Metalloproteinase-3 genotype as a predictor of cardiovascular risk in hypertensive adolescents.
Hypertension develops as a result of cardiac hypertrophy and fibrosis or as a result of exchange of the extracellular matrix. In particular, matrix metalloproteinase (MMP)-3 is a major enzyme involved in the reconstruction of the arterial intima through activation of other MMPs. We analyzed MMP-3 genotypes in hypertensive and normotensive adolescents and sought to determine if a particular genotype is a predictor of cardiovascular complications. Forty-four hypertensive adolescents and 59 healthy adolescents were included in this study. Serum aldosterone, renin, insulin, angiotensin converting enzyme (ACE), insulin, homocysteine, vitamin B(12), folate, MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitors of matrix metalloproteinases (TIMP)-1, and TIMP-2 were measured. MMP-3 genotypes were analyzed using a polymerase chain reaction (PCR) primer. The carotid intima media thickness (IMT), diameter, and brachial ankle pulse wave velocity (baPWV) were evaluated using ultrasound. In hypertensive adolescents, blood pressure, anthropometric data, carotid IMT, baPWV, serum pro-MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were no different between the 6A/6A group and the 5A/6A group. Serum MMP-9 was higher in the 5A/6A group than in the control group. Aldosterone, insulin, and homocysteine were higher in the 6A/6A group than in the control group, and vitamin B(12) and folate were lower in the 6A/6A group than in the control group. In conclusion, serum MMP-3 levels were not significantly different in different MMP-3 genotypes in hypertensive adolescents. However, few patients were included in this study. Further investigation is necessary to clarify the relationship between MMP-3 genotype and cardiovascular risk.


Polymorphism around cog extends into adjacent structural genes.
The recombination hotspot cog overlaps a highly polymorphic 950-bp region of linkage group I in Neurospora crassa. The sequence of this region in the four strains, Lindegren 25a, Lindegren A, Emerson A and St. Lawrence 74A, each differs from the others by 1.4% or more. Comparison of the sequence of St. Lawrence 74A and Lindegren 25a each side of cog shows a high level of sequence heterology extending in both directions, including the coding sequences for his-3 and a putative gene lpl with homology to yeast lysophospholipase. The St. Lawrence 74A and Lindegren 25a sequences of his-3, centromere-proximal to cog, differ at 14 nucleotides, resulting in six amino-acid variations between the predicted protein sequences. In lpl, distal from cog, the sequences differ at 19 nucleotides leading to five amino-acid differences between the predicted proteins. Sequence heterology between St. Lawrence 74A and Lindegren 25a peaks either side of cog and then declines with distance. At the am locus on linkage group V, heterology is much less but peaks close to a weak recombination hotspot 5' of the coding sequence. Uneven distribution of polymorphism along chromosomes has been explained by a hitch-hiking hypothesis in which selection for advantageous mutations causes local fixation of unselected variation. We suggest that new mutations arising from errors in recombination also contribute to the uneven distribution of polymorphism.


Effectiveness of transmeatal low power laser irradiation for chronic tinnitus.
To evaluate effectiveness of 5 mW laser irradiation in the treatment of chronic tinnitus. Prospective, randomised, double-blind study. This investigation included 66 ears in 45 patients with chronic unilateral or bilateral tinnitus. A 5 mW laser with a wavelength of 650 nm, or placebo laser, was applied transmeatally for 15 minutes, once daily for a week. A questionnaire was administered which asked patients to score their symptoms on a five-point scale, before and two weeks after laser irradiation. A decrease of one scale point, regarding the loudness, duration and degree of annoyance of tinnitus, was accepted to represent an improvement. The loudness, duration and degree of annoyance of tinnitus were improved, respectively, in up to 48.8, 57.7 and 55.5 per cent of the patients in the active laser group. No significant improvement was observed in the placebo laser group. Transmeatal, low power (5 mW) laser irradiation was found to be useful for the treatment of chronic tinnitus.


Arthropods as the Engine of Nutrient Cycling in Arid Ecosystems.
Nutrient dynamics in most terrestrial ecosystems are regulated by moisture-dependent processes. In drylands, nutrient dynamics are often weakly associated with annual precipitation, suggesting that other factors are involved. In recent years, the majority of research on this topic focused on abiotic factors. We provide an arthropod-centric framework that aims to refocus research attention back on the fundamental role that macro-arthropods may play in regulating dryland nutrient dynamics. Macro-arthropods are prevalent in drylands and include many detritivores and burrowing taxa that remain active during long dry periods. Macro-arthropods consume and process large quantities of plant detritus and transport these nutrients to the decomposer haven within their climatically buffered and nutritionally enriched burrows. Consequently, arthropods may accelerate mineralization rates and generate a vertical nutrient recycling loop (VRL) that may assist in explaining the dryland decomposition conundrum, and how desert plants receive their nutrients when the shallow soil is dry. The burrowing activity of arthropods and the transportation of subterranean soil to the surface may alter the desert microtopography and promote desalinization, reducing resource leakage and enhancing productivity and species diversity. We conclude that these fundamental roles and the arthropods' contribution to nutrient transportation and nitrogen fixation makes them key regulators of nutrient dynamics in drylands.


A proteoglycan that activates fibroblast growth factors during early neuronal development is a perlecan variant.
Cells in the early embryonic vertebrate nervous system are dependent on members of the fibroblast growth factor (FGF) family for their proliferation and subsequent differentiation. These growth factors will only bind to their specific high affinity cell surface receptors after formation of a ternary complex with the glycosaminoglycan heparan sulfate. Such specific heparan sulfates are secreted as proteoglycans from neural precursor cells and localise to their surfaces. One such proteoglycan, HSPG-PRM (Perlecan-related molecule), was isolated through its ability to potentiate neural cell responses to either FGF-1 or FGF-2. In this study, we have verified the relative molecular mass of the core protein of PRM as 45,000 and obtained partial amino acid sequence from it. The sequences bore significant homology to native perlecan. A probe generated by reverse transcriptase polymerase chain reaction using oligonucleotides designed from the protein sequence used on northern blots of RNA from a neuroepithelial cell line detected perlecan at 12.6 kilobases, as well as novel transcripts at 6.5 and 3.5 kilobases. The latter species appears by virtue of its size and abundance to be the novel PRM transcript. PRM appears to be encoded by the same gene as perlecan, as genomic Southern blotting only detected a single gene. Polyclonal antibodies raised against the PRM molecule detected a single proteoglycan species at 290x10(3) with a core protein of 45x10(3). Polyclonal anti-perlecan antibodies cross-reacted with PRM confirming their relatedness, although immunohistochemical studies revealed a differential staining pattern for PRM as compared to perlecan within the developing nervous system. The PRM molecule was shown to be localised to several different tissues of the developing embryo, indicating that it plays a broad role. We conclude that PRM is a variant of perlecan that is differentially glycosylated in a manner that confers highly specific functions at critical stages of neural development and tissue growth.


Lipid rafts, ceramide and molecular transcytosis.
Transcytosis, a widely described process concerning transport of macromolecules between the apical and basolateral sides in various cell types, is extremely important for multicellular organisms to selectively exchange materials in different microenvironments while maintaining cellular and body homeostasis. Uncontrolled transcytosis is involved in a wide range of pathophysiological processes. Lipid rafts (LRs), the sphingolipid and cholesterol-enriched membrane microdomains, enable to form different functional membrane macrodomains or platforms upon stimulations. In particular, ceramide-enriched membrane microdomains play extremely critical roles in LRs clustering or platform formations. Notably, various transcytosis-related molecules are tightly correlated with LRs and ceramide. We attempt to summarize the basic and advanced information about the roles of different types of transcytosis in human health and diseases, and the types and functions of LRs involved in transcytosis, as well as multiple transcytosis-related molecules associated with LRs and ceramide. It is hoped that all information and discussions could provide much more comprehensive insights into the understanding of the association of LRs with transcytosis, as well as shed some new light on the translational significance in this area.


Amino-terminal pro-B-type natriuretic peptide testing for inpatient monitoring and treatment guidance of acute destabilized heart failure.
Although typically elevated at presentation in the context of destabilized heart failure (HF), amino-terminal pro-B-type natriuretic peptide (NT-proBNP) values typically decrease rapidly among patients who have a favorable response to therapy. Given this, it is natural to examine the relation between NT-proBNP and therapeutic interventions for acute HF. Both presentation and posttreatment NT-proBNP concentrations have some value for prognostication of recurrent HF hospitalization or death. However, the percent change in NT-proBNP after treatment for acute HF may be a more powerful method for risk stratification. Although prospective studies on the effect of NT-proBNP measurement in guiding therapy in acute destabilized HF are lacking, observational data suggest that a 30% decrease in NT-proBNP values during hospitalization is a reasonable goal. If a baseline measure of NT-proBNP is not available, an NT-proBNP level <4,000 ng/L after acute treatment is an alternative goal. Because the criteria for determining restabilization from destabilized HF prominently include clinical and routine laboratory testing rather than NP measures, the frequency of NT-proBNP measurement should not be excessive in patients with acute HF, with measures at baseline/presentation and after perceived recompensation to evaluate for the desired decrease in NT-proBNP concentrations. A remeasurement of NT-proBNP may also be useful for evaluation of new or worsened symptoms. In those patients without a decrease in NT-proBNP despite perceived recompensation from HF, a review of adequacy of treatment, goals of therapy, and consideration of prognosis is recommended.


Tenon excision with fibrin glue-assisted reattachment of conjunctiva flap (T.E.F.A.R.C) for the treatment of conjunctivochalasis.
To observe the surgical outcome of "Tenon Excision with Fibrin Glue-Assisted Reattachment of Conjunctiva Flap" (T.E.F.A.R.C.) for the treatment of symptomatic conjunctivochalasis (CCH). This is a retrospective case series of CCH patients undergoing T.E.F.A.R.C. from January 2017 to December 2020 were reviewed. Seven patients (14 eyes) with symptomatic CCH received T.E.F.A.R.C. in both eyes. The symptoms before and after the procedures were compared and surgical complication was evaluated. The mean follow-up time was 13.7 ± 2.14 months. After the operation, resolution of the symptoms was reported in 12 eyes (86%). The grade of CCH decreased from 3 to 0 in all 14 eyes, and the restoration of inferior conjunctival surface and fornix within 1 day was also observed in all eyes. Most patients had localized injection and mild chemosis after the operation, which mostly recovered within 3 weeks. No complication or recurrence of CCH was reported after 1 year of follow-up. In conclusion, T.E.F.A.R.C. is a simple and effective treatment option for CCH with less surgical complication. Future larger studies are needed to confirm its clinical applicability.


Population Muscle Strength Predicts Olympic Medal Tallies: Evidence from 20 Countries in the PURE Prospective Cohort Study.
National sporting achievement at the Olympic Games is important for national pride and prestige, and to promote participation in sport. Summer Olympic Games medal tallies have been associated with national wealth, and also social development and healthcare expenditure. It is uncertain however, how these socioeconomic factors translate into Olympic success. The objective of this study was therefore to examine the relationship between population muscle strength and Olympic medal tallies. This study of handgrip strength represents a cross-sectional analysis of the Prospective Urban Rural Epidemiology (PURE) study, which is an ongoing population cohort study of individuals from high-, middle-, and low-income countries. Within participating countries, households from both urban and rural communities were invited to participate using a sampling strategy intended to yield a sample that was representative of the community. Households were eligible if at least one member was aged 35-70 years and if they intended living at the same address for a further four years. A total of 152,610 participants from these households, located in 21 countries, were included in this analysis. Handgrip strength was measured using a Jamar dynanometer. Olympic medal tallies were made over the five most recent Summer Games. There was a significant positive association between national population grip strength (GS) and medal tally that persisted after adjustment for sex, age, height, average daily caloric intake and GDP (total and per capita). For every 1kg increase in population GS, the medal tally increased by 36% (95% CI 13-65%, p = 0.001) after adjustment. Among countries that won at least one medal over the four most recent Summer Olympic Games, there was a close linear relationship between adjusted GS and the natural logarithm of the per capita medal tally (adjusted r = 0.74, p = 0.002). Population muscle strength may be an important determinant of Summer Olympic Games medal success. Further research is needed to understand whether population muscle strength is modifiable, and whether this can improve Olympic medal success. Extreme outcomes may reflect the average attributes of the population from which the individual experiencing the extreme outcome is drawn.


Anesthetic Management of a Child With Unspecified Mitochondrial Disease in an Outpatient Dental Setting.
Mitochondrial disease (MD) represents a category of metabolic disorders with a wide range of symptoms across a variety of organ systems. It occurs with an incidence of greater than 1:5000 and can be difficult to specifically diagnose because of the variety of clinical presentations and multiple genomic origins. Although phenotypically variable, MD symptoms often include hypotonia, cardiac defects, dysautonomia, and metabolic dysfunction. Mitochondrial disease presents a unique challenge in terms of anesthetic management, as many anesthetic drugs suppress mitochondrial function. Additional considerations may need to be made in order to evaluate the patient's metabolic compensation prior to surgery. This article presents an in-depth discussion of a case involving a nearly 10-year-old boy with a history of an unspecified form of MD, who presented for endodontic treatment of tooth No. 30 under deep sedation. The article also provides a thorough review of the current literature surrounding the anesthetic management of patients with MD.


Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes.
To establish a polyexposure score (PXS) for type 2 diabetes (T2D) incorporating 12 nongenetic exposures and examine whether a PXS and/or a polygenic risk score (PGS) improves diabetes prediction beyond traditional clinical risk factors. We identified 356,621 unrelated individuals from the UK Biobank of White British ancestry with no prior diagnosis of T2D and normal HbA1c levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 nongenetically ascertained exposure and lifestyle variables for the PXS in prospective T2D. We computed the clinical risk score (CRS) and PGS by taking a weighted sum of eight established clinical risk factors and >6 million single nucleotide polymorphisms, respectively. In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Individuals in the top 10% of PGS, PXS, and CRS had 2.00-, 5.90-, and 9.97-fold greater risk, respectively, compared to the remaining population. Addition of PGS and PXS to CRS improved T2D classification accuracy, with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively. For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. However, the concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models.


Post-haemorrhagic anaemia in sea bass, Dicentrarchus labrax (L.), caused by blood feeding of Ceratothoa oestroides (Isopoda: Cymothoidae).
The effects of the fish parasitic isopod, Ceratothoa oestroides (Risso), on haematological parameters of its cage-cultured sea bass host, Dicentrarchus labrax (L.), were studied. Analyses of blood parameters (cell counts, haemoglobin content and haematocrit) were carried out on parasitized and unparasitized sea bass from a fish farm in Turkey. Parasitized fish had significantly lowered erythrocyte counts, haematocrit and haemoglobin values and significantly increased leucocyte counts. Blood feeding by C. oestroides thus produces a post-haemorrhagic anaemia and the fish appear to mount an immune response to the presence of parasites.


239 cases of high fever in viral upper respiratory infection (URI) treated with xiang shi qing jie (XSQJ) bag tea.
XSQJ bag tea was used to treat 239 cases of high fever caused by viral upper respiratory infection, widely spreading in summer and autumn. For comparison, a control group treated by penicillin combined with Ganmao Qingre Chongji or Banlangen Chongji was set up. The results showed the effect of XSQJ bag tea on the time of abating fever, resolving symptoms and physical signs were significantly better than that of the control group.


Modulation of hormone-induced calcium oscillations by intracellular pH in rat hepatocytes.
Single isolated rat hepatocytes were used to investigate the influence of intracellular pH (pHi) on hormone-induced cytosolic Ca2+ oscillations, using videofluorescence microscopy. Although pHi did not vary after alpha-adrenergic stimulation, manipulations of pHi induced pronounced alterations in the frequency of oscillations. Increasing the resting pHi with ammonium chloride (5-20 mM), trimethylammonium (2-10 mM), or triethylammonium (1.2-8 mM) reduced the frequency of oscillations. A change in pHi of > 0.25 was sufficient to reversibly inhibit oscillations. This effect could be overcome by increasing the agonist concentration or by adding 8-bromoadenosine 3',5'-cyclic monophosphate, an agent known to potentiate the alpha-adrenergic response. Cellular acidification, obtained by the ammonium prepulse method as well as by application of acetate or the ionophore nigericin, in the continuous presence of agonist was accompanied by a modest frequency increase of the oscillations, leading in some cases to an overstimulated state. This study indicates that pHi, within a range of values expected to occur in vivo (0.1-0.2 pH units), exerts a chronotropic effect on phenylephrine-induced Ca2+ oscillations. In contrast, oscillations induced by ADP or vasopressin were pHi invariant.


Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens. Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes. In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group. The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.


Functional diversity in fungal fatty acid synthesis: the first acetylenase from the Pacific golden chanterelle, Cantharellus formosus.
Acetylenic specialized metabolites containing one or more carbon-carbon triple bonds are widespread, being found in fungi, vascular and lower plants, marine sponges and algae, and insects. Plants, moss, and most recently, insects, have been shown to employ an energetically difficult, sequential dehydrogenation mechanism for acetylenic bond formation. Here, we describe the cloning and heterologous expression in yeast of a linoleoyl 12-desaturase (acetylenase) and a bifunctional desaturase with Delta(12)-/Delta(14)-regiospecificity from the Pacific golden chanterelle. The acetylenase gene, which is the first identified from a fungus, is phylogenetically distinct from known plant and fungal desaturases. Together, the bifunctional desaturase and the acetylenase provide the enzymatic activities required to drive oleate through linoleate to crepenynate and the conjugated enyne (14Z)-dehydrocrepenynate, the branchpoint precursors to a major class of acetylenic natural products.


Does Drosophila sechellia escape parasitoid attack by feeding on a toxic resource?
Host shifts can drastically change the selective pressures that animals experience from their environment. Drosophila sechellia is a species restricted to the Seychelles islands, where it specializes on the fruit Morinda citrifolia (noni). This fruit is known to be toxic to closely related Drosophila species, including D. melanogaster and D. simulans, releasing D. sechellia from interspecific competition when breeding on this substrate. Previously, we showed that larvae of D. sechellia are unable to mount an effective immunological response against wasp attack, while larvae of closely-related species can defend themselves from parasitoid attack by melanotic encapsulation. We hypothesized that this inability constitutes a trait loss due to a reduced risk of parasitoid attack in noni. Here we present a lab experiment and field survey aimed to test the hypothesis that specialization on noni has released D. sechellia from the antagonistic interaction with its larval parasitoids. Our results from the lab experiment suggest that noni may be harmful to parasitoid wasps. Our results from the field survey indicate that D. sechellia was found in ripe noni, whereas another Drosophila species, D. malerkotliana, was present in unripe and overripe stages. Parasitic wasps of the species Leptopilina boulardi emerged from overripe noni, where D. malerkotliana was the most abundant host, but not from ripe noni. These results indicate that the specialization of D. sechellia on noni has indeed drastically altered its ecological interactions, leading to a relaxation in the selection pressure to maintain parasitoid resistance.


Preventive treatments for recurrence after curative resection of hepatocellular carcinoma--a literature review of randomized control trials.
To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications reporting randomized control trial indexed in PubMed. The treatment approaches presented above included pre-operative transcatheter arterial chemoembolization (TACE), post-operative TACE, systemic or locoregional chemotherapy, immunotherapy, Interferons and acyclic retinoic acid. Although no standard treatment has been established, several approaches presented promising results, which were both effective and tolerable in post-operative patients. Pre-operative TACE was not effective on prolonging survivals, while post-operative TACE was shown with both disease-free survival and overall survival benefits in some papers, however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities. Adoptive immunotherapy using LAK cells was proved to be beneficial to patients' survival in a recent paper. Interferon alpha and Interferon beta can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities; in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.


Health-compromising behaviors: why do adolescents smoke or drink?: identifying underlying risk and protective factors.
To better understand the motivation for adolescent smoking and drinking and to identify the underlying risk and protective factors associated with these behaviors among adolescents. Cross-sectional, school-based survey of students in grades 5 through 12. A nationally representative sample of 2574 boys and 2939 girls in grades 7 through 12 from 297 public, private, and parochial schools across the United States who participated in The Commonwealth Fund Survey of the Health of Adolescent Girls and Boys in 1997. Sex-specific adjusted relative risks (RRs) and 95% confidence intervals (CIs) comparing self-reported regular smokers and regular drinkers by risk and protective factors with adolescents reporting none of these behaviors. Adolescent boys and girls were equally likely to be regular smokers (11.2%). The prevalence rate of regular drinking was only slightly higher for boys (22.4%) than it was for girls (19.3%). The rates of both health-risk behaviors were significantly higher for those reporting risk factors, and the strengths of associations varied by sex. Sex differences also emerged in motivation for engaging in these behaviors. When we adjusted for demographic characteristics, exposure to childhood abuse (RR, 4.1; 95% CI, 2.4-7.0) and stressful life events (RR, 2.4; 95% CI, 1.1-5.4) were strongly associated with increased risk for boys' regular smoking. Similar associations were found for regular drinking. For girls, a history of abuse (RR, 1.8; 95% CI, 1.1-2.8), violence within the family (RR, 2.2; 95% CI, 1.6-3.2), depressive symptoms (RR, 1.6; 95% CI, 1.0-2.4), and stressful life events (RR, 3.1; 95% CI, 1.8-5.6) were significantly associated with increased risk for regular smoking. Similar associations were again found for regular drinking. Parental support was protective against both health-risk behaviors for both sexes. Participation in extracurricular activities was associated with lower risk for regular smoking for boys (RR, 0.4; 95% CI, 0.2-0.7) and for girls (RR, 0.3; 95% CI, 0.2-0.5); however, there was no significant association between drinking behavior and participation in activities. The increased risk for regular smoking and regular drinking among adolescents with a history of abuse, family violence, depressive symptoms, and stressful life events suggests that routine screening for abuse, violence, and other family experiences should be an essential component of adolescent health care visits. Effective prevention programs to reduce smoking and drinking among adolescents should recognize that health-risk behaviors may be associated with other negative life experiences and that the strength of these associations differs by sex.


Heparan sulphate proteoglycan as mediator of some adhesive responses and cytoskeletal reorganization of cells on fibronectin matrices: independent versus cooperative functions.
Fibronectin is a multifunctional glycoprotein which promotes the adhesion of a variety of cell types to extracellular matrices, including artificial tissue culture substrata. Biochemical analyses of substratum adhesion sites indicated important functions for cell-surface heparan sulphate proteoglycan (HS-PG) in directly mediating adhesive responses by the binding of heparan sulphate sequences to fibronectin. In addition, fibronectin has a binding domain for a cell surface 'receptor' (possibly a 140K glycoprotein) important in these responses. To differentiate the relative importance of these two binding activities, a proteolytically generated cell-binding fragment of fibronectin has been isolated which binds to the 140K 'receptor' but not to HS or to collagen. Platelet factor 4 (PF4), a tetravalent HS-binding protein, provides a model of the tetravalent HS-binding activity of fibronectin, as supported by affinity chromatography studies (these studies also reveal the complexity of HS-PG metabolism in adhesion sites). Responses are measured on substrata coated with the cell-binding fragment of fibronectin, intact fibronectin, or PF4, singly or in combination. Fibroblast-like BALB/c 3T3 cells form both close and tight-focal adhesive contacts with associated microfilament stress fibres on intact fibronectin. Whereas HS-PG binding appears to mediate the formation of close contacts and linear microfilament bundles, a cooperative relationship exists between the HS- and the cell-binding activities of the intact fibronectin molecule in the formation of focal contacts and stress fibres. Human dermal fibroblasts generate different adhesive responses on HS-binding or cell-binding substrata, which are dependent on whether cells have been grown in medium with ascorbate to maximize production of their own collagenous matrix. As with 3T3 cells, focal contact and stress fibre formations of dermal cells require both binding activities in the intact fibronectin molecule. A third system consists of neuroblastoma tumour cells which adhere and extend neurites on fibronectin. Cell-body adherence, but not neurite extension, occurs on HS-binding matrices whereas neurite extension requires only fibronectin's cell-binding activity; the responses of primary peripheral neurons were exactly the opposite and CNS neurons did not respond at all. These studies indicate the diversity of molecular mechanisms by which various cells interact with the multifunctional fibronectin molecule in order to perform specialized functions, as well as the independent or cooperative functions of heparan sulphate proteoglycan on the cell surface in mediating these responses.


Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease.
Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.


Social impact analysis of the effects of a telemedicine intervention to improve diabetes outcomes in an ethnically diverse, medically underserved population: findings from the IDEATel Study.
We examined the social impact of the telemedicine intervention effects in lower- and higher-socioeconomic status (SES) participants in the Informatics for Diabetes Education and Telemedicine (IDEATel) study. We conducted a randomized controlled trial comparing telemedicine case management with usual care, with blinded outcome evaluation, in 1665 Medicare recipients with diabetes, aged 55 years or older, residing in federally designated medically underserved areas of New York State. The primary trial endpoints were hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and systolic blood pressure levels. HbA1c was higher in lower-income participants at the baseline examination. However, we found no evidence that the intervention increased disparities. A significant moderator effect was seen for HbA1c (P = .004) and systolic blood pressure (P = .023), with the lowest-income group showing greater intervention effects. Lower-SES participants in the IDEATel study benefited at least as much as higher-SES participants from telemedicine nurse case management for diabetes. Tailoring the intensity of the intervention based on clinical need may have led to greater improvements among those not at goal for diabetes control, a group that also had lower income, thereby avoiding the potential for an innovative intervention to widen socioeconomic disparities.


Syntheses, characterization, and in vitro degradation of ethyl cellulose-graft-poly(epsilon-caprolactone)-block-poly(L-lactide) copolymers by sequential ring-opening polymerization.
Well-defined ethyl cellulose-graft-poly(epsilon-caprolactone) (EC-g-PCL) graft copolymers were successfully synthesized via ring-opening polymerization (ROP) of epsilon-caprolactone (CL) with an ethyl cellulose (EC) initiator and a tin 2-ethylhexanoate (Sn(Oct)2) catalyst in xylene at 120 degrees C. Then, novel ethyl cellulose-graft-poly(epsilon-caprolactone)-block-poly(L-lactide) (EC-g-PCL-b-PLLA) graft-block copolymers were prepared by ROP of L-lactide (L-LA) with a hydroxyl-terminated EC-g-PCL macroinitiator and Sn(Oct)2 catalyst in bulk at 120 degrees C. Various graft and block lengths of EC-g-PCL and EC-g-PCL-b-PLLA copolymers were obtained by adjusting the molar ratios of CL monomer to EC and the L-LA monomer to CL. The thermal properties and crystalline morphologies of EC-g-PCL and EC-g-PCL-b-PLLA copolymers were different from those of linear PCL. The in vitro degradation rate of EC-g-PCL-b-PLLA was faster than those of linear PCL and EC-g-PCL due to the presence of PLLA blocks.


Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism.
In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates. Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator. Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure. The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations.


Imaging active urokinase plasminogen activator in prostate cancer.
The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease expressed by cancer cells and the surrounding tumor microenvironment. Using a human fragment antigen-binding phage display library, we identified a human antibody termed U33 that selectively inhibited the active form of the protease urokinase plasminogen activator (uPA, PLAU). In the full-length immunoglobulin form, U33 IgG labeled with near-infrared fluorophores or radionuclides allowed us to noninvasively detect active uPA in prostate cancer xenograft models using optical and single-photon emission computed tomography imaging modalities. U33 IgG labeled with (111)In had a remarkable tumor uptake of 43.2% injected dose per gram (%ID/g) 72 hours after tail vein injection of the radiolabeled probe in subcutaneous xenografts. In addition, U33 was able to image active uPA in small soft-tissue and osseous metastatic lesions using a cardiac dissemination prostate cancer model that recapitulated metastatic human cancer. The favorable imaging properties were the direct result of U33 IgG internalization through an uPA receptor-mediated mechanism in which U33 mimicked the function of the endogenous inhibitor of uPA to gain entry into the cancer cell. Overall, our imaging probe targets a prostate cancer-associated protease, through a unique mechanism, allowing for the noninvasive preclinical imaging of prostate cancer lesions.


Association of Lp-PLA2 G994T gene polymorphism with risk of ischemic stroke in Chinese population.
The association between lipoprotein-associated phospholipase A2 (Lp-PLA2) G994T gene polymorphism and the risk of ischemic stroke is unclear. The aim of this study is to investigate the influence of Lp-PLA2 G994T genetic variant on the pathogenesis of ischemic stroke in Chinese population. A total of 348 patients with a clinical diagnosis of ischemic stroke and 260 gender-matched control subjects under physical examination were recruited from hospitals and genotyped for G994T gene polymorphism. The results showed that there was a significant difference in the genotype distribution between the two groups and people with GT or TT genotype were associated with the higher risk of ischemic stroke even after adjusting the effects of potential confounding factors. In addition, both ischemic stroke patients and control subjects carrying T allele showed relatively lower Lp-PLA2 activity and higher oxLDL level. Therefore, Lp-PLA2 G994T gene polymorphism may be an independent risk factor of ischemic stroke in Chinese population.


Nickel-catalyzed allyl-allyl coupling reactions between 1,3-dienes and allylboronates.
A regiospecific allyl-allyl coupling reaction between 1,3-dienes and allylboronates has been demonstrated under nickel catalysis. Salient features of this method include the earth-abundant metal catalyst, excellent regioselectivity and good functional group tolerance. Notably, even congested allyl substrates can also be applied to this protocol, thus allowing for the rapid preparation of a series of valuable 1,5-dienes.


A unified Watson-Crick geometry drives transcription of six-letter expanded DNA alphabets by E. coli RNA polymerase.
Artificially Expanded Genetic Information Systems (AEGIS) add independently replicable unnatural nucleotide pairs to the natural G:C and A:T/U pairs found in native DNA, joining the unnatural pairs through alternative modes of hydrogen bonding. Whether and how AEGIS pairs are recognized and processed by multi-subunit cellular RNA polymerases (RNAPs) remains unknown. Here, we show that E. coli RNAP selectively recognizes unnatural nucleobases in a six-letter expanded genetic system. High-resolution cryo-EM structures of three RNAP elongation complexes containing template-substrate UBPs reveal the shared principles behind the recognition of AEGIS and natural base pairs. In these structures, RNAPs are captured in an active state, poised to perform the chemistry step. At this point, the unnatural base pair adopts a Watson-Crick geometry, and the trigger loop is folded into an active conformation, indicating that the mechanistic principles underlying recognition and incorporation of natural base pairs also apply to AEGIS unnatural base pairs. These data validate the design philosophy of AEGIS unnatural basepairs. Further, we provide structural evidence supporting a long-standing hypothesis that pair mismatch during transcription occurs via tautomerization. Together, our work highlights the importance of Watson-Crick complementarity underlying the design principles of AEGIS base pair recognition.


Biomarkers for cognitive aging part II: oxidative stress, cognitive assessments, and medication adherence.
The purpose of this study was to further examine potential biomarkers of cognitive aging by looking at the associations among oxidative stress, cognitive abilities, and medication adherence in a community-based sample of middle-aged and older adults (n = 42; mean age = 69 years) prescribed at least one medication for hypertension. In addition to measures described in Part I, "Biomarkers for Cognitive Aging," a 12-hr urine collection for F(2)-isoprostanes served as an indicator of oxidative stress. Participants completed a battery of cognitive assessments and 8 weeks of electronic medication monitoring for adherence to one antihypertensive agent. Oxidative stress was significantly associated with logical memory, immediate (r = -.38, p < .01) and delayed recall (r = -.42, p < .01), and recognition memory (r = -.42, p < .01) from the Wechsler Memory Scale III, number of perseveration errors (r = .26, p < .05) and categories achieved (r = -.26, p < .01) on the Wisconsin Card Sorting Test (WSCT), and medication adherence (r = -.34, p <.05). Findings indicate that a biomarker of oxidative stress, F(2)-isoprostanes corrected for vitamin E, is significantly associated with cognitive measures and a functional outcome.


Selecting the diameter of a radial head implant: an assessment of local landmarks.
Little information exists on radial head implant diameter sizing methods. When the native head is absent due to extensive comminution or previous excision, the lesser sigmoid notch may be a useful landmark for sizing. We evaluated the reliability of native radial head measurements, and the lesser sigmoid notch, as landmarks for radial head implant diameter sizing. We examined 27 fresh frozen ulnae and their corresponding radial heads. The maximum, minimum, and dish diameters of the radial heads were measured. A radial head implant diameter was selected based on the congruency of the trial implants with the radius of curvature of the lesser sigmoid notch. Intraobserver and interobserver reliability for all measurements and implant selection were assessed using intraclass correlation coefficients (ICC). Correlations between the native radial head measurements and the selected radial head implant diameter or the lesser sigmoid notch radius of curvature were assessed using the Pearson correlation coefficient (PCC). Radial head diameter measurements demonstrated strong to excellent intraobserver (ICC ≥ 0.75) and interobserver reliability (ICC ≥ 0.82). The lesser sigmoid notch sizing method showed poor interobserver reliability (ICC = 0.34). Only a moderate correlation was found between the native radial head and the lesser sigmoid notch (PCC ≤ 0.80) or the selected radial head implant size (PCC ≤ 0.59). Radial head diameter measurements showed excellent reliability, suggesting that the excised radial head, when available, should be used to select the implant diameter. The reliability of using the lesser sigmoid notch for sizing the diameter of radial head implants was only moderate, suggesting this is an unreliable landmark for implant diameter sizing.


Oligomerisation mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.
Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognise ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerisation, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function. While DTX3L and PARP9 are known to heterodimerize, they assemble into a high molecular weight oligomeric complex, but the nature of the oligomeric structure, including whether this contributes to the ADP-ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N-terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å 2 and a smaller one of 415 Å 2 . Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1-D2 deletion mutant showed the domain is dispensable for DTX3L-PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP-ribosylated androgen receptor. Our results suggest that homo-oligomerisation of DTX3L is important for mono-ADP-ribosylation reading by the DTX3L-PARP9 complex and to a ligand-regulated transcription factor.


Less frequently reported gram-negative fermentative rods.
The clinical significance and distinguishing characteristics of less frequently reported gram-negative fermentative rods (Pasteurella, Yersinia, Vibrio, Aeromonas and Plesiomonas, Enterobacter agglomerans, and Chromobacterium) are described. Increased awareness of these organisms, a knowledge of possible sites in which they cause infection, and identification criteria which will separate them from similar bacteria will prepare the clinical microbiologist for the isolation and identification of these "unusual" organisms.


Correlation of carotenoid production, decreased membrane fluidity, and resistance to oleic acid killing in Staphylococcus aureus 18Z.
Staphylococcus aureus is susceptible to killing by host-derived fatty acids. Studies were performed to test for a correlation between carotenoid production by S. aureus and protection against oleic acid. Oleic acid killing of cells grown in carotenoid expression medium was determined as the dosage of oleic acid in 2 M NaCl-2 mM EDTA that would kill 20% of the cells in 60 min at 37 degrees C (i.e., the 20% lethal dose). Compared with the wild-type strain (18Z), a carotenoid-deficient mutant strain (18Z-76) and strain 18Z grown in a medium that suppressed carotenoid production both showed increased sensitivity to oleic acid. Spontaneous revertants of strain 18Z-76 that regained the ability to produce carotenoids were as resistant to oleic acid as the wild-type strain. Oleic acid was shown by fluorescence polarization to decrease polarization values. Lower polarization values indicate a more-fluid membrane. To determine whether protection against oleic acid killing might depend on carotenoid stabilization of membranes, fluorescence polarization values were determined for strains showing different levels of carotenoid production. An indirect correlation was found between membrane fluidity and carotenoid production. We were able to conclude that there is a direct correlation between carotenoid production (i.e., cell pigmentation), cell membrane stability, and resistance to oleic acid-induced cell killing.


Epidemiological trends of trauma in tertiary care centre in dakshina kannada district of karnataka, India.
To study the pattern and burden of trauma cases which presented to a tertiary care centre in an upcoming Dakshina Kannada District of Karnataka, India. This was an epidemiological study. Data was collected by purposive sampling technique. Study period lasted from Jan 2013 to Aug 2013. Collected data was analyzed. The annual incidence of trauma at our centre was 15.96% (1140 cases). Most of the injuries were reported in 21-30 years age group. The male to female ratio was approximately 2.3:1. Limb injury (66.92%) constituted the commonest form of injury. Among the various injuries, fall was the commonest cause of injury (60.78%), followed by RTA (16.75%) and assault (11.6%). A majority of the cases were admitted during night time (61.24%). There has been an alarming increase in the number of trauma cases in the past decade. The target age group being the most productive one; it affects the economy directly . There is a need of urgent protective measures which are required for the benefit of the community.


Alphaviruses as tools in neurobiology and gene therapy.
The broad host range and superior infectivity of alphaviruses have encouraged the development of efficient expression vectors for Semliki Forest virus (SFV) and Sindbis virus (SIN). The generation of high-titer recombinant alphavirus stocks has allowed high-level expression of a multitude of nuclear, cytoplasmic, membrane-associated and secreted proteins in a variety of different cell lines and primary cell cultures. Despite the viral cytopathogenic effects, functional assays on recombinant proteins are possible for a time-period of at least 24 hours post-infection. The high percentage (80-95%) of primary neurons infected with SFV has allowed localization and functional studies of recombinant proteins in these primary cell cultures. Through multiple infection studies the interaction of receptor and G protein subunits has become feasible. Establishment of efficient scale-up procedures has allowed production of large quantities of recombinant protein. Potential gene therapy applications of alphaviruses could be demonstrated by injection of recombinant SIN particles expressing beta-galactosidase into mouse brain. Tissue/cell specific infection has been achieved by introduction of an IgG-binding domain of protein A domain into one of the spike proteins of SIN. This enabled efficient targeting of infection to human lymphoblastoid cells.


Medium-term results of a mobile bearing total knee replacement.
Mobile bearing total knee arthroplasty kinematically allows the advantages of large and congruent surface contact and low contact pressures, while preserving flexion, extension, and rotation in knee motion. In allowing for these degrees of freedom, the interface between bone and component also is protected from high stress. The Self Aligning I total knee arthroplasty initially was implanted in patients after its development at the authors' institution in 1990. Between 1990 and 1994, 141 patients with osteoarthritis of the knee underwent 172 total knee replacements using this system. At average followup of 5.6 years (range, 5-8 years), clinical results using this system showed a 94% satisfaction rate (good or very good). Two revision surgeries have been performed for polyethylene wear, with none of the remaining knees showing evidence of discernible wear. Complications included four cases of deep infection, four cases where a press fit femoral component failed (nonporous coated) and the patients required revision surgery, four traumatic fractures (three patellar and one supracondylar), one popliteal artery occlusion, and one revision for stiffness. Three patients required manipulation under anesthesia for arthrofibrosis. Kaplan-Meier survival curves show the probability of survival to be 91.7%, with revision surgery for any reason as an end point, and 98.8% for revision surgery because of polyethylene wear as an end point. Following the initial learning curve with this prosthesis, the medium term results using this system show maintenance of clinical success. No progressive evidence of polyethylene wear with time has been found, supporting the concept of mobile bearing arthroplasty in extending the service life of total knee arthroplasty.


Experiments and modeling of nonlinear frequency response of oscillations of a sessile droplet subjected to horizontal vibrations.
In this paper, we experimentally studied the response frequency of oscillations of a sessile water droplet, subjected to horizontal vibrations at varying excitation frequency (5-250 Hz and 40 kHz) and amplitude (0.015 mm to 0.5 mm for low frequencies and 600nm for ultrasonic frequency), as well as static contact angle of the glass substrate ([Formula: see text], [Formula: see text] , [Formula: see text], [Formula: see text]). The droplets were pinned during the experiments and non-axisymmetric oscillation modes were excited due to the horizontal vibrations. For the first time, we observed that at a sufficiently high vibration amplitude, when the excitation frequency is lower than the smallest natural frequency of the sessile droplet, the droplet oscillates at a response frequency multiple of the excitation frequency. At higher excitation frequencies up to several hundreds of Hz, the droplet oscillates nearly at the excitation frequency. At ultrasonic excitation frequency, however, the droplet cannot follow the excitations, since there is a physical limitation for forming infinite modes (infinite wavenumber) on the surface of a small droplet. We have modeled these behaviors with a nonlinear mass-spring-damper system by combining two established models: the Duffing and Van der Pol equations, in order to simulate both nonlinear damping and stiffness.


Research review: implementing change in the work redesign process.
Recent technological and management innovations have placed increasing pressure on health information managers to become change agents in their respective health care organizations. This article focuses on how different groups of health care employees perceive and adapt to change. Findings suggest the way change is perceived and inculcated into daily routines is dependent on past experiences with change. To successfully implement change, therefore, management should take a personal rather than structural approach.


Use of coimmobilized biological systems to degrade toxic organic compounds.
The concept of coimmobilizing cell mass (and/or enzyme) and adsorbent in a hydrogel matrix for biodegradation of toxic organic chemicals was introduced. Under defined experimental conditions, the coimmobilized system using activated carbon and Phanerochaete chrysosporium was compared with nonimmobilized systems for the degradation of pentachlorophenol (PCP). It was demonstrated that the coimmobilized system degraded PCP more effectively than the nonimmobilized system. A solid substrate included in the coimmobilized system could support the biodegradation. Isolation of the degrading agents from a model interrupting microorganism by the coimmobilized capsule membrane reduced the interference on the biodegradation. In simulated contaminated soil extract and sand, the coimmobilized system also exhibited higher degradative ability and stability than the nonimmobilized systems.


Metagene projection characterizes GEN2.2 and CAL-1 as relevant human plasmacytoid dendritic cell models.
Plasmacytoid dendritic cells (pDC) play a major role in the regulation of adaptive and innate immunity. Human pDC are difficult to isolate from peripheral blood and do not survive in culture making the study of their biology challenging. Recently, two leukemic counterparts of pDC, CAL-1 and GEN2.2, have been proposed as representative models of human pDC. Nevertheless, their relationship with pDC has been established only by means of particular functional and phenotypic similarities. With the aim of characterizing GEN2.2 and CAL-1 in the context of the main circulating immune cell populations we have performed microarray gene expression profiling of GEN2.2 and carried out an integrated analysis using publicly available gene expression datasets of CAL-1 and the main circulating primary leukocyte lineages. Our results show that GEN2.2 and CAL-1 share common gene expression programs with primary pDC, clustering apart from the rest of circulating hematopoietic lineages. We have also identified common differentially expressed genes that can be relevant in pDC biology. In addition, we have revealed the common and differential pathways activated in primary pDC and cell lines upon CpG stimulatio. R code and data are available in the supplementary material. firstname.lastname@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Targeting mitochondrial fitness as a strategy for healthy vascular aging.
Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations ('research gaps') for future investigation.


Subjective evaluation of the effectiveness of whole-body cryotherapy in patients with osteoarthritis.
One of the treatments for osteoarthritis (OA) is whole-body cryotherapy (WBC). The aim of this study is to assess the effect of whole-body cryotherapy on the clinical status of patients with osteoarthritis (OA), according to their subjective feelings before and after the application of a 10-day cold treatment cycle. The aim is also to assess the reduction of intensity and frequency of pain, the reduction of the painkiller medication used, and to assess the possible impact on physical activity. The study involved 50 people, including 30 women (60%) and 20 men (40%). Thirty-one patients had spondyloarthritis (62% of respondents), 10 had knee osteoarthritis (20%), and 9 hip osteoarthritis (18%). The overall average age was 50.1 ±10.9 years; the youngest patient was 29 years old and the oldest 73 years old. The average age of the women was 6 years higher. The study used a questionnaire completed by patients, and consisted of three basic parts. The modified Laitinen pain questionnaire contained questions concerning the intensity and frequency of pain, frequency of painkiller use and the degree of limited mobility. The visual analogue scale (VAS) was used in order to subjectively evaluate the therapy after applying the ten-day treatment cycle. According to the subjective assessment of respondents, after the whole-body cryotherapy treatments, a significant improvement occurred in 39 patients (78%), an improvement in 9 patients (18%), and no improvement was only declared by 2 patients (4%). Whole-body cryotherapy resulted in a reduction in the frequency and degree of pain perception in patients with osteoarthritis. WBC reduced the number of analgesic medications in these patients. It improved the range of physical activity and had a positive effect on the well-being of patients.


Increased risk of hypertension, proteinuria and preeclampsia in pregnant Saudi females with IgA nephropathy.
IgA nephropathy is fairly prevalent in Saudi Arabia. In this paper we examine the natural history of pregnancies and their impact on renal function in Saudi females affected by this condition. We followed a series of 12 patients, documented to have IgA nephritis by kidney biopsy, during their gestation. We monitored their blood pressure, serum creatinine, creatinine clearance, 24-hour protein before conception and at the third trimester of pregnancy. We also documented any maternal or fetal complications. All patients had well-controlled blood pressure, normal renal function, and proteinuria of less than one gram per day prior to conception. During pregnancy, all patients (100%) developed hypertension-requiring treatment and three of them (25%) developed preeclampsia. One patient (8.3%) had hemolysis, elevated liver enzymes, and, low platelets syndrome. All patients had worsening of their proteinuria during pregnancy from 535.2 (101.4) to 2179.2 (636.6) mg/24 h (p < 0.01) with a decrease in creatinine clearance from 88.6 (7.6) mls/min to 77.4 (5.9) mls/min (p < 0.05). No fetal complications were observed. We conclude that pregnancies in patients, even with mild IgA nephritis, require close observation as there is an increased incidence of worsening hypertension and preeclampsia.


Curcumin: therapeutical potential in ophthalmology.
Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.


L-ascorbic acid stimulates expression of smooth muscle-specific markers in smooth muscle cells both in vitro and in vivo.
The dedifferentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the progression of atherosclerosis and restenosis after angioplasty. Thus, factors that stimulate smooth muscle cell differentiation should be useful for therapy for these diseases. Previously, we found that l-ascorbic acid (L-Asc) induces the expression of smooth muscle-specific genes in a pluripotent bone marrow stromal cell line, TBR-B. This finding suggests that l-Asc stimulates the differentiation of smooth muscle cells. In the present study, we investigated the effects of l-Asc and its derivatives on the differentiation state of VSMCs in vitro and in vivo. l-Asc and its long-lasting derivatives stimulated the production of smooth muscle-specific myosin heavy chain-1 (SM1) and calponin 1 in a dose-dependent manner in rat cultured VSMCs, and the elevated production of SM1 and calponin 1 was maintained for at least 2 weeks. Moreover, oral administration of 3 g/kg of l-Asc to the balloon-injured rats induced a higher expression of SM1 and calponin 1 in the injured arteries compared with that from administration of the delivery vehicle alone. These data demonstrated new biologic activity, such as the stimulation of VSMC differentiation, of l-Asc and its long-lasting derivatives. In addition, these compounds may serve as useful tools for analysis of the differentiation of VSMCs and for therapy for vascular diseases.


Amino acids loaded chitosan/collagen based new membranes stimulate angiogenesis in chorioallantoic membrane assay.
Chitosan/collagen-based hydrogels were studied for their promising role in skin tissue engineering applications due to their unique biocompatibility and biodegradation properties. Amino acids are not only the mean of protein building units but also support endothelial cells proliferation and trigger angiogenesis during wound healing. The purpose of this study was to prepare amino acid based pro-angiogenic materials. Three structurally closed amino acids (AA) (arginine, alanine and phenylalanine) were loaded into chitosan/collagen hydrogels (ACC hydrogels) to study their effect on angiogenesis. In this study the ACC hydrogels were prepared through freeze drying procedure and their angiogenic potential was studied by chorioallantoic membrane assay (CAM assay). FTIR analysis was performed to confirm that there was no chemical change took place in polymeric materials during synthesis procedures. Results revealed that, arginine-loaded hydrogels were the most porous, with more interconnected pores and also the maximum growth of blood vessels were found around and inside the arginine loaded scaffold. The qualitative analysis for blood vessels showed the significant difference between control, chitosan/collagen alanine loaded hydrogel (CH-Ala), chitosan/collagen phenylalanine loaded hydrogel (CH-Phe) and chitosan/collagen arginine loaded hydrogel (CH-Arg) materials. Among these studied materials the CH-Arg was found more capable for angiogenesis.


Somatostatin: widespread abnormality in tissues of spontaneously diabetic mice.
Diabetic mice of the C57BL/6J obob and C57BL/Ks dbdb strains show a reduction in pancreatic somatostatin concentration accompanied in the obob strain by a striking decrease in the number of somatostatin-containing cells in the islets. Somatostatin concentration is also decreased in the stomach but increased in the hypothalamus. These findings suggest different control mechanisms for somatostatin in the hypothalamus compared to the gut and pancreas and exclude a primary genetic abnormality of somatostatin cells in the mutants.


Anti-vaccine activists, Web 2.0, and the postmodern paradigm--an overview of tactics and tropes used online by the anti-vaccination movement.
Websites opposing vaccination are prevalent on the Internet. Web 2.0, defined by interaction and user-generated content, has become ubiquitous. Furthermore, a new postmodern paradigm of healthcare has emerged, where power has shifted from doctors to patients, the legitimacy of science is questioned, and expertise is redefined. Together this has created an environment where anti-vaccine activists are able to effectively spread their messages. Evidence shows that individuals turn to the Internet for vaccination advice, and suggests such sources can impact vaccination decisions - therefore it is likely that anti-vaccine websites can influence whether people vaccinate themselves or their children. This overview examines the types of rhetoric individuals may encounter online in order to better understand why the anti-vaccination movement can be convincing, despite lacking scientific support for their claims. Tactics and tropes commonly used to argue against vaccination are described. This includes actions such as skewing science, shifting hypotheses, censoring dissent, and attacking critics; also discussed are frequently made claims such as not being "anti-vaccine" but "pro-safe vaccines", that vaccines are toxic or unnatural, and more. Recognizing disingenuous claims made by the anti-vaccination movement is essential in order to critically evaluate the information and misinformation encountered online.


Differentiation of Human Tonsil-Derived Mesenchymal Stem Cells into Schwann-Like Cells Improves Neuromuscular Function in a Mouse Model of Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited motor and sensory neuropathy, and is caused by duplication of PMP22, alterations of which are a characteristic feature of demyelination. The clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. Therefore, we investigated the potential of Schwann-like cells differentiated from human tonsil-derived stem cells (T-MSCs) for use in neuromuscular regeneration in trembler-J (Tr-J) mice, a model of CMT1A. After differentiation, we confirmed the increased expression of Schwann cell (SC) markers, including glial fibrillary acidic protein (GFAP), nerve growth factor receptor (NGFR), S100 calcium-binding protein B (S100B), glial cell-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), which suggests the differentiation of T-MSCs into SCs (T-MSC-SCs). To test their functional efficiency, the T-MSC-SCs were transplanted into the caudal thigh muscle of Tr-J mice. Recipients' improved locomotive activity on a rotarod test, and their sciatic function index, which suggests that transplanted T-MSC-SCs ameliorated demyelination and atrophy of nerve and muscle in Tr-J mice. Histological and molecular analyses showed the possibility of in situ remyelination by T-MSC-SCs transplantation. These findings demonstrate that the transplantation of heterologous T-MSC-SCs induced neuromuscular regeneration in mice and suggest they could be useful for the therapeutic treatment of patients with CMT1A disease.


Importance of Internet surveillance in public health emergency control and prevention: evidence from a digital epidemiologic study during avian influenza A H7N9 outbreaks.
Outbreaks of human infection with a new avian influenza A H7N9 virus occurred in China in the spring of 2013. Control and prevention of a new human infectious disease outbreak can be strongly affected by public reaction and social impact through the Internet and social media. This study aimed to investigate the potential roles of Internet surveillance in control and prevention of the human H7N9 outbreaks. Official data for the human H7N9 outbreaks were collected via the China National Health and Family Planning Committee website from March 31 to April 24, 2013. We obtained daily posted and forwarded number of blogs for the keyword "H7N9" from Sina microblog website and a daily Baidu Attention Index (BAI) from Baidu website, which reflected public attention to the outbreak. Rumors identified and confirmed by the authorities were collected from Baidu search engine. Both daily posted and forwarded number and BAI for keyword H7N9 increased quickly during the first 3 days of the outbreaks and remained at a high level for 5 days. The total daily posted and forwarded number for H7N9 on Sina microblog peaked at 850,000 on April 3, from zero blogs before March 31, increasing to 97,726 on April 1 and to 370,607 on April 2, and remaining above 500,000 from April 5-8 before declining to 208,524 on April 12. The total daily BAI showed a similar pattern of change to the total daily posted and forwarded number over time from March 31 to April 12. When the outbreak locations spread, especially into other areas of the same province/city and the capital, Beijing, daily posted and forwarded number and BAI increased again to a peak at 368,500 and 116,911, respectively. The median daily BAI during the studied 25 days was significantly higher among the 7 provinces/cities with reported human H7N9 cases than the 2 provinces without any cases (P<.001). So were the median daily posted and forwarded number and daily BAI in each province/city except Anhui province. We retrieved a total of 32 confirmed rumors spread across 19 provinces/cities in China. In all, 84% (27/32) of rumors were disseminated and transmitted by social media. The first 3 days of an epidemic is a critical period for the authorities to take appropriate action through Internet surveillance to prevent and control the epidemic, including preparation of personnel, technology, and other resources; information release; collection of public opinion and reaction; and clarification, prevention, and control of rumors. Internet surveillance can be used as an efficient and economical tool to prevent and control public health emergencies, such as H7N9 outbreaks.


Randomized clinical trial of four adhesion strategies in posterior restorations-18-month results.
To evaluate the 18-month clinical performance of four adhesive strategies in posterior composite restorations placed in private practice. Upon approval by an institutional review board, 144 restorations were inserted in 45 subjects (average age = 32.6) to treat caries lesions or to replace existing restorations in vital molars and premolars. The adhesives OptiBond FL (three-step etch-and-rinse), OptiBond SOLO Plus (two-step etch-and-rinse), OptiBond XTR (two-step self-etch), and OptiBond All-in One (one-step self-etch) were applied as per manufacturer's (Kerr Co.) instructions followed by a nanofilled resin composite (Filtek Z350XT, 3M ESPE) under rubber dam isolation. Restorations were evaluated at baseline and at 18 months using United States Public Health Service (USPHS)-modified criteria and high-resolution digital photographs. Statistical analyses included the McNemar and the Mann-Whitney non-parametric tests (p < 0.05). A total of 137 restorations were evaluated after 18 months. The number of alfa ratings did not change significantly from baseline to 18 months for any of the adhesion strategies. When the 18-month evaluation criteria were pooled by pairs of adhesives, none of the adhesives resulted in a significantly different number of alfa ratings for any of the criteria compared with the other adhesives. Bonding strategy did not influence the clinical performance of posterior composite restorations under the clinical conditions used in this study. When used in ideal clinical conditions, the composition of current dentin adhesives may be more clinically relevant than their adhesion strategy.


Hormonal contraception and risk of cancer.
Fear from increased cancer risk is one of the most significant reasons for low acceptance of reliable contraceptive methods and low compliance. In this review, we included all cohort and case-control studies published in English up to December 2008. They were identified through a search of the literature using Pubmed and EMBASE. Data about breast cancer risk indicate a slightly increased risk among current users of oral contraceptives (OC), an effect which disappears 5-10 years after stopping. Combined OC have a significant protective effect on the risk of ovarian cancer, and the protection increases with duration of use (relative risk decreased by 20% for each 5 years of use). The significant risk reduction has been confirmed for BRCA 1 and 2 mutation carriers. The risk of endometrial cancer is reduced by about 50% in ever users, a benefit which is greater with increasing duration of use. An association has been found between increased risk of cervical cancer and long-term OC use. Current OC use has been associated with an excess risk of benign liver tumours and a modest increased risk of liver cancer. None of large prospective cohort studies with prolonged follow-up has observed an increased overall risk of cancer incidence or mortality among ever users of OC, indeed several have suggested important long-term benefits. Specifically, protective effect of OC can be used as chemoprevention in young women who are BRCA mutation carriers. Women wishing to use combined OC can be reassured that their decision is unlikely to place them at higher risk of developing cancer.


Direct identification of gram-positive cocci from routine blood cultures by using AccuProbe tests.
Rapid and reliable identification of bacteria directly from blood cultures is important in clinical practice to guide appropriate antibiotic therapy. In this study, the performance of the AccuProbe (Gen-Probe, Inc., San Diego, Calif.) in direct identification of Staphylococcus aureus, Streptococcus pneumoniae, enterococci, and group A and B streptococci from positive blood culture bottles was evaluated by using 6-year routine clinical laboratory blood culture material from Paijat-Hame Central Hospital, Lahti, Finland. With the enterococcal and group A and B streptococcal probes, the diagnostic performance of the test was excellent at a cutoff value of 50,000 relative light units (RLU) as recommended by the manufacturer. However, with the S. aureus probe, although the specificity was very high (99.8%), the sensitivity was low (72.4%). To improve the clinical usability of the direct AccuProbe identification, optimal cutoff values for the individual AccuProbe tests were defined by using receiver-operating characteristic analysis. Consequently, cutoff values for S. aureus and S. pneumoniae tests were adjusted to 30,000 RLU and for enterococci and to 55,000 RLU for group A and B streptococci. With these adjustments, the performance of the AccuProbe tests, especially that for S. aureus, was significantly improved.


Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice.
Hydrogen selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied. In this study, we investigated the effects of hydrogen-rich saline on the prevention of liver injury induced by obstructive jaundice in rats. Male Sprague-Dawley rats (n=56) were divided randomly into four experimental groups: sham operated, bile duct ligation (BDL) plus saline treatment [5 ml/kg, intraperitoneal (i.p.)], BDL plus low-dose hydrogen-rich saline treatment (5 ml/kg, i.p.) and BDL plus high-dose hydrogen-rich saline treatment (10 ml/kg, i.p.). The liver damage was evaluated microscopically 10 days after BDL. Serum alanine aminotransferase and aspartate aminotransferase levels, tissue malondialdehyde content, myeloperoxidase activity, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and high-mobility group box 1 levels were all increased significantly by BDL. Hydrogen-rich saline reduced levels of these markers and relieved morphological liver injury. Additionally, hydrogen-rich saline markedly increased the activities of anti-oxidant enzymes superoxide dismutase and catalase and downregulated extracellular signal-regulated protein kinase (ERK)1/2 activation. Hydrogen-rich saline attenuates BDL-induced liver damage, possibly by the reduction of inflammation and oxidative stress and the inhibition of the ERK1/2 pathway.


Measuring and Improving Evidence-Based Patient Care Using a Web-Based Gamified Approach in Primary Care (QualityIQ): Randomized Controlled Trial.
Unwarranted variability in clinical practice is a challenging problem in practice today, leading to poor outcomes for patients and low-value care for providers, payers, and patients. In this study, we introduced a novel tool, QualityIQ, and determined the extent to which it helps primary care physicians to align care decisions with the latest best practices included in the Merit-Based Incentive Payment System (MIPS). We developed the fully automated QualityIQ patient simulation platform with real-time evidence-based feedback and gamified peer benchmarking. Each case included workup, diagnosis, and management questions with explicit evidence-based scoring criteria. We recruited practicing primary care physicians across the United States into the study via the web and conducted a cross-sectional study of clinical decisions among a national sample of primary care physicians, randomized to continuing medical education (CME) and non-CME study arms. Physicians "cared" for 8 weekly cases that covered typical primary care scenarios. We measured participation rates, changes in quality scores (including MIPS scores), self-reported practice change, and physician satisfaction with the tool. The primary outcomes for this study were evidence-based care scores within each case, adherence to MIPS measures, and variation in clinical decision-making among the primary care providers caring for the same patient. We found strong, scalable engagement with the tool, with 75% of participants (61 non-CME and 59 CME) completing at least 6 of 8 total cases. We saw significant improvement in evidence-based clinical decisions across multiple conditions, such as diabetes (+8.3%, P<.001) and osteoarthritis (+7.6%, P=.003) and with MIPS-related quality measures, such as diabetes eye examinations (+22%, P<.001), depression screening (+11%, P<.001), and asthma medications (+33%, P<.001). Although the CME availability did not increase enrollment in the study, participants who were offered CME credits were more likely to complete at least 6 of the 8 cases. Although CME availability did not prove to be important, the short, clinically detailed case simulations with real-time feedback and gamified peer benchmarking did lead to significant improvements in evidence-based care decisions among all practicing physicians. ClinicalTrials.gov NCT03800901; https://clinicaltrials.gov/ct2/show/NCT03800901.


Enhancement of hydrolytic activity of sphingolipid ceramide N-deacylase in the aqueous-organic biphasic system.
Lysoglycosphingolipids were produced from glycosphingolipids by using sphingolipid ceramide N-deacylase, which cleaves the N-acyl linkage between fatty acids and sphingosine bases in various glycosphingolipids. The enzyme reaction was done in a biphasic media prepared with water;-immiscible organic solvent and aqueous buffer solution containing the enzyme. We investigated the effects of organic solvents and detergents on lysoglycosphingolipid production in the biphasic system. Among the organic solvents tested, n-butylbenzene, cumene, cyclodecane, cyclohexane, n-decane, diisopropylether, n-heptadecane, and methylcyclohexane promoted hydrolysis of GM1, whereas benzene, chloroform, ethyl acetate, and toluene inhibited GM1 hydrolysis. Hydrolysis of asialo GM1, GD1a, GalCer, and sulfatide was also enhanced by the addition of n-decane. The hydrolytic activity of the enzyme was enhanced by the addition of 0.8% sodium taurodeoxycholate or sodium cholate to the aqueous phase. The most effective hydrolysis of various glycosphingolipids by the enzyme was thus obtained in the aqueous-n-decane biphasic system containing 0.8% sodium taurodeoxycholate. Under this condition, the fatty acids released from GM1 by the action of the enzyme were trapped and diffused into the organic phase, while lysoGM1 remained in the aqueous phase. Thus the almost complete hydrolysis of GM1 was achieved using the biphasic system, while at most 70% of hydrolysis was obtained using normal aqueous media possibly due to the inhibition of hydrolysis reaction by accumulation of fatty acids in the reaction mixture.


Clinical Efficacy of the Transradial Approach in Percutaneous Intervention for a Malfunctioning Arteriovenous Fistula.
To evaluate the effectiveness of the transradial artery approach (TRA) for treating malfunctioning arteriovenous fistulas (AVFs) in patients on hemodialysis. A retrospective analysis was conducted in this single-center study of TRA endovascular procedures in 73 patients (43 male and 30 female; mean age of 67.4 years (range, 42-92 years) with malfunctioning AVFs, between January 2008 and April 2019. Patients' baseline and lesion characteristics, technical and clinical success, and complications were evaluated, and functional patency was analyzed using the Kaplan-Meier method. Radial artery approaches were successful in all patients. Angioplasty performed using the TRA achieved technical and clinical success rates of 98.6%(72/73) and 91.7%(67/73), respectively. The median primary patency time was 18.8 ± 15.9 months. The primary functional patency rates at 3, 6, and 12 months were 82.1%, 68.6%, and 63.9%, respectively. There were no major complications or adverse events, such as hand ischemia, related to the radial artery approach. In selected cases, the TRA can be used complementary to the transvenous approach to treat malfunctioning AVFs.


Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).
Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.


Vascular endothelial growth factor-C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium.
We have previously reported expression of vascular endothelial growth factor (VEGF)-A and -C in glomerular podocytes and actions of VEGF-A on glomerular endothelial cells (GEnC) that express VEGF receptor-2 (VEGFR-2). Here we define VEGFR-3 expression in GEnC and investigate the effects of the ligand VEGF-C. Renal cortex and cultured GEnC were examined by microscopy, and both cell and glomerular lysates were assessed by Western blotting. VEGF-C effects on trans-endothelial electrical resistance and albumin flux across GEnC monolayers were measured. The effects of VEGF-C156S, a VEGFR-3-specific agonist, and VEGF-A were also studied. VEGF-C effects on intracellular calcium ([Ca2+]i) were measured using a fluorescence technique, receptor phosphorylation was examined by immunoprecipitation assays, and phosphorylation of myosin light chain-2 and VE-cadherin was assessed by blotting with phospho-specific antibodies. GEnC expressed VEGFR-3 in tissue sections and culture, and VEGF-C increased trans-endothelial electrical resistance in a dose-dependent manner with a maximal effect at 120 minutes of 6.8 Omega whereas VEGF-C156S had no effect. VEGF-C reduced labeled albumin flux by 32.8%. VEGF-C and VEGF-A increased [Ca2+]i by 15% and 39%, respectively. VEGF-C phosphorylated VEGFR-2 but not VEGFR-3, myosin light chain-2, or VE-cadherin. VEGF-C increased GEnC monolayer integrity and increased [Ca2+]i, which may be related to VEGF-C-S particular receptor binding and phosphorylation induction characteristics. These observations suggest that podocytes direct GEnC behavior through both VEGF-C and VEGF-A.


Expression of the RNA component of human telomerase (hTR) in prostate cancer, prostatic intraepithelial neoplasia, and normal prostate tissue.
Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. While telomerase is undetectable in most normal somatic tissues, telomerase activation has been detected by a polymerase chain reaction (PCR)-based assay (TRAP) in many immortal cell lines and various cancers, including prostate cancers. To investigate the role of telomerase in prostate cancer at the cellular level, the expression of one of the ribonucleoprotein complexes, the RNA component of human telomerase (hTR), was studied in normal, preneoplastic, and cancerous prostate tissues using a non-radioactive in situ hybridization procedure. Nine human prostates resected at the time of radical prostatectomy were studied. In each case, archival paraffin-embedded samples from normal tissue, prostatic intraepithelial neoplasia (PIN) lesions, the putative precancerous lesion, and prostate carcinomas were selected for in situ hybridization. hTR mRNA expression was detected in carcinomatous glands of seven out of the nine cancers (75 per cent). Furthermore, in seven out of the eight cases showing PIN lesions, the epithelial cells of PIN foci also expressed hTR mRNA. By contrast, in normal tissue, epithelial cells were negative, whereas hTR mRNA expression was detected in the basal cells. The detection of hTR mRNA in PIN lesions clearly strengthens the link between PIN and carcinomatous glands and suggests that telomerase expression occurs early in prostate carcinogenesis. Furthermore, this study confirms previous experimental data suggesting that the basal cell layer is the stem cell compartment in prostate.


Lipogenesis in rabbit adipose tissue.
Previous reports that rabbit adipose tissue does not synthesize fatty acids at significant rates led us to study in detail the pathways of lipogenesis and glyceroneogenesis in this tissue. We found that rabbit adipose tissue has a low capacity for denovo fatty acid synthesis from glucose but a high capacity for synthesis from pyruvate and acetate. The tissue can also convert pyruvate to glyceride-glycerol via the dicarboxylic acid shuttle and gluconeogenic pathways. Experiments with hydroxycitrate, a potent inhibitor of citrate cleavage enzyme, demonstrated that this is an obligatory enzyme in lipogenesis from pyruvate. The lipogenic system of rabbit adipose tissue resembles that of a ruminant in that it is adapted to utilize acetate rather than glucose. However, in contrast to ruminant tissues, the limited ability to convert glucose to fatty acid results not from a deficiency in the enzymes concerned with the transport of acetyl units out of the mitochondria but from a block prior to the level of pyruvate, most likely at the hexokinase and pyruvate kinase reactions.


[Diabetes mellitus in connection with a hereditary disease].
Diabetes mellitus is usually subdivided into type I (insulin-dependent) and type II (relative insulin shortage and reduced sensitivity to insulin). Diabetes may also be related to pregnancy, malnutrition, pancreatic disease, pharmaceuticals, endocrine diseases and hereditary disorders. The hereditary diseases which may be associated with diabetes mellitus or impaired glucose tolerance can be subdivided into syndromes (such as maternally inherited diabetes and deafness, Down, Turner and Klinefelter syndrome), metabolic diseases (like cystic fibrosis and haemochromatosis) and endocrine diseases (like polyglandular autoimmune insufficiency syndrome and familial phaeochromocytoma). Although diabetes mellitus as part of a hereditary disorder is infrequent, the possibility should be kept in mind with a view to a correct diagnosis. In patients with diabetes mellitus a hereditary disorder may be involved, while patients with a hereditary disorder run a higher risk of developing diabetes mellitus.


Radiographic Outcomes of a Mobile-Bearing Total Ankle Replacement.
Contemporary total ankle prostheses embody design changes intended to address weaknesses in first-generation implants. Due to these changes, outcomes of the newer designs are of particular interest. We have previously published self-reported patient outcomes for the STAR (Scandinavian Total Ankle Replacement) prosthesis. The present study documents radiographic outcome measurements for the STAR prosthesis at intermediate to long-term follow-up. Of 89 consecutive ankle replacements performed between July 1998 and April 2007, 79 had a minimum follow-up of 2 years and were followed prospectively. Serial radiographs were measured by 2 of the authors, including varus, valgus, alpha, beta, and gamma angles, as well as point contact ratio. Inter- and intrarater reliability was calculated and reported. A "severe" subgroup of patients with preoperative coronal plane deformity exceeding 10 degrees was assessed separately. Preoperative and immediate postoperative measurements were compared and maintenance of correction evaluated on subsequent radiographs. Heterotopic ossification and pericomponent lucency were documented and followed, and subsequent procedures were recorded to follow survivorship. The mean follow-up was 8.0 years. Of the 79 ankles, 25 underwent a secondary surgery (31.6%). Coronal correction averaged 5.1 degrees (P < .001), and this was maintained to final follow-up. The severe subgroup (n = 21), with a mean preoperative coronal angulation of 16.1 degrees, was corrected to 4.6 degrees at final follow-up (P < .001). The severe subgroup had a higher secondary surgery rate at 33.3%, with metallic component revision or failure occurring in 3 cases (14.3%) compared to 8 (10.1%) in the entire cohort. The heterotopic ossification rate was 100%, slightly higher than prior reports. STAR prosthesis survivorship was similar to that documented in prior studies of second-generation implants in European patient cohorts. Statistically significant correction in coronal alignment was achieved immediately after surgery and maintained until a final mean follow-up of 8 years, even in patients with preoperative deformity greater than 10 degrees. Level III, retrospective cohort study.


Snoring in patients with chronic rhinosinusitis after endoscopic sinus surgery.
In patients with chronic rhinosinusitis (CRS), we assessed quality of life (QOL) of chronic rhinosinusitis (CRS) patients with different self-reported snoring frequencies after endoscopic sinus surgery (ESS), and explored factors associated with pre-ESS snoring and post-ESS snoring reduction. This prospective cohort study was conducted in a tertiary referral center in Chengdu, China. Adult patients with medically recalcitrant CRS receiving initial ESS were engaged. Self-reported snoring was measured at baseline and 3-year follow-up, along with Sino-Nasal Outcome Test-22 and snoring visual analog scale assessment. Mouth breathing (MB), demographics, behavior, comorbidity factors, and objective CRS severity were considered. In 210 patients who completed this study, 63 (30%) patients reported pre-ESS habitual snoring, and post-operative habitual snoring was observed in 52 (25%) patients. The presence of self-reported snoring was correlated with worse CRS QOL at baseline and 3-year follow-up. Obesity (odds ratio [OR] = 4.30; 95% confidence interval [CI], 1.64-11.28; p < 0.01) and posterior-to-anterior ethmoid sinus ratio greater than one (PE/AE, OR = 0.32; 95% CI, 0.10-0.99; p = 0.05) were associated with pre-ESS snoring in univariable and multivariable analysis. The post-operative reduction of snoring frequency was related with patient age over 65 (OR = 11.55; 95%CI, 1.35-98.79; p = 0.03) and bilateral opacification in the Lund-Mackay system (OR = 8.04; 95%CI, 1.24-51.90; p = 0.03) in multivariable analysis. Pre-operative snoring and MB were associated with increased risk of post-operative snoring (p < 0.01 for each comparison). Post-ESS, self-reported snoring was associated with worse CRS QOL. Obesity and PE/AE > 1 were risk factors of pre-operative snoring. Advanced age and bilateral opacification were associated with greater improvement of snoring after ESS.