Efectividad de certolizumab pegol en psoriasis en una cohorte de pacientes con artritis psoriásica / Effectiveness of Certolizumab Pegol in the Treatment of Psoriasis in a Cohort of Patients With Psoriatic Arthritis

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Effectiveness of ustekinumab in patients with psoriatic arthritis in a real-world, multicenter study.

OBJECTIVE: To assess the effectiveness and survival of ustekinumab (UST) among patients with psoriatic arthritis (PsA) treated under routine clinical care. METHODS: Multicenter study. Epidemiological and clinical data was collected through electronic medical records of all patients with PsA who started UST in 15 hospitals of Spain. RESULTS: Two hundred and one patients were included, 130 (64.7%) with 45 mg and 71 (35.3%) with 90 mg. One hundred and thirty one patients (65.2%) had previously received another biological therapy. The median baseline DAS 28 ESR was 3.99, and Psoriasis Area and Severity Index (PASI) was 3. Overall, there was a significant decrease in DAS66/68 CRP, swollen joint count (SJC), tender joint count (TJC), and PASI in the first month of treatment, with earlier improvement in skin (PASI) than joints outcomes. Survival was numerically lower in patients with UST 45 mg (58.1%) than 90 mg (76.1%), although significant differences were not found (p = 0.147). When comparing naïve and < 1 TNF blocker versus > 2 TNF blocker-experienced patients, a significantly earlier response was seen in the former group regarding SJC (p = 0.029) at 1 month. Fifty-one patients (25.3%) stopped UST due to joint inefficacy and 4 patients due to adverse events (1.9%). Drug survival was significantly better in patients with fewer lines of previous biological agents (p = 0.003 for < 1 TNF blocker versus > 2 TNF blocker users). CONCLUSIONS: UST was effective in PsA patients in a routine clinical care setting. Patients with UST 90 mg and fewer lines of previous biologics achieved better and faster responses. Key Points • Largest cohort of patients with PsA in treatment with UST with specific rheumatological indication. • First cohort of patients with PsA comparing effectiveness of UST according to 45/90 mg dose.

Artritis paradójica por ixekizumab en un paciente con psoriasis en placas / Paradoxical Arthritis Due to Ixekizumab in a Patient With Plaque Psoriasis

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Detection of Leishmania DNA and blood meal sources in phlebotomine sand flies (Diptera: Psychodidae) in western of Spain: Update on distribution and risk factors associated.

Leishmaniosis caused by Leishmania infantum is present in Mediterranean countries, with high prevalence in areas of the center and south of Spain. However, in some regions such as Extremadura (in southwest of Spain), data has not been updated since 1997. The aim of this work was (i) to provide information about the distribution of phlebotomine sand fly species in western of Spain (Extremadura region), (ii) to determine risk factors for the presence of sand fly vectors and (iii) to detect Leishmania DNA and identify blood meal sources in wild caught females. During 2012-2013, sand flies were surveyed using CDC miniature light-traps in 13 of 20 counties in Extremadura. Specimens were identified morphologically and females were used for molecular detection of Leishmania DNA by kDNA, ITS-1 and cyt-B. In addition, blood meals origins were analyzed by a PCR based in vertebrate cyt b gene. A total of 1083 sand flies of both gender were captured and identified. Five species were collected, Phlebotomus perniciosus (60.76%), Sergentomyia minuta (29.92%), P. ariasi (7.11%), P. papatasi (1.48%) and P. sergenti (0.74%). The last three species constitute the first report in Badajoz, the most southern province of Extremadura region. Leishmania DNA was detected in three out of 435 females (one P. pernicious and two S. minuta). Characterization of obtained DNA sequences by phylogenetic analyses revealed close relatedness with Leishmania tarentolae in S. minuta and L. infantum in P. perniciosus. Haematic preferences showed a wide range of hosts, namely: swine, humans, sheep, rabbits, horses, donkeys and turkeys. The simultaneous presence of P. perniciosus and P. ariasi vectors, the analysis of blood meals, together with the detection of L. infantum and in S. minuta of L. tarentolae, confirms the ideal conditions for the transmission of this parasitosis in the western of Spain. These results improve the epidemiological knowledge of leishmaniosis and its vectors in this part of Spain, highlighting the need for ongoing entomological and parasitological surveillance.

Detection of Zoonotic Protozoa Toxoplasma gondii and Sarcocystis suihominis in Wild Boars from Spain.

Food safety regulations require the control of the presence of protozoa in meats destined for human consumption. Wild boar (Sus scrofa) meat may constitute a source of zoonoses. A 23.8% (688/2881) seroprevalence of anti-Toxoplasma gondii antibodies and 72.2% (662/910) Sarcocystis sarcocysts prevalence were detected among wild boars hunted in Southwestern areas of Spain. Identity of Sarcocystis spp. was performed by RFLP-PCR and sequencing, detecting S. miescheriana (7/8) and the zoonotic S. suihominis (1/8). Risk assessment studies of these coccidian in meats destined to human consumption are needed.

IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients.

Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.

Bioluminescence-based high-throughput screen identifies pharmacological agents that target neurotransmitter signaling in small cell lung carcinoma.

BACKGROUND: Frontline treatment of small cell lung carcinoma (SCLC) relies heavily on chemotherapeutic agents and radiation therapy. Though SCLC patients respond well to initial cycles of chemotherapy, they eventually develop resistance. Identification of novel therapies against SCLC is therefore imperative. METHODS AND FINDINGS: We have designed a bioluminescence-based cell viability assay for high-throughput screening of anti-SCLC agents. The assay was first validated via standard pharmacological agents and RNA interference using two human SCLC cell lines. We then utilized the assay in a high-throughput screen using the LOPAC(1280) compound library. The screening identified several drugs that target classic cancer signaling pathways as well as neuroendocrine markers in SCLC. In particular, perturbation of dopaminergic and serotonergic signaling inhibits SCLC cell viability. CONCLUSIONS: The convergence of our pharmacological data with key SCLC pathway components reiterates the importance of neurotransmitter signaling in SCLC etiology and points to possible leads for drug development.

The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer.

More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing α4 and ß2 subunits and homomeric nicotinic acetylcholine receptors containing the α7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the α5, α3 and ß4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer.

ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus.

Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the alpha 3 and beta 4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis.

Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial.

Pregabalin (PRE) acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha(2)-delta subunit of voltage-gated calcium channels. In this randomised, double-blind comparison trial with naltrexone (NAL), we aimed to investigate the efficacy of PRE on alcohol drinking indices. Craving reduction and improvement of psychiatric symptoms were the secondary endpoints. Seventy-one alcohol-dependent subjects were detoxified and subsequently randomised into two groups, receiving 50 mg of NAL or 150-450 mg of PRE. Craving (VAS; OCDS), withdrawal (CIWA-Ar) and psychiatric symptoms (SCL-90-R) rating scales were applied. Alcohol drinking indices and craving scores were not significantly different between groups. Compared with NAL, PRE resulted in greater improvement of specific symptoms in the areas of anxiety, hostility and psychoticism, and survival function (duration of abstinence from alcohol). PRE also resulted in better outcome in patients reporting a comorbid psychiatric disorder. Results from this study globally place PRE within the same range of efficacy as that of NAL. The mechanism involved in the efficacy of PRE in relapse prevention could be less related to alcohol craving and more associated with the treatment of the comorbid psychiatric symptomatology.

Evaluation of a novel access and closure device for NOTES applications: a transcolonic survival study in the porcine model (with video).

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) is a novel, potentially less invasive alternative to laparoscopic surgery. However, the problems of transluminal access and closure represent significant obstacles to its successful introduction in humans. OBJECTIVE: Our purpose was to evaluate the feasibility and safety of a novel device designed for transluminal access and closure. DESIGN: Experimental endoscopic study of transcolonic incision and closure with use of a prototype device in a survival porcine model. SUBJECTS: Four adult female Yorkshire pigs were used in the study. INTERVENTIONS: While under general anesthesia, the animals were prepped with multiple tap water enemas followed by instillation of an antibiotic suspension and povidone-iodine lavage. At a distance of 15 to 20 cm from the anus, the prototype device deployed a circumscribing purse-string suture around the planned incision site and subsequently used a blade mechanism to create a 2.5-cm linear incision. The peritoneum was then accessed with a standard double-channel enodoscope. The transcolonic incision was then closed by cinching and securing the purse-string suture with a titanium knot by use of a separate hand-activated suture-locking device. All animals were allowed to eat immediately after recovering from general anesthesia. MAIN OUTCOME MEASUREMENTS: The animals were monitored daily for signs of peritonitis and sepsis and were electively killed on day 14. The peritoneal cavity was examined for peritonitis, and the colonic incision site was examined for wound dehiscence, pericolic abscess formation, and gross adhesions. Tissue samples from both incisional and random peritoneal sites were obtained for histologic examination. RESULTS: Transcolonic incision and closure were successful in all 4 animals. The device performed in a rapid and reproducible fashion. All animals recovered without septic complications. At necropsy, there was no evidence of peritonitis, abscesses, or wound dehiscence. Salpingocolonic and colovesicular adhesions were noted in 3 of 4 animals. Histologic examination revealed microabscesses at the incision site in all animals. CONCLUSIONS: The prototype incision and closure device represents a promising solution to the problems of transluminal access for NOTES. The presence of incision-related adhesions and microabscesses signal the need for further refinement in aseptic technique.

Alcohol protracted withdrawal syndrome: the role of anhedonia.

AIMS: The aim of the present study is to characterize the relevance of withdrawal symptoms during the first 12 months of abstinence and their relation to anhedonia and craving. METHODS: 102 detoxified subjects meeting clinical criteria for Alcohol Dependence in Remission were recruited at various time since the detoxification and subdivided into four groups according to the length of abstinence (group 1: 15-30 days; group 2: 30-90 days; group 3: 90-180 days; group 4: 180-360). Withdrawal symptomatology was assessed through the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The Visual Analogue Scale (VAS) for craving, the Snaith-Hamilton Pleasure Scale (SHAPS) and the Subscale for Anhedonia in the Scale for the Assessment of Negative Symptoms (SANSanh) where the other instruments employed. RESULTS: Both anhedonia and withdrawal symptoms were identified in all the groups considered. SHAPS score and VAS for craving showed a significant difference between group 1 and groups 2, 3, and 4. As to CIWA-Ar items, apart from "orientation/clouding of sensorium" that was higher in groups 3 and 4 with respect to both groups 1 and 2, withdrawal symptoms were not significantly different between the periods considered. SHAPS and SANSanh were positively correlated to CIWA-Ar total score, "nausea and vomiting," and "headache/fullness in head." DISCUSSION: The results of this study suggest the relevance of protracted withdrawal well beyond the limited period following the abrupt cessation of alcohol intake. The clinical dimension of anhedonia cannot be separated from the other behavioral symptoms of withdrawal and should be considered as part of the same process.

Endoscopic evaluation of the defunctionalized stomach by using ShapeLock technology (with video).

BACKGROUND: Patients with Roux-en-Y gastric bypass (RYGB) present a unique problem if they require diagnostic or therapeutic interventions for which the pancreatobiliary limb or the defunctionalized stomach must be accessed. Novel shape-locking guides have been reported in the literature to reduce looping during colonoscopy, and a new guide is now available to assist with enteroscopy. OBJECTIVE: To use ShapeLock technology to permit evaluation of the defunctionalized stomach. DESIGN: Observational case series. SETTING: Tertiary-care center. PATIENTS: Nine patients with a history of RYGB referred for repeat endoscopic evaluation after initial enteroscopy failed to reach the excluded stomach. INTERVENTIONS: After achieving appropriate levels of sedation, a standard enteroscope was back-loaded with the ShapeLock enteroscopy guide and was inserted through the mouth. The device was moved through the gastrojejunal (GJ) anastomosis, along the Roux limb, and into the distal pancreatobiliary limb. The device was then locked, which allowed the enteroscope to be advanced to the defunctionalized stomach. RESULTS: The ShapeLock guide was able to be advanced to the excluded stomach and perform a thorough examination of the pancreatobiliary limb in 8 of 9 patients, without complications. In 1 patient, the diameter of the GJ anastomosis prevented passage of the device. CONCLUSIONS: The ShapeLock enteroscopy guide can allow access to the upper-GI tract in patients after RYGB, provided the GJ anastomosis is of adequate diameter. This study suggested that the technique is safe and has the potential to allow therapeutic interventions in the defunctionalized stomach and duodenum, including ERCP.

Concurrent infection with Trichinella spiralis and other helminths in pigs.

The aim of this study was to investigate possible influence of different helmintosis in the development of Trichinella spiralis in experimental infected pigs. Forty-two Iberian pigs were allocated to six groups. Three groups were single inoculated with Ascaris suum, Metastrongylus apri or T. spiralis, respectively. Two groups were co-infected with T. spiralis and A. suum or T. spiralis and M. apri, respectively, while the last group included uninfected control pigs. Clinical signs were only observed in pigs with single or concurrent M. apri infections, with more severe respiratory symptoms in pigs with mixed M. apri infection. The number of A. suum and M. apri lung larvae, intestinal larvae of A. suum and adult M. apri were reduced in pigs with mixed Trichinella infections compared to pigs with single infections. In contrast, the number of liver white spots was higher in pigs with mixed infections. While T. spiralis muscular larval burdens were increased in pigs concomitantly infected with M. apri, they were reduced in pigs concomitantly infected with A. suum, compared to pigs receiving single infections with either of these helminths. Pigs with single or mixed A. suum infections showed higher eosinophil levels compared to the remaining groups. IgGt, IgG1, IgG2 and IgM against T. spiralis antigen could not be detected in pigs with single Ascaris or Metastrongylus infections, indicating that no cross-antibodies were produced. IgGt, IgG1 and IgM antibodies were detected earlier and generally at higher levels in mixed T. spiralis infections compared to single T. spiralis infections. The results suggest that T. spiralis had a low synergistic interaction with M. apri in concomitantly infected pigs, and an antagonistic interaction in concurrent infection with A. suum.

Transcolonic endoscopic abdominal exploration: a NOTES survival study in a porcine model.

BACKGROUND: Published reports on NOTES (natural orifice transluminal endoscopic surgery) have thus far been limited to the transgastric method. OBJECTIVE: The aim of this study was to assess the transcolonic approach as a means of accessing and systematically exploring the abdominal cavity in a survival study design. DESIGN: Six pigs were placed under general anesthesia and were prepped with multiple tap-water enemas, followed by instillation of a cefazolin suspension and a povidone-iodine lavage. Equipment was prepared with a high-level chemical disinfection, and an aseptic technique was used. An incision was made in the anterior colonic wall, and abdominal exploration was performed by using a double-channel endoscope. The incision was subsequently closed with endoscopic clips, endoloops, or a prototype closure device. PATIENTS: Six female Yorkshire pigs that weighed 25 to 30 kg. RESULTS: Stomach, liver, gallbladder, spleen, small bowel, colon, and peritoneal surfaces were identified in all animals in less than 3 minutes. The lower pelvic organs were not consistently visualized. All animals were alive for 14 days without apparent complications. At necropsy, the colonic incision sites were completely closed and appeared well healed. Microscopic inflammatory changes were seen at the closure site in all animals, including microabscesses. Incision-related adhesions were identified in 4 of 6 animals. CONCLUSIONS: This study demonstrated the use of a novel transcolonic approach to successfully access and explore the abdominal cavity. In contrast to the transgastric method, a transcolonic approach provides more consistent identification of structures in the upper abdomen and provides better en face orientation and scope stability. Therapeutic interventions in the upper abdomen, including organ resection, may be more tenable by using a transcolonic method; however, further studies are needed to address issues of sterility and colonic closure.

Transcolonic endoscopic cholecystectomy: a NOTES survival study in a porcine model (with video).

BACKGROUND: Transgastric cholecystectomy is a natural orifice transluminal endoscopic surgery (NOTES) procedure that has been reported in 2 nonsurvival studies. Both studies detail substantial technical limitations, with only a 33% success rate when limited to 1 gastric incision site, despite the use of a multichannel locking endoscope. OBJECTIVE: The aim of this study was to evaluate the feasibility and technical limitations of transcolonic cholecystectomy in a survival model. DESIGN: Animal feasibility study. INTERVENTIONS: Five pigs, under general anesthesia, were prepared with tap-water enemas, a peranal antibiotic lavage, and a Betadine rinse. A dual-channel endoscope was advanced into the peritoneum through an anterior, transcolonic incision 15 to 20 cm from the anus. After cystic duct and artery ligation, dissection of the gallbladder was achieved by using grasping and cutting instruments. After removing the gallbladder, the colonic incision was closed by using Endoloops and/or endoclips. The animals lived for 2 weeks after the procedure, then they were euthanized, and a necropsy was performed. RESULTS: All 5 gallbladders were successfully resected. Four of the 5 animals flourished in the postoperative period, with appropriate weight gain. In 1 animal, complete closure of the colonic incision was not possible, and it was euthanized at 48 hours for suspected peritonitis. CONCLUSIONS: This study reports the first transcolonic organ resection and demonstrates the first successful NOTES cholecystectomy in a survival model. The transcolonic approach provided improved endoscope stability and biliary exposure compared with the transgastric route, and complete incision closure appeared critical for procedural success.

Adsorptive granulocyte/monocyte apheresis for the treatment of refractory rheumatoid arthritis: an open pilot multicentre trial.

OBJECTIVE: To assess the efficacy and safety of adsorptive granulocyte and monocyte apheresis (GCAP) in patients with refractory rheumatoid arthritis (RA). METHODS: Patients with active and refractory RA were treated with weekly GCAP sessions using a column filled with acetate beads (Adacolumn) over five consecutive weeks. Clinical assessments and response to therapy were analysed at weeks 5, 7, 12 and 20 in an open multicentre trial. The primary outcome measure of clinical response was 20% improvement in the American College of Rheumatology criteria (ACR20) at week 20. EULAR (European League Against Rheumatism) response criteria, based on the disease activity score for 28 joints (DAS28) and disability using the Health Assessment Questionnaire (HAQ), were also assessed. RESULTS: Of 27 patients, 81.5% were women with mean disease duration of 14.4 yr. The mean number of previous disease-modifying antirheumatic drugs (DMARDs) was 3.7, and 48.1% of patients had previously failed on biologicals. On an intention-to-treat basis, 40.7% of patients achieved an ACR20 and 44.4% a therapeutic EULAR response at week 20. These percentages were 50 and 54.5% in 22 patients who completed the trial. In the 10 completers who had previously failed on biologicals, an ACR response was achieved in four patients (ACR20, two; ACR50, one; ACR70, one). A significant decrease was recorded in different ACR response components, including the tender joint and swollen joint counts, pain score and patient and physician global disease assessments, as well as the DAS28 index; most of them improved after week 5. ESR and CRP, but not the HAQ score, had decreased significantly at week 20. The treatment was well tolerated and only one serious adverse event related to the study procedure was documented (sepsis due to a catheter infection). CONCLUSIONS: GCAP treatment led to significant clinical improvement in a subset of patients with RA who had failed to respond to DMARDs or biologicals. Further large, placebo-controlled studies are warranted to fully assess the therapeutic value of GCAP for refractory RA.