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Background: Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome., Methods: We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711., Findings: The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups., Interpretation: EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training., Funding: Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

The assessment of memory decline in people with intellectual disability (ID) is more difficult than in the general population, due to a lack of appropriate instruments and to preexisting cognitive impairment. The aim of this study was to describe performance of healthy adults with Down syndrome (healthy-DS; prospectively cohort) on a Spanish version of the modified Cued Recall Test (mCRT). We also recruited retrospectively a cohort of DS subjects with Dementia of the Alzheimer's Type (DS-DAT). Healthy-DS obtained higher scores on free recall and total score than DS-DAT. Age was the main factor associated with decreasing mCRT scores. The mCRT was useful in DS subjects with ID at the upper end of the spectrum or ID in the middle range of the spectrum, and discriminated well between DS subjects with and without DAT.

Logic models of signaling pathways are a promising way of building effective in silico functional models of a cell, in particular of signaling pathways. The automated learning of Boolean logic models describing signaling pathways can be achieved by training to phosphoproteomics data, which is particularly useful if it is measured upon different combinations of perturbations in a high-throughput fashion. However, in practice, the number and type of allowed perturbations are not exhaustive. Moreover, experimental data are unavoidably subjected to noise. As a result, the learning process results in a family of feasible logical networks rather than in a single model. This family is composed of logic models implementing different internal wirings for the system and therefore the predictions of experiments from this family may present a significant level of variability, and hence uncertainty. In this paper, we introduce a method based on Answer Set Programming to propose an optimal experimental design that aims to narrow down the variability (in terms of input-output behaviors) within families of logical models learned from experimental data. We study how the fitness with respect to the data can be improved after an optimal selection of signaling perturbations and how we learn optimal logic models with minimal number of experiments. The methods are applied on signaling pathways in human liver cells and phosphoproteomics experimental data. Using 25% of the experiments, we obtained logical models with fitness scores (mean square error) 15% close to the ones obtained using all experiments, illustrating the impact that our approach can have on the design of experiments for efficient model calibration.

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS.

Background and Aims: Successful treatment of patients with irritable bowel syndrome (IBS) often remains elusive. Recent studies in Australia, the United Kingdom and New Zealand have suggested the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in the management of these patients. The aims of this study were to determine whether a diet low in FODMAPs improves symptoms in patients with functional gastrointestinal disorders (FGID) in Spain and to analyze the predictors of a good response., Patients and Methods: A prospective study was carried out in consecutive patients with FGID type IBS and functioanl abdominal bloating. At inclusion all patients underwent an assessment through a baseline demographic questionnaire of symptoms of anxiety and depression and quality of life. A hydrogen breath test with lactose and fructose was performed and a low FODMAPs diet was indicated for 2 months by expert dietitians. These tests were taken as a reference. A positive response was defined as an improvement of at least 5 points out of a possible 10 in the symptom questionnaire., Results: We included 30 patients (24 women, 39 [12] years). The response to the low FODMAPs diet was positive in controlling overall symptoms and specific symptoms such as functioanl abdominal bloating, abdominal pain, diarrhea, flatulence, nausea and fatigue in more than 70% of patients (P<.05). By contrast, constipation was controlled in only 48% of patients (P>.05). Adherence to the diet was good in 87% of patients and was a predictor of positive response in the univariate analysis., Conclusions: A diet low in FODMAPs is associated with symptom improvement in patients with IBS and functioanl abdominal bloating. Adherence to the diet was a determining factor., (Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.)

Background: High-concentration-capsaicin-patches (Qutenza®) have been put on the market as a treatment for peripheral neuropathic pain. A minimum infrastructure and a determinate skill set for its application are required. Our aim was to assess the feasibility of treatment with high-concentration-capsaicin-patches in clinical practice in a variety of refractory peripheral neuropathic pain syndromes in non-diabetic patients., Methods: Observational, prospective, single-center study of patients attended to in the Pain Unit of a tertiary hospital, ≥ 18 year-old non-responders to multimodal analgesia of both genders. The feasibility for the application of capsaicin patch in clinical practice was evaluated by means of the number of patients controlled per day when this one was applied and by means of the times used for patch application., Results: Between October 2010 and September 2011, 20 consecutive non-diabetic patients (7 males, 13 females) with different diagnoses of refractory peripheral neuropathic pain syndromes, with a median (range) age of 60 (33-88) years-old were treated with a single patch application. The median (range) number of patients monitored per day was not modified when the capsaicin patch was applied [27 (26-29)] in comparison with it was not applied [28 (26-30)]. The median (range) total time to determine and mark the painful area was 9 (6-15) minutes and of patch application was 60 (58-65) minutes. No important adverse reactions were observed., Conclusion: High-concentration-capsaicin-patch treatment was feasible in our unit for the treatment of a population with refractory peripheral neuropathic pain. The routine of our unit was not affected by its use.

Background and Aims: Noncardiac chest pain (NCCP) often represents a diagnostic and therapeutic challenge. Given that gastroesophageal reflux disease (GERD) is the most common cause of NCCP, initial treatment with proton-pump inhibitors (PPI) has been proposed for all patients (PPI testing), reserving esophageal function testing solely for non-responders. The aim of the present study was to provide evidence on the clinical utility of PPI testing with high-dose pantoprazole in patients with NCCP., Patients and Methods: We carried out a study of diagnostic performance with a cohort design in patients with NCCP, who had been assessed by the Cardiology Service. All patients underwent upper endoscopy, esophageal manometry, and 24h esophageal pH monitoring before PPI testing with pantoprazole 40 mg every 12h for 1 month. Before and after treatment, we assessed the severity (intensity and frequency) of chest pain, quality of life, and anxiety and depression by means of specific questionnaires. The diagnosis of GERD was based on a pathological finding of esophageal pH monitoring. A positive response to PPI testing was defined as an improvement in chest pain >50% compared with the baseline score after 1 month of PPI therapy., Results: We included 30 consecutive patients (17 men/13 women) with a mean age of 49 years. Of these 30 patients, 20 with NCCP had GERD (67%, 95%CI: 47%-83%). A positive response to PPI therapy was observed in 13 of the 30 (43%) patients with NCCP: 11 of the 20 (55%) patients in the GERD-positive group and 2 of the 10 (20%) in the GERD-negative group. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PPI testing was 55%, 80%, 85%, 47% and 63%, respectively. A significant reduction in chest pain after pantoprazole therapy (P=.003) and a slight non significant improvement in anxiety and depression was achieved in the GERD-positive group as compared to the GERD-negative group., Conclusions: In NCCP, PPI testing with pantoprazole has a low sensitivity for the diagnosis of GERD, placing in doubt the strategy of reserving functional study to non-responders to antisecretory therapy. Esophageal function testing and accurate diagnosis would allow appropriate targeted therapy for all patients with NCCP., (Copyright © 2013 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.)

Oral human papillomavirus (HPV) infections are less prevalent than genital and anal infections. However, the incidence of oropharyngeal squamous cell carcinomas has increased significantly over the last 2 decades in several countries. At least 90% of these cancers are associated with oncogenic type HPV16. Oral HPV infections are notably more frequent in men than in women, and the incidence of HPV-positive oropharyngeal squamous cell carcinomas has increased, predominantly among mid-adult men. Nevertheless, little is known about the progression of oral HPV infection to cancer, and it remains unclear which medical interventions should be applied to modify the natural history of the disease. This narrative review aimed at non-experts in HPV infection provides an update on oral HPV infection and its clinical management in men. Furthermore, using the cervix as a reference anatomical site, the lessons learned from investigations on cervical HPV infection are also addressed.

We report a case of a 73-year-old female who developed unbearable neuropathic pain after a herpes zoster episode. The pain persisted and could not be controlled despite multimodal analgesia. In addition to postherpetic neuralgia, myelitis and complex regional pain syndrome were diagnosed during the evolution of neuropathic pain. This complex neuropathic pain was resolved after sympathetic ganglion block., (© 2013 The Authors Pain Practice © 2013 World Institute of Pain.)

Motivation: Logic modeling is a useful tool to study signal transduction across multiple pathways. Logic models can be generated by training a network containing the prior knowledge to phospho-proteomics data. The training can be performed using stochastic optimization procedures, but these are unable to guarantee a global optima or to report the complete family of feasible models. This, however, is essential to provide precise insight in the mechanisms underlaying signal transduction and generate reliable predictions., Results: We propose the use of Answer Set Programming to explore exhaustively the space of feasible logic models. Toward this end, we have developed caspo, an open-source Python package that provides a powerful platform to learn and characterize logic models by leveraging the rich modeling language and solving technologies of Answer Set Programming. We illustrate the usefulness of caspo by revisiting a model of pro-growth and inflammatory pathways in liver cells. We show that, if experimental error is taken into account, there are thousands (11 700) of models compatible with the data. Despite the large number, we can extract structural features from the models, such as links that are always (or never) present or modules that appear in a mutual exclusive fashion. To further characterize this family of models, we investigate the input-output behavior of the models. We find 91 behaviors across the 11 700 models and we suggest new experiments to discriminate among them. Our results underscore the importance of characterizing in a global and exhaustive manner the family of feasible models, with important implications for experimental design., Availability: caspo is freely available for download (license GPLv3) and as a web service at http://caspo.genouest.org/., Supplementary Information: Supplementary materials are available at Bioinformatics online., Contact: santiago.videla@irisa.fr.

Background: Anal cancer is caused by human papillomavirus (HPV). Moreover, human immunodeficiency virus (HIV) is an additional risk factor for anal cancer. Therefore, when designing preventive protocols for HIV-infected men, it is important to detect high-risk (HR) oncogenic HPV genotypes present in their anal canals. However, most studies have focused only on men who have sex with men (MSM)., Objective: To estimate the prevalence of HPV and describe its genotype distribution using anal cytology and histology specimens from HIV-infected populations of MSM and men who have sex with women (MSW)., Design: Crosssectional study of the CARH·MEN cohort., Setting: Single-center prospective cohort of HIV-infected men attending the Outpatient HIV Clinic of Hospital Germans Trias i Pujol (Spain), where they undergo annual screening for HPV infection of the anus, penis and mouth., Patients: Four hundred eighty-three HIV-infected men (341 MSM, 142 MSW) with no current or previous history of anal condylomata., Main Outcome Measures: HPV genotypes detected (multiplex-PCR), cytology results (Papanicolaou test) and histology results (biopsy-based)., Results: Cytological abnormalities were detected in 40% of MSM (129/321; 95%CI, 35-46) and 20% of MSW (26/131; 95%CI, 13-28) (OR=2.7; 95%CI, 1.7-4.4). All high-grade squamous intraepithelial lesions (HSIL) were positive for HR-HPV in both groups. High-resolution anoscopy was performed in 146 patients (120 MSM, 26 MSW) with abnormal cytological diagnoses. Lesions were visualized in 80 MSM (67%) and 14 MSW (54%) (OR=1.7 [95%CI, 0.7-4.0]). Histological diagnosis was anal intraepithelial neoplasia (AIN)-1 in 51 MSM (64%) and 6 MSW (43%), AIN-2 in 9 MSM (11%) and 3 MSW (21%), AIN-3 in 7 MSM (9%) and 1 MSW (7%), and normal in 13 MSM (16%) and 4 MSW (29%). HPV16 was the most prevalent HR genotype., Limitations: Study limitations include its crosssectional design., Conclusions: Anal cancer screening should be offered to all HIV-infected men, regardless of their sexual orientation.

Background: We studied the type-specific infection of human papillomavirus (HPV) at the anal canal and penile site in a cohort of HIV-infected men., Methods: Prevalence, clearance, and incidence of specific HPV types in the anal canal and penis were determined in 733 HIV-infected men from the Spanish CAn Ruti HIV+ Men ([CARH•MEN]) cohort (538 men who have sex with men [MSM] and 195 heterosexual men)., Results: In both groups, the most prevalent high-risk type was HPV-16 (anal canal [31.6% MSM; 6.8% heterosexual] and penis [4.8% MSM; 6.8% heterosexual]). The most prevalent low-risk type was HPV-6 (anal canal [23.2% MSM; 12.8% heterosexual], penis [8.1% MSM; 8.9% heterosexual]). Anal prevalence was significantly higher in MSM, as was incidence, except for HPV-16, which was similar between male groups (5.9 new cases per 1000 person-months [95% confidence interval, 4.3-7.9] in MSM; 4.4 [95% confidence interval, 2.5-7.2] in heterosexual men; P > 0.05). The anal clearance rate of the different HPV types and retention time of infection were similar in both groups, as well as the HPV infection of the penis., Conclusions: HIV-infected MSM had a high prevalence of HPV infection at the anal canal; however, heterosexual HIV-infected men were also at risk for acquiring and sustaining persistent high-risk HPV types at the anal and penile site and are at risk for developing dysplasia in the future. All HIV-infected men should be recommended for routinely anal HPV screening.

Male circumcision is associated with a lower risk of penile human papillomavirus (HPV) infection in human immunodeficiency virus (HIV) uninfected men. Few studies have evaluated the role of male circumcision in penile HPV infection in HIV-infected men. The aim of this cross-sectional study was to examine the association between male circumcision and the prevalence of penile HPV infection among HIV-infected men-both men who have sex with men (MSM) and heterosexual men. Samples from 706 consecutive men included in the CARH-MEN cohort (overall 24% circumcised: 26% of MSM, 18% of heterosexual men) were examined by Multiplex-PCR. In the overall group (all HIV-infected men included), the prevalence of any penile HPV infection was 22% in circumcised men and 27% in uncircumcised men (OR = 1.0, 95% CI 0.6-1.6, adjusted analysis). In the circumcised group the overall prevalence of HPV infection was 22% in MSM and 24% in the heterosexual men, whereas in the uncircumcised group the prevalence was 26% and 28%, respectively. The prevalence of high-risk HPV types tended to be lower in the circumcised MSM (14% vs 21%, OR = 0.6, 95% CI 0.3-1.1, p 0.088), but it was similar in the heterosexual men (18% in circumcised vs 20% in uncircumcised). These results suggest that male circumcision may be associated with a lower prevalence of oncogenic high-risk penile HPV infection in HIV-infected MSM., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Background: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years., Objective: The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects., Study Design: This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study., Setting: The study was conducted in a phase I clinical unit., Subjects and Methods: A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration-time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG)., Results: In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng·h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng·h/mL, CV 22.8%]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8% for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90% CI: 92.46, 105.83). The most common adverse event was somnolence., Conclusions: Exposure to doxylamine was proportional over the therapeutic dose range of 12.5-25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.

Aims: To assess the effectiveness and safety of infrared coagulation (IRC) for the ablation of anal intraepithelial neoplasia (AIN) and to provide data on the prevalence of AIN in HIV-infected patients., Patients and Methods: We performed a single-center, retrospective cohort study based on data collected from a prospectively compiled database of outpatients attended in the Clinical-Proctology-HIV-Unit (first visit). The effectiveness (normal anal cytology after 12 months of IRC) and safety of IRC were estimated., Results: Between January 2005 and December 2011, a total of 69 (5%) patients with biopsy-proven AIN-2 or AIN-3 from among 1518 patients (1310 men; 208 women) were treated with IRC. The prevalence of cytological abnormalities was 49.5% [751/1518; (atypical squamous cells of unknown significance, 14%; low-grade squamous intraepithelial lesions, 27.5%; high-grade squamous intraepithelial lesions, 8%)]. High-resolution anoscopy revealed intra-anal condylomata in 31% of patients (236/751), nonvisualized lesions in 30% (227/751), and visualized lesions (from which biopsy specimens were taken) in 38% (288/751). The histological diagnosis was: AIN-1, 52% (151/288); AIN-2, 15% (44/288); AIN-3, 9% (25/288); normal, 19% (56/288); and nonevaluable, 4% (12/288). IRC was applied in-office in 66 patients (three refused to undergo treatment). At 12 months, all patients (n = 56) had a normal anal cytology result. Seven (13%) patients had biopsy-proven recurrence [mean (range) time-to-recurrence, 30 (18-43) months]. High-risk-human papilloma virus (HPV) infection was detected in all anal lesions (HPV-16 was the most common genotype). Agreement between cytological and histological results was poor., Conclusion: A high prevalence of AIN was found in both HIV-infected men and HIV-infected women. Although randomized clinical trials are lacking, IRC ablation of AIN-2 and AIN-3 lesions without concomitant condylomata could help prevent anal squamous cell carcinoma.

Introduction: Worldwide incidence of thyroid cancer has increased in recent decades., Objective: To provide evidence of the diagnostic and care efficiency of a monographic thyroid nodule clinic integrating clinical examination, ultrasound examination, and cytology with on site evaluation., Patients and Methods: Patients attending the monographic thyroid nodule clinic from January 2004 to June 2010. Two periods may be distinguished based on availability of ultrasound equipment at the time of the visit: a first period (P1: 01/2004-09/2007) where no ultrasound equipment was available at the clinic and FNA by palpation was performed, and a second period (P2: 10/2007-06/2010) where this equipment was available and ultrasound-guided FNA was performed., Results: A total of 1036 patients [P1: 537 (52%), P2: 499 (48%)] were seen and enrolled. Diagnostic efficiency (P1 vs P2): 143 vs 181 patients were seen annually, p<0.001; FNA number/nodule: 1.68 vs 1.17, p<0.001; percent FNAs with inadequate material: 26% vs 5.3%, p<0.001; mean (SD) nodule size: 23.6 (12.4) vs 21.7 (11.7) mm, p 0.040; proportion of nodules examined less than 10mm in size: 9.9% vs 13.7%, p 0.030. Care efficiency: mean time (range) from the first visit to surgery indication: 332 (0-2177) vs 108 (0-596) days, p<0.001; proportion of patients referred for surgery due to suspect cytology/other reasons: 1.06 vs 2.21, p<0.001; and operated benign neoplasm/pathology: 0.47 vs 0.93, p=0.002., Conclusion: A monographic thyroid nodule clinic integrating clinical examination, ultrasound, and cytology evaluated on site increases diagnostic and care efficiency in patients with thyroid nodules., (Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.)

Aim: The aim of this study was to characterize the natural history of human papillomavirus (HPV) infection at anal canal, penile, and oral sites in HIV-positive men based on their sexual behavior., Methods: This is a single-center, prospective cohort study. The prevalence, clearance, and incidence of HPV infection at anal, penile, and oral sites were studied in HIV-positive men who have sex with men (MSM) and heterosexual individuals using multiplex polymerase chain reaction. Risk factors associated with HPV infection were analyzed., Results: In total, 733 patients (538 MSM, 195 heterosexual) were included in the study between 2005 and 2009. The prevalence, clearance, and incidence of HPV infection were 73%, 30%, and 36% at anal site; 26%, 56%, and 17% at penile site; and 16%, 44%, and 11% at oral site, respectively. At anal site, MSM had a higher HPV prevalence (84% vs. 42%; odds ratio,7.3; 95% confidence interval [CI], 5.2-10.6) mainly for multiple (≥3) HPV types, higher incidence rate (324 vs. 92 new HPV-infected person per 1000 person-years [hazard ratio, 8.1; 95% CI, 3.8-17.3]), and a lower clearance rate (125 vs. 184 cleared HPV-infected person per 1000 person-years [hazard ratio, 0.5; 95% CI, 0.3-0.9]) than did heterosexuals. Similar prevalence, clearance, and incidence rates of penile and oral HPV infection were found between groups. The most common high-risk HPV type for the 3 body sites studied was the HPV-16. Finally, a similar proportion of heterosexuals (7%) and MSM (6%) presented concurrent HPV infections (anal-penile-oral sites). History of anal warts was associated with higher HPV prevalence in the 3 body parts., Conclusions: Although MSM presented the highest risk of anal HPV infection, heterosexual men also showed a remarkable prevalence of anal HPV infection and a comparable risk to MSM for penile and oral HPV infection. Taking into account all these results, the careful inspection of the anal canal, penile, and oral sites should at least be routine in each clinic visit of HIV-infected men independently of their sexual behavior.

Background: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available., Objective: The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions., Study Design: This was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study., Setting: The study was conducted in a phase I clinical unit., Subjects and Methods: A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography., Results: In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [C(max)] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUC(t)] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean C(max) 120.99 ng/mL, CV 15.0%; mean AUC(t) 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed : fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for C(max) and AUC(t) were within the range of 80-125%., Conclusion: High-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.

Background: Genital infections with low-risk (LR) and high-risk (HR) human papillomavirus (HPV) genotypes are associated with ano-genital condylomata and anal squamous cell cancer. HPV-related pathologies in HIV-infected men are a serious concern. In this study, the prevalence of anal condylomata and their association with cytological abnormalities and HPV infection in the anal canal in HIV-infected men [men who have sex with men (MSM) and heterosexuals] were estimated., Methods: This was a cross-sectional study based on the first visits of patients in the Can Ruti HIV-positive Men (CARH·MEN) cohort. Anal condylomata were assessed by clinical and proctological examination. Samples from the anal canal were collected for HPV genotyping and cytological diagnoses., Results: A total of 640 HIV-infected men (473 MSM and 167 heterosexuals) were included in the study. The overall prevalence of anal condylomata was 25% [157 of 640; 95% confidence interval (CI) 21-28%]; in MSM it was 28% and in heterosexuals it was 15% [odds ratio (OR) 2.2; 95% CI 1.4-3.5]. In patients with anal condylomata, HPV infection in the anal canal was more prevalent (92% vs. 67% in those without anal condylomata; OR 8.5; 95% CI 3.2-22). This higher HPV prevalence involved at least two HPV genotypes (OR 4.0; 95% CI 2.2-7.1), mainly HR genotypes (OR 3.3; 95% CI 1.7-6.4). Similarly, the cumulative prevalence of HPV-6 and HPV-11 was higher in patients with anal condylomata (63% vs. 19% in those without anal condylomata). Having anal condylomata was associated with higher prevalences of cytological abnormalities (83% vs. 32% in those without anal condylomata; OR 6.9; 95% CI 3.8-12.7) and high-grade squamous intraepithelial lesions (HSILs) (9% vs. 3% in those without anal condylomata; OR 9.0; 95% CI 2.9-28.4) in the anal canal., Conclusions: HIV-infected men with anal condylomata were at risk of presenting HSILs and harbouring multiple HR HPV infections in the anal canal. Although MSM presented the highest prevalence of anal condylomata, heterosexual men also had a clinically important prevalence. Our findings emphasize the importance of screening and follow-up for condylomata in the anal canal in HIV-infected men., (© 2012 British HIV Association.)

Human papillomavirus genotyping is being considered in cervical screening programs and for monitoring the effectiveness of HPV vaccination. Both approaches require access to fast, easy and high-throughput technology. The aim of this study was to compare a new commercial assay (f-HPV typing™) with the Hybrid Capture II® (HC2) to detect HPV infection. The F-HPV typing is a multiplex fluorescent PCR method recognizing E6 and E7 regions of 13 high-risk (HR) HPV types, the same set of HR-types targeted HC2 test. A subset of 157 cervical samples was tested with both assays. The percentage of positive HR-HPV DNA samples was 24% (37/155) by HC2 and 33% (49/155) by f-HPV typing. Concordant results were found in 133/155 (overall agreement, 85.8%; Cohen's kappa=0.65). The analytical sensitivity and specificity of f-HPV were 97.6 and 93, respectively. In conclusion, this study shows that the f-HPV assay provides a good alternative to HC2 to detect HPV infection, allowing simple and rapid HPV genotyping and detecting multiple infections., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The effectiveness of Tranexamic Acid (TXA, antifibrinolytic drug) in reducing allogeneic blood transfusion requirements has not been tested in revision total knee arthroplasty. The aim of this study was to assess the effectiveness of TXA after two intravenous doses of 1 g each. Between April 2006 and February 2010, 68 consecutive patients (19 male, 49 female) of 74 +/- 6 [m +/- SD] years of age were included and divided into three groups: control (28 patients), in which TXA was not administered but was not contraindicated; TXA (19 patients) who received TXA, and NO-TXA (21 patients), who were not administered TXA because of a contraindication. The proportions of patients transfused were 54%, 32% and 62% respectively in the control, TXA and NO-TXA group; the median numbers of RBC units transfused were respectively 2 [range: 1-4], 2 [range: 2-2] and 2.5 [range: 1-5], (p = 0.057). Mean total estimated blood loss was 1693 mL (SD: 689) in the control group, 1196 mL (SD: 665) in the TXA group and 2454 mL (SD: 2166) in the NO-TXA group, (p = 0.015). No adverse events were reported. TXA administration appeared as an effective and safe means of reducing blood transfusion requirements and blood loss in revision total knee arthroplasty.

Background: Women infected with human immunodeficiency virus (HIV) are at increased risk of developing precancerous and cancerous lesions in cervix because of persistence of oncogenic human papillomavirus (HPV) infection. Scarce information about the HPV genotypes attributed to cervical cancer in the HIV-infected population is available, especially in countries with a low prevalence of this pathology., Objective: The objective of the study was to assess the prevalence and distribution of HPV types, and the viral integration of HPV-16 and HPV-18 in cervical squamous cell carcinoma of HIV-infected and HIV-negative women., Methods: A total of 140 formaldehyde-fixed paraffin-embedded specimens from 31 HIV-infected and 109 matched HIV-negative women, with a diagnosis of in situ or invasive cervical carcinoma, were identified between 1987 and 2010 from different hospitals of the Barcelona area, Spain. Human papillomavirus genotyping and integration were analyzed by standardized polymerase chain reaction., Results: Similar prevalence and distribution of HPV genotypes were detected in cervical cancers (in situ and invasive) regardless of HIV condition. The most common types were as follows: HPV-16 (58% in HIV-positive vs 72% in HIV-negative) and HPV-33 (16% vs 8%). In invasive cervical carcinoma, HPV-18 was significantly more prevalent in HIV-positive women (14% vs 1%; P = 0.014). The proportion of samples with integrated forms of HPV-16 (39% vs 45%) and HPV-18 (50% vs 50%) was similar in both groups., Conclusions: The prevalence and distribution of principal HPV types involved in the carcinogenesis process of the cervix were similar in HIV-infected and noninfected women, although a tendency toward a lower HPV-16 and a higher HPV-18 prevalence in invasive cervical carcinoma was detected in HIV-positive women. Similar percentage of HPV-16 and HPV-18 viral integration was found in formaldehyde-fixed paraffin-embedded specimens of cervical cancer regardless of the HIV infection status.

The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4(+) T cell count <200 cells/mm(3) [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir.

Background: Clinical audits are critical and systematic quality analysis of medical care. Total hip arthroplasty (THA) is a routine practice and cost-effective, although there is little information on the quality of care of it., Objective: To evaluate the impact of a clinical audit cycle in the quality of care in the primary THA procedures for non-traumatic cause., Patients and Methods: A series of two audits (first audit in 2005 and second one in 2007) were performed. Patients of both sexes with non-traumatic primary THA and with a follow-up of 6 months were included. Time (days) in hospital stay and the rate (percentage) of readmissions were used as indicators of management; and as indicators of clinical practice: the index (percentage) of dislocation and the rate (percentage) of infection. Both audits were compared with respect to these indicators., Results: A total of 160 patients (79 and 81, first and second audit respectively) were analysed. Management indicators: median (range) of hospital stay was 8 (7-78) and 7 (6-16), p<0.001, and the percentage of readmissions 5% (4/79) and 0 (0/81), p=0.057. Indicators of clinical practice: the rate of dislocation was 8% (6/79) and 0 (0/81), p=0.013, and the rate of infection 1% (1/79) and 1% (1/81), p=1. A multivariate analysis did not find other factors related to these indicators., Conclusions: The implementation of a clinical audit cycle has improved the quality of care of primary THA procedures for non-traumatic cause., (Copyright © 2010 SECA. Published by Elsevier Espana. All rights reserved.)

Ritonavir-related adverse events have been reported in patients taking tipranavir/ritonavir at the licensed dosage of 500/200 mg twice daily (bid). The aim of this open-label, prospective, single-arm pilot study was to evaluate the efficacy and safety of a ritonavir dose reduction to 100 mg bid guided by the tipranavir virtual inhibitory quotient (vIQ) in HIV-infected patients receiving tipranavir/ritonavir 500/200 mg bid whose viral load was <50 copies/ml and whose tipranavir vIQ was >60. Viral load, blood chemistry, and tipranavir and ritonavir trough concentrations (C(trough)) in plasma were determined at baseline and up to 48 weeks. If the tipranavir vIQ fell to <40, the ritonavir dose was increased to 200 mg bid. The primary endpoint was the percentage of treatment failure after 48 weeks. Eleven patients were enrolled. At baseline, the median (IQR) CD4+ T-cell count and vIQ were 380 (231-520) cells/mm(3) and 233.4 (73.8-584.8), respectively. Ten patients (90.9%) maintained a viral load <50 copies/ml at week 48. Geometric mean (95% confidence interval) tipranavir C(trough) decreased from 24.7 (12.9-47.5) mg/l at baseline to 13.6 (7.1-26.2) mg/l at week 48 (p = 0.194), but the ritonavir dose had to be raised in only one patient. Median triglycerides and ALT concentrations decreased from 177.2 (132.9-292.4) mg/dl and 59 (23-128) IU/l at baseline to 158.0 (131.0-186.0) mg/dl and 28 (20-71) IU/l at week 48 (p = 0.047, p = 0.041), respectively. As a conclusion, ritonavir-dose reduction to 100 mg bid as a treatment-simplification strategy guided by the tipranavir vIQ in patients receiving salvage therapy with tipranavir/ritonavir 500/200 mg bid seems to be safe enough to be tested in adequately powered clinical trials.

Background: Genomic integration of high-risk human papillomavirus into the cellular genome is considered an important event in the pathogenesis of cervical cancer related to the progression from premalignant cervical lesions to invasive cervical carcinoma., Objective: This cross-sectional study was aimed to characterize the viral integration of HPV-16, HPV-18, HPV-52 and HPV-58 in cervical cells., Study Design: HPV genotypes were determined by PCR and HPV integration by multiplex PCR in HIV-1-infected women without a background of HPV-related pathology., Results: This study included 251 cervical cells samples of consecutive HIV-positive women who were visited between 1999 and 2003. The overall prevalence of HPV infection was 53% (133/251, 95%CI: 47-59%). The most prevalent genotypes were HPV-16 (27%), HPV-33 (15%), HPV-52 (8%) and HPV-58 (8%). The prevalence of abnormal cervical cytology was 33% (83/251, 95%CI: 27-39%). The overall prevalence of HPV integration was 11% (27/251, 95%CI: 7-15%), and the prevalence of HPV-16 integration was 33% (22/67, 95%CI: 22-45%), HPV-18 integration was 30% (3/10, 95%CI: 7-65%) and HPV-52 integration was 10% (2/19, 95%CI: 1-32%). No HPV-58 integration was detected. The percentage of HPV-16 and HPV-18 integration increased with the severity of the cervical lesions, HPV-16 integration was almost 70% and HPV-18 integration was 50% in high-grade squamous intraepithelial lesions. Integration was the most important risk factor associated with cervical dysplasia (OR=30.6, 95%CI: 3.5-270.6)., Conclusion: HPV integration might represent a good biomarker of the evolution from HPV infection to cervical cancer. Further prospective studies are required to validate our findings., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Human papillomavirus (HPV) infection is the cause of cervical cancer. Integration of HPV-16 DNA in cervical cells is considered to be a key event in the progression towards invasive cancer, but little is known about this event in anal carcinogenesis. The integration could be a useful biomarker for cancer progression. Optimized assays are needed to determine the value of real-time detection of HPV integration in longitudinal studies, and this approach is only possible with a high-throughput assay. The aim of this study was to develop a new multiplex real-time PCR assay based on simultaneous amplification of the E2 and E6 HPV open reading frames (ORFs) in order to assess the physical status (episomal and/or integrated) of HPV-16 in anal cells of HIV-positive men. The comparative threshold (Ct) cycle values for E2 and E6 obtained for SiHA cells and artificial mixtures of episomal and integrated DNA were as expected: similar Ct for episomal forms and absence of E2 amplification for integrated forms. The multiplex real-time PCR was tested in 77 consecutive samples from individual HIV-infected patients with HPV-16 anal infection. The integration of HPV-16 was detected in 25 (32%) patients: 23 as mixed (episomal and integrated) and two as completed integrated forms. The integration occurs in the early stage of anal lesions and was associated with the severity of the lesions (p 0.004). The multiplex real-time PCR assay developed in the course of this study was shown to be a simple, sensitive, specific and inexpensive technique which may be applied routinely to detect HPV-16 integration.

Background: The integration of HPV-16 DNA into the host genome is considered an important event in the progression of premalignant cervical lesions to cervical cancer. The aim of our study was to assess the prevalence of HPV-16 integration in anal cytologic specimens of HIV-1 infected men and its association with risk factors. PATIENTS METHODS: This cross-sectional study included 269 HIV-infected males. Detection and typing of HPV-infection was done by multiplex PCR, and integration of HPV-16 by real-time PCR., Results: The overall anal HPV-infection prevalence was 78% (209/269), 29% (77/269) for HPV-16 infection, and 9% (25/269) for HPV-16 integration. In HPV-16 infected group, the integration prevalence represented 32% (25/77). The only risk factor associated with HPV-16 integration was the time since HIV diagnosis (OR = 1.2, 95% CI: 1.0-1.3; P = 0.010). The risk factors associated with abnormal cytology results were: HPV infection (OR = 17.8, 95% CI: 6.8-46.6), HPV-16 infection (OR = 4.6, 95% CI: 2.5-8.4), and presence of HPV-16 integrated forms (OR = 11.7, 95% CI: 1.5-93.5). Moreover, in the multivariate analysis, the HPV-16 integration continued representing the most important risk factor (OR = 20, 95% CI: 1.6-226) for anal cytologic abnormalities., Conclusion: HPV-16 infection and its integration in anal cells were highly prevalent in HIV-infected men. The assessment of HPV-16 integration rather than HPV-infection could be a good biomarker for predicting anal precancerous lesions in HIV-positive men.

Background: Pelvic floor damage is a major clinical problem usually attributed to obstetric injury. We speculated that constipation may also be an aetiological and preventable factor resulting from repeated stress on the perineum over many years, and this study aimed to test this hypothesis., Methods: A total of 600 women attending a gynaecological clinic were assessed using a structured questionnaire gathering data on pelvic floor damage, constipation and obstetric trauma. Complete data were available on 596 subjects., Key Results: The prevalence of pelvic floor damage was 10% (61/596). In this group, constipation was identified in 31% (19/61) of women and obstetric trauma in 31% (19/61). In the group without pelvic floor damage, constipation was present in 16% (86/535) and obstetric trauma in 16% (83/535). In univariate analysis, pelvic floor damage was associated with age (OR: 1.05; 95% CI: 1.03-1.08; P < 0.0001), constipation (OR: 2.36; 95% CI: 1.31-4.26; P < 0.0001) and obstetric trauma (OR: 2.46; 95% CI: 1.37-4.45; P < 0.0028). In multivariate analysis, the OR for age was 1.05 (95% CI: 1.03-1.08; P < 0.0001), for constipation 2.35 (95% CI: 1.27-4.34; P < 0.0001) and for obstetric trauma 1.37 (95% CI: 0.72-2.62; P = 0.3398)., Conclusions & Inferences: Constipation appears to be as important as obstetric trauma in the development of pelvic floor damage. Thus, a more proactive approach to recognizing and treating constipation might significantly reduce the prevalence of this distressing problem.

Background: We explored a treatment simplification strategy to darunavir/ritonavir 900/100 mg once daily guided by the darunavir virtual inhibitory quotient (vIQ) in patients receiving salvage therapy with darunavir/ritonavir 600/100 mg twice daily., Methods: Open-label, randomized pilot study in HIV-infected patients on darunavir/ritonavir 600/100 mg twice daily (viral load <50 copies/ml; darunavir vIQ >2). Thirty patients were randomized to darunavir/ritonavir 900/100 mg once daily (once-daily group, n=15) or 600/100 mg twice daily (twice-daily group, n=15). Viral load, blood chemistry, and darunavir and ritonavir trough plasma concentrations (C(trough)) were determined up to 48 weeks. If the darunavir vIQ fell to <1.5, the dosage was switched to 600/100 mg twice daily. The primary end point was the percentage of 48-week treatment failure., Results: Patients had taken a mean 11.6 (sd +/-3.9) antiretroviral regimens before darunavir/ritonavir administration. The proportion of patients without 48-week treatment failure was 86.7% in both groups. The median (interquartile range [IQR]) darunavir C(trough) decreased from 3.09 mg/l (IQR 2.43-3.93) at baseline to 1.60 mg/l (IQR 1.25-2.04) at week 48 (P=0.001) in the once-daily group. Three once-daily group patients switched to darunavir/ritonavir 600/100 mg twice daily. Fewer patients had triglyceride levels >200 mg/dl at week 48 in the once-daily group (20.0%) than in the twice-daily group (20.0% versus 57.1%; P=0.046)., Conclusions: Treatment simplification to darunavir/-ritonavir 900/100 mg once daily guided by the darunavir vIQ in treatment-experienced HIV-infected patients receiving darunavir/ritonavir 600/100 mg twice-daily seems to be safe enough to be tested in adequately powered clinical trials.

Background and Aims: Recurrent bleeding from gastrointestinal (GI) angiodysplasia remains a therapeutic challenge. Identification of factors predicting poor outcome of haemorrhage from angiodysplasia would help us to select the patients who may likely benefit from further therapy. Thus, we analysed risk factors for recurrence of acute GI haemorrhage from angiodysplasia., Patients and Methods: 62 patients admitted consecutively with acute GI bleeding from angiodysplasia, between June 2002 and June 2006, were included. Bivariate, multivariate and survival analysis were performed to identify risk factors for recurrence of bleeding after hospital discharge., Results: Recurrence of acute haemorrhage after hospital discharge occurred in 17 of 57 (30%) patients (38 men; mean age: 74+/-6 years), after a mean follow-up (33+/-40 months). On Cox analysis, earlier history of bleeding with a high bleeding rate, over anticoagulation and the presence of multiple lesions were predictive factors of recurrence in a multivariate analysis. In contrast, endoscopic argon plasma coagulation (APC) therapy was not associated with lower rates of recurrent bleeding., Conclusion: In patients with acute GI haemorrhage from angiodysplasia, earlier bleeding with a high bleeding rate, over anticoagulation and multiple angiodisplasic lesions predict an increased risk of recurrent bleeding. Although there is a trend towards better management with endoscopic APC therapy for the prevention of recurrence of bleeding, endoscopic APC therapy is not predictive of a lower rate of recurrence.

The spectrum of complications emerging in successfully treated HIV-infected patients has dramatically changed since the advent of HAART. Typical AIDS-defining illnesses have been substituted by new comorbid conditions that threaten even those patients who maintain virologic suppression. Proper management of cardiovascular risk, and early diagnosis of AIDS-related and, particularly, non-AIDS-related malignancies (including papilomavirus-related neoplasms) must be introduced into the routine of care. Hot areas of investigation include HIV-associated neurocognitive disorders, hepatitis B and C coinfection, non-alcoholic fatty liver disease, progressive multifocal leukoencephalopathy and tuberculosis. Bone and kidney long-term toxicities and lipoatrophy remain as issues of paramount importance. The identification and early treatment of immune reconstitution disease is also of major interest, specially in those patients starting their antiretroviral treatment with severe CD4 cell depletion. The present review focuses on these twelve areas of increasing interest for physicians currently facing successfully treated HIV+ patients.

Aim: To study the epidemiology of different human papillomavirus (HPV) genotypes in cervical samples of HIV-1-infected women with normal Papanicolau smears., Design: : Retrospective analysis of a prospective cohort., Patients and Methods: We selected HIV-1-infected women with 2 consecutive normal Papanicolau smears at baseline and at least 1 baseline and 1 follow-up cervical sample. HPV infection was assessed by second-generation hybrid capture (HC-2) and multiplex polymerase chain reaction (mPCR). HPV genotypes were determined by mPCR., Results: From a cohort of 139 women followed up to 4 years, 93 women meeting the inclusion criteria were analyzed. The mean period between samples was 20 months (range, 6-44 months). HPV baseline prevalence was 63% [59/93; 95% confidence interval (CI), 53% to 73%] using polymerase chain reaction and 41% (38/93; 95% CI, 31% to 51%) using HC-2, P = 0.007 (kappa, 0.45; P = 0.001). The most prevalent high oncogenic risk genotypes (HR-HPV) were HPV-16 (28%), HPV-33 (18%), HPV-52 (12%), HPV-58 (11%), and HPV-39 (11%). Infection with multiple HPV genotypes was detected in >40% of women. HPV infection persisted at follow-up in 86% (51/59; 95% CI, 77% to 95%) by polymerase chain reaction and 76% (29/38; 95% CI, 62% to 90%) by HC-2. HPV infection persisted in 55% of women with samples available beyond 3 years. The actuarial probabilities of clearance and incidence of HPV infection at 36 months were 16% and 45%, respectively., Conclusions: HPV infection is highly prevalent and persistent among HIV-1-infected women with normal Papanicolau smears. HR-HPV genotypes other than HPV-16 (HPV-33, HPV-52) are frequently detected in HIV-infected women. mPCR provides better surveillance of HPV infection than HC-2 methods.

Background: We determined whether coformulated zidovudine/lamivudine/abacavir plus tenofovir could maintain immune status in comparison with a genotype-guided salvage regimen in highly pretreated patients., Method: This was a randomized pilot control-arm study. The primary endpoint was the proportion of patients who maintained their CD4+ T-cell count at Week 48., Results: Thirteen patients were randomized to the study arm and 10 to the control arm. At 48 weeks, 8 (64%) patients in the study arm and 10 (100%) in the control arm maintained their immune status (p = .09). No new AIDS-defining events occurred. Three patients (27%) in the study arm and 5 (50%) in the control arm achieved an undetectable viral load (p = .39). When a fully suppressive regimen was initiated, 69% of patients in the study arm (9 patients) and 60% (6 patients) in the control arm reached <50 copies at 96 weeks (p = .98)., Conclusion: Although no statistically significant differences in immunological course were observed between the arms, the control group achieved better results after 48 weeks. This transient therapy could be reserved for specific patients in whom the risk of incomplete adherence or toxicity compromises efficacy while they are awaiting a fully active drug, without jeopardizing viral efficacy when a fully suppressive regimen is initiated.

Calcium dobesilate has shown to improve endothelial function. This proof-of-concept clinical trial was done to check whether it may improve erectile dysfunction in diabetic men. Male diabetic patients with a diagnosis of erectile dysfunction were randomized to receive either calcium dobesilate 1 g twice per day or placebo for 6 weeks. The International Index of Erectile Function (IIEF) was chosen as the primary efficacy measurement. Statistical procedures included a pre-scheduled adaptive interim analysis to recalculate sample size. Relevant, but not significant differences in the mean change from baseline in the primary end-point (IIEF questions 3, 4 and 7) favouring dobesilate with respect to placebo were observed. Such differences reached statistical significance in some secondary end-points, including IIEF global as well as the erectile function and intercourse satisfaction domains' scores. Some patients experienced an important placebo effect. Results suggest that dobesilate may be of help to treat diabetic erectile dysfunction. Co-administration with phosphodiesterase inhibitors warrants further investigation.

Objectives: To provide evidence for the long-term effect of highly active antiretroviral therapy (HAART) on the incidence of cervical squamous intraepithelial lesions (SILs) among HIV-positive women with normal cytology test and CD4 count above 350 cells/mm(3)., Patients and Methods: A retrospective cohort study was carried out in HIV-positive women with two consecutive normal cervical cytological tests (Papanicolaou test) and at least one subsequent test, without previous cervical history of SIL or cancer diagnosis, and with an immunological status >350 CD4 cells/mm(3). The patients were divided into two groups: treated with HAART (HAART group) or not treated with HAART (NO-HAART group), during the period of time between cytology tests included in the survival analysis and time until SIL., Results: Between January 1997 and December 2006, 127 women were included: 90 in the HAART group and 37 in the NO-HAART group. Both groups of patients were similar with respect to demographic data, except for HIV viral load and previous HAART inclusion (P < 0.001). SIL was diagnosed in 27 of 90 (30%) patients in the HAART group and in 7 of 37 (19%) patients in the NO-HAART group (OR = 1.84, 95% CI: 0.72-4.69, P = 0.202). The actuarial probability of remaining free of SIL at 3 years was 70% in the HAART group and 78% in the NO-HAART group. No variable was associated with an increased risk of developing SILs., Conclusions: These results suggest that when the patients' immunological status is above 350 CD4 cells/mm(3), the HIV-infected women treated with HAART present a similar cervical SIL incidence to women not on HAART.

Background: Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)-HIV-coinfected patients., Methods: A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients (n = 104) were compared. All patients received PEG-IFN-alpha2a 180 microg/week plus ribavirin 800-1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000-1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12., Results: The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV-HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR., Conclusions: Differences in efficacy of PEG-IFN-alpha2a plus ribavirin treatment between HCV-HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.

Our case illustrates the first report of an HIV-infected patient with a nasopharyngeal squamous cell carcinoma with viremia by one Epstein-Barr virus (EBV) and seropositivity by two high risk oncogenic human papilloma viruses (HPV)-types (HPV-16 and HPV-33), previous to his death. This patient presented a fatal fast-evolution.

Objectives: The efficacy and safety of lopinavir/ritonavir monotherapy has been explored with promising results in well-controlled, randomized clinical trials. However, less information about its clinical usefulness in routine clinical practice is currently available. The objective of this study was to assess the effectiveness and safety of monotherapy with lopinavir/ritonavir as a treatment simplification strategy in HIV-infected patients with viral suppression outside a clinical trial setting., Methods: Fifty-one subjects who were switched to lopinavir/ritonavir monotherapy and whose HIV-1 RNA was <50 copies/mL were included in this retrospective study. Data were obtained from a prospectively compiled database. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the incidence of adverse events and changes in CD4+ T cell count and in lipid profile., Results: Two patients lost viral suppression, seven patients interrupted lopinavir/ritonavir monotherapy because of adverse events and four patients were lost before completing 48 weeks of follow-up. Thus, 38/40 (95.0%) patients maintained viral suppression when only subjects whose outcomes were available up to week 48 were considered and 38/51 (74.5%) patients maintained viral suppression when subjects who discontinued therapy or who were lost to follow-up were considered as treatment failures. The mean CD4+ T cell count significantly increased, from 541 (280) cells/mm3 at baseline to 609 (212) cells/mm3 at week 48 of follow-up (P=0.034). This increase was similar to that observed in the 48 weeks prior to lopinavir/ritonavir monotherapy (P=0.792). Although total cholesterol remained unchanged, there was a significant decrease in triglyceride levels during follow-up (P=0.029)., Conclusions: Monotherapy with lopinavir/ritonavir is safe and effective as a treatment simplification approach in HIV-1-infected patients with sustained viral suppression in routine clinical practice, particularly in those patients already receiving a lopinavir/ritonavir-based antiretroviral regimen.

The influence of HAART on the evolution to cervical squamous intraepithelial lesions (SIL) among HIV(+) women with a normal cytological test in the HAART era was studied. A retrospective cohort study (1997-2005) of HIV-infected women treated with HAART was conducted. Those with a normal cervical cytology (Papanicolaou test) and at least one subsequent test were included. Survival (time until diagnosis of SIL), univariate, and multivariate analyses were performed. A total of 133 HIV-infected patients treated with HAART were included. The incidence of SIL was 35% (47 patients). SIL was diagnosed in 36 of 110 (33%) patients with a baseline and final immunological status of >200 CD4 cells/microl and in 6 of 9 (67%) patients with a baseline and final immunological status of < or =200 CD4 (OR: 0.24, 95% CI: 0.06-1.03, p = 0.041). SIL was diagnosed in 10 of 60 (17%) patients with an undetectable baseline and final HIV viral load and in 36 of 70 (51%) patients with a detectable HIV viral load (OR: 0.19, 95% CI: 0.07-0.46, p < 0.001). A high incidence of SIL (cancer precursor lesions) was observed among HIV(+) women without a background of cervical pathology. The effect of HAART on the control of HIV replication and of immunological status (>200 CD4) through the follow-up was associated with a reduction of SIL.

Objective: Polyethylene glycol (PEG) has been suggested to protect against pathogen colonization by improving colonic barrier function. We aimed to establish whether PEG 4000 affects colonic barrier function and the development of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats., Materials and Methods: PEG was included in the drinking water for a period of 48 h before intracolonic administration of TNBS., Results and Discussion: PEG increased colonic surface hydrophobicity and diminished luminal bacterial load. Moreover, PEG markedly reduced mucosal damage and inflammation induced by TNBS. This protection effect appeared to be independent of its laxative properties since the laxatives mannitol or senna extracts had no effect on TNBS colitis. Using everted colonic sacs, pretreatment with PEG produced a lasting reduction in epithelial permeability to mannitol and dextran-70 K that correlated with decreased surface hydrophobicity., Conclusion: Our results suggest that the protective effect of PEG on TNBS colitis is associated with reinforcement of the epithelial barrier.

Background and Aims: Capsule endoscopy (CE) is superior to push enteroscopy and small bowel barium radiography in detecting the source of obscure GI bleeding. We now compared whether CE has a superior diagnostic yield than CT angiography (CTA) or standard mesenteric angiography (ANGIO) in patients with obscure GI bleeding., Methods: From June 2004 to October 2005, consecutive patients admitted for OGIB underwent both CTA and ANGIO, followed by CE, performed blindly by independent examiners within the next 7 days. The primary end point of the study was the diagnostic yield for each technique, defined as the frequency of detection of lesions with a high probability of bleeding., Results: Twenty-eight patients (16 men and 12 women, mean age 74 +/- 2 yr) with OGIB (overt bleeding in 20 cases and chronic occult in 8) were prospectively evaluated. CTA or standard angiography could be performed in 25 of 28 patients (applicability 86%), because of contrast allergy (1 patient) and chronic renal failure (2 patients). A source of bleeding was detected by CE in a greater proportion of patients, 72% (18 of 25, 95% CI 50.6-87.9%), than CTA, 24% (6 of 25, 95% CI 9.4-45.1%, P= 0.005 vs CE), or ANGIO, 56% (14 of 25, 95% CI 34.9-75.6%, P= NS). Similarly, CE was able to diagnose 100% of patients diagnosed by CTA and 86% of patients diagnosed by ANGIO. Moreover, CE was positive in 12 of 19 (63%) negative cases on CTA and in 6 of 11 (55%) negative cases on ANGIO. As a result of the CE findings, therapeutic intervention was undertaken in 9 of 19 (47%) patients with positive results., Conclusion: CE detects more lesions than CTA or standard mesenteric angiography in patients with obscure GI bleeding and has a therapeutic impact in almost half of the patients with positive findings.

Objectives: Preliminary studies suggested that octreotide may be therapeutic in bleeding angiodysplasia. Our aim was to investigate the efficacy of long-term octreotide therapy in the prevention of rebleeding from gastrointestinal angiodysplasia., Methods: A cohort of 32 patients diagnosed with bleeding from angiodysplasia was treated with octreotide 50 mu 12 h subcutaneously for a 1-2 yr period. This cohort was compared with an external control group (38 patients who had received placebo [1 tablet/day] in a concurrent randomized clinical trial for the same period., Results: Two patients of the octreotide group were lost to follow-up. Treatment failure occurred in seven of 30 (23%) patients in the octreotide group and in 17 of 35 (48%) in the placebo group (three dropouts before first visit) (P= 0.043). The actuarial probability of remaining free of rebleeding at 1 and 2 yr of follow-up was 77% and 68%, respectively, for the octreotide group and 55% and 36%, respectively, for the placebo group (log rank P= 0.030). Multivariate proportional hazards-regression analysis showed that octreotide therapy and previous bleeding episodes were positive and negative predictors of efficacy, respectively. No significant differences between the groups were observed according to number of bleeding episodes (0.4 +/- 0.7 vs 0.9 +/- 1.5, P= 0.070) and transfusion requirements (1.1 +/- 2.6 vs 0.7 +/- 1.5 units); however, iron requirements were lower in the octreotide than in the placebo group (22 +/- 62 vs 166 +/- 267 units; P < 0.001). Likewise, major adverse events (1 vs 1) and mortality (0 vs 1) were similar between groups., Conclusions: This study suggests that octreotide treatment may be beneficial in preventing rebleeding from gastrointestinal angiodysplasia.

Nitric oxide (NO) is implicated in the pathophysiology of intestinal inflammation. Intestinal mast cells may amplify inflammatory response and mucosal injury in inflammatory bowel disease. Our aim was to examine the role of NO and intestinal mast cells by investigating the effects of NO synthase (NOS) inhibitors and a mast cell stabilizer during induction of dextran sulfate sodium (DSS) colitis. Colitis was induced by 4% DSS in drinking water, in rats pretreated with L-NAME or aminoguanidine. In another set of experiments, we investigated the effect of ketotifen in this setting. Inhibition of NO by L-NAME worsened DSS-induced inflammation, however, aminoguanidine had no effect. On the other hand, ketotifen abolished the deleterious effects of L-NAME on colonic inflammation, suggesting that hyperactivation of mast cells by NOS inhibition amplifies mucosal injury induced by DSS. Our results suggest that constitutive isoforms of NOS prevent mast cell activation.