Comorbidities in rheumatoid arthritis: analysis of hospital discharge records

Objective: Arthritis is often associated with comorbidities. For many of them, such as hypertension, cardiovascular disease, chronic pulmonary disease, and upper gastrointestinal disease, arthritis and its treatment may also represent a risk factor. This study is concerned with an evaluation of the frequency of comorbidities in a cohort of patients with rheumatoid arthritis (RA). Methods: The discharge diagnoses of patients with RA during the period 1 January 1997 to 31 December 2000 were retrieved from the database of the Department of Internal Medicine of the University of Genova, Italy. The diagnosis of RA was made if the patient's discharge record contained the code 714 of the International Classification of Diseases, IX revision, as first 3 numbers. The other diagnoses were also recorded along with demographic data, type and duration of hospital stay, and performed procedures. Results: During the study period, 427 patients with RA were admitted to the hospital for a total number of 761 admissions, which represented 2.2% of total admissions. Ninety-one (21.3%) patients did not have comorbidities, whereas 336 (78.6%) had one or more comorbidities. The most frequently observed comorbidities were cardiovascular diseases (34.6%), including hypertension (14.5%) and angina (3.5%), followed by gastrointestinal (24.5%), genito-urinary (18.7%) and respiratory (17%) diseases. There was a male predominance (p=0.004) within patients with comorbidities, who were significantly older (64.2±3.2 years vs. 57.2±4.2 years; p<0.001) and required longer periods of hospital stay (22.7 days vs. 12.5 days; p<0.001). Conclusions: Comorbidities are present in nearly 80% of RA inpatients. Comorbidity is a good predictor of health outcome, health services utilization, and medical costs. Because RA comorbidity can act as confounder, it should be considered in epidemiologic studies and clinical trials

Sustainability of Underground Hydro-Technologies: From Ancient to Modern Times and toward the Future

An underground aqueduct is usually a canal built in the subsurface to transfer water from a starting point to a distant location. Systems of underground aqueducts have been applied by ancient civilizations to manage different aspects of water supply. This research reviews underground aqueducts from the prehistoric period to modern times to assess the potential of achieving sustainable development of water distribution in the sectors of agriculture and urban management, and provides valuable insights into various types of ancient underground systems and tunnels. The review illustrates how these old structures are a testament of ancient people’s ability to manage water resources using sustainable tools such as aqueducts, where the functionality works by using, besides gravity, only “natural” engineering tools like inverted siphons. The study sheds new light on human’s capability to collect and use water in the past. In addition, it critically analyzes numerous examples of ancient/historic/pre-industrial underground water supply systems that appear to have remained sustainable up until recent times. The sustainability of several underground structures is examined, correlated to their sound construction and regular maintenance. Moreover, several lessons can be learned from the analysis of ancient hydraulic works, particularly now, as many periodically hydrologic crises have occurred recently, overwhelmingly impacted by climate change and/or over-exploitation and degradation of available water resources

Sustainability of underground hydro-technologies: from ancient to modern times and toward the future

An underground aqueduct is usually a canal built in the subsurface to transfer water froma starting point to a distant location. Systems of underground aqueducts have been applied byancient civilizations to manage different aspects of water supply. This research reviews undergroundaqueducts from the prehistoric period to modern times to assess the potential of achieving sustainabledevelopment of water distribution in the sectors of agriculture and urban management, and providesvaluable insights into various types of ancient underground systems and tunnels. The review illustrateshow these old structures are a testament of ancient people's ability to manage water resources usingsustainable tools such as aqueducts, where the functionality works by using, besides gravity, only"natural" engineering tools like inverted siphons. The study sheds new light on human's capabilityto collect and use water in the past. In addition, it critically analyzes numerous examples ofancient/historic/pre-industrial underground water supply systems that appear to have remainedsustainable up until recent times. The sustainability of several underground structures is examined,correlated to their sound construction and regular maintenance. Moreover, several lessons canbe learned from the analysis of ancient hydraulic works, particularly now, as many periodicallyhydrologic crises have occurred recently, overwhelmingly impacted by climate change and/orover-exploitation and degradation of available water resources

High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation

The autoimmune/lymphoproliferative syndrome (ALPS) displays defective function of Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion of CD4/CD8 double-negative (DN) T cells. Dianzani autoimmune/lymphoproliferative disease (DALD) is an ALPS variant lacking DN cells. Both forms have been ascribed to inherited mutations hitting the Fas system but other factors may be involved. A pilot cDNA array analysis on a DALD patient detected overexpression of the cytokine osteopontin (OPN). This observation was confirmed by enzyme-linked immunosorbent assay (ELISA) detection of higher OPN serum levels in DALD patients (n = 25) than in controls (n = 50). Analysis of the OPN cDNA identified 4 polymorphisms forming 3 haplotypes (A, B, and C). Their overall distribution and genotypic combinations were different in patients (N = 26) and controls (N = 158) (P <.01). Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing DALD than haplotype A homozygotes. Several data suggest that these haplotypes influence OPN levels: (1) in DALD families, high levels cosegregated with haplotype B or C; (2) in healthy controls, haplotype B or C carriers displayed higher levels than haplotype A homozygotes; and (3) in AB and AC heterozygotes, mRNA for haplotype B or C was more abundant than that for haplotype A. In vitro, exogenous OPN decreased activation-induced T-cell death, which suggests that high OPN levels are involved in the apoptosis defect

Impact of dense-water flow over a sloping bottom on open-sea circulation: Laboratory experiments and an Ionian Sea (Mediterranean) example

The North Ionian Gyre (NIG) displays prominent inversions on decadal scales. We investigate the role of internal forcing induced by changes in the horizontal pressure gradient due to the varying density of Adriatic Deep Water (AdDW), which spreads into the deep layers of the northern Ionian Sea. In turn, the AdDW density fluctuates according to the circulation of the NIG through a feedback mechanism known as the bimodal oscillating system. We set up laboratory experiments with a two-layer ambient fluid in a circular rotating tank, where densities of 1000 and 1015ĝ€¯kgĝ€¯m-3 characterize the upper and lower layers, respectively. From the potential vorticity evolution during the dense-water outflow from a marginal sea, we analyze the response of the open-sea circulation to the along-slope dense-water flow. In addition, we show some features of the cyclonic and anticyclonic eddies that form in the upper layer over the slope area. We illustrate the outcome of the experiments of varying density and varying discharge rates associated with dense-water injection. When the density is high (1020ĝ€¯kgĝ€¯m-3) and the discharge is large, the kinetic energy of the mean flow is stronger than the eddy kinetic energy. Conversely, when the density is lower (1010ĝ€¯kgĝ€¯m-3) and the discharge is reduced, vortices are more energetic than the mean flow - that is, the eddy kinetic energy is larger than the kinetic energy of the mean flow. In general, over the slope, following the onset of dense-water injection, the cyclonic vorticity associated with current shear develops in the upper layer. The vorticity behaves in a two-layer fashion, thereby becoming anticyclonic in the lower layer of the slope area. Concurrently, over the deep flat-bottom portion of the basin, a large-scale anticyclonic gyre forms in the upper layer extending partly toward a sloping rim. The density record shows the rise of the pycnocline due to the dense-water sinking toward the flat-bottom portion of the tank. We show that the rate of increase in the anticyclonic potential vorticity is proportional to the rate of the rise of the interface, namely to the rate of decrease in the upper-layer thickness (i.e., the upper-layer squeezing). The comparison of laboratory experiments with the Ionian Sea is made for a situation when the sudden switch from cyclonic to anticyclonic basin-wide circulation took place following extremely dense Adriatic water overflow after the harsh winter in 2012. We show how similar the temporal evolution and the vertical structure are in both laboratory and oceanic conditions. The demonstrated similarity further supports the assertion that the wind-stress curl over the Ionian Sea is not of paramount importance in generating basin-wide circulation inversions compared with the internal forcing

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Non-invasive monitoring of Streptococcus pyogenes vaccine efficacy using biophotonic imaging.

Streptococcus pyogenes infection of the nasopharynx represents a key step in the pathogenic cycle of this organism and a major focus for vaccine development, requiring robust models to facilitate the screening of potentially protective antigens. One antigen that may be an important target for vaccination is the chemokine protease, SpyCEP, which is cell surface-associated and plays a role in pathogenesis. Biophotonic imaging (BPI) can non-invasively characterize the spatial location and abundance of bioluminescent bacteria in vivo. We have developed a bioluminescent derivative of a pharyngeal S. pyogenes strain by transformation of an emm75 clinical isolate with the luxABCDE operon. Evaluation of isogenic recombinant strains in vitro and in vivo confirmed that bioluminescence conferred a growth deficit that manifests as a fitness cost during infection. Notwithstanding this, bioluminescence expression permitted non-invasive longitudinal quantitation of S. pyogenes within the murine nasopharynx albeit with a detection limit corresponding to approximately 10(5) bacterial colony forming units (CFU) in this region. Vaccination of mice with heat killed streptococci, or with SpyCEP led to a specific IgG response in the serum. BPI demonstrated that both vaccine candidates reduced S. pyogenes bioluminescence emission over the course of nasopharyngeal infection. The work suggests the potential for BPI to be used in the non-invasive longitudinal evaluation of potential S. pyogenes vaccines

A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model

Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS