Effectiveness and safety profile of tofacitinib and baricitinib in rheumatoid arthritis patients: results from a 24-month real-life prospective study in Southern-Italy.

The primary objectives of the study were to evaluate the efficacy and safety of tofacitinib and baricitinib up to 24 months of follow-up in patients with rheumatoid arthritis (RA) treated in Southern Italy. Patients' data, activity index, and clinimetric scores were collected at baseline (T0), six (T6), twelve (T12), and twenty-four (T24) months following treatment initiation. At six, twelve, and twenty-four months, adverse events and treatment cessation were also recorded. Sixty-eight patients (mean age: 62.2±10.9 years; mean RA duration: 15±9.6 years) were enrolled over a period of 12 weeks. At baseline, twenty-four patients (35.3%) were treated with tofacitinib, and forty-four patients (64.7%) were treated with baricitinib. The baseline mean disease activity was moderate as measured by DAS28- ESR (5.0±1.0), DAS 28 CRP (4.69±0.94), and SDAI (26.87±10.73) score. Before beginning JAKinhibs therapy, thirty-two patients (61.8%) were taking bDMARDs, while the remaining thirty-six (38.2%) were bDMARDs-naïve. The 24-month retention rate for JAKinhibs was 91.1%. Six months after beginning treatment with JAKinhibs, a statistically significant improvement was observed in all evaluated activity indices and clinimetric scores. Improvement was confirmed during the 12- and 24-month follow-up evaluations. The positive correlation between baseline-T6 SDAI delta and discontinuation of JAKinhibs (p=0.02) suggests that RA worsening in the first six months may be a predictor of therapy withdrawal. Patients with RA responded favorably to tofacitinib and baricitinib in this prospective, real-world study from a single center in Southern Italy. Efficacy was observed despite an underlying persistent and treatment-resistant disease.

Shallow bore-hole three-axial fiber Bragg grating strain sensor for Etna volcano monitoring.

We present the realization, installation, and first results of a three-axial Fiber Bragg Grating (FBG) strain sensor prototype. This sensor has been developed in the framework of the Mediterranean supersite volcanoes (http://www.med-suv.eu, 2013) project and, in particular, with the aim at contributing to the study and monitoring of Etna volcano. The FBG sensor was installed in the facilities of the Serra La Nave Astrophysical Observatory (Catania, Italy) about 7 km south-west from the summit craters, at an elevation of about 1740 m. The three-axial device showed a dynamic range of some hundreds of microstrains with microstrain resolution (submicrostrain concerning the vertical component). That is a good trade-off among performances, cost, and power consumption. The sensor structure and its read-out system are innovative in their assembly and offers practical advantages in comparison with traditional strain meters. As a demonstration of the performances of our device, the data of about 28 months of operation are presented together with the records of some local, regional, and teleseismic events. The sensor along the vertical axis showed to be the best performing one, having a power spectral density of about -90 dB re. 1ε2/Hz around one day period.

Volcanoes in Italy and the role of muon radiography.

Cosmic-ray muon radiography (muography), an imaging technique that can provide measurements of rock densities within the top few 100 m of a volcanic cone, has now achieved a spatial resolution of the order of 10 m in optimal detection conditions. Muography provides images of the top region of a volcano edifice with a resolution that is considerably better than that typically achieved with other conventional methods (i.e. gravimetric). We expect such precise measurements, to provide us with information on anomalies in the rock density distribution, which can be affected by dense lava conduits, low-density magma supply paths or the compression with the depth of the overlying soil. The MUon RAdiography of VESuvius (MURAVES) project is now in its final phase of construction and deployment. Up to four muon hodoscopes, each with a surface of roughly 1 m2, will be installed on the slope of Vesuvius and take data for at least 12 months. We will use the muographic profiles, combined with data from gravimetric and seismic measurement campaigns, to determine the stratigraphy of the lava plug at the bottom of the Vesuvius crater, in order to infer potential eruption pathways. While the MURAVES project unfolds, others are using emulsion detectors on Stromboli to study the lava conduits at the top of the volcano. These measurements are ongoing: they have completed two measurement campaigns and are now performing the first data analysis.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Clinical manifestation of selective IgA deficiency evidence after anti-TNF-α treatment in a psoriatic arthritis patient: case report.

It is known that the use of anti-TNF-α drugs is related to an increased incidence of infective diseases. This therapy can not be administered to patients having active infections and it has to be considered with caution in case of acquired or congenital immunodeficiency diseases. We report the case of a 28-years-old man affected by psoriatic arthritis; he developed some infections during treatment with TNF-α blockers. The infections were caused by a selective IgA deficiency, that was not evident before the anti-TNF-α blockers administration and disappeared after withdrawing the biological therapy. This case-report draws our attention to the possibility of cases of subclinical immunodeficiency, unknown by the patients, but important in the prognosis and in the therapeutic approach to these diseases. Therefore, it is important to evaluate carefully the immunologic status of patients during the pre-therapeutic screening for TNF-α blocking therapy.

[Methotrexate in the treatment of peripheral arthritis in ulcerative colitis]. / Il methotrexate nella terapia dell'artrite periferica in corso di rettocolite ulcerosa.

OBJECTIVE: To evaluate efficacy of methotrexate treatment in peripheral arthritis of ulcerative colitis. METHODS: We studied 18 patients (10/8 M/F; mean age: 38.90 yrs; range: 21-65 yrs), with peripheral arthritis (14 with polyarticular, 4 with oligoarticular subset) associate ulcerative colitis. Methotrexate 20 mg/week was administered in our patients, who were already receiving mesalazina for inflammatory bowel disease. At baseline, after 3 (T1), 6 (T2) and 12 months (T3) serological parameters (ESR and CRP), functional status (HAQ) and disease activity (VAS, GH, Ritchie articular index) were evaluated. RESULTS: During the therapy a significant improvement was observed in disease activity, functional status and serological parameters since T1. ESR and CRP did not change at T2 and T3. Instead VAS, GH, Ritchie articular index and HAQ had a significant and gradual improvement from T1 to T3. CONCLUSION: Methotrexate treatment was efficacious in the treatment of peripheral arthritis associate ulcerative colitis. This drug induced improvement in disease activity, functional status and serological parameters after 3 months of therapy.

Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study.

OBJECTIVE: Analysis of the association between psoriatic arthritis (PsA) clinical forms and MICA gene transmembrane polymorphisms. METHODS: Patients were classified as having peripheral asymmetric oligoarthritis (AO), peripheral symmetric poly-arthritis (PA) and spondylitis (SP), or disease combinations (PA/SP, OA/SP). Two hundred and twenty-six patients with PsA were typed for MICA exon 5 microsatellite (TM) by heteroduplex analysis and compared with 225 normal controls. RESULTS: MICA-TM microsatellite typing revealed that, among the different clinical forms of PsA, only the combined PA/SP subset shows a significant positive association with MICA-A9 and a lower frequency of MICA-A4, A5 genotype in PsA patients with a decrease, only in the PA/SP cohort, of all MICA-A5 combinations except MICA-A5, -A9. CONCLUSION: These results suggest a role for genes within the HLA region in the pathogenesis of PsA, and reinforce the idea that the different forms of PsA may have heterogeneous genetic basis.

Clinical presentation of psoriatic arthritis.

Psoriatic arthritis is a spondyloarthropathy which occurs in patients with skin and/or nail psoriasis. Basing its characterization on morphological purposes, several types of arthritis have been described. Alternatively, we propose a simplified classification into three subsets, focusing on the levels of expression of cutaneous and articular elements which devise this syndrome. The first is established psoriatic arthritis which occurs in patients with evident or remittent skin and/or nail psoriasis. Its clinical spectrum consists of the five subsets classically described by Moll and Wright in 1973. The second is psoriatic arthritis "sine psoriasis" which occurs in subjects without psoriasis but with a family history of the disease in first or second-degree relatives. The third is early psoriatic arthritis which consists of an articular involvement of recent onset, occurring in subjects belonging to established or sine psoriasis subsets.

Cigarette smoking and appendectomy are risk factors for extraintestinal manifestations in ulcerative colitis.

OBJECTIVE: Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce. METHODS: The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC. RESULTS: In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529-6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542-4.442) or smoking alone (1.947, 95% CI 1.317-2.879). CONCLUSIONS: In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.

Ketamine blocks a taste-mediated conditioned motor response in perinatal rats.

Brain N-methyl-D-aspartate (NMDA) glutamate receptors have been implicated as important mediators of both learning and neuronal development. The current study investigated how ketamine HCl (a well-known NMDA-receptor blocking drug) would influence taste-mediated conditioned motor responses in perinatal rats. Dams pregnant with E19 rat fetuses were injected with 0, 50, or 100 mg/kg ketamine HCl (IP). One-half hour later, a reversible spinal block was performed on the dam, and fetuses received an oral injection of 10 microl 0.3% Saccharin (SAC) or water while in utero. After the oral injection, fetuses received either saline or LiCl (81 mg/kg, IP). The uterus was replaced and, 2 days later (E21), rats received oral lavage with SAC. Rats in other litters were born via a normal vaginal delivery and were exposed to SAC on postnatal day 3 (P3). Observations of motor responses were recorded immediately after the oral lavage of SAC. If SAC had been paired with LiCl in utero, both E21 and P3 pups exhibited a conditioned suppression of orofacial movements (compared to controls). Both doses of ketamine significantly attenuated this taste-mediated conditioned motor response. These data reinforce the current conception of the fetus and neonate as sophisticated sensors and responders to the uterine and extrauterine environment. Further, our findings indicate a role for NMDA receptors in the formation of a conditioned motor response in fetal rats.

Ketamine blocks a taste recognition memory in fetal rats.

Decisions about novelty/familiarity are critical in determining whether or not information should be attended to, and possibly encoded, for long-term storage. We have reported that fetal and neonatal rats exhibit an increase in orofacial movements (e.g., perseverative mouthing and mouth movements, and licks) upon tasting saccharin (SAC), if it was experienced previously. E19 rat fetuses can acquire this taste recognition memory and retain it for at least 5 days (P3). In the current study, we sought to evaluate the role of N-methyl-D-aspartate (NMDA) receptors in establishing a taste recognition memory. Pregnant Sprague-Dawley rats received ketamine (NMDA receptor antagonist) (doses: 0, 50, or 100 mg/kg, i.p.). One-half hour later, we performed a reversible spinal block on each pregnant dam, and E19 fetuses received an oral injection of 10 microl, 0.3% SAC or water (control) while in utero. The uterus was replaced and the pups were later born via a normal vaginal delivery. On P3, all pups experienced oral lavage of 10 microl, 0.3% SAC, and motor responses were recorded. As expected, non-drugged control neonates tasting familiar SAC exhibited significantly more perseverative mouth movements, as well as total mouth movements and licks, than did pups tasting novel SAC. However, this taste recognition memory response was not observed in rats exposed to ketamine in utero. The data suggest that early non-associative taste memories may be disrupted by NMDA receptor blockade.

Drug use and prescribing problems in the community-dwelling elderly: a study of three state Medicaid programs.

This paper describes a study of drug use and drug-related problems in community-dwelling elderly (> or =65 years) Medicaid recipients in Maryland, Iowa, and Washington from 1989 through 1996. A claim-by-claim review of Medicaid prescriptions was conducted to detect 5 types of prescribing problems (dose, duration of therapy, duplicative therapy, drug-drug interactions, and contraindications or initial therapy). The study examined 8 drug categories: angiotensin-converting enzyme (ACE) inhibitors, antidepressant agents, antipsychotic agents, benzodiazepines, calcium channel blockers, digoxin, histamine2-receptor antagonists, and nonsteroidal anti-inflammatory drugs. The total number of persons with prescriptions in any of the 8 drug classes increased over the 8-year period, with the greatest growth in ACE inhibitors. Mean annual drug use per person declined in Maryland but increased in Washington and Iowa. Despite increasing use, the overall incidence of prescribing problems fell dramatically in all 3 states, particularly for dose- and duration-related criteria. Except in the area of drug-drug interactions, this elderly population was less likely to have received a prescription falling outside commonly accepted drug utilization review criteria for 8 major drug classes in 1996 than in 1989.

Superantigen-activated T cells redirected by a bispecific antibody inhibit vesicular stomatitis virus replication in vitro and in vivo.

A bispecific Ab (BsAb) that binds the TCR on T cells and the G protein of the vesicular stomatitis virus (VSV) can redirect staphylococcal enterotoxin B (SEB)-activated T cells to kill VSV-infected cells and to inhibit VSV replication in vitro. Inhibition of virus replication in our system is dependent upon the specificity of the Ab for the viral protein. IFN-gamma does not play a very important role in this phenomenon, which is mainly mediated by the release of Pfp from CD8+ T cells. We have used a Stat1 knockout mouse model in which VSV infection is lethal. Infusion of staphylococcal enterotoxin-activated B T cells and bispecific Ab significantly slowed virus progression and prolonged the survival of VSV-infected Stat1 knockout mice in vivo.

Interfacing managed care and long-term care: understanding the issues.

Both marketplace forces and legislative initiatives are forcing the traditional fee-for-service long-term health care sector into the managed care arena. To identify and address the issues surrounding quality and cost-effective pharmaceutical use at the interface between managed care and long-term care, the Philadelphia College of Pharmacy and Science convened a day-long conference between managed care and long-term care medical and pharmacy directors. This paper outlines the discussion and recommendations in respect to these issues.

Identification of a set of proteins (C' and C) encoded by the bicistronic P gene of the Indiana serotype of vesicular stomatitis virus and analysis of their effect on transcription by the viral RNA polymerase.

Previous work (C.F. Spiropoulou and S.T. Nichol, 1993, J. Virol. 67, 3103-3110) has demonstrated the existence in cells infected with the New Jersey serotype of vesicular stomatitis virus (VSV) of two small carboxy-coterminal proteins encoded by the P mRNA. These proteins have been named C' and C. We are interested in studying the function of these proteins in the virus life cycle. Toward this end, we have cloned the ORF encoding the potential C' protein of the Indiana serotype as a histidine-tagged fusion protein, purified the expressed protein from Escherichia coli, and used the fusion protein as an immunogen to raise antiserum in a rabbit. We have used this anti-C' protein serum to demonstrate that both of the predicted C' and C proteins are synthesized in cells infected with the Indiana serotype of VSV. In addition we have localized a portion of these proteins to nucleocapsids isolated from infected cells, suggesting that they may play a role in RNA synthesis. Reconstitution of the viral polymerase activity by expressing the L and P protein subunits with or without the C proteins failed to demonstrate any effect of the presence of these latter proteins on reconstituted transcription using purified nucleocapsids as templates. However, we have been able to show a dramatic stimulation of the polymerase activity in purified virions by the addition of purified C' protein to in vitro transcription reactions. Both the level and the fidelity of mRNA synthesis are stimulated by this protein. Evidence for the specificity of this effect comes from the fact that stimulation appears to be serotype specific; C' protein of the Indiana serotype stimulates transcription by purified Indiana serotype virions but has a minimal effect on transcription by purified virions of the New Jersey serotype. We are continuing our studies to determine the mechanism of this stimulation.

Analysis of human parainfluenza virus 3 receptor binding variants: evidence for the use of a specific sialic acid-containing receptor.

In order for the fusion protein (F) of the human parainfluenza virus type 3 (HPF3) to promote membrane fusion and viral entry, the haemagglutinin-neuraminidase (HN) glycoprotein must interact with its receptor. Sialoglycoconjugates are known to be the receptors for the HPF3 HN, however specific attachment factors or receptors for HPF3 have not been identified. In this report we describe the analysis of variants of HPF3 with increased fusion-promoting phenotypes that were selected by treatment with viral neuraminidase. The results suggest that for HPF3, the virus is specific in its use of sialic acid receptors; the majority of sialic-acid containing molecules are not targets for HPF3.

Inhibition of VSV genome RNA replication but not transcription by monoclonal antibodies specific for the viral P protein.

The growth of vesicular stomatitis virus requires two distinct RNA synthetic events: transcription of messenger RNA molecules and replication of the viral genome RNA. We report the use of a panel of monoclonal antibodies directed against the viral phosphoprotein P in an attempt to assess the role of this protein in RNA synthesis. Using extracts derived from virus-infected cells, we show that several anti-P monoclonal antibodies can have an inhibitory effect on genome RNA replication by binding to a soluble form of the P protein. We also show that the P protein to which one of these antibodies (6D11) is directed is not complexed with the N protein and that the amount of soluble P protein that binds to the 6D11 antibody in immunoprecipitation reactions can be increased by treating extracts with alkaline phosphatase. In addition, phosphatase treatment of infected cell extracts results in an increased level of genome RNA replication. These results suggest that a soluble subspecies of the P protein that functions in genome RNA replication exists in infected cells and that this species of the P protein is not required for transcription.

Normal replication of vesicular stomatitis virus without C proteins.

The expression of two small basic proteins (C and C') encoded by a second open reading frame of the New Jersey serotype of vesicular stomatitis virus (VSV) P gene was reported previously (Spiropoulou and Nichol, J. Virol., 67, 3103-3110, 1993). Here we found that the Indiana serotype virus also expressed C and C' proteins from this reading frame. We eliminated C and C' expression by making a single base change that introduced a stop codon in the C and C' coding sequence, but left the P-protein sequence unchanged. This mutated P gene supported normal replication and packaging of VSV minigenomes encoding G and M proteins. The mutated P gene was also recombined into an infectious clone of VSV that was used to recover virus. The mutant virus no longer expressed the C and C' proteins but showed growth kinetics identical to wild-type virus. The amounts of viral mRNAs and proteins synthesized were indistinguishable in mutant and wild-type virus infected cells as were the yields and composition of mutant and wild-type virus particles. The kinetics of host protein-synthesis shut-off were also identical for both viruses. Although the C and C' proteins were dispensable for VSV growth in tissue culture, they are known to be conserved in all vesiculoviruses, and thus perhaps play a role in viral pathogenesis or transmission by insect vectors.

Hemagglutinin-neuraminidase of human parainfluenza 3: role of the neuraminidase in the viral life cycle.

The function of neuraminidase in the life cycle and pathogenesis of human parainfluenza virus type 3 (HPF3) was studied by analyzing a variant of HPF3 that has decreased neuraminidase enzymatic activity. The variant virus is more fusogenic than the wild-type virus during an acute infection. Cloning and sequencing of the fusion (F) and hemagglutinin-neuraminidase (HN) genes from this variant revealed a single amino acid change in the HN protein and no alterations in the F protein sequence. Analysis of the growth properties of this variant revealed a delay in release of virus particles into the supernatant. Addition of exogenous neuraminidase to the culture resulted in increased release of infections viral particles, suggesting that the viral neuraminidase is important for release of HPF3 from the infected cell surface. In addition, the behavior of the variant virus during high-multiplicity infection and in the presence of exogenous neuraminidase provided evidence that the neuraminidase of HPF3 determines the outcome of viral infection (cytopathic versus persistent) in cell culture.

Relative affinity of the human parainfluenza virus type 3 hemagglutinin-neuraminidase for sialic acid correlates with virus-induced fusion activity.

The ability of enveloped viruses to cause disease depends on their ability to enter the host cell via membrane fusion events. An understanding of these early events in infection, crucial for the design of methods of blocking infection, is needed for viruses that mediate membrane fusion at neutral pH, such as paramyxoviruses and human immunodeficiency virus. Sialic acid is the receptor for the human parainfluenza virus type 3 (HPF3) hemagglutinin-neuraminidase (HN) glycoprotein, the molecule responsible for binding of the virus to cell surfaces. In order for the fusion protein (F) of HPF3 to promote membrane fusion, the HN must interact with its receptor. In the present report, two variants of HPF3 with increased fusion-promoting phenotypes were selected and used to study the function of the HN glycoprotein in membrane fusion. Increased fusogenicity correlated with single amino acid changes in the HN protein that resulted in increased binding of the variant viruses to the sialic acid receptor. These results suggest that the avidity of binding of the HN protein to its receptor regulates the level of F protein-mediated fusion and begin to define one role of the receptor-binding protein of a paramyxovirus in the membrane fusion process.