Biomarkers and Bacterial Pneumonia Risk in Patients with Treated HIV Infection: A Case-Control Study

Background: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIVinfected patients do not currently exist. Methods: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1:1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. Results: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 mg/mL in cases vs. 1.93 mg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). Conclusions: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Una mappa per la porta del non ritorno: l'appartenenza nella letteratura nera canadese

La presente tesi dimostra che la letteratura nera canadese può costituire una critica al concetto di appartenenza, così come è stato sempre rappresentato nel Canada anglofono. Più specificatamente, prende in considerazione tre scrittori contemporanei – George Elliott Clarke, Austin Clarke e Dionne Brand – che mettono in evidenza, seppure non nei termini classici, ciò che Stuart Hall descrive come “quegli aspetti delle nostre identità che scaturiscono dal nostro ‘appartenere’ a distinte culture etniche, razziali, linguistiche, religiose e soprattutto nazionali” (Stuart Hall, Modernity 596). Ognuno di essi, infatti, pone in evidenza il senso di appartenenza culturale in modo incerto, ambivalente e perfino estremamente critico. L’analisi dei loro testi, inoltre, è imprescindibile, dallo studio di tre discorsi (termine da intendersi secondo la definizione proposta da Ian Angus): il nazionalismo, il multiculturalismo e la diaspora che sembrano condizionare e limitare i termini semantici, concettuali e politici dell’appartenenza culturale, specialmente nell’ambito degli studi canadesi e postcoloniali. In realtà, autori quali Austin Clarke e Dionne Brand, offrendo una prospettiva unica ed originale da cui avviare una critica a tali concetti, propongono dei ‘linguaggi di appartenenza’ diversi e, di conseguenza, modi alternativi di manifestare e concretizzare, non solo un attaccamento culturale, ma anche un impegno politico profondo. Il lavoro è composto dall’Introduzione, in cui vengono esplicitate le ragioni dell’argomento scelto; il Capitolo I, che funge da impianto metodologico alla ricerca, spiega il concetto di appartenenza; da tre Capitoli centrali, ciascuno dedicato ad un singolo autore, che esaminano una serie di opere, di ogni singolo autore, al fine di esaminare e giudicare i tre discorsi; e dalla Conclusione che contiene delle considerazioni sul ruolo della letteratura nera canadese all’interno degli studi canadesi contemporanei e postcoloniali.

Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease

In this thesis is described the design and synthesis of potential agents for the treatment of the multifactorial Alzheimer’s disease (AD). Our multi-target approach was to consider cannabinoid system involved in AD, together with classic targets. In the first project, designed modifications were performed on lead molecule in order to increase potency and obtain balanced activities on fatty acid amide hydrolase and cholinesterases. A small library of compounds was synthesized and biological results showed increased inhibitory activity (nanomolar range) related to selected target. The second project was focused on the benzofuran framework, a privileged structure being a common moiety found in many biologically active natural products and therapeutics. Hybrid molecules were designed and synthesized, focusing on the inhibition of cholinesterases, Aβ aggregation, FAAH and on the interaction with CB receptors. Preliminary results showed that several compounds are potent CB ligands, in particular the high affinity for CB2 receptors, could open new opportunities to modulate neuroinflammation. The third and the fourth project were carried out at the IMS, Aberdeen, under the supervision of Prof. Matteo Zanda. The role of the cannabinoid system in the brain is still largely unexplored and the relationship between the CB1 receptors functional modification, density and distribution and the onset of a pathological state is not well understood. For this reasons, Rimonabant analogues suitable as radioligands were synthesized. The latter, through PET, could provide reliable measurements of density and distribution of CB1 receptors in the brain. In the fifth project, in collaboration with CHyM of York, the goal was to develop arginine analogues that are target specific due to their exclusively location into NOS enzymes and could work as MRI contrasting agents. Synthesized analogues could be suitable substrate for the transfer of polarization by p-H2 molecules through SABRE technique transforming MRI a more sensitive and faster technique.

Function of liver activation-regulated chemokine/CC chemokine ligand 20 is differently affected by cathepsin B and cathepsin D processing

Chemokine processing by proteases is emerging as an important regulatory mechanism of leukocyte functions and possibly also of cancer progression. We screened a large panel of chemokines for degradation by cathepsins B and D, two proteases involved in tumor progression. Among the few substrates processed by both proteases, we focused on CCL20, the unique chemokine ligand of CCR6 that is expressed on immature dendritic cells and subtypes of memory lymphocytes. Analysis of the cleavage sites demonstrate that cathepsin B specifically cleaves off four C-terminally located amino acids and generates a CCL20(1-66) isoform with full functional activity. By contrast, cathepsin D totally inactivates the chemotactic potency of CCL20 by generating CCL20(1-55), CCL20(1-52), and a 12-aa C-terminal peptide CCL20(59-70). Proteolytic cleavage of CCL20 occurs also with chemokine bound to glycosaminoglycans. In addition, we characterized human melanoma cells as a novel CCL20 source and as cathepsin producers. CCL20 production was up-regulated by IL-1alpha and TNF-alpha in all cell lines tested, and in human metastatic melanoma cells. Whereas cathepsin D is secreted in the extracellular milieu, cathepsin B activity is confined to cytosol and cellular membranes. Our studies suggest that CCL20 processing in the extracellular environment of melanoma cells is exclusively mediated by cathepsin D. Thus, we propose a model where cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas.

Congenital hypotrichosis and partial anodontia in a crossbred beef calf

Clinical examination, skin biopsies, skull radiographs, and DNA analysis of a 2-day-old Red Angus-Charolais-Simmental cross bull calf confirmed the diagnosis of congenital hypotrichosis and anodontia defect (HAD), also called anhidrotic ectodermal dysplasia, which is a rare anomaly caused by a deletion in the bovine EDA gene on the X chromosome.

Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4)

BACKGROUND: Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds. RESULTS: We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families. CONCLUSION: We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly.

Superovulation of Beef Heifers with Follicle Stimulating Hormone or Human Menopausal Gonadotropin: Acute Effects on Hormone Secretion

The effects of superovulatory treatment (follicle stimulating hormone [FSH] versus human menopausal gonadotropin [HMG]) and of route of administration (intramuscular versus intravenous) of prostaglandin F2a (PGF2a) on hormonal profiles were determined in 32 Angus x Hereford heifers for breeding and subsequent embryo collection and transfer. Heifers were superstimulated either with FSH (total of 26 milligrams) or HMG (total of 1,050 international units) beginning on days 9 to 12 of an estrous cycle and PGF2a (40 milligrams) was administered at 60 and 72 hours after the beginning of superovulatory treatments. Heifers were artificially inseminated three times at 12-hour intervals beginning 48 hours after PGF2a treatment. Blood serum samples were collected immediately before treatments began and at frequent intervals until embryo collection 288 hours later. Concentrations of luteinizing hormone (LH) and FSH were not affected by hormone treatments, route of PGF2a injection, or interactions between them. Estradiol-17ß (E2-17ß) levels were higher in HMG- than in FSH-treated heifers 60 hours after gonadotropin treatment. Peak concentration of E2-17ß occurred earlier in HMGthan in FSH-treated heifers and earlier in heifers injected with PGF2a intramuscularly than those injected intravenously. Progesterone concentrations were not influenced by treatment or route of PGF2a administration. The progesterone:E2-17ß ratio was higher in FSH- than in HMG-treated heifers 24 hours after the LH peak. The high steroid hormone concentrations in superovulated beef heifers before and after ovulation may lead to asynchrony between stages of embryonic development, a situation that may interfere with the pregnancy outcome of superovulated embryos in recipient animals.

Effects of Feeding Cobalt Dextro Lac (CDL) on Feedlot Performance and Carcass Value of Finishing Steers Fed Wet Corn Gluten Feed

A 192-day experiment involving 144 young Angus steers fed growing and finishing diets containing 20% corn gluten feed was conducted to evaluate feeding a soluble source of readily available cobalt. No benefits were observed in rate of gain, feed intake or carcass value by feeding the available source of cobalt.

The Effects of Feeding a Live Microbial Product on Feedlot Performance and Carcass Value of Finishing Steers Fed Wet Corn Gluten Feed

This experiment was conducted to evaluate the efficacy of daily feeding a live microbial preparation containing two live organisms to finishing cattle. One organism was a lactobacillus, and the other was a propionibacterium, thought to work in concert to improve fermentation in the rumen and overall digestion. The study was conducted with Angus steers with an average initial weight of 550 lbs that were fed a finishing ration containing 50% wet corn gluten feed on a dry basis for 184 days. Feeding the microbial product improved daily gain and feed efficiency 1.7% and 2.4%, respectively, but the differences were not statistically significant. The microbial preparation increased carcass weights 1% but had no effects on quality or yield grades. It is concluded that potential benefits of this product are more likely to be greater when cattle are fed high grain rations rather than diets containing high concentrations of corn gluten feed.

Programmed Feeding of Protein to Finishing Beef Steers

Six-hundred pound Angus steer calves were fed cornbased finishing diets for 180 days to determine the effects of stepwise reduction of protein in the diet on performance and carcass characteristics. Reducing protein in the diet, but satisfying the requirements projected by the National Research Council model for Nutrient Requirements of Beef Cattle, did not affect performance or carcass measurements. Further reduction in protein content of the diet, so the projected requirement of the rumen microorganisms was not being met, did not affect performance or carcass measurements. It is concluded that quantity of protein fed to finishing cattle can be programmed and abstantially reduced. These reductions will result in substantially less nitrogen excreted in manure from larger feedlots.

Relative Value of White Corn When Fed to Finishing Cattle and Its Effects on Color of Carcass Fat

White corn was compared with yellow corn in a 180-day finishing trial with 600 lb. Angus steers fed 90% concentrate diets. Steers fed yellow corn consumed 3.3% less feed and were 3.8% more efficient in feed utilization. Rate of gain and carcass characteristics were similar for steers fed white or yellow corn. The color of subcutaneous fat over the ribs was significantly whiter from carcasses of steers fed white corn compared with those fed yellow corn. The results of this study indicate that white corn may be used instead of barley to produce whiter fat in beef carcasses.