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For patients experiencing acute coronary syndrome, early symptom recognition is paramount; this is challenging without chest pain presentation. The aims of this scoping review were to collate definitions, proportions, symptoms, risk factors and outcomes for presentations without cardiac chest pain. Full-text peer reviewed articles covering acute coronary syndrome symptoms without cardiac chest pain were included. MEDLINE, CINAHL, Scopus and Embase were systematically searched from 2000 to April 2023 with adult and English limiters; 41 articles were selected from 2,954. Dyspnoea was the most reported (n=39) and most prevalent symptom (11.6-72%). Neurological symptoms, fatigue/weakness, nausea/ vomiting, atypical chest pain and diaphoresis were also common. Advancing age appeared independently associated with presentations without cardiac chest pain; however, findings were mixed regarding other risk factors (sex and diabetes). Patients without cardiac chest pain had worse outcomes: increased mortality, morbidity, greater prehospital and intervention delays and suboptimal use of guideline driven care. There is a need for structured data collection, analysis and interpretation., Competing Interests: Disclosure: AC has received a future fellowship grant from the Australian Research Council; PO has received consulting fees from The Paramedic Foundation and the Australian Health Professional Regulatory; is on the boards of The Paramedic Network, the American Paramedic Association and the Australasian College of Paramedicine Community Paramedic Working Party; and is director of the Global Paramedic Higher Education Council. All other authors have no conflicts of interest to declare. Authors’ contributions: Conceptualisation: MP and MAR; data curation: MP; formal analysis: MP, AC and MAR; funding acquisition: not applicable; investigation: MP and CT; methodology: MP and MAR; project administration: MP; resources: MP; software: not applicable; supervision: AC and MAR; validation: MP, AC and MAR; visualisation: MP; writing – original draft preparation: MP; writing – review & editing: MP, AC, CT, PO and MAR., (Copyright © The Author(s), 2024. Published by Radcliffe Group Ltd.)

Background: The influence of indications for Helicobacter pylori investigation on prescriptions and effectiveness is unknown. The aim of the study was to assess the impact of indications for H. pylori investigation on prescriptions, effectiveness, compliance, and tolerance., Methods: International, prospective, non-interventional registry of the management of H. pylori infection by European gastroenterologists (Hp-EuReg). Treatment-näive patients registered from 2013 to 2023 at e-CRF AEG-REDCap were analyzed. The effectiveness was assessed by modified intention-to-treat analysis., Results: Overall, 53,636 treatment-naïve cases from 34 countries were included. Most frequent indications were: dyspepsia with normal endoscopy (49%), non-investigated dyspepsia (20%), duodenal ulcer (11%), gastric ulcer (7.7%), and gastroesophageal reflux disease (GERD) (2.6%). Therapy effectiveness varied by indication: duodenal ulcer (91%), gastric ulcer (90%), preneoplastic lesions (90%), dyspepsia with normal endoscopy (89%), GERD (88%), and non-investigated dyspepsia (87%). Bismuth-metronidazole-tetracycline and clarithromycin-amoxicillin-bismuth quadruple therapies achieved 90% effectiveness in all indications except GERD. Concomitant clarithromycin-amoxicillin-tinidazole/metronidazole reached 90% cure rates except in patients with non-investigated dyspepsia; whereas sequential clarithromycin-amoxicillin-tinidazole/metronidazole proved optimal (≥90%) in patients with gastric ulcer only. Adverse events were higher in patients treated for dyspepsia with normal endoscopy and duodenal ulcer compared with the remaining indications (23% and 28%, p < 0.001). Therapeutic compliance was higher in patients with duodenal ulcer and preneoplastic lesions (98% and 99%, p < 0.001)., Conclusion: In Europe, patients with gastric or duodenal ulcers and preneoplastic lesions showed higher H. pylori treatment effectiveness. Bismuth and non-bismuth quadruple therapies achieved optimal results in almost all indications., Trial Registration: ClinicalTrials.gov identifier: NCT02328131., (© 2024 The Author(s). Helicobacter published by John Wiley & Sons Ltd.)

Background: Iodine plays an important role in thyroid physiology and biochemistry. The thyroid is capable of producing different iodolipids such as 2-iodohexadecanal (2-IHDA). Data from different laboratories have shown that 2-IHDA inhibits several thyroid parameters and it has been postulated as intermediary on the action of iodide function., Objective: To explore different mechanisms involved during the involution of the hyperplastic thyroid gland of Wistar rats towards normality induced by 2-IHDA., Methods: Goiter was induced by the administration of MMI for 10 days, then the treatment was discontinued and Wistar rats were injected with 2-IHDA or KI., Results: During involution, 2-IHDA treatment reduced PCNA expression compared to spontaneous involution. KI treatment caused an increase of Caspase-3 activity and TUNEL-positive cells. In contrast, 2-IHDA failed to alter this value but induced an increase of LC3B expression. KI but not 2-IHDA led to an increase in peroxides levels, catalase and glutathione peroxidase activity., Conclusions: We demonstrated that 2-IHDA, in contrast to iodide, did not lead to an increase in oxidative stress or apoptosis induction, indicating that the involution triggered by 2-IHDA in Wistar rats, is primarily due to the inhibition of cell proliferation and the induction of autophagy., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Published by Elsevier Inc.)

Background: Management of Helicobacter pylori (H. pylori) infection requires co-treatment with proton pump inhibitors (PPIs) and the use of antibiotics to achieve successful eradication., Aim: To evaluate the role of dosage of PPIs and the duration of therapy in the effectiveness of H. pylori eradication treatments based on the 'European Registry on Helicobacter pylori management' (Hp-EuReg)., Methods: Hp-EuReg is a multicentre, prospective, non-interventionist, international registry on the routine clinical practice of H. pylori management by European gastroenterologists. All infected adult patients were systematically registered from 2013 to 2022., Results: Overall, 36,579 patients from five countries with more than 1000 patients were analysed. Optimal (≥90%) first-line-modified intention-to-treat effectiveness was achieved with the following treatments: (1) 14-day therapies with clarithromycin-amoxicillin-bismuth and metronidazole-tetracycline-bismuth, both independently of the PPI dose prescribed; (2) All 10-day (except 10-day standard triple therapy) and 14-day therapies with high-dose PPIs; and (3) 10-day quadruple therapies with clarithromycin-amoxicillin-bismuth, metronidazole-tetracycline-bismuth, and clarithromycin-amoxicillin-metronidazole (sequential), all with standard-dose PPIs. In first-line treatment, optimal effectiveness was obtained with high-dose PPIs in all 14-day treatments, in 10- and 14-day bismuth quadruple therapies and in 10-day sequential with standard-dose PPIs. Optimal second-line effectiveness was achieved with (1) metronidazole-tetracycline-bismuth quadruple therapy for 14- and 10 days with standard and high-dose PPIs, respectively; and (2) levofloxacin-amoxicillin triple therapy for 14 days with high-dose PPIs. None of the 7-day therapies in both treatment lines achieved optimal effectiveness., Conclusions: We recommend, in first-line treatment, the use of high-dose PPIs in 14-day triple therapy and in 10-or 14-day quadruple concomitant therapy in first-line treatment, while standard-dose PPIs would be sufficient in 10-day bismuth quadruple therapies. On the other hand, in second-line treatment, high-dose PPIs would be more beneficial in 14-day triple therapy with levofloxacin and amoxicillin or in 10-day bismuth quadruple therapy either as a three-in-one single capsule or in the traditional scheme., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Introduction: Iodide is an essential micronutrient for the synthesis of thyroid hormones and its imbalance is involved in the origin of different thyroid pathological processes. Selenium (Se) is another essential trace element that contributes to thyroid preservation through the control of the redox homeostasis. Different studies have demonstrated that sodium-iodide-symporter (NIS) is downregulated in the presence of iodide excess and Se supplementation reverses this effect. We also demonstrated that NOX4-derived ROS are involved in NIS repression induced by iodide excess. The aim of this study was to investigate how Se bioavailability is decisive in the sensitivity to iodide excess on a differentiated rat thyroid cell line (FRTL-5)., Results: We demonstrated that siRNA-mediated silencing of Nox4 suppressed AKT phosphorylation induced by iodide excess. Iodide increases TGF-β1 mRNA expression, AKT phosphorylation, ROS levels and decreases GPX1 and TXRND1 mRNAs expression while Se reversed these effects. Furthermore, iodide induced Nrf2 transcriptional activity only in Se-supplemented cultures, suggesting that Se positively influences Nrf2 activation and selenoenzyme response in FRTL-5. Se, also inhibited NF-κB phosphorylation induced by iodide excess. In addition, we found that iodide excess decreased total phosphatase activity and PTP1B and PTEN mRNA expression. Se supply restored only PTEN mRNA expression. Finally, we studied the 2-α-iodohexadecanal (2-IHD) effects since it has been proposed as intermediary of iodide action on thyroid autoregulation. 2-IHD stimulated PI3K/AKT activity and reduced NIS expression by a ROS-independent mechanism. Also, we found that 2-IHD increased TGF-β1 mRNA and TGF-β inhibitor (SB431542) reverses the 2-IHD inhibitory effect on NIS mRNA expression, suggesting that TGF-β1 signaling pathway could be involved. Although Se reduced 2-IHD-induced TGFB1 levels, it could not reverse its inhibitory effect on NIS expression., Conclusion: Our study suggests that Se bioavailability may improve the expression of antioxidant genes through the activation of Nrf2, interfere in PI3K/AKT signaling and NIS expression by redox modulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The recommended schedule for single capsule bismuth quadruple therapy (scBQT, Pylera) includes a proton pump inhibitor (PPI) two times a day and three scBQT capsules four times a day. Four times a day treatments are inconvenient and reduce adherence. In contrast, adherence improves with three times a day schedules. In clinical practice, many gastroenterologists use four capsule scBQT three times a day. However, the effectiveness and safety of this latter approach remain uncertain., Aim: To assess the effectiveness and safety of scBQT administered three times a day in the patients included in the European Registry on Helicobacter pylori Management (Hp-EuReg)., Methods: All Spanish adult patients registered in the Asociación Española de Gastroenterología Research Electronic Data Capture (REDCap) database from June 2013 to March 2021 receiving 10-day scBQT were analysed. Modified intention-to-treat effectiveness, adherence and the safety of scBQT given three times a day were calculated and compared with the four times a day schedule. A multivariate analysis was performed to determine independent factors predicting cure of the infection., Results: Of the 3712 cases, 2516 (68%) were four times a day and 1196 (32%) three times a day. Mean age was 51 years, 63% were women and 15% had a peptic ulcer. The three times a day schedule showed significantly better overall cure rates than four times a day (1047/1112, 94%; 95% CI 92.7 to 95.6 vs 2207/2423, 91%; 95% CI 89.9 to 92.2, respectively, p=0.002). Adherence and safety data were similar for both regimens. In the multivariate analysis, three times a day dosage, first-line therapy, use of standard or high-dose PPIs and adherence over 90% were significantly associated with cure of the infection., Conclusions: ScBQT prescribed three times a day was more effective than the traditional four times a day schedule. No differences were observed in treatment adherence or safety., Competing Interests: Competing interests: XC has received research grants and fees for lectures from Allergan. JPG has served as speaker, consultant and advisory member for or has received research funding from Mayoly Spindler, Allergan, Diasorin, Gebro Pharma and Richen. OPN received research funding from Allergan and Mayoly Spindler. Dr Bordin served as a lecturer for Astellas, AstraZeneca, KRKA, and Abbott. FM is a consultant for PHATHOM and DaVoltera and has received grants from Allergan, bioMerieux and Mobidiag. The remaining authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The synergy of superparamagnetic iron oxide nanoparticles (SPIONs) and ionizing radiation (IR), attributed to reactive oxygen species (ROS) and DNA double-strand breaks (DSBs) increase, was widely investigated in different cancers, but scarcely in melanoma. Herein, SPIONs were evaluated as radiosensitizers in A-375 human melanoma cells. Moreover, the effect of the combined treatment of SPIONs and gamma irradiation (SPIONs-IR) was assessed at the DNA level, where DSBs induction and their repair capacity were studied. SPIONs were synthesized, stabilized by poly(ethylene glycol) methyl ether and physicochemically characterized by high resolution-transmission electron microscopy (HR-TEM), X-ray diffraction and magnetometry and dynamic light scattering. The obtained nanoparticles showing superparamagnetic behavior and low dispersion in shape and sizes were tested in A-375 cells. The intracellular internalization of SPIONs was verified by HR-TEM and quantified by inductively coupled plasma atomic emission spectroscopy. Cells treated with SPIONs exhibited high ROS levels without associated cytotoxicity. Next, a significant radiosensitization in SPIONs-IR vs. control (IR) cells was demonstrated at 1 Gy of gamma radiation. Furthermore, a decreased DSBs repair capacity in SPIONs-IR vs. IR-treated cells was evidenced by the size increase of persistent phosphorylated H2AX foci at 24 h post-irradiation. In conclusion, these nanoparticles show the potential to radiosensitize melanoma cells by the induction of unrepairable DNA damage., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Central venous catheter (CVC) placement is a routine procedure but is potentially associated with severe complications. Relatively small studies investigated if the use of ultrasound is effective in bridging the skill gap between proficient and not proficient operators, while patient safety during training remains a controversial topic. The first aim of this study was to evaluate if resident proficiency affects the failure rate in CVC positioning under ultrasound guidance. In addition, it aimed to investigate the different rate of complications between proficient and non proficient residents., Methods: We conducted a cohort study including CVC placed by residents at the University Hospital of Padova, from November 1, 2012 to July 9, 2020 comparing proficient and non proficient residents. To avoid bias the two cohorts were matched using propensity score., Results: A total of 356 residents positioned 2310 CVC during the 8 year study period. Among them, two groups of 1060 CVCs each were matched with a propensity score analysis. There was no difference in the failure rate among the groups (2.8 vs 2.7%, p-value 0.895). Moreover, cohorts had the same rate of hematomas, catheter tip malposition, arterial puncture and pneumothorax. No cases of hemothorax were reported., Conclusions: We found the same rate of success and incidence of adverse complications among cohorts, meaning that the process of skill acquisition is safe as long as appropriate training and direct supervision by a senior consultant are available., (© 2021. The Author(s).)

Background: We present the first case of a patient with obstructive sleep apnea syndrome (OSA), where drug induced sleep endoscopy was helpful to suspect a non-acid reflux disease and showed an improvement in a swollen epiglottis after treatment. Patient ameliorated significantly his disease only with medical therapy., Case Presentation: A 54-year-old man without significant anatomical findings with obstructive sleep apnea syndrome and non-acid gastroesophageal reflux disease (GERD) disease whose Apnea- hypopnea index (AHI) was significantly reduced with the intake of 500 mg of sodium alginate twice a day for 6 months. Conventional digestive tests such as esophagoscopy and simple- and double-channel 24-h pH-metry suggested mild GERD. Conventional proton-pump inhibitor treatment with pantoprazole (40 mg daily) was started without any improvement in his sleep. Multichannel intraluminal 24-h impedanciometry indicated the presence of severe pathological GER of gaseous origin. The patient's AHI decreased from 25.3 at baseline to 8 after treatment with sodium alginate. A drug-induced sleep endoscopy study showed the changes before and after this treatment and was helpful for the diagnosis., Conclusions: Thus, medical treatment can be a therapeutic option in some patients with OSA. Multichannel 24-h impedanciometry should be performed when nonacid GERD is suspected.

Introduction: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the "European Registry on Helicobacter pylori management.", Methods: Systematic prospective noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control., Results: The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7%), diarrhea (7%), nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies., Discussion: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance., Competing Interests: The remaining list of authors, their affiliations, contributions and conflicts of interests are listed in Supplementary file 1. Contribution Log, available online at http://links.lww.com/AJG/B961., (Copyright © 2021 by The American College of Gastroenterology.)

Background: There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation., Objective: To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy., Methods: Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line., Results: Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases., Conclusions: Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

The management of Helicobacter pylori infection has to rely on previous local effectiveness due to the geographical variability of antibiotic resistance. The aim of this study was to evaluate the effectiveness of first and second-line H. pylori treatment in Spain, where the empirical prescription is recommended. A multicentre prospective non-interventional registry of the clinical practice of European gastroenterologists concerning H. pylori infection (Hp-EuReg) was developed, including patients from 2013 until June 2019. Effectiveness was evaluated descriptively and through a multivariate analysis concerning age, gender, presence of ulcer, proton-pump inhibitor (PPI) dose, therapy duration and compliance. Overall, 53 Spanish hospitals were included, and 10,267 patients received a first-line therapy. The best results were obtained with the 10-day bismuth single-capsule therapy (95% cure rate by intention-to-treat) and with both the 14-day bismuth-clarithromycin quadruple (PPI-bismuth-clarithromycin-amoxicillin, 91%) and the 14-day non-bismuth quadruple concomitant (PPI-clarithromycin-amoxicillin-metronidazole, 92%) therapies. Second-line therapies were prescribed to 2448 patients, with most-effective therapies being the triple quinolone (PPI-amoxicillin-levofloxacin/moxifloxacin) and the bismuth-levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-amoxicillin) prescribed for 14 days (92%, 89% and 90% effectiveness, respectively), and the bismuth single-capsule (10 days, 88.5%). Compliance, longer duration and higher acid inhibition were associated with higher effectiveness. "Optimized" H. pylori therapies achieve over 90% success in Spain.

About 95 % of people diagnosed with glioblastoma die within five years. Glioblastoma is the most aggressive central nervous system tumour. It is necessary to make progress in the glioblastoma treatment so that advanced chemotherapy drugs or radiation therapy or, ideally, two-in-one hybrid systems should be implemented. Tyrosine kinase receptors-inhibitors and boron neutron capture therapy (BNCT), together, could provide a therapeutic strategy. In this work, sunitinib decorated-carborane hybrids were prepared and biologically evaluated identifying excellent antitumoral- and BNCT-agents. One of the selected hybrids was studied against glioma-cells and found to be 4 times more cytotoxic than sunitinib and 1.7 times more effective than 10 B-boronophenylalanine fructose complex when the cells were irradiated with neutrons., (© 2020 Wiley-VCH GmbH.)

Background: Different bismuth quadruple therapies containing proton-pump inhibitors, bismuth salts, metronidazole, and a tetracycline have been recommended as third-line Helicobacter pylori eradication treatment after failure with clarithromycin and levofloxacin., Aim: To evaluate the efficacy and safety of third-line treatments with bismuth, metronidazole, and either tetracycline or doxycycline., Methods: Sub-study with Spanish data of the "European Registry on H pylori Management" (Hp-EuReg), international multicenter prospective non-interventional Registry of the routine clinical practice of gastroenterologists. After previous failure with clarithromycin- and levofloxacin-containing therapies, patients receiving a third-line regimen with 10/14-day bismuth salts, metronidazole, and either tetracycline (BQT-Tet) or doxycycline (BQT-Dox), or single capsule (BQT-three-in-one) were included. Data were registered at AEG-REDCap database. Univariate and multivariate analyses were performed., Results: Four-hundred and fifty-four patients have been treated so far: 85 with BQT-Tet, 94 with BQT-Dox, and 275 with BQT-three-in-one. Average age was 53 years, 68% were women. Overall modified intention-to-treat and per-protocol eradication rates were 81% (BQT-Dox: 65%, BQT-Tet: 76%, BQT-three-in-one: 88%) and 82% (BQT-Dox: 66%, BQT-Tet: 77%, BQT-three-in-one: 88%), respectively. By logistic regression, higher eradication rates were associated with compliance (OR = 2.96; 95% CI = 1.01-8.84) and no prior metronidazole use (OR = 1.96; 95% CI = 1.15-3.33); BQT-three-in-one was superior to BQT-Dox (OR = 4.46; 95% CI = 2.51-8.27), and BQT-Tet was marginally superior to BQT-Dox (OR = 1.67; 95% CI = 0.85-3.29)., Conclusion: Third-line H pylori eradication with bismuth quadruple treatment (after failure with clarithromycin and levofloxacin) offers acceptable efficacy and safety. Highest efficacy was found in compliant patients and those taking 10-day BQT-three-in-one or 14-day BQT-Tet. Doxycycline seems to be less effective and therefore should not be recommended., (© 2020 John Wiley & Sons Ltd.)

Background: Experience in Helicobacter pylori eradication treatment of patients allergic to penicillin is very scarce. A triple combination with a PPI, clarithromycin (C), and metronidazole (M) is often prescribed as the first option, although more recently the use of a quadruple therapy with PPI, bismuth (B), tetracycline (T), and M has been recommended., Aim: To evaluate the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin in the "European Registry of H pylori management" (Hp-EuReg)., Methods: A systematic prospective registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H pylori infection. An e-CRF was created on AEG-REDCap. Patients with penicillin allergy were analyzed until June 2019., Results: One-thousand eighty-four patients allergic to penicillin were analyzed. The most frequently prescribed first-line treatments were as follows: PPI + C + M (n = 285) and PPI + B + T + M (classic or Pylera ® ; n = 250). In first line, the efficacy of PPI + C + M was 69%, while PPI + B + T + M reached 91% (P < .001). In second line, after the failure of PPI + C + M, two rescue options showed similar efficacy: PPI + B + T + M (78%) and PPI + C + levofloxacin (L) (71%) (P > .05). In third line, after the failure of PPI + C + M and PPI + C + L, PPI + B + T + M was successful in 75% of cases., Conclusion: In patients allergic to penicillin, a triple combination with PPI + C + M should not be generally recommended as a first-line treatment, while a quadruple regimen with PPI + B + T + M seems to be a better option. As a rescue treatment, this quadruple regimen (if not previously prescribed) or a triple regimen with PPI + C + L could be used but achieved suboptimal (<80%) results., (© 2020 John Wiley & Sons Ltd.)

Research question: Urine LH testing may be useful to confirm an LH surge after the GnRH agonist (GnRHa) trigger prior to oocyte retrieval in IVF. Design: A prospective cohort study, including oocyte donors undergoing ovarian stimulation, treated with a GnRHa trigger for final oocyte maturation. Urine LH testing was performed at home, 12 h after the GnRHa trigger. In the case of a negative result, serum LH and progesterone measurements were done that same day. Donors with no serum LH peak after trigger were re-scheduled using a dual trigger, with GnRHa and hCG. Results: Three hundred and fifty nine oocyte donors were included in the analysis. Three hundred and fifty six donors had positive urine LH tests, followed by oocyte retrieval. In one case, the LH test was positive, however, no oocytes were retrieved (false positive 1/356). Three LH tests were negative in urine: in one of these three cases, LH was tested again in blood, confirming an LH rise, consistent with an optimal response to the GnRHa trigger; in the other two cases, serum LH was <15 mUI/mL, after which the oocyte retrieval was re-scheduled for 36 h after an being re-triggered, resulting in the retrieval of 19 and 22 MII oocytes, respectively. Considering the cost analysis, it would be a significantly cost-saving strategy, as blood testing would have costed 14,840€ vs. only 185.5€ in urine LH kits. Conclusions: Urinary testing of the LH surge after GnRHa trigger is easy, safe, reliable, and convenient. In addition, LH urine testing allows identifying donors and patients who could benefit from a rescue hCG trigger after an unsuccessful GnRHa trigger., (Copyright © 2020 Cozzolino, Matey, Alvarez, Toribio, López, Perona, Henzenn, Piró, Humaidan and Garcia-Velasco.)

Mesial temporal lobe epilepsy with hippocampal sclerosis represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. Mesial temporal lobe epilepsy is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by single nucleotide polymorphisms in regulatory elements (expression quantitative trait loci, eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies. We performed a whole (gene and exon-level) transcriptome analysis on cortical tissue samples (Brodmann areas 20 and 21) from 86 patients with mesial temporal lobe epilepsy with hippocampal sclerosis and 75 neurologically healthy controls. Genome-wide genotyping data from the same individuals (patients and controls) were analysed and paired with the transcriptome data. We report potential epilepsy-risk eQTLs, some of which are specific to tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis. We also found large transcriptional and splicing deregulation in mesial temporal lobe epilepsy with hippocampal sclerosis tissue as well as gene networks involving neuronal and glial mechanisms that provide new insights into the cause and maintenance of the seizures. These data (available via the 'Seizubraineac' web-tool resource, www.seizubraineac.org) will facilitate the identification of new therapeutic targets and biomarkers as well as genetic risk variants that could influence epilepsy and pharmacoresistance., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups., Aims: We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE., Methods: In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n = 276), postoperative cognitive change (n = 126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n = 37 and 34)., Results: mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients., Conclusions: Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE., (© 2018 John Wiley & Sons Ltd.)

Radiotherapy is one of the leading treatments for clinical cancer therapy. External beam radiotherapy has been proposed as an adjuvant treatment for patients bearing differentiated thyroid cancer refractory to conventional therapy. Our purpose was to study the combined effect of HDAC inhibitors (HDACi) and ionizing irradiation in thyroid cancer cell lines (Nthy-ori 3-1, WRO, TPC-1 and 8505c). HDACi radiosensitized thyroid cancer cells as evidenced by the reduction of survival fraction, whereas they had no effect in the normal cells. HDACi enhanced radiation-induced cell death in WRO cells. Gamma-H2AX foci number increased and persisted long after ionizing exposure in the HDACi-treated cells (WRO and TPC-1). Moreover, the expression of the repair-related gene Ku80 was differentially modulated only in the cancer cells, by the compounds at the protein and/or mRNA levels. We present in vitro evidence that HDACi can enhance the radiosensitivity of human thyroid cancer cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Iodine is not used only by the thyroid to synthesize thyroid hormones but also directly influences a number of thyroid parameters such as thyroid proliferation and function. Several iodinated lipids, biosynthesized by the thyroid, were postulated as intermediaries in the action of iodide. Among these, iodolactone (IL-δ) and 2-iodohexadecanal (2-IHDA) have shown to inhibit several thyroid parameters. The antiproliferative effect of IL-δ is not restricted to the thyroid gland. IL-δ exhibits anti-tumor properties in breast cancer, neuroblastoma, glioblastoma, melanoma and lung carcinoma cells suggesting that IL-δ could be used as a chemotherapeutic agent. Moreover in a colon cancer cell line (HT-29), IL-δ induced cell death, and this effect was mediated by reactive oxygen species (ROS) generation. The aim of the present study was to analyze the sources of reactive oxygen species induced by IL-δ and to explore the contribution of ROS induced by IL-δ on cell proliferation and apoptosis., Methodology and Results: Cancer thyroid follicular (WRO) and papilar (TPC-1) cells lines were treated with IL-δ. Proliferation and apoptosis was analyzed. IL-δ caused a significant loss of cell viability on WRO and TPC-1 cells in a concentration dependent manner and induced apoptosis after 3 h of treatment. Furthermore, IL-δ (10 μM) increased ROS production (39% WRO and 20% TPC-1). The concomitant treatment of WRO and TPC-1 cells with Trolox or NAC plus IL-δ abrogated the augment of ROS induced by IL-δ exposure. Additionally Trolox and NAC reversed the effect of IL-δ on cell proliferation and apoptosis. Only in WRO cells IL-δ upregulates NADPH oxidase NOX4 expression, and siRNA targeted knock-down of NOX4 attenuates ROS production, apoptosis (p < 0.05) and the inhibitory effect of IL-δ on cell proliferation and PCNA expression (p < 0.05)., Conclusions: The antiproliferative and pro-apoptotic effect of IL-δ is mediated by different mechanisms and pathway involving different sources of ROS generation depending on the cellular context., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Rising trends in eosinophilic esophagitis (EoE) have been repeatedly linked to declining Helicobacter pylori (H. pylori) infection, mostly in retrospective studies. We aimed to prospectively evaluate this inverse association., Methods: Prospective case-control study conducted in 23 centers. Children and adults naïve to eradication therapy for H. pylori were included. Cases were EoE patients, whereas controls were defined by esophageal symptoms and <5 eos/HPF on esophageal biopsies. H. pylori status was diagnosed by non-invasive (excluding serology) or invasive testing off proton pump inhibitor (PPI) therapy for 2 weeks. Atopy was defined by the presence of IgE-mediated conditions diagnosed by an allergist., Results: 808 individuals, including 404 cases and 404 controls (170 children) were enrolled. Overall H. pylori prevalence was 38% (45% children vs. 37% adults, p 0.009) and was not different between cases and controls (37% vs. 40%, p 0.3; odds ratio (OR) 0.97; 95% confidence interval (CI) 0.73-1.30), neither in children (42% vs. 46%, p 0.1) nor in adults (36% vs. 38%, p 0.4). Atopy (OR 0.85; 95%CI 0.75-0.98) and allergic rhinitis (OR 0.81; 95%CI 0.68-0.98) showed a borderline inverse association with H. pylori infection in EoE patients. This trend was not confirmed for asthma or food allergy., Conclusions: H. pylori infection was not inversely associated with EoE, neither in children nor in adults. A borderline inverse association was confirmed for atopy and allergic rhinitis, but not asthma of food allergy. Our findings question a true protective role of H. pylori infection against allergic disorders, including EoE.

Purpose: Patients with the same histopathologic diagnosis of cutaneous melanoma treated with identical protocols of boron neutron capture therapy (BNCT) have shown different clinical outcomes. The objective of the present studies was to evaluate the biodistribution of boronophenilalanina ((10)BPA) for the potential application of BNCT for the treatment of melanoma on an individual basis., Methods and Materials: The boronophenilalanine (BPA) uptake was evaluated in 3 human melanoma cell lines: MEL-J, A375, and M8. NIH nude mice were implanted with 4 10(6) MEL-J cells, and biodistribution studies of BPA (350 mg/kg intraperitoneally) were performed. Static infrared imaging using a specially modified infrared camera adapted to measure the body infrared radiance of small animals was used. Proliferation marker, Ki-67, and endothelial marker, CD31, were analyzed in tumor samples., Results: The in vitro studies demonstrated different patterns of BPA uptake for each analyzed cell line (P<.001 for MEL-J and A375 vs M8 cells). The in vivo studies showed a maximum average boron concentration of 25.9 ± 2.6 μg/g in tumor, with individual values ranging between 11.7 and 52.0 μg/g of (10)B 2 hours after the injection of BPA. Tumor temperature always decreased as the tumors increased in size, with values ranging between 37 °C and 23 °C. A significant correlation between tumor temperature and tumor-to-blood boron concentration ratio was found (R(2) = 0.7, rational function fit). The immunohistochemical studies revealed, in tumors with extensive areas of viability, a high number of positive cells for Ki-67, blood vessels of large diameter evidenced by the marker CD31, and a direct logistic correlation between proliferative status and boron concentration difference between tumor and blood (R(2) = 0.81, logistic function fit)., Conclusion: We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Aim was to evaluate the efficacy and tolerability of a moxifloxacin-containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed., Methods: Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days. Eradication was confirmed by (13)C-urea-breath-test. Compliance was determined through questioning and recovery of empty medication envelopes., Results: 250 patients were consecutively included (mean age 48 ± 15 years, 11% with ulcer). Previous (failed) therapy included: standard triple (n = 179), sequential (n = 27), and concomitant (n = 44); 97% of patients took all medications, 4 were lost to follow-up. Intention-to-treat and per-protocol eradication rates were 82.4% (95% CI, 77-87%) and 85.7% (95% CI, 81-90%). Cure rates were similar independently of diagnosis (ulcer, 77%; dyspepsia, 82%) and previous treatment (standard triple, 83%; sequential, 89%; concomitant, 77%). At multivariate analysis, only age was associated with eradication (OR = 0.957; 95% CI, 0.933-0.981). Adverse events were reported in 25.2% of patients: diarrhoea (9.6%), abdominal pain (9.6%), and nausea (9.2%)., Conclusion: 14-day moxifloxacin-containing triple therapy is an effective and safe second-line strategy in patients whose previous standard triple therapy or non-bismuth quadruple (sequential or concomitant) therapy has failed, providing a simple alternative to bismuth quadruple regimen., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

We have previously reported the radioprotective effect of propylthiouracil (PTU) on thyroid cells. The aim of the present study was to analyze whether tumor cells and normal cells demonstrate the same response to PTU. Human colon carcinoma cells were irradiated with γ-irradiation with or without PTU. We evaluated the clonogenic survival, intracellular reactive oxygen species levels, catalase, superoxide dismutase and glutathione peroxidase activities, and apoptosis by nuclear cell morphology and caspase-3 activity assays. Cyclic AMP (cAMP) levels were measured by radioimmunoassay. PTU treatment increased surviving cell fraction at 2 Gy (SF2) from 56.9 ± 3.6 in controls to 75.0 ± 3.5 (p < 0.05) and diminished radiation-induced apoptosis. In addition, we observed that the level of antioxidant enzymes' activity was increased in cells treated with PTU. Moreover, pretreatment with PTU increased intracellular levels of cAMP. Forskolin (p < 0.01) and dibutyryl cAMP (p < 0.05) mimicked the effect of PTU on SF2. Co-treatment with H89, an inhibitor of protein kinase A, abolished the radioprotective effect of PTU. PTU reduces the toxicity of ionizing radiation by increasing cAMP levels and also possibly through a reduction in apoptosis levels and in radiation-induced oxidative stress damage. We therefore conclude that PTU protects both normal and cancer cells during exposure to radiation in conditions mimicking the radiotherapy.

Background: IL-δ (5-hydroxy-6 iodo-8,11,14-eicosatrienoic delta lactone) an iodinated arachidonic acid (AA) derivative, is one of the iodolipids biosynthesized by the thyroid. Although IL-δ regulates several thyroid parameters such as cell proliferation and goiter growth it was found that this iodolipid inhibits the growth of other non thyroid cell lines., Objectives: To study the effect of IL-δ on cell proliferation and apoptosis in the colon cancer cell line HT-29., Results: Treatment with IL-δ reduced cell viability in a concentration-dependent manner: 1μM 20%, 5μM 25%, 10μM 31%, 50μM 47% and caused a significant decrease of PCNA expression (25%). IL-δ had pro-apoptotic effects, evidenced by morphological features of programmed cell death such as pyknosis, karyorrhexis, cell shrinkage and cell blebbing observed by fluorescence microscopy, and an increase in caspase-3 activity and in Bax/Bcl-2 ratio (2.5 after 3h of treatment). Furthermore, IL-δ increased ROS production (30%) and lipid peroxidation levels (19%), suggesting that apoptosis could be a result of increased oxidative stress. A maximum increase in c-fos and c-jun protein expression in response to IL-δ was observed 1h after initiation of the treatment. IL-δ also induced a tumour growth delay of 70% compared to the control group in NIH nude mice implanted with HT-29 cells., Conclusion: Our study shows that IL-δ inhibits cell growth and induces apoptosis in the colon cancer cell line, HT-29 and opens the possibility that IL-δ could be a potential useful chemotherapy agent., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Many epidemiologic studies have shown that the exposure to high external radiation doses increases thyroid neoplastic frequency, especially when given during childhood or adolescence. The use of radioprotective drugs may decrease the damage caused by radiation therapy and therefore could be useful to prevent the development of thyroid tumors. The aim of this study was to investigate the possible application of 6-propyl-2-thiouracil (PTU) as a radioprotector in the thyroid gland. Rat thyroid epithelial cells (FRTL-5) were exposed to different doses of γ irradiation with or without the addition of PTU, methimazole (MMI), reduced glutathione (GSH) and perchlorate (KClO4). Radiation response was analyzed by clonogenic survival assay. Cyclic AMP (cAMP) levels were measured by radioimmunoassay (RIA). Apoptosis was quantified by nuclear cell morphology and caspase 3 activity assays. Intracellular reactive oxygen species (ROS) levels were measured using the fluorescent dye 2',7'-dichlorofluorescein-diacetate. Catalase, superoxide dismutase and glutathione peroxidase activities were also determined. Pretreatment with PTU, MMI and GSH prior to irradiation significantly increased the surviving cell fraction (SF) at 2 Gy (P < 0.05), while no effect was observed with KClO4. An increase in extracellular levels of cAMP was found only in PTU treated cells in a dose and time-dependent manner. Cells incubated with agents that stimulate cAMP (forskolin and dibutyril cAMP) mimicked the effect of PTU on SF. Moreover, pretreatment with the inhibitor of protein kinase A, H-89, abolished the radioprotective effect of PTU. PTU treatment diminished radiation-induced apoptosis and protected cells against radiation-induced ROS elevation and suppression of the antioxidant enzyme's activity. PTU was found to radioprotect normal thyroid cells through cAMP elevation and reduction in both apoptosis and radiation-induced oxidative stress damage.

Background: Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function., Methods: We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T(4) levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments., Results: Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results., Conclusions: Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.).

Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. Hypoalgesia was observed in NET KO mice, and to a lesser extent in SERT KO mice. The magnitude of this hypoalgesia in NET KO mice was so profound that it limited the assessment of drug-induced analgesia. Nonetheless, the necessary exclusion of these subjects because of profound baseline hypoalgesia strongly supports the role of norepinephrine and NET in basal nociceptive behavior while indicating a much smaller role for serotonin and SERT. To further clarify the role of NET and SERT in basal nociceptive sensitivity further experiments were conducted in SERT KO and NET KO mice across a range of temperatures. NET KO mice were again found to have pronounced thermal hypoalgesia compared to WT mice in both the hotplate and tail-flick tests, while only limited effects were observed in SERT KO mice. Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no change in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice., (Published by Elsevier Ltd.)

Purpose: DNA lesions produced by boron neutron capture therapy (BNCT) and those produced by gamma radiation in a colon carcinoma cell line were analyzed. We have also derived the relative biologic effectiveness factor (RBE) of the neutron beam of the RA-3- Argentine nuclear reactor, and the compound biologic effectiveness (CBE) values for p-boronophenylalanine ((10)BPA) and for 2,4-bis (α,β-dihydroxyethyl)-deutero-porphyrin IX ((10)BOPP)., Methods and Materials: Exponentially growing human colon carcinoma cells (ARO81-1) were distributed into the following groups: (1) BPA (10 ppm (10)B) + neutrons, (2) BOPP (10 ppm (10)B) + neutrons, (3) neutrons alone, and (4) gamma rays ((60)Co source at 1 Gy/min dose-rate). Different irradiation times were used to obtain total absorbed doses between 0.3 and 5 Gy (±10%) (thermal neutrons flux = 7.5 10(9) n/cm(2) sec)., Results: The frequency of micronucleated binucleated cells and the number of micronuclei per micronucleated binucleated cells showed a dose-dependent increase until approximately 2 Gy. The response to gamma rays was significantly lower than the response to the other treatments (p < 0.05). The irradiations with neutrons alone and neutrons + BOPP showed curves that did not differ significantly from, and showed less DNA damage than, irradiation with neutrons + BPA. A decrease in the surviving fraction measured by 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay as a function of the absorbed dose was observed for all the treatments. The RBE and CBE factors calculated from cytokinesis block micronucleus (CBMN) and MTT assays were, respectively, the following: beam RBE: 4.4 ± 1.1 and 2.4 ± 0.6; CBE for BOPP: 8.0 ± 2.2 and 2.0 ± 1; CBE for BPA: 19.6 ± 3.7 and 3.5 ± 1.3., Conclusions: BNCT and gamma irradiations showed different genotoxic patterns. To our knowledge, these values represent the first experimental ones obtained for the RA-3 in a biologic model and could be useful for future experimental studies for the application of BNCT to colon carcinoma., (Copyright © 2011. Published by Elsevier Inc.)

Objective: Functional gastrointestinal disorders (FGID) may appear after acute gastroenteritis. The aim of this study was to evaluate the possible mechanisms (inflammation, visceral hypersensitivity, psychological and immunogenetic factors) related to the development of postinfectious (PI) FGID 3 years after a Salmonella outbreak., Material and Methods: Biopsies of the antrum, and right- and left colon from 16 PI-FGID patients, 8 PI control patients, and 18 healthy controls (H-controls) were processed for immunohistochemistry, cytokines, and mast-cell electron microscopy. DNA was typed for cytokine gene polymorphisms. Visceral sensitivity (satiety test and rectal barostat) and psychological factors (SCL-90 and vital events) were assessed., Results: The number of mast cells and T lymphocytes was similar among the groups in all locations. Mast cells within 5 microm of nerve fibers of both PI groups were increased compared to H-controls: (stomach: 5.6+/-1.2 versus 6.6+/-1.5 versus 2.5+/-1.1; right colon: 9.7+/-1.3 versus 8.0+/-1.3 versus 4.1+/-1.7; left colon: 8.9+/-0.9 versus 8.5+/-1.8 versus 2.2+/-2.0 per field) (p<0.05). No differences in the production of IL-1beta, IL-1ra, IL-6, and IL-10 or in their genotypes were found. PI-FGID patients showed a lower pain threshold to rectal distention (29+/-2 versus 37+/- 2 mmHg; p<0.05). Scores for anxiety (0.63+/-0.11 versus 0.28+/-0.14) and somatization (1.01+/-0.15 versus 0.45+/-0.15) were higher in PI-FGID patients than in PI controls (p<0.05). The number of stressful life events was not significantly different between both PI groups., Conclusions: Three years after salmonellosis, PI-FGID patients showed no evidence of inflammation in the gastric or colonic mucosa, but visceral sensitivity and anxiety/somatization levels were increased. The close anatomical mast cell-nerve fibers relation does not seem to be related to the FGID but to the infection itself.

Background and Objective: Although constipation affects quality of life, questionnaires hardly exist for its evaluation. We aimed to develop and validate a questionnaire able to measure the quality of life in patients with constipation., Patients and Method: A Spanish multicenter study was performed in 2 stages: a) questionnaire development (open interview to patients with constipation, pilot questionnaire, quantitative and factorial analysis, Rasch analysis, and specific questionnaire design), and b) questionnaire validation in 136 patients. These patients were divided in 2 groups: a) reliability group (n = 55; no need to begin or change treatment; re-tested after 15 days), and b) sensibility to change group (n = 81; need to begin or change treatment; re-tested after 3 months). We collected clinical and socio-demographic data and we evaluated the quality of life through the general questionnaire EuroQoL-5D (EQ-5D) and the specific one, design in the previous stage (25 items). After that, we analysed feasibility, reliability and validity (of content, convergent and longitudinal)., Results: The trial questionnaire was obtained during the development stage and the results were 51 items that were later reduced to 25 in the validation stage. A total of 126 patients (93% women; mean age [standard deviation]: 43.4 [1] years) completed the study properly. The answer average time was 12 min. The content validity process reduced the questionnaire to 20 items (CVE-20) within 4 domains: emotional, general physical, rectal physical and social. The reliability was good in relation to the general punctuation (Cronbach alpha coefficient = 0.87), being in the different domains of 0.79, 0.73, 0.75 and 0.60, respectively. The construct validity showed a good correlation between the CVE-20 results and constipation severity. The CVE-20 score positively correlated with EQ -5D changes. The test and re-test reliability were good: interclass correlation coefficient = 0.89 (ranging from 0.80 to 0.88 in the different domains). The clinically relevant and minimal difference was 17 points (95% confidence interval, 11-23). The content validity showed a strong correlation between CVE-20 and constipation severity., Conclusions: The CVE-20 is the first specific questionnaire in Spanish language for constipated patients; it is valid, reliable, sensitive to changes and it meets the psychometric requirements to be applied in daily practice and clinical trials.

Purpose: To analyze the possible increase in efficacy of boron neutron capture therapy (BNCT) for undifferentiated thyroid carcinoma (UTC) by using p-boronophenylalanine (BPA) plus 2,4-bis (alpha,beta-dihydroxyethyl)-deutero-porphyrin IX (BOPP) and BPA plus nicotinamide (NA) as a radiosensitizer of the BNCT reaction., Methods and Materials: Nude mice were transplanted with a human UTC cell line (ARO), and after 15 days they were treated as follows: (1) control, (2) NCT (neutrons alone), (3) NCT plus NA (100 mg/kg body weight [bw]/day for 3 days), (4) BPA (350 mg/kg bw) + neutrons, (5) BPA + NA + neutrons, and (6) BPA + BOPP (60 mg/kg bw) + neutrons. The flux of the mixed (thermal + epithermal) neutron beam was 2.8 x 10(8) n/cm(2)/sec for 83.4 min., Results: Neutrons alone or with NA caused some tumor growth delay, whereas in the BPA, BPA + NA, and BPA + BOPP groups a 100% halt of tumor growth was observed in all mice at 26 days after irradiation. When the initial tumor volume was 50 mm(3) or less, complete remission was found with BPA + NA (2 of 2 mice), BPA (1 of 4), and BPA + BOPP (7 of 7). After 90 days of complete regression, recurrence of the tumor was observed in BPA + NA (2 of 2) and BPA + BOPP (1 of 7). The determination of apoptosis in tumor samples by measurements of caspase-3 activity showed an increase in the BNCT (BPA + NA) group at 24 h (p < 0.05 vs. controls) and after the first week after irradiation in the three BNCT groups. Terminal transferase dUTP nick end labeling analysis confirmed these results., Conclusions: Although NA combined with BPA showed an increase of apoptosis at early times, only the group irradiated after the combined administration of BPA and BOPP showed a significantly improved therapeutic response.

Background & Aims: It has been reported that some patients develop functional digestive disorders, particularly irritable bowel syndrome (IBS), after acute gastroenteritis (AGE). However, the presence of dyspepsia has not been specifically addressed. We prospectively evaluated development of dyspepsia and IBS during a 1-year follow-up in a cohort of adult patients affected by a Salmonella enteritidis AGE outbreak., Methods: Questionnaires were sent to 1878 potential participants at baseline and 3, 6, and 12 months; 677 had experienced a Salmonella enteritidis AGE on June 23, 2002, and 1201 had not (randomly selected controls, matched for village of residence, age, and sex). At 12 months, 271 patients and 335 controls returned the questionnaires. Data permitted the establishment of dyspepsia and IBS diagnosis by Rome II criteria., Results: Before the AGE outbreak, the prevalence of dyspepsia was similar in cases and controls (2.5% vs 3.8%); the prevalence of IBS was also similar (2.9% vs 2.3%). At 3, 6, and 12 months, the prevalence of both dyspepsia and IBS had increased significantly in exposed compared with unexposed subjects. Overlap between dyspepsia and IBS was frequent. At 1 year, the relative risk for development of dyspepsia was 5.2 (95% confidence interval, 2.7-9.8) and for IBS was 7.8 (95% confidence interval, 3.1-19.7). Prolonged abdominal pain and vomiting during AGE were positive predictors of dyspepsia. No predictive factors for IBS were found., Conclusions: Salmonella gastroenteritis is a significant risk factor not only for IBS but also for dyspepsia; at 1 year of follow-up, 1 in 7 and 1 in 10 subjects developed dyspepsia or IBS, respectively.

Objectives: To investigate the effect on hot flushes of a soy isoflavone extract alone (Study A) and with the addition of a supplement of polyunsaturated fatty acids, PUFAs (Study B)., Methods: Subjects were postmenopausal women (29 in Study A, 28 in Study B) with more than five troublesome hot flushes per day. Both studies were double-blind randomized placebo-controlled trials with cross-over design, of 24-week duration. After a 2-week observation period, they were randomized to receive two capsules per day providing 60mg of isoflavones or placebo for 12 weeks; thereafter, women who had taken isoflavones were given placebo for a second 12-week period, and vice-versa. Women in the Study B were given also two capsules per day containing a PUFA supplement for the entire 24-week test period., Results: Both studies showed the isoflavone extract to have no greater efficacy on hot flushes than the placebo. During the 24 weeks of the Study B there was a progressive and highly significant reduction in the number of hot flushes, independent of whether the women had begun with isoflavones or with placebo., Conclusion: In these two trials the isoflavone extract did not show greater efficacy on the hot flushes than the placebo. The reduction of hot flushes observed in the Study B might be due to the PUFA supplement. PUFAs, particularly Omega (Omega) 3-fatty acids, could reduce hot flushes through their influence on neuronal membranes and/or the modulation of the neurotransmitter function and the serotoninergic system. Studies specifically designed to document the action of PUFAs on hot flushes would be welcome.

Background & Aims: Retrospective studies found an association between past sexual, physical, or psychological abuse and functional gastrointestinal disorders (FGIDs). However, there are no studies evaluating such an association concurrently with the ongoing abuse. Our aim was to investigate the prevalence of the main FGIDs, functional dyspepsia and irritable bowel syndrome, in 70 women reporting a situation of domestic violence to the police and to evaluate the level of psychological distress and its relationship with the presence of FGID., Methods: Through an interview between a social worker and the woman reporting abuse, digestive symptoms, psychological status, and type of abuse were recorded. These data were matched against police records. Functional dyspepsia and irritable bowel syndrome were diagnosed according to Rome II criteria., Results: Seventy-one percent of the women had an FGID: 67% functional dyspepsia, 47% irritable bowel syndrome, and 43% both. In two thirds of the cases, FGID onset occurred simultaneously with or soon after abuse onset. Only 34% of the women had sought medical attention for FGID symptoms. No differences were found between women with or without FGID regarding age and type or duration of abuse; psychological distress tended to be more severe in the group of women with FGIDs., Conclusions: Most women who suffer domestic violence (reported to the police) have functional dyspepsia and/or irritable bowel syndrome and also have elevated psychological distress. This has important implications, not only for comprehensive health care of women in a situation of abuse, but also for medical treatment of women with FGIDs.

A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE.

Seventeen alpha-hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia not linked to human leukocyte antigen and characterized by the coexistence of hypertension caused by the hyperproduction of mineralocorticoid precursors and sexual abnormalities, such as male pseudohermaphroditism and sexual infantilism in female, due to impaired production of sex hormones. Both 17alpha-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17 gene located on chromosome 10q24-q25. Mutations in the CYP17 gene have been recognized to cause the 17alpha-hydroxylase/17,20-lyase deficiency syndrome. Here, we describe two phenotypically and hormonally affected Italian patients with 17alpha-hydroxylase/17,20-lyase deficiency. The family history revealed consanguinity of the parents. Linkage and haplotype analyses using microsatellites on chromosome 10q24-q25 demonstrated that the two affected individuals were homozygous at these loci. The mutation screening of the CYP17 gene identified a new Phe93Cys missense mutation in exon 1. The amino acid substitution is located in a highly conserved region of the protein and is not a polymorphism because it is not present in one hundred normal alleles. In vitro functional studies showed that the Phe93Cys mutated CYP17 retains only 10% of both 17alphahydroxylase and 17,20-lyase activities, according to the severe phenotype. Our results shed more light on the structure-function relationship of the CYP17 protein indicating that Phe 93 is crucial for both enzymatic activities.

Background: Tissue Polypeptide-specific Antigen (TPS) and CA 15.3 are two of the most widely studied tumor markers in the serum of breast cancer patients. TPS is a tumor associated proliferative marker which belongs to the cytoskeleton. CA 15.3 is a high molecular weight glycoprotein of clinical relevance in the monitoring of treatment and the detection of recurrence in breast cancer patients., Patients and Methods: Serum values of TPS and CA 15.3 were measured in a prospective series of patients with primary breast cancer (n=267) and benign breast disease (n=46). The cut-off levels (95% specificity) determined for each test were 80 U/I for TPS and 30 k/U/l for CA 15.3., Results: The diagnostic sensitivity was 0.31 for TPS and 0.32 for CA 15.3 for the detection of breast cancer. Serum TPS levels in breast cancer patients showed a relatively low positivity rate (33%), which was comparable with that of CA 15.3. Higher concentrations of TPS were found in cases with locally more advanced disease as well as in G3 tumors. By contrast, CA 15.3 basal levels were solely related to tumor size and nodal involvement. TPS and CA 15.3 levels were not related to estrogen and progesterone receptor status, peritumoral vessel invasion, multifocality and the in situ component of the tumor. After primary treatment, 20 patients developed distant metastases. In metastatic breast cancer patients TPS was more frequently and more markedly elevated than CA 15.3. In progressive disease, elevated values of TPS and CA 15.3 were found in 85% and 50%, respectively. The mean lead time was 10 months for TPS and 14 months for CA 15.3. Increasing values of TPS were independent of the site of metastasis, whereas elevated levels of CA 15.3 were mainly related to visceral metastasis. Local recurrences were usually associated with low levels of TPS and CA 15.3. By contrast, elevated values of TPS in locally recurred cases indicated rapidly progressive disease., Conclusions: Our study indicates that TPS and CA 15.3 are not helpful in distinguishing patients with breast cancer from patients with benign breast lesions. Nevertheless, at the time of diagnosis increased serum levels of the markers may facilitate the selection of high risk patients for whom additional treatment and careful follow up studies should be undertaken. Furthermore, TPS seems to be a reliable tumor marker for the early diagnosis of metastatic breast carcinoma independent of the site of metastasis, while increasing values of CA 15.3 are mainly related to visceral involvement.

The risk of Down's syndrome pregnancies can be estimated by quantitation of maternal serum markers, namely alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin (triple test). A prospective study of 2892 pregnant women (median age 33.5 years) is reported. The detection rate of Down's syndrome pregnancies was 80% (confidence intervals 45%-100%) when a risk of 1:380 or greater was considered "screen positive", the false positive rate was 13.3% (confidence intervals 12.0%-14.5%). The importance of the accurate assessment of gestational age and the time of blood sampling are emphasized. Our findings are compared with similar studies performed in other laboratories.

The effectiveness of maternal serum alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin in screening for Down's syndrome (DS) was evaluated on 840 women who underwent amniocentesis for fetal karyotype on account of their age. The risk of a DS pregnancy was established using the method of Wald et al. (1988b), which combines the age-specific risk with that indicated by the levels of the three serum markers. In women over 35, at cut-off risk levels of 1:250 and 1:380, the false-positive rate was 24 and 34 per cent, respectively. In all nine cases of DS, the estimated risk was higher than 1:250. The best screening strategy with the lowest false-positive rate was obtained by combining the three serum markers. The results suggest that this kind of screening can be proposed during genetic counselling for women under 35 and older women wishing to avoid the risk of miscarriage induced by amniocentesis.