Search

Background Atrial fibrillation (AF) is common in patients with the HeartMate II (HMII) left ventricular assist device (LVAD), but the impact of AF on clinical outcomes is uncertain. Objectives This study sought to determine the effect of AF on outcomes in patients with the HMII LVAD. Methods Records of 106 patients who underwent HMII implantation at a single center were reviewed. The associations of paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PeAF) with survival, heart failure (HF) hospitalization, bleeding, and thromboembolism were examined using Kaplan-Meier survival analysis and Cox proportional hazards regression. Results Mean age was 56.6 ± 11.4 years, 87.7% of the implants were intended as a bridge to transplantation, and median length of support was 217 days (range: 1 to 952 days). AF was present in 55 patients (51.9%); 36 patients (34.0%) had PAF and 19 (17.9%) had PeAF. Twenty-one patients (19.8%) died, and 18 (17.0%) were hospitalized for HF. There were 0.75 major bleeding events and 0.28 thromboembolic events per patient year of follow-up. PAF was not associated with increased mortality, HF hospitalization, bleeding, or thromboembolism. PeAF, however, was an independent predictor of the composite endpoint of death or HF hospitalization (hazard ratio: 3.54; 95% confidence interval: 1.52 to 8.25; p < 0.01). Although there was no increase in bleeding or thromboembolism, patients with AF had thromboembolic events at higher international normalized ratios (INRs). Conclusions Although PAF is not associated with worse outcomes in patients with the HMII LVAD, PeAF may be associated with increased mortality and HF hospitalization. Patients with AF also may have thromboembolic events at higher INR levels. [ABSTRACT FROM AUTHOR]

Abstract: Vcsa1 plays an important role in the erectile physiology of the rat. We conducted experiments to determine if erectile function, testosterone levels and Vcsa1 expression were correlated. In orchiectomized rats, total testosterone in blood fell from an average of 4ng/ml to <0.04ng/ml. Erectile function was significantly lower compared to controls and Vcsa1 expression was significantly (>6-fold) decreased. Injection of orchiectomized animals with testosterone (2mg in 100ml sesame oil every 4 days for 2 weeks) restored average levels of testosterone to 2ng/ml, increased erectile function and significantly increased Vcsa1 expression. In isolated corporal cells there was testosterone dependent Vcsa1 expression. However, intracorporal injection of orchiectomized animals with a plasmid expressing Vcsa1 or its gene product Sialorphin (previously demonstrated to improve erectile function in old animals) gave no significant improvement in erectile function. Also, the ability of Sialorphin to reduce tension in corporal smooth muscle strips isolated from orchiectomized animals was impaired compared to controls. [Copyright &y& Elsevier]

Abstract: XK, a putative membrane transporter, is a component of the XK/Kell complex of the Kell blood group system. XK''s substrate is unknown but absence of the protein, as occurs in the McLeod phenotype, is associated with red cell acanthocytosis and late onset central nervous system and neuromuscular abnormalities known as the McLeod syndrome. We have cloned two cDNAs, XPLAC (GenBank accession no.AY589511) and XTES (GenBank accession no. AY989815), which are closely related to XK and define them together as the XK family. XPLAC has a 2.9 kb cDNA that encodes 462 amino acids and XTES has a 1.6 kb cDNA coding 459 amino acids. The predicted molecular weights are 53.6 kDa for XPLAC and 53.4 kDa for XTES, which are similar to that of XK, which is 50.9 kDa. Unlike XK which is ubiquitously expressed XPLAC is expressed mostly in placenta and adrenal gland while XTES is exclusively expressed in primate testis. XPLAC has 37% and XTES has 31% amino acid identity with XK protein and they are predicted to have a similar topology to XK. XPLAC, like XK, has 3 exons and is located on X chromosome at q22.1, while XTES has 4 exons and is located at 22q11.1. Phylogenetic analysis shows that there are at least 5 additional vertebrate genes that are evolutionarily distantly related to the XK family. A domain with consensus sequences (ced-8 domain) for the extended family is described. [Copyright &y& Elsevier]

Abstract: The peak stages of the extreme floods inundating the town of Rome are known since the XV century. This record covering more than 500 years can be considered as a censored sample of the population of the peak flood stages at the site. To evaluate the peak flow of the observed events the following information is available: (a) a long record of daily stage measurements up to the XVIII century; (b) several records of daily rainfall depth measurement at two rain gauges in the Tiber catchment, extending at least up to the middle of the XIX century; (c) detailed surveys executed immediately after the great flood of 1870, including the elevation plan of the town, a survey of the riverbed and the flood hydrograph of the 1870 flood; (d) a less detailed survey of the riverbed executed in 1744; (e) a rich iconography, showing the conditions of the Tiber banks from the XVI century onward; (f) contemporary descriptions of several extreme floodings; and (g) a rich series of flow measurements and bed surveys after the great flood of 1870 to present days. A two-dimensional hydrodynamic model was used to simulate the flooding of the old town in order to determine the flow–discharge relationship, thus allowing reconstruction of a record of the past extreme floods. A statistical analysis was developed for evaluating the risk hazard, using the censored sample of all the extreme floods from the XV century and the sample of all the maximum annual floods from the end of the XVIII century. [Copyright &y& Elsevier]

A case of systemic ropivacaine toxicity from a continuous thoracic paravertebral block in an adult patient who received a lobectomy is presented. The catheter was placed by the surgeon. Eleven hours after the start of the infusion, the patient experienced an arrhythmia leading to death. The total venous plasma concentration of ropivacaine was high (3.2 μg/mL). Furthermore, the patient had severe hypoalbuminemia (albumin 24 g/L), which resulted in the increase of the unbound ropivacaine plasma concentration that was responsible for the toxic side effects. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which reports a case of a 75-year old patient who experienced transcient blindness following a sub-Tenon anesthesia for ophthalmic surgery.

Objective: We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16–related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. Study Design: In all, 21 patients with HPV 16–related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. Results: Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. Conclusion: These promising data warrant further development of TG4001 in CIN 2/3 treatment. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this work was to compare the in vitro effects of levofloxacin and ciprofloxacin on pre-formed biofilms and planktonic populations of Stenotrophomonas maltophilia isolates from device-associated infections recovered over the period 2004–2008 at a university hospital in Argentina. For planktonic susceptibility studies, the minimum inhibitory concentrations (MICs) of fluoroquinolones were determined by the broth microdilution method. From the 32 isolates recovered, 84.4% were sensitive to levofloxacin and 43.8% were sensitive to ciprofloxacin. Biofilm susceptibility was evaluated by the minimum re-growth concentration (MRC) assay. Stenotrophomonas maltophilia isolates sensitive to fluoroquinolones according to their MICs were highly resistant according to the MRC values. Thus, currently used concentrations of fluoroquinolones cannot be used in monotherapy for eradication of a biofilm. Nevertheless, these agents could be used for the lock technique. Interestingly, for some isolates fluoroquinolone concentrations achievable during therapy caused a reduction in viable cells of 99% and promoted disruption of biofilms, evaluated by spectrophotometric and microscopic analysis. These results suggest that fluoroquinolones, particularly levofloxacin due to its better pharmacokinetic parameters, are candidates for synergy studies. [Copyright &y& Elsevier]

Scedosporium species rank the second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF), after Aspergillus fumigatus . In CF, these fungi may cause various respiratory infections similar to those caused by A. fumigatus , including bronchitis and allergic broncho-pulmonary mycoses. Diagnosis of these infections relies on the detection of serum antibodies using crude antigenic extracts. However, many components of these extracts are common to Scedosporium and Aspergillus species, leading to cross-reactions. Here, 5 recombinant proteins from S. apiospermum or S. boydii were produced, and their value in serodiagnosis of Scedosporium infections was investigated by enzyme-linked immunosorbent assay. Two of them, corresponding to the Scedosporium catalase A1 or cytosolic Cu,Zn-superoxyde dismutase, allowed the detection of Scedosporium infection, and the differentiation with an Aspergillus infection. These recombinant proteins therefore may serve as a basis for the development of a standardized serological test. [ABSTRACT FROM AUTHOR]

Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl4 administration to WT and IRF3-, Toll/Interleukin-1R (TIR) domain-containing adapter-inducing interferon-β (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl4. Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl4. In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors,TRAMor TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver. [ABSTRACT FROM AUTHOR]

Scedosporium boydii is an opportunistic filamentous fungus which may be responsible for a large variety of infections in both immunocompetent and immunocompromised individuals. This fungus belongs to the Scedosporium apiospermum species complex which usually ranks second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Species of the S . apiospermum complex are able to chronically colonize the CF airways suggesting pathogenic mechanisms allowing persistence and growth of these fungi in the respiratory tract. Few putative virulence factors have been purified and characterized so far in the S. apiospermum complex including a cytosolic Cu,Zn-superoxide dismutase (SOD) and a monofunctional catalase (catalase A1). Upon microbial infection, host phagocytes release reactive oxygen species (ROS), such as hydrogen peroxide, as part of the antimicrobial response. Catalases are known to protect pathogens against ROS by degradation of the hydrogen peroxide. Here, we identified the S. boydii catalase A1 gene ( CATA1 ) and investigated its expression in response to the environmental conditions encountered in the CF airways and to the oxidative stress. Results showed that S. boydii CATA1 gene expression is not affected by hypoxia, hypercapnia or pH changes. In contrast, CATA1 gene was overexpressed in response to a chemically induced oxidative stress with a relative gene expression 37-fold higher in the presence of 250 μM H 2 O 2 , 20-fold higher with 250 μM menadione and 5-fold higher with 2 mM paraquat. Moreover, S. boydii CATA1 gene expression progressively increased upon exposure to activated THP-1-derived macrophages, reaching a maximum after 12 h (26 fold). Activated HL60-derived neutrophils and activated human peripheral blood neutrophils more rapidly induced S. boydii CATA1 gene overexpression, a maximum gene expression level being reached at 75 min (17 fold) and 60 min (15 fold), respectively. In contrast expression of the gene encoding the Cu,Zn-SOD ( SODC gene) was not affected by H 2 O 2 , menadione, paraquat or in co-culture with phagocytic cells. These results suggest that S. boydii CATA1 gene is highly stimulated by the oxidative burst response whereas SODC gene is constitutively expressed. [ABSTRACT FROM AUTHOR]

Abstract: The mRNA encoding full length chloroplastic Cu–Zn SOD (superoxide dismutase) of Cucumis melo (Cantaloupe melon) was cloned. This sequence was then used to generate a mature recombinant SOD by deleting the first 64 codons expected to encode a chloroplastic peptide signal. A second hybrid SOD was created by inserting ten codons to encode a gliadin peptide at the N-terminal end of the mature SOD. Taking account of codon bias, both recombinant proteins were successfully expressed and produced in Escherichia coli. Both recombinant SODs display an enzymatic activity of ∼5000Umg−1 and were shown to be stable for at least 4h at 37°C in biological fluids mimicking the conditions of intestinal transit. These recombinant proteins were capable in vitro, albeit at different levels, of reducing ROS-induced-apoptosis of human epithelial cells. They also stimulated production and release in a time-dependent manner of an autologous SOD activity from cells located into jejunum biopsies. Nevertheless, the fused gliadin peptide enable the recombinant Cu–Zn SOD to maintain a sufficiently sustained interaction with the intestinal cells membrane in vivo rather than being eliminated with the flow. According to these observations, the new hybrid Cu–Zn SOD should show promise in applications for managing inflammatory bowel diseases. [Copyright &y& Elsevier]

Abstract: Background: Despite the advent of effective oral therapies for erectile dysfunction (ED), many patients are not successfully treated, and side effects have been documented. Objective: To further evaluate the potential utility of naked DNA-based gene transfer as an attractive treatment option for ED. Design, setting and participants: The effects of gene transfer on erectile function and sexual behavior were evaluated in eight male cynomolgus monkeys with ED secondary to moderately severe, diet-induced atherosclerosis. Intervention: Following establishment of baseline characteristics, animals were subjected to intracavernous injection of a smooth-muscle–specific gene transfer vector (pSMAA-hSlo) encoding the pore-forming subunit of the human large-conductance, calcium-sensitive potassium channel (Maxi-K). Measurements: For the sexual behavior studies, 2 wk of baseline data were obtained, and then animals were placed in the presence of estrogen-implanted females (n =2) three times per week for 30min, and sexual behavior was recorded. The intracavernous pressure response to papaverine injection was also monitored. Results and limitations: Dramatic changes in erectile function and sexual behavior were observed after intracorporal gene transfer. The frequency of partial (6±2 to 10±2) and full (2±1.5 to 5±1.4) erections were significantly increased, with a parallel 2–3-fold increase in the duration of the observed erections. The frequency and latency of ejaculation were increased and decreased, respectively. Frequency and duration of grooming by the female were increased, and the latency decreased. Increased latency and decreased frequency of body contact was also observed, and this is characteristic of the typical drop in consort intimacy that occurs after mating in most macaque species. In addition, an increased responsiveness to intracavernous papaverine injection was observed. Conclusions: The data indicate that intracorporal Maxi-K–channel gene transfer enhances erectile capacity and sexual behavior; the data imply that increased erectile function per se may lead to increased sexual function. [Copyright &y& Elsevier]

The present study was conducted to evaluate in vitro and in vivo the antioxidant and anti-inflammatory properties of a cantaloupe melon (Cucumis melo LC., Cucurbitaceae) extract (CME) selected for its high superoxide dismutase activity. Peritoneal macrophages were pre-activated in vitro with 300 IU of interferon-γ (IFN-γ) and were then challenged in culture with IgGl/anti-IgG1 immune complexes (IgG1IC) in presence of various CME extracts. The subsequent production of free radicals (superoxide anion, nitric oxide, and peroxynitrite) and of pro-(TNF-α) and anti-(IL-10) inflammatory cytokines was evaluated. The CME inhibited in a dose-dependent manner the production of superoxide anion with a maximal effect at 100 μg/ml. This inhibitory effect of CME appeared to be closely linked to the SOD activity because it was dramatically decreased after heat inactivation of the SOD activity (HI-CME). In addition, the CME inhibited the production of peroxynitrite strengthening the antioxidant properties of this CME rich in SOD activity. The production of the pro- and anti-inflammatory cytokines, namely TNF-α and IL-10, being conditioned by the redox status of macrophages we also evaluated the effect of CME and HI-CME on the IgG1IC-induced cytokine production. When the SOD activity was present in the CME it promoted the IgG1IC-induced production of IL-10 instead of TNF-α. These data demonstrated that, in addition to its antioxidant properties, the anti-inflammatory properties of the CME extract were principally related to its capacity to induce the production of IL-10 by peritoneal macrophages. The particular properties of wheat gliadin (Triticum vulgare, Poaceae) for the oral delivery of functional proteins led us to test it in a new nutraceutical formula based on its combination with the CME thus monitoring the SOD activity release during the gastro-intestinal digestive process. In these experiments C57BL/6 mice were supplemented orally everyday during 28 days with: (1) the placebo, (2) the CME extract alone, (3) the gliadin, (4) the CME/gliadin combination, or (5) the HI-CME/gliadin combination (SOD inactivated). At the end of the supplementation period all the animals were injected intra-peritoneal (i.p.) with the pro-inflammatory cytokine IFN-γ (300 IU) and peritoneal macrophages were harvested 24 h after to test their capacities to produce free radicals, TNF-α and IL-10 after triggering with IgG1IC. We demonstrated that animals supplemented during 28 days with the CME/gliadin combination were protected against the pro-inflammatory properties of IFN-γ while the other products were inefficient. These data did not only indicate that the SOD activity is important for the antioxidant and anti-inflammatory properties of the CME extract, but also demonstrated that when the SOD activity is preserved during the digestive process by its combination with wheat gliadin it is possible to elicit in vivo the pharmacological effects of this antioxidant enzyme. [Copyright &y& Elsevier]