.


Pupillary assessment of sensory block level during combined epidural/general anesthesia.
Currently, no reliable method exists to determine the level of sensory block during combined epidural/general anesthesia. However, the pupil dilates markedly in response to noxious electrical stimulation during general anesthesia. Presumably, sensory block produced by epidural anesthesia decreases or obliterates this autonomic response. Accordingly, we tested the hypothesis that pupillary dilation in response to noxious stimulation would predict the level of sensory block achieved during combined epidural/general anesthesia. We studied eight volunteers and ten patients during combined epidural/general anesthesia. The volunteers were given an epidural infusion of 2% 2-chloroprocaine while general anesthesia was maintained with 0.8% isoflurane and 60% N2O. In the patients, an epidural infusion of 0.25% bupivacaine was combined with isoflurane and vecuronium. Noxious electrical stimulation was administered to dermatomal segments in a caudal-to-rostral progression. A twofold increase in pupil size following electrical stimulation was considered the predicted block level in volunteers. In patients, an increase in pupil size exceeding 50% was considered the predicted level. After general anesthesia was discontinued, observers blinded to the pupillary measurements independently determined the actual epidural block level using pain in response to a pinprick as the criterion. The level predicted by pupillary responses was within two dermatomal segments of the actual level in all the volunteers. The predicted and actual block levels were within two segments in eight of the ten patients and never differed by more than four dermatomes. We conclude that dilation of the pupil in response to electrical stimulation is an accurate test of the sensory block level during combined epidural/general anesthesia.


Investigation of ATP6V1B1 and ATP6V0A4 genes causing hereditary hearing loss associated with distal renal tubular acidosis in Iranian families.
Hearing defects are the most common sensory disorders, affecting 1 out of every 500 newborns. ATP6V1B mutations are associated with early sensorineural hearing loss, whereas ATP6V0A4 mutations are classically associated with either late-onset sensorineural hearing loss or normal hearing. ATP6V1B1 and ATP6V0A4 genetic mutations cause recessive forms of distal renal tubular acidosis. Ten unrelated deaf Iranian families with distal renal tubular acidosis were referred to the Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran. All exons of the ATP6V1B1 and ATP6V0A4 genes were sequenced in affected family members. We identified a previously reported ATP6V1B1 frameshift mutation (P385fsX441) in two families and a nucleotide substitution in exon 10 (P346R) in three families. In addition, one patient was homozygous for a novel nucleotide substitution in exon 3. ATP6V1B1 genetic mutations were detected in more than half of the families studied. Mutations in this gene therefore seem to be the most common causative factors in hearing loss associated with distal renal tubular acidosis in these families.


Short communication: Effectiveness at 48 weeks of switching from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV type 1-infected patients in a Brazilian cohort.
The effectiveness of switching from enfuvirtide to raltegravir in HIV-1-infected patients on a suppressive antiretroviral regimen has been poorly studied in the clinical practice of developing countries. We conducted a multicenter retrospective cohort study in HIV-1-infected, multidrug-experienced adults (≥18 years old) with plasma HIV-1-RNA <400 copies/ml for at least 4 months on an enfuvirtide-containing therapy between 2005 and 2010, in whom the attending physician switched from enfuvirtide to raltegravir. Effectiveness endpoints were measured at week 48 after switch. Analyses were conducted on an intent-to-treat basis and two strategies for handling missing outcome data were used (hereafter, strategies 1 and 2). Overall, 87 patients were eligible for analysis. At baseline, the median CD4(+) T cell count was 400 cells/μl and 91.9% of patients had <50 HIV-1-RNA copies/ml. At week 48, the proportions of patients with plasma HIV-1-RNA <50 and <400 copies/ml were, respectively, 86.2% (95% CI=77.1; 92.7%) and 88.5% (95% CI=79.9; 94.3%) (strategies 1 and 2) and 89.7% (95% CI=81.3; 95.2%) and 90.8% (95% CI=82.7; 95.9%) (strategies 1 and 2). This was a -10.3% (95% CI=-2.8; -17.9%) and -9.2% (95% CI=-2; -16.4%) difference from baseline in the proportion of patients with plasma HIV-1-RNA <400 copies/ml. The median increase in CD4(+) T cell counts was 41 and 64 cells/μl (p<0.001) (strategies 1 and 2). No patient withdrew raltegravir or developed opportunistic infections, but one was diagnosed with HIV-related dementia. In conclusion, switching from enfuvirtide to raltegravir in patients on a virologically suppressive regimen is an effective strategy even in a Brazilian clinical setting.


Parental explanatory models of ADHD: gender and cultural variations.
This study describes parents' explanatory models of Attention Deficit Hyperactivity Disorder (ADHD) and examines model variation by child characteristics. Children with ADHD (N = 182) were identified from a school district population of elementary school students. A reliable coding system was developed for parental responses obtained in ethnographic interviews in order to convert qualitative into numerical data for quantitative analysis. African-American parents were less likely to connect the school system to ADHD problem identification, expressed fewer worries about ADHD-related school problems, and voiced fewer preferences for school interventions than Caucasian parents, pointing to a potential disconnect with the school system. More African-American than Caucasian parents were unsure about potential causes of and treatments for ADHD, indicating a need for culturally appropriate parent education approaches.


Sequential enzymes of linoleic acid oxidation in corn germ: lipoxygenase and linoleate hydroperoxide isomerase.
Linoleic acid oxidation catalyzed by lipoxygenase (lipoxidase) activity in extracts of defatted corn germ does not terminate in the product, linoleic acid hydroperoxide, unless the lipoxygenase is first partially purified. If purification is not attempted, the hydroperoxide product exists only as a barely detectable intermediate in the synthesis of three products. One of these was identified as 9-hydroxy-10-oxo-cis-12-octadecenoic acid formed from the hydroperoxide by the enzyme, linoleate hydroperoxide isomerase. Another product, 13-hydroxy-10-oxo-trans-11-octadecenoic acid, is believed to be formed by an isomerase also. The third product was the linoleate ester of one of the hydroxy-oxo-fatty acids, 9-(cis-9,cis-12-octadecadienoyl)-10-oxo-cis-12-octadecenoic acid. It is not known if the synthesis of the ester is enzyme-catalyzed. When a mixture of 13-hydroperoxy-cis-9,trans-11-octa-decadienoic acid and 9-hydroperoxy-trans-10,cis-12-octa-decadienoic acid from soybean lipoxygenase oxidation of linoleic acid was used as a substrate, 13-hydroxy-12-oxo-cis-9-octadecenoic acid and 9-hydroxy-12-oxo-trans-10-octadecenoic acid were formed as the major products of catalysis by linoleate hydroperoxide isomerase(s) from corn. Smaller quantities of 9-hydroxy-10-oxo-cis-12-octadecenoic acid and 13-hydroxy-10-oxo-trans-11-octadecenoic acid were also formed.


Rosuvastatin was Effective in Acute Heart Failure and Slow Coronary Flow: A Hypothesis-generating Case Report.
Slow coronary flow phenomenon (SCFP) is characterized by angiographically normal coronary arteries with delayed run-off of contrast medium across the vasculature. Its etiology and clinical significance are still not completely known; however, acute congestive heart failure (CHF) is rare in this context. A 71 year-old woman with SCFP presented with acute CHF complicated by ventricular tachycardia. Treated with rosuvastatin (20 mg/day for 6 days) and inotropic drug infusion she had a complete recovery of left ventricular function and normalization of serum levels of the high-sensitivity C-reactive protein (hs-CRP), which were increased (3.6 mg/L) during the acute phase. This case illustrates that the anti-inflammatory properties of rosuvastatin may deserve specific clinical tests not only during the chronic phase but also in the acute phase of CHF patients.


Limited Antimycobacterial Efficacy of Epitope Peptide Administration Despite Enhanced Antigen-Specific CD4 T-Cell Activation.
Infection with Mycobacterium tuberculosis is associated with inconsistent and incomplete elimination of the bacteria, despite development of antigen-specific T-cell responses. One mechanism used by M tuberculosis is to limit availability of antigen for activation of CD4 T cells. We examined the utility of systemic administration of epitope peptides to activate pre-existing T cells in mice infected with M tuberculosis. We found that systemic peptide administration (1) selectively activates T cells specific for the epitope peptide, (2) loads major histocompatibility complex class II on lung macrophages and dendritic cells, (3) activates CD4 T cells in the lung parenchyma, (4) and has little antimycobacterial activity. Further studies revealed that CD4 T cells in lung lesions are distant from the infected cells, suggesting that, even if they can be activated, the positioning of CD4 T cells and their direct interactions with infected cells may be limiting determinants of immunity in tuberculosis.


Rapid changes in tree leaf chemistry induced by damage: evidence for communication between plants.
Potted poplar ramets showed increased concentrations and rates of synthesis of phenolic compounds within 52 hours of having 7 percent of their leaf area removed by tearing, as did undamaged plants sharing the same enclosure. Damaged sugar maple seedlings responded in a manner similar to that of the damaged poplars. Nearby undamaged maples had increased levels of phenolics and hydrolyzable and condensed tannin within 36 hours, but exhibited no change in rates of synthesis. An airborne cue originating in damaged tissues may stimulate biochemical changes in neighboring plants that could influence the feeding and growth of phytophagous insects.


Microsurgical anatomy of the anterior perforating arteries.
The anterior perforating arteries, the group of arteries that enter the brain through the anterior perforated substance (APS), were examined using X 3 to X 40 magnification in 50 cerebral hemispheres obtained from 25 adult cadavers. These arteries arose from the internal carotid, middle and anterior cerebral, and the anterior choroidal arteries. The carotid branches to the APS arose distal to the origin of the anterior choroidal artery. The anterior choroidal artery branches arose from the main or superior branch of the artery. The middle cerebral artery branches to the APS (the lenticulostriate arteries) arose from the M1 and M2 segments and were divided into medial, intermediate, and lateral groups, each of which had a characteristic configuration. The anterior cerebral artery branches arose from the A1 segment and from the recurrent artery. The internal carotid and anterior choroidal artery branches entered the posterior half of the central portion of the APS. The lenticulostriate branches entered the middle and posterior portions of the lateral half of the APS. The A1 segment gave rise to branches which entered the medial half of the APS above the optic nerve and chiasm. The recurrent artery sent branches into the anterior two-thirds of the full mediolateral extent of the APS. The relationship of these branches to the cerebral structures above the APS and to the common aneurysm sites is reviewed.


[Hemodynamics of the lower extremities following lumbar sympathectomy].
Peripheral blood circulation was studied in 72 patients (85 extremities) with obliterative arteriosclerosis of lower extremities within 7 days following lumbar sympathectomy with the help of occlusive plethysmography. The outcomes of lumbar sympathectomy were shown to be independent of the level of lesions of lower extremity arteries, changes in plethysmography indices depending on their initial level and stage of the disease.


Some surgical aspects of gynecologic cancer.
The most important developments in gynecologic oncology in recent years have been the advent of supervoltage irradiation that allows the delivery of better and safer therapy; the diligent search for new cancerostatic drugs and hormones and their clinical application, singly and in combination; and studies suggesting the possibility of immunotherapy. Conversely, few noteworthy developments have emerged in the operative management of gynecologic malignancy, even though refinements of surgical technique, improved preoperative and postoperative care, and better control of infectious problems gradually have decreased the operative morbidity and mortality rates and have improved the survival rates significantly. Surgery continues to be the dominant therapy. Irradiation, chemotherapy, and hormones are therapeutic adjuvants in the management of ovarian, endometrial, cervical, vulvar, and other genital malignancies. As a result of earlier diagnosis, with the greatly diminished incidence of far-advanced carcinoma of the cervix, primary surgery is having a larger role in the management of the early stages of this lesion. Aggressive surgical removal of advanced, dissemenated ovarian carcinoma is worthwhile; diminishing the volume of the lesion significantly improves the response of residual tumor to adjuvant therapy.


BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth.
We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27; conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27 phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor, or Dex, to improve patient outcome in MM.


Assessing peer entry and play in preschoolers at risk for maladjustment.
This study evaluated the psychometric properties of an observational rating system for assessing preschoolers' peer entry and play skills: Observed Peer Play in Unfamiliar Settings (OPPUS). Participants were 84 preschoolers at risk for psychopathology. Reliability and concurrent validity are reported. The 30-min paradigm yielded reliable indexes of engaging and disruptive behavior. Adequate interrater reliability and stability were obtained with minimally trained observers. OPPUS scores were related in expected ways to independent observations of disruptive and engaging behavior during parent-child interactions. OPPUS scores were associated with parent-rated self-control and internalizing behaviors. OPPUS scores were associated with parent ratings of play skills for children with school experience and assertiveness for children without school experience. The OPPUS is a useful, brief method for assessing peer entry and play behaviors in preschoolers.


Meeting Report: Hackathon-Workshop on Darwin Core and MIxS Standards Alignment (February 2012).
The Global Biodiversity Information Facility and the Genomic Standards Consortium convened a joint workshop at the University of Oxford, 27-29 February 2012, with a small group of experts from Europe, USA, China and Japan, to continue the alignment of the Darwin Core with the MIxS and related genomics standards. Several reference mappings were produced as well as test expressions of MIxS in RDF. The use and management of controlled vocabulary terms was considered in relation to both GBIF and the GSC, and tools for working with terms were reviewed. Extensions for publishing genomic biodiversity data to the GBIF network via a Darwin Core Archive were prototyped and work begun on preparing translations of the Darwin Core to Japanese and Chinese. Five genomic repositories were identified for engagement to begin the process of testing the publishing of genomic data to the GBIF network commencing with the SILVA rRNA database.


Mental capacity law.
What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article provided information about mental capacity law. It outlined how capacity assessments are undertaken, and how best-interests decisions should be made for those who lack capacity.


Estimating the incubation period of acute Q fever, a systematic review.
Estimates of the incubation period for Q fever vary substantially between different reviews and expert advice documents. We systematically reviewed and quality appraised the literature to provide an evidence-based estimate of the incubation period of the Q fever by the aerosolised infection route. Medline (OVIDSP) and EMBASE were searched with the search limited to human studies and English language. Eligible studies included persons with symptomatic, acute Q fever, and defined exposure to Coxiella burnetti. After review of 7115 titles and abstracts, 320 records were screened at full-text level. Of these, 23 studies contained potentially useful data and were quality assessed, with eight studies (with 403 individual cases where the derivation of incubation period was possible) being of sufficient quality and providing individual-level data to produce a pooled summary. We found a median incubation period of 18 days, with 95% of cases expected to occur between 7 and 32 days after exposure.


Human platelet-rich plasma improves the nesting and differentiation of human chondrocytes cultured in stabilized porous chitosan scaffolds.
The clinical management of large-size cartilage lesions is difficult due to the limited regenerative ability of the cartilage. Different biomaterials have been used to develop tissue engineering substitutes for cartilage repair, including chitosan alone or in combination with growth factors to improve its chondrogenic properties. The main objective of this investigation was to evaluate the benefits of combining activated platelet-rich plasma with a stabilized porous chitosan scaffold for cartilage regeneration. To achieve this purpose, stabilized porous chitosan scaffolds were prepared using freeze gelation and combined with activated platelet-rich plasma. Human primary articular chondrocytes were isolated and cultured in stabilized porous chitosan scaffolds with and without combination to activated platelet-rich plasma. Scanning electron microscopy was used for the morphological characterization of the resulting scaffolds. Cell counts were performed in hematoxylin and eosin-stained sections, and type I and II collagen expression was evaluated using immunohistochemistry. Significant increase in cell number in activated platelet-rich plasma/stabilized porous chitosan was found compared with stabilized porous chitosan scaffolds. Chondrocytes grown on stabilized porous chitosan expressed high levels of type I collagen but type II was not detectable, whereas cells grown on activated platelet rich plasma/stabilized porous chitosan scaffolds expressed high levels of type II collagen and type I was almost undetectable. In summary, activated platelet-rich plasma increases nesting and induces the differentiation of chondrocytes cultured on stabilized porous chitosan scaffolds.


Expressing RNA aptamers inside cells to reveal proteome and ribonome function.
Small RNA molecules can participate in complex regulatory networks not merely through Watson-Crick interactions with other RNAs (as in anti-sense RNA), but also by forming discrete structures that bind protein or low-molecular weight targets. RNA aptamers derived from in vitro selections (SELEX) are being used inside cells for at least four purposes: (1) to antagonise normal cellular proteins as a means of elucidating their biological roles; (2) as decoys to natural RNA-binding proteins to reveal their functions or those of structural elements within naturally occurring transcripts; (3) as regulatory modules to govern the expression of exogenous genes; and (4) to antagonise disease-related targets for potential biomedical applications. This paper summarises recent advances in each of these areas, the parameters that influence successful application and the potential for future developments. The use of aptamers in vivo may serve as a paradigm for understanding how some non-coding RNAs and other elements of the ribonome exert their influence on the intracellular proteome, and is thus becoming an important tool for modern cell and molecular biology.


Tumour-associated angiogenesis in human colorectal cancer.
Tumour angiogenesis is a critical step in the growth, metastatic spread and regrowth of colorectal cancer. Angiogenesis specific to tumour is a complicated process, the mechanisms of which remain unclear. Metastasis of colorectal cancer may result from passive entry into the circulation secondary to the effect of angiogenic factors. The survival and growth of colorectal tumour and thus their metastases are dependent on the balance of endogenous angiogenic and anti-angiogenic factors such that the outcome favours increased angiogenesis. Angiogenesis has become an attractive target for anticancer drug development, based on its important roles in tumour growth, invasion and metastasis. Several growth factors have been identified that regulate angiogenesis in colorectal cancer; the most important of these are vascular endothelial growth factors (VEGF), and of the several angiogenic factors, VEGF expression at the deepest invasive site of tumour is the most statistically significant prognostic indicator in advanced colorectal carcinoma. In this review article, we provide an overview on angiogenic factors and their receptors, and discuss the role of newly identified tumour endothelial markers (TEMs) that are involved in tumour-associated angiogenesis in colorectal cancer.


Improving diabetes care among patients overdue for recommended testing: a randomized controlled trial of automated telephone outreach.
The study's objective was to assess the effects of automated telephone outreach with speech recognition (ATO-SR) on diabetes-related testing. We identified 1,200 health plan members who were overdue for diabetes-related testing and randomly allocated 600 to ATO-SR and 600 to usual care (no intervention). The intervention included three interactive calls encouraging recommended testing. The primary outcome was retinopathy testing, since this was the health plan's principal goal. Tests for glycemia, hyperlipidemia, and nephropathy were secondary outcomes. In total, 232 participants (39%) verbally responded to the calls. There was no difference between the intervention and the usual care groups in the primary outcome (adjusted hazard ratio 0.93 [95% CI 0.71-1.22]) and no effect of the intervention on any of the secondary outcomes. Fewer than 40% of the patients randomized to ATO-SR interacted verbally with the system. The intervention had no effect on the study's outcomes.


[Status of trace organic pollution in the network water came from Huangpu River].
To investigate the status of trace organic pollution of the network water came from Huangpu River in Shanghai. An analytical method combining solid-phase extraction technique with gas chromatography coupled to mass spectrometry (SPE-GC/MS) was adopted for determination of trace organic chemicals in water samples. The resins containing XAD-2/402 (1:3) as solid sorbent enriched organic materials from drinking water, and 30% acetone-methanol was employed as elution solvent. 18 GC/MS methods were selected according to the priority substances of hazardous substances in drinking water recommended by US EPA. 142 kinds (10 categories) of organic pollutants were detected from drinking water, including phthalate esters, phenolic compounds, amines, alcohols/acids/esters, aliphatic hydrocarbons, alkyl halides, mono-/poly-cyclo aromatic compounds, heterocyclic compounds, aldehydes/ketones and others. Dibutyl phthalate(DBP), 4-cumylphenol and N-phenyl-beta-naphthylamine were found with relative high levels in the water samples. DBP and dioctyl phthalate (DOP) were considered by EPA to control the priority list of hazardous substances. Herbicides such as atrazine and linuron, and estrogen (3-deoxyestradiol) came from drinking water were also detected. Pollutants of drinking water came from Huangpu River as water source were complex. Most of the pollutants detected were not listed into Standards for Drinking Water Quality in China (GB5749-2006), so obviously, their comprehensive harmful effect should be further taken into account.


Association of asthma and sleep insufficiency among South Korean adolescents: analysis of web-based self-reported data from the Korean youth risk behavior web-based survey.
Objectives: Weekend oversleep or catch-up sleep is common among adolescents, but relatively few data are available with regard to its effects on asthma. Our aim was to investigate whether weekend oversleep is associated with ever having asthma among Korean adolescents. Methods: We analyzed web-based self-reported data from the Korean Youth Risk Behavior Web-based Survey in 25,927 physician-diagnosed adolescent asthma cases and 266,160 non-asthma cases. Self-report questionnaires were used to assess socioeconomic status, health behaviors, psychological factors and sleep patterns. Multiple logistic regression after adjusting for factors was used to determine the association between sleep and asthma. Results: The asthma group slept less (≤5 hours: 23.9% vs. 22.8%) had a later weekend bedtime (≥1:00 AM: 58.1% vs. 57.8%), and an earlier weekend wake time (≤7:00 AM: 18.1% vs. 17.0%) compared to the non-asthma group. After multiple logistic regression, a sleep duration ≤5 hours (odds ratio (OR), 1.09; 95% confidence interval (CI), 1.04-1.14) and weekend "early bird" (weekend wake time ≤7:00 AM: OR, 1.03; 95% CI, 1.00-1.07) were significantly associated with an increased frequency of asthma. Long weekend catch-up sleep (weekend sleep duration minus weekday sleep duration ≥2 hours) was significantly associated with a decreased frequency of asthma (OR, 0.98; 95% CI, 0.94-0.99). Conclusion: Long weekend catch-up sleep, as an indicator of insufficient weekday sleep, is associated with a decreased frequency of asthma in Korean adolescents.


Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insect stings.
This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insect venom that were reported primarily in the Journal of Allergy and Clinical Immunology from 2002 through 2003. Among the topics highlighted are new insights into the pathogenesis of atopic dermatitis and potential strategies for more effective treatment of the atopic march. Patients should remain supine with raised legs during anaphylactic shock because upper body elevation could result in sudden death from loss of venous return to the heart. A major advance in food allergy was that humanized, monoclonal anti-IgE antibody showed protection against peanut-induced anaphylaxis. In addition to studies elucidating mechanisms of drug hypersensitivity, a clinical study showed patients with a history of prior penicillin allergy with negative penicillin allergy test results are unlikely to experience reactions or resensitization on subsequent oral courses of penicillin. Lastly, there are new recommendations for patients with convincing insect sting reaction histories but negative skin test responses to venom.


Segmental spinal dysgenesis associated with occult dysraphism: Considerations on management strategies.
Segmental spinal dysgenesis is a rare and challenging entity especially when associated with occult dysraphism. Experience with a female patient followed during a period of 10 years spanning from 5 to 15 years of age is reported. During that period the girl underwent three spinal operations consisting in one decompression and spinal cord untethering, one posterior instrumented fusion and a spinal cord re-untethering. Clinical and radiological features are discussed and considerations on optimization of management strategies are made.


Assessment of motion of a swing leg and gait rehabilitation with a gravity balancing exoskeleton.
The gravity balancing exoskeleton, designed at University of Delaware, Newark, consists of rigid links, joints and springs, which are adjustable to the geometry and inertia of the leg of a human subject wearing it. This passive exoskeleton does not use any motors but is designed to unload the human leg joints from the gravity load over its range-of-motion. The underlying principle of gravity balancing is to make the potential energy of the combined leg-machine system invariant with configuration of the leg. Additionally, parameters of the exoskeleton can be changed to achieve a prescribed level of gravity assistance, from 0% to 100%. The goal of the results reported in this paper is to provide preliminary quantitative assessment of the changes in kinematics and kinetics of the walking gait when a human subject wears such an exoskeleton. The data on kinematics and kinetics were collected on four healthy and three stroke patients who wore this exoskeleton. These data were computed from the joint encoders and interface torque sensors mounted on the exoskeleton. This exoskeleton was also recently used for a six-week training of a chronic stroke patient, where the gravity assistance was progressively reduced from 100% to 0%. The results show a significant improvement in gait of the stroke patient in terms of range-of-motion of the hip and knee, weight bearing on the hemiparetic leg, and speed of walking. Currently, training studies are underway to assess the long-term effects of such a device on gait rehabilitation of hemiparetic stroke patients.


Probability distributions for locations of calling animals, receivers, sound speeds, winds, and data from travel time differences.
A new nonlinear sequential Monte Carlo technique is used to estimate posterior probability distributions for the location of a calling animal, the locations of acoustic receivers, sound speeds, winds, and the differences in sonic travel time between pairs of receivers from measurements of those differences, while adopting realistic prior distributions of the variables. Other algorithms in the literature appear to be too inefficient to yield distributions for this large number of variables (up to 41) without recourse to a linear approximation. The new technique overcomes the computational inefficiency of other algorithms because it does not sequentially propagate the joint probability distribution of the variables between adjacent data. Instead, the lower and upper bounds of the distributions are propagated. The technique is applied to commonly encountered problems that were previously intractable such as estimating how accurately sound speed and poorly known initial locations of receivers can be estimated from the differences in sonic travel time from calling animals, while explicitly modeling distributions of all the variables in the problem. In both cases, the new technique yields one or two orders of magnitude improvements compared with initial uncertainties. The technique is suitable for accurately estimating receiver locations from animal calls.


Isolation and characterization of type VIII collagen synthesized by cultured rabbit corneal endothelial cells. A conventional structure replaces the interrupted-helix model.
Radioactive proline-labeled type VIII collagen was biosynthesized in the presence of beta-aminoproprionitrile by rabbit corneal endothelial cells and isolated from the culture medium. Type VIII was purified in the presence of protease inhibitors and at neutral pH by ultrafiltration, precipitation with 3.9 M NaCl, sedimentation in sucrose gradients, and DEAE-Sephacel chromatography. The major components of this collagen, VIII-1, -2, and -3, exhibited apparent molecular weights of greater than 194,000, 124,000, and 61,000, respectively, and were shown to contain identical CNBr peptides. Following separation of VIII-1, -2, and -3 from each other and any residual proteases by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, exposure to acetic acid led to the conversion of VIII-1 to VIII-2 and VIII-3. Thus, VIII-1 is not a continuous single peptide chain, and the preliminary interrupted-helix model of the type VIII structure (Benya, P. D. (1980) Renal Physiol. 3, 30-35) was revised. VIII-3 appears to be the parent alpha 1 (VIII)-chain, with VIII-2 and VIII-1 representing beta- and gamma-chain configurations stabilized by strong noncovalent acid-labile interactions and beta-aminoproprionitrile-insensitive covalent cross-links. Based on two-dimensional CNBr peptide mapping, the alpha-chain is composed of six peptides. Mr 5,300-19,600. The terminal peptides are pepsin sensitive and correlate with two noncollagenous domains, NC1 (Mr 14,700) and NC2 (Mr 4-5,000). NC1 contains the site of acid-labile chain association.


The effect of polydeoxyribonucleotide on the treatment of radiating leg pain due to cystic mass lesion in inner aspect of right sciatic foramen: A CARE compliant case report.
Radiating leg pain usually originates from the lumbar spine and occasionally from peripheral lesions. Here we report a case involving a patient with radiating pain in the right leg who exhibited 2 suspicious lesions, including 1 spinal lesion and 1 extraspinal cystic mass lesion, on magnetic resonance imaging. Polydeoxyribonucleotide sodium (PDRN) was recently noted as such a substitute. PDRN has anti-inflammatory effects, as it lowers the expression of inflammatory cytokines including interleukin-6 and tumor necrosis factor-alpha. A 51-year-old man (weight, 93 kg; height, 168 cm) working as a bus driver presented at the pain clinic with continuous right buttock pain, radiating leg pain and a tingling sensation involving the calf and dorsum of the foot, since 1 week. He was definitively diagnosed using differential blocks, which revealed the cyst to be the actual cause of the pain. Surgical resection was not feasible because of the position of the cyst; therefore, corticosteroid injection under ultrasonographic guidance was attempted. However, this provided short-term relief. Subsequently, a solution containing PDRN was injected around the piriformis muscle and repeated 3 more times at intervals of 2 weeks. After PDRN injection, we conducted two follow-up monitoring every two months for 2 months. Last follow-up, the patient no longer complained of pain. this resulted in relatively long-term relief from pain. The findings from this case suggest that PDRN is an effective alternative for steroids in patients with radiating leg pain, although its efficacy and safety needs to be evaluated in further large-scale studies.


Time averages in continuous-time random walks.
We investigate the time-averaged square displacement (TASD) of continuous-time random walks with respect to the number of steps N which the random walker performed during the data acquisition time T. We prove that in each realization the TASD grows asymptotically linear in the lag time τ and in N, provided the steps cannot accumulate in small intervals. Consequently, the fluctuations of the latter are dominated by the fluctuations of N, and fluctuations of the walker's thermal history are irrelevant. Furthermore, we show that the relative scatter decays as 1/sqrt[N], which suppresses all nonlinear features in a plot of the TASD against the lag time. Parts of our arguments also hold for continuous-time random walks with correlated steps or with correlated waiting times.


Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.
DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.


[A study of high-resolution computed tomography (HRCT) findings of resected small pulmonary nodules 2 cm or less in diameter with reference to the malignant nature].
To identify the characteristics of peripheral small lung mass lesions on high-resolution computed tomography (HRCT) and discriminate between malignant and benign, 223 mass lesions 2 cm or less resected surgically were evaluated about following points. 1) Density : 90.7% of lesions with mixed solid and ground-glass opacity (GGO) components were adenocarcinomas. Pure GGO lesions without scale-down between several months were all adenocarcinomas or atypical adenomatous hyperplasia (AAH). Thereby, patients with these findings are good candidates for surgical resection. 2) Spicular or pleural indentation :75.2% (88 of 117 cases) of adenocarcinomas and all squamous cell carcinomas (18 cases) showed these findings, but 26.6% (41 of 154 cases) of positive cases were benign lesion (non-specific inflammation, mycobacterisis, and so on). Accordingly, they are not peculiar to malignancy. 3) Satellite lesion : all lesions with this one showed benign, therefore it was thought that this finding could exclude malignant lesion. Thus, recognition of certain characteristics at HRCT can be helpful in discrimination between small malignant mass and benign mass.


Regulation of endothelial permeability in the primate corpora lutea: implications for ovarian hyperstimulation syndrome.
In a developing human corpus luteum, a closely regulated cellular communication system exists between the luteal steroidogenic cells and endothelial cells. This system guaranties the vascularization process during luteal formation. The process is combined with rapid release of large amounts of progesterone into the bloodstream. The regulation of endothelial proliferation and permeability by LH and human chorionic gonadotropin (hCG) is integral to this process. On the cellular level, endothelial permeability is regulated by intercellular junctions, such as adherens junctions (AJ) and tight junctions (TJ), which act as zipper-like structures between interacting endothelial cells. Several cell junctional proteins are localized to the corpus luteum, including Occludin, Nectin 2, Claudin 1, and Claudin 5, as well as, vascular endothelial (VE)-Cadherin. It has been assumed that regulation of AJ- and TJ-proteins is of particular importance for permeability, and accordingly, for the functionality of the corpus luteum in early pregnancy, because treatment with hCG induces downregulation of juntional proteins in the luteal vessels. The effect of hCG on the adhesive molecules is mediated by VE growth factor (VEGF). On a functional level, the hCG-dependent and VEGF-mediated decrease in junctional proteins causes a decrease in the density of cell-cell closure and, accordingly, an increase in endothelial permeability. In doing so, the different junctional proteins are not only directly influenced by VEGF but also interact among themselves and influence each other reciprocally. Disturbances in this strictly, regulated interactions may explain the development of pathologies with increased vascular permeability, such as the ovarian hyperstimulation syndrome.


The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases.
Male sex differentiation is driven by 2 hormones, testosterone and anti-müllerian hormone (AMH), responsible for the regression of müllerian ducts in male fetuses. Mutations inactivating AMH or its receptor AMHRII lead to the persistent müllerian duct syndrome (PMDS) in otherwise normally virilized 46,XY males. Our objective was to review the clinical, anatomical, and molecular features of PMDS based upon a review of the literature and upon 157 personal cases. Three clinical presentations exist: bilateral cryptorchidism, unilateral cryptorchidism with contralateral hernia, and transverse testicular ectopia. Abnormalities of male excretory ducts are frequent. Testicular malignant degeneration occurs in 33% of adults with the disorder, while cancer of müllerian derivatives is less frequent. Fertility is rare but possible if at least one testis is scrotal and its excretory ducts are intact. Eighty families with 64 different mutations of the AMH gene have been identified, mostly in exons 1, 2, and 5. AMHRII gene mutations representing 58 different alleles have been discovered in 75 families. The most common mutation, a 27-bp deletion in the kinase domain, was found in 30 patients of mostly Northern European origin. In 12% of cases, no mutation of AMH or AMHRII has been detected, suggesting a disruption of other pathways involved in müllerian regression.


Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations.
Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations. Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate. Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.


Comparison of amounts of collagen and elastin in pleura and parenchyma of dog lung.
Pressure-volume characteristics of the lung have been thought to be due primarily to the properties of the network of alveolar septa. However, Hajji et al. (J. Appl. Physiol.: Respirat . Environ. Exercise Physiol. 47: 175-181, 1979) attributed a substantial role to the visceral pleura. Seeking a structural explanation for this result, we compared the relative amounts of collagen fibrils and elastin fibers in the visceral pleura and alveolar parenchyma using stereological measurements in five canine lobes. We found about one-fifth as much collagen and one-tenth as much elastin in the pleura as in the alveolar parenchyma. This structural result confirms the functional conclusions of Hajji et al. We argue that such a substantial structure is not needed for protection against overinflation but may have to do with stabilization of lobe shape or handling of frictional forces.


Reliability of assessment of protein structure prediction methods.
The reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student's t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.


Altered expression of miRNA-21 and its targets in the hippocampus after traumatic brain injury.
Traumatic brain injury (TBI) initiates many different signaling cascades throughout the brain that impact both pathophysiological and neuroprotective processes. Cellular mechanisms that can modulate these processes may play an important role in determining the nature and extent of the damage suffered after TBI and therefore influence overall outcome after injury. MicroRNAs (miRNAs) are an important class of noncoding regulatory RNAs providing an epigenetic mechanism for the regulation of protein expression levels of target genes. We report that miR-21 expression is significantly up-regulated in the hippocampus after rodent TBI, with expression levels peaking by 3 days postinjury and returning to near sham levels by 15 days postinjury. In situ localization of miR-21 transcripts indicates widespread expression in normal brain, with a pronounced increase in expression after TBI evident throughout the cortex and hippocampus, including the dentate gyrus and CA3 cell layer. We used a combination of the miRanda, TargetScan, and PicTar prediction algorithms to identify 99 potential target genes that possess miR-21 binding sites within their 3' untranslated regions. Analysis of these genes' annotated Gene Ontology molecular function and biological process terms revealed an overrepresentation of genes involved in enzyme-linked receptor signaling, transcriptional regulation, and developmental processes. These results suggest that increased miR-21 expression in the hippocampus may influence multiple components of TBI pathophysiology.