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BackgroundAtrial cardiomyopathy (AtCM) is emerging as an independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are histological hallmarks of atCM. However, the contribution of various etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been robustly quantified. We aimed to evaluate the association between histological features of atCM and the clinical phenotype.MethodsWe examined left (LA, n=95) and right (RA, n=76) atrial appendages sampled from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed using the JavaCyte algorithm, following staining with agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex and age to histological characteristics were determined in a multivariate model. K-means clustering of 6 histological features was performed to identify different types of atCM.ResultsIn both LA and RA, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41µm,p=0.01; RA:+0.89±0.43µm,p=0.032), whereas total extracellular matrix (ECM) content was unchanged in AF. Men had larger cardiomyocytes (LA:+1.87±0.72μm,p=0.012), while women had a higher degree of endomysial fibrosis (LA:+0.99±0.51µm,p=0.048). Heart failure patients showed more endomysial fibrosis (LA:+1.79±0.41µm,pConclusionsAtCM phenotypes vary with patient characteristics. Fibrotic atCM is associated with female sex, persistent AF and heart failure, while hypertrophic features are more common in men.

Introduction Compelling evidence supports that regular moderate exercise has a positive impact on cardiovascular disease (CVD) incidence and prognosis [1]. Nevertheless, emerging clinician and experimental data in healthy individuals suggests that long-term, high-intensity endurance exercise might increase vascular stiffness and enhance coronary calcification [2,3]. In patients with CV risk factors, it has been hypothesized that the beneficial effects of strenuous exercise on risk factors could outweigh its deleterious effects, but this remains unproven [4]. Purpose To analyze how increasing doses of exercise impinge on the vascular system in a murine model of aged rats with metabolic syndrome and kidney disease. Methods Seven-week-old male Zucker obese rats, a metabolic syndrome model, were subjected to left nephrectomy. At 26 weeks of age, rats were assigned to a sedentary (SED), moderate intensity (MOD, 15 cm/s, 40 min/day), or high intensity (INT, 25 cm/s, 60 min/day) group, and trained 5 days/week for 10 weeks. An echocardiogram and a glucose tolerance test were performed 24 hours after the last training bout. At sacrifice, vascular reactivity was assayed in the descending thoracic aorta, and EC50 calculated for every experiment. Expression of oxidant and antioxidant mRNA markers was analyzed in thoracic perivascular adipose tissue (tPVAT). Cytokines levels (TNFα, IL10, IL6, Selectin, ICAM1 and Adiponectin) were analyzed in plasma samples. Results Rats in the INT group had a significantly lower body weight (10.99±0.35 g/mm vs 12.23±0.58 g/mm) and a higher heart weight (32.44±0.72 mg/mm vs 31.28±0.78 mg/mm), indexed by tibia length, than the SED group. Both MOD and INT exercise improved glucose tolerance compared with SED (Fig 1a). On echocardiography, INT rats presented with LV septum hypertrophy and dilation, mildly reduced ejection fraction and fractional shortening compared with SED. Aortic diameter was also increased in the INT group (3.62±0.11 mm vs 3.25±0.13 mm). In vascular reactivity assays, the MOD group showed improved endothelial function, indicated by a larger carbachol-induced relaxation than SED and INT (Fig. 1b). However, MOD and INT were no longer different after adding the antioxidant Tempol (Fig1c). No differences were found in tunica media fibrosis amongst the groups (19.12±0.45%; 26.97±2.52%; 25.98±2.14%). In tPVAT, the mRNA expression of prooxidants (NOX2, p47) was higher, and antioxidant markers (SOD2, GCH1) was lower in the INT group than MOD and SED (Fig. 2). TNFα levels were higher in plasma of INT rats than SED. Conclusion In a rodent model, both intense and moderate exercise improved the CV risk profile, but only moderate training improved vascular function. Oxidative stress may, at least partially, account for the lack of benefits of intensive exercise. Our results suggest that the deleterious effects of strenuous physical activity could persist even in individuals with CV risk factor. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciόn Sanitaria (FIS), Instituto de Salud Carlos III

Funding Acknowledgements SEC-Bayer research project 2018, Spanish Society of Cardiology. Research project 2018, FIS, Insituto de Salud Carlos III. OnBehalf none Pulmonary vein (PV) isolation (PVI) by point-by-point radiofrequency application (PPRF) results in longer procedures than cryoablation. In addition, it is associated with more oesophageal lesions. The aim of this study was to evaluate the feasibility, safety and 1-year efficacy of PVI by high power short duration (HPSD) PPRF in patients with atrial fibrillation (AF). METHODS PPRF around the PV was performed in 125 patients (P) distributed in two groups. Conventional PPRF with 30W/≤30 s under luminal oesophageal temperature monitoring was performed in the first 47 P (Group 1). 68 P were enrolled in the HPSD (Group 2). Power was set to 50 W and delivered to reach a predefined lesion index value (LSI≥5 or AI≥350) in the first 18 P (Group 2A). 30 P underwent PPRF with 60 W for 7-10 s (Group 2B) and the last 30 P underwent PPRF with 70W for 9 s (Group 2C). Oesophageal endoscopy was performed after ablation in all P. RESULTS 17 (36%) P in Group 1 and 30 (38%) in Group 2 had persistent AF. PVI of all targeted veins was achieved in 96% and 100% of P in both groups (p = 0,6). Total RF time was 30 [27-42], 25[ 20-29], 16 [14-20] and 13 [11-16] in Groups 1, 2A, 2B and 2C respectively (p 30 s) was 59% in Group 1, 88% in group 2A, 77% in group 2B and 87% in group 2C (p = 0.019). CONCLUSIONS PVI by HPSD PPRF is feasible and results in high 1-year efficacy in P with AF. This approach appears safe and associated with low incidence of oesophageal damage especially when short application time and 60 or 70W are used. However, this latter power setting is associated with slightly better 1-year efficacy than HPSD PPRF using 60W. Abstract Figure. Recurrences of atrial arrhythmias (>30 s

Background Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. Trial registration European Clinical Trials Database: EudraCT 2018–001476-37. ClinicalTrials.gov, ID: NCT04233996.

Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

Many cardiac pathologies involve changes in tissue structure. Conventional analysis of structural features is extremely time-consuming and subject to observer bias. The possibility to determine spatial interrelations between these features is often not fully exploited. We developed a staining protocol and an ImageJ-based tool (JavaCyte) for automated histological analysis of cardiac structure, including quantification of cardiomyocyte size, overall and endomysial fibrosis, spatial patterns of endomysial fibrosis, fibroblast density, capillary density and capillary size. This automated analysis was compared to manual quantification in several well-characterized goat models of atrial fibrillation (AF). In addition, we tested inter-observer variability in atrial biopsies from the CATCH-ME consortium atrial tissue bank, with patients stratified by their cardiovascular risk profile for structural remodeling. We were able to reproduce previous manually derived histological findings in goat models for AF and AV block (AVB) using JavaCyte. Furthermore, strong correlation was found between manual and automated observations for myocyte count (r = 0.94, p p p p p

Introduction re-entry mechanisms around mitral and tricuspid annuli are frequent causes of left and right atrial flutter (AFt) respectively in patients with ipsilateral atrial pathology. However, clinical and electrophysiological characteristics of other types of atrial re-entries that could involve both AV annuli are less known. Purpose characterize biannular atrial flutters. Methods 4 patients with AFt were submitted for ablation (aged 30, 31, 58 and 61 yo; 2 females). All had a cardiac congenital disease with a prior surgical procedure: 3 atrial septal defects (ASD) with surgical repair and 1 with transposition of the great arteries (TGA) with Senning repair. The AFt had a cycle length (CL) of 290, 315, 330 y 340 ms respectively and 1:1 AV conduction in 3 of them. For the electrophysiological study, a multipolar catheter (20 or 24 poles) was placed in the right atrium (RA) in every patient, showing counterclockwise and clockwise activation in 1 and 3 patients, respectively. Coronary sinus (CS) activation was proximal to distal in one patient and distal to proximal in the other 2. No CS activation could be obtained in the patient with Senning repair. Results each AFt was mapped by entrainment from different sites of the RA, showing post-pacing intervals (PPI) similar to the CL of the AFt around the tricuspid annulus in all of them and also from proximal and distal CS in the 3 patients with ASD. Access to the native left atrium (LA) was achieved in the patient with Senning repair, showing PPIs around the mitral annulus that were similar to the LC of the tachycardia. In 2 patients the attempt to get to the LA through the interatrial septum (IAS) could not be achieved and was unattempted in the other one. Recordings and PPIs of the LA roof were obtained from the right branch of the pulmonary artery in 2 patients. Counterclockwise AFt and clockwise AFt by single biannular perimitrotricuspid rotation in 1 and 3 patients respectively. The AFt was ended and no reinduction was possible after radiofrequency application that achieved cavotricuspid isthmus block in all of the patients. Conclusions reentry around both AV annuli is possible as a single loop, counterclockwise or clockwise, of simultaneous rotation as a clinical mechanism of Aft. This type of AFt seems to be associated to absence or severe damage in the IAS.

Aims Pulmonary vein (PV) isolation (PVI) by point-by-point radiofrequency application (PPRF) results in longer procedures than cryoballoon ablation. In addition, it is associated with more esophageal lesions. The aim of this study was to evaluate the feasibility and safety of PVI by high power short duration (HPSD) PPRF in patients with atrial fibrillation. Methods PPRF around the PVs was done in 125 consecutive patients distributed in two chronologically successive groups. Conventional PPRF with 30W for ≤30 s under luminal esophageal temperature monitoring was performed in the first 47 patients (Group 1). 68 patients were enrolled in the HPSD (Group 2). Power was set to 50 W and delivered to reach a predefined lesion index value (LSI ≥5 or Abl-I ≥350) in the first 18 patients (Group 2A). 30 patients underwent PPRF with 60W for 7–10 s (Group 2B) and the last 30 patients underwent PPRF with 70W for 9 s (Group 2C). Esophageal endoscopy was performed after ablation in all patients. Results PVI of all targeted veins was achieved in 96% and 100% of patients of groups 1 and 2 respectively (p=0.6). Total RF time was 30 [27–43], 25 [20–29], 16 [14–20] and 14 [11–16] min in groups 1, 2A and 2B and 2C respectively (p First-pass PVI was achieved in 56%, 57% and 85% of left PV (p=0.038) and in 56%, 60% and 82% of right PV (p=0.13) in groups 50W, 60W and 70W respectively. The carina was the most frequent location of persistent conduction when first-pass failed. Reconnections occurred in 6%, 3% and 11% of left PV (p=0.6) and in 6%, 7% and 4% (p=0.63) of right PV in groups 50W, 60W and 70W respectively. Adenosine test was systematically used in groups 60W and 70W: the incidence of dormant conduction was 23% and 22% (p=0.9) in left PV and 20% and 22% (p=0.8) in right PV respectively. The incidence of esophageal lesions was 28% in Group 1, 2% in Group 2A, and 0% in groups 2B and 2C (p Total RF time Conclusions PVI is feasible with HPSD PPRF in most patients using shorter total RF times. This approach appears associated with very low incidence esophageal damage than the conventional one, especially when 60W/70W and shorter application time are used. Acknowledgement/Funding Grant of the Spanish Society of Cardiology

Summary Background Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. Methods This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered ( NCT01254630 and EudraCT 2010-023156-89). Findings Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI −1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI −17·8 to 41·3). Interpretation The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Funding Merck & Co, Inc.

Table S1. Frequency and type of CDKN2A/ARF/CDKN2B gene deletions as detected by qPCR in adult T-ALL (n = 64). Table S2. Comparison between the CNA status of the CDKN2A/ARF and CDKN2B genes in adult T-ALL as assessed by qPCR, SNP-array and iFISH techniques. Table S3. Adult T-ALL: prognostic factors for overall survival. Table S4. Adult T-ALL patient characteristics at diagnosis and follow-up. Table S5. (A) RCN values obtained for the CDKN2A/ARF and CDKN2B genes in selected samples with a 100% blast cell content. (B). Most robust cut-off values to distinguish between normal, heterozygous and homozygous genotypes. The mean and standard deviation (SD) of the values obtained in panel A are indicated for each genotype. Figure S1. Prognostic impact of the CDKN2B gene CNA status on overall survival of adult T-ALL patients (n = 62). In panel A all CDKN2B gene deletions were analyzed together, while in panel B bi-allelic and mono-allelic CDKN2B gene deletions were separately considered. Figure S2. Flowchart summarizing the HR-20011 PETHEMA treatment protocol, including the time points at which MRD assessment was performed (highlighted in red). Figure S3. Calibration curves used to calculate RCN values according to the different percentage contamination of the sample by normal (i.e. non-blastic) cells. In panel A, a pure (100% blasts) homozygous sample was mixed with different amounts of normal (2 N) DNA, as shown on the x-axis. RCN values are shown on the y-axis. In panel B a pure (100%) heterozygous sample was mixed with different amounts of normal (2 N) DNA, as shown on the x-axis; RCN values are depicted on the y-axis. (PDF 274 kb)

Plastic scintillation microspheres (PSm) represent one of the most promising options for monitoring alpha and beta radioactivity in river water. For that reason, a study of the stability of PSm packed into a cell against the continuous flow of river water with different degrees of turbidity was performed over a period of 100 h. The results showed that the volume of the cell became stable after 15 h of pumping and continued to be stable throughout the 100 h of the experiment. During this period of time, the detection efficiency of the PSm, in terms of efficiency*volume, presented mean values of 0.75(3)% for 3H and 272(11)% for 90Sr/90Y. No dependence on flow time or river water type was observed. The background was also constant for 100 h and for the different water types, although 222Rn should be removed from the water beforehand to prevent its accumulation in the PSm. Since PSm did not present any degradation throughout the whole experiment, PSm can undoubtedly be used for monitoring radioactivity with low reagent consumption, low waste generation and low maintenance costs.

Fecal colonization by extended-spectrum-β-lactamase-producing Escherichia coli in 912 stool samples collected from 154 neutropenic patients with cancer, hospitalized at two teaching institutions, was prospectively studied. Forty-nine (31.8%) patients were colonized, 22 of them at hospital admission. Most strains were clonally unrelated and carried a CTX-M-9 group enzyme.

La enfermedad de Behcet es una enfermedad rara en nuestro medio. Se trata de una vasculitis sistemica que cursa con afectacion mucocutanea (parte principal del diagnostico), ocular, digestiva y musculoesqueletica principalmente. Se describe un caso de presentacion atipica que comienza con afectacion digestiva.

The purpose of this study was to assess the risk factors for, and the clinical relevance of, faecal carriage by extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC) in neutropenic cancer patients (NCP). An observational prospective multicentre cohort study was conducted over 2 years at two teaching hospitals. Patients with acute leukaemia or undergoing stem cell transplantation were included during neutropenia episodes. Rectal swabs were obtained at hospital admission and weekly thereafter until discharge or death. ESBL-EC colonized episodes were compared with non-colonized episodes. ESBL-EC strains were studied by PCR and isoelectric focusing, and molecular typing was performed by pulsed field gel electrophoresis (PFGE). Among 217 episodes of neutropenia, the prevalence of ESBL-EC faecal carriage was 29% (14% at hospital admission). Multivariate analysis identified previous antibiotics as the only independent risk factor for ESBL-EC faecal colonization (OR 5.38; 95% CI 2.79-10.39). Analysis of ESBL-EC isolates revealed a polyclonal distribution with CTX-M predominance (81.3%). E. coli bacteraemia was mainly caused by non-ESBL producing strains and its rate was similar in both groups (13% vs. 11%). We found no association between ESBL-EC carriage and an increased risk of ESBL-EC bacteremia or a negative influence on other clinical outcomes, including length of hospitalisation, early and overall mortality rates. ESBL-EC faecal colonization is frequent in NCP but difficult to identify by epidemiological or clinical features on presentation. Prior antibiotic therapy is the major associated risk factor. In this setting colonization does not appear to have a significant clinical relevance. Thus, routine testing for ESBL-EC faecal carriage does not seem to be beneficial.

Systemic to pulmonary fistula is an unusual entity and its association with hematological diseases like Hodgkin’s is extremely rare. We present a case of a 26-year-old woman with a thoracic mass and large arteriovenous fistula. The diagnosis of Hodgkin’s disease, nodular sclerosis, was obtained by a biopsy of the supraclavicular lymph node. We achieved an excellent response after combined treatment with chemotherapy, radiotherapy and arterial embolization with complete disappearance of the mass.

T]his work introduces a flexible and reusable architecture designed to facilitate the development of remote sensing applications. Based on it, we are developing a helicopter system, called Red-Eye, devoted to the detection, control and analysis of wild land forest fires in the Mediterranean area. The design of the proposed system is composed of five main components. Each component will work collaboratively to constitute a platform of high added value. The general architecture designed for wildfire monitoring is being tailored for two relevant objectives within the particular Mediterranean scenario: tactical day/night fire front evolution, and post-fire hot-spot detection.

Background Administering treatment by the right route improves patient safety and reduces healthcare spending. Purpose To assess the medical acceptance of sequential treatment (ST) proposals made by the pharmacy in accordance with agreed guidelines and to evaluate the cost savings. Materials and methods For 2 months, the pharmacist twice a week, recorded patients continuing intravenous antibiotic treatment for more than 72 h. Following clinical and analytical standards previously accepted by the Drugs Committee, each patient was evaluated, and if they complied with all aspects necessary to make the transition to oral treatment, this was recommended to the doctor in the clinical record. The antibiotics that were analysed were those with high bioavailability. Results Over two months we noted 76 patients, but only 16 met the requirements for treatment change. The rest of the patients, 60 (79%), were not candidates for oral treatment due to: Fasting treatment (35%) Discharge of patients from hospital (31.6%) Altered lab test results (23.3%) Palliative care (5%) Death of patient (1.7%) To ensure patient compliance (1.7%) Diagnosis did not favour a change of treatment (1.7%) Conclusions The level of medical acceptance of the ST was high (76.9%), but the percentage of patient candidates was low (21%) because the average hospital stay is short (5.9 days) and the majority of patients had altered gastrointestinal absorption. Amoxicillin/clavulanic acid was the antibiotic most often administered orally, but more money was saved (275.26 €) by changing to oral treatment with fluoroquinolones. No conflict of interest.

To analyse the etiology, diagnostic methods and response to therapy in 30 episodes of pneumonia diagnosed in 17 patients with chronic lymphocytic leukemia (CLL) between 1995 and 2000.In each episode of pneumonia the following data were analysed: age, gender, treatment of CLL, antiinfectious prophylaxis, granulocytopenia, CD4/CD8 lymphocytes ratio, hipogammaglobulinemia, origin of pneumonia (nosocomial or community-acquired), localisation, respiratory insufficiency, need for mechanical ventilation, antimicrobial therapy and response. Diagnostic methods included blood and sputum cultures, fiberoptic bronchoscopy and search for antigens in urine (Legionella pneumophila serogroup 1, galactomannan, and Streptococcus pneumoniae).Median age of the series was 60 yr. (range 50-86) and 12 patients were male. Chlorambucil and prednisone were used in 13 cases and fludarabine in 8. Granulocytopenia was present in 14 episodes, hypogammaglobulinemia was seen in 22 and CD4/CD8 ratio was lower than 1 in 8 out of 14 evaluable cases. Etiology of pneumonia was established in 16 episodes (53%). Fiberoptic bronchoscopy was the most useful technique (83% of positive diagnoses) followed by blood cultures (38%). Two patients were diagnosed of aspergillosis at autopsy. Pneumococcus was the most frequent agent (5 cases) followed by Pseudomonas aeruginosa (4), Pneumocystis carinii (2) and Aspergillus fumigatus (2). One out of the two patients with P. carinii pneumonia had received fludarabin and the remaining was treated with prednisone for long time. Ten patients (30%) had died: P. aeruginosa (3 cases), P. carinii (2), A. fumigatus (2), Mycobacterium xenopi (1), and unknown microorganism (2).In this series of CLL patients the frequency of etiologic diagnosis of pneumonias was good. Pneumococcus was the most frequent microorganism. Pneumonias caused by opportunistic microorganisms were associated to the treatment with fludarabin or prednisone and were associated to a high mortality rate.

The optimal vehicle to ensure adequate penetration of 5-aminolaevulinic acid (ALA) for its use in photodynamic therapy (PDT) of skin lesions has not been determined.We aimed to study the effects of ALA in various vehicle formulations [saline lotion with and without dimethylsulphoxide (DMSO), cream, liposomes and vaseline] after topical application in a murine subcutaneous adenocarcinoma model.The effect of DMSO on porphyrin synthesis and ALA penetration through the skin was studied by measuring the uptake of 14C label from ALA, ALA and porphobilinogen accumulation, and some haem enzyme activities. The tissue distribution and kinetics of porphyrin synthesis after topical application of ALA entrapped in large multilamellar liposomes was also determined.ALA in saline lotion, alone or with 10% DMSO, proved to be the most efficient vehicle for tumour porphyrin accumulation (mean +/- SD 1.75 +/- 0.25 and 2.09 +/- 0.39 microg g-1, respectively), whereas cream and liposomes induced lower levels and identical porphyrin accumulation (0.60 microg g-1). Using ALA + DMSO saline lotion, a higher porphyrin accumulation was found in skin overlying the tumour tissue and in the first 2 mm of tumour, probably due to increased ALA penetration, or greater interconversion to porphyrins, or greater retention of ALA and/or porphyrins.These findings reinforce the importance of the vehicle in topical ALA-based PDT, and explain the mechanism of action of DMSO in enhancing protoporphyrin IX biosynthesis in superficial lesions.

In spite of not being considered as an AIDS defining illness, Hodgkin's disease (HD) has specific clinical and biological features in HIV-infected patients.Study of clinicopathologic and analytic characteristics, Epstein-Barr virus (EBV) detection (polymerase chain reaction), and prognosis in 15 patients with HD and HIV infection.Thirteen patients had B symptoms, 10 extranodal involvement and 12 advanced HD. The most frequent histologic subtypes were mixed cellularity (6) and lymphocyte depletion (6). The mean (SD) of CD4 lymphocytes was 0.10 (0.08) x 10(9)/l. The presence of EBV in lymph node biopsy was demonstrated in 3 out of 4 patients investigated. Complete remission (CR) was achieved in 7 out of 14 treated cases (50%), the median overall survival was 26 months and the 2 year event-free survival probability was 60%.In HIV-infected patients, HD presents in advanced stages, unfavourable histologic subtypes, frequent extranodal involvement and B symptoms. The prognosis is poor, mainly because of a low CR rate.

A partial deficiency of Porphobilinogen deaminase (PBG-D) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1:125,000. Here, two new mutations and three previously reported were found in the PBG-D gene in 12 Argentinean AIP patients corresponding to 5 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 2 Multiplex PCR reactions, then all coding exons and flanking intronic regions were sequenced. The new mutations are 453-455delAGC in exon 9 which results in the loss of an alanine residue at position 152, and one new point mutation in the splicing aceptor site in the last position of intron 8 (IVS8-1GT) which leds to a 15 bp deletion because a cryptic site (first AG upstream) is used. Both mutations produce amino acid deletion without frameshift effect. To further characterize the 453-455delAGC mutation, the pKK-PBGD construct for the mutant allele was expressed in E. coli, the enzymatic activity of the recombinant protein was 1.3% of the mean level expressed by the normal allele. Finally, three missense mutations, previously reported, were identified in three unrelated families.

Acute intermittent porphyria (AIP), the most common hepatic porphyria, results from the half-normal activity of hydroxymethylbilane synthase (HMB-synthase; EC 4.3.1.8), the third enzyme in the heme biosynthetic pathway. Because life-threatening acute neurologic attacks of this autosomal dominant disease are triggered by various ecogenic factors (e.g., certain drugs, hormones, alcohol, and starvation), efforts have been directed to identify and counsel presymptomatic heterozygotes in affected families to avoid the precipitating factors. Thus, to determine the nature of the mutations causing AIP in 26 unrelated enzyme-confirmed patients from Argentina, a long-range polymerase chain reaction method was developed to amplify the entire 10-kb gene in two fragments for efficient cycle sequencing and mutation detection. Eight new mutations were identified including two missense mutations (Q34P and G335S), four small deletions (728delCT, 815delAGGA, 948delA, and 985del12), a single base insertion (666insA), and a splice site mutation (IVS12(+1)). In addition, five previously reported mutations (G111R, R173W, Q204X, R201W, and 913insC) were detected. Notably, G111R was identified in 12 of the 26 (46%) presumably unrelated propositi; however, haplotype analysis with intragenic and flanking markers indicated an ancestral founder. Expression of the two new missense mutations (Q34P and G335S) in f1 E. coli resulted in 2.5% or less of the normal expressed enzyme, confirming their defective function. Thus, eight new and five previously reported HMB-synthase mutations, including a common lesion, were detected, permitting accurate identification and counseling of presymptomatic carriers in these 26 unrelated Argentinean AIP families with this dominant porphyria.

To analyze the usefulness of bone marrow (BM) study in the diagnosis of fever of unknown origin (FUO) in patients infected by the human immunodeficiency virus (HIV) in a single center during a period of 42 months.182 episodes of FUO in 162 patients p3th HIV infection were studied. Age, sex, risk factor for HIV infection, hemoglobin level, counts of leucocytes, neutrophils, lymphocytes, CD4 positive lymphocytes, platelets and levels of hepatic enzymes, albumin and beta 2-microglobulin were studied. BM aspirate was performed in all episodes for cytologic and microbiologic examination, and BM biopsy was done in 43. Analysis of factors related with the probability of diagnosis by BM examination was carried out.The median age was 33 years (range, 22-70), and 123 were males. Drug abuse was the most frequent risk factor for HIV infection (63%). One hundred thirty patients had previous AIDS diagnosis before they were evaluated for unexplained fever. A specific diagnosis was achieved in 161 episodes (88%) and the most frequent diagnoses were Mycobacterium spp. (55%) and Leishmania spp. (14%) infections. Fifty-four episodes (30%) were diagnosed by BM examination, and in 36 (20%) BM study was the only diagnostic tool. Examination of the BM aspirate yielded the diagnosis in 40 out of the 178 episodes (13%), whereas BM biopsy was a diagnostic tool in 8 (19%); in 9 additional cases (21%) granulomas were observed. Microbiologic study of BM smears for mycobacterial infections was positive in 28 of the 143 episodes (19%), and the culture for Leishmania was positive in 2 out of the 42 cases. The presence of thrombocytopenia (75 x 10(9)/l) and elevated serum levels of aspartate-aminotransferase (AST) (100 U/l) were the factors associated with a high probability to obtain the diagnosis through BM study.In patients infected by the HIV and unexplained fever, BM examination is an useful procedure for the diagnosis, particularly in areas where infections by Mycobacterium spp. and Leishmania are prevalent. So that, in our setting, systematic use of this procedure is justified for diagnosis of FUO in those patients.

To analyze the etiology, treatment response and prognostic factors in 88 episodes of pneumonia in patients with hematological malignancies diagnosed in one center during a period of 30 months.88 episodes of pneumonia in 69 adult patients were studied. Age, sex, hematological malignancy and its treatment, existence of neutropenia and hypogammaglobulinemia, administration of immunosuppressive agents, type (hospital or community-acquired) and localization of pneumonia, presence of respiratory failure and treatment response were reported. For etiologic diagnosis of pneumonias, cultures of blood, sputum, pleural fluid and bronchoalveolar lavage (BAL), as well as Legionella pneumophila, Aspergillus fumigatus and Streptococcus pneumoniae antigen detection in urine were performed. Univariate and multivariate analyses of prognostic factors for pneumonia evolution were carried out.The median age was 63 years. Acute leukemias (AL) were the predominant hematological malignancies. Microbiologic documentation was obtained in 40 (45%) of pneumonias. Fiberoptic bronchoscopy with BAL (71%) was the diagnostic procedure with highest yield followed by blood cultures (25%). Streptococcus pneumoniae (13) was the most frequent isolated pathogen, followed by Legionella pneumophila (6) and Pseudomonas aeruginosa (6). A significantly higher prevalence of Streptococcus pneumoniae was observed in community-acquired pneumonia. The overall mortality rate was 20%. Respiratory failure (p = 0.0009), existence of neutropenia (p = 0.0023), age equal or higher than 60 years (p = 0.012) and prolonged administration of immunosuppressive agents (p = 0.015) were the prognostic factors associated with unfavourable evolution of pneumonias in the multivariate analysis.The etiologic diagnosis of pneumonia in patients with hematological malignancies was only achieved in a half of cases. In our series, the high prevalence of Legionella pneumophila can be attributed to the special epidemiologic characteristics of our hospital. Prognostic factors of pneumonia are related to individual factors as well as to the hematological status of patients.

We have investigated the efficacy of the Photodynamic Therapy (PDT) from 5-aminolevulinic acid (ALA) in combination with an antineoplastic agent using an in vitro-in vivo model developed in our laboratory. The alkylant cyclophosphamide (CY) was chosen because there is evidence of the porphyrinogenic properties of this drug. Male BALB/c mice bearing a transplantable mammary adenoarcinoma were given two doses of 35 mg de CY/kg wt. i.p. and 9 mg/kg wt intratumorally. At 16, 22 and 40 hrs after the last injection of CY the animals were sacrificed and explants of 2 mg of tumor were incubated 2 hrs in a medium containing 0.6 mM ALA; and then irradiated with a He-Ne laser. Innocula of 1 mm3 of irradiated and non-irradiated tissue were then injected subcutaneously under the right and left flanks of a normal mouse, respectively. The efficacy of the treatment was determined following the growth of the tumor from day 10 after tumor implantation. Under the present conditions a 30% increased efficacy was observed in the case of the explants treated with CY 40 hrs after the last i.p. injection. Porphyrins in the liver and tumor and other tissues of the injected mice were also determined; except for a slight increase in tumor and liver, 40 and 22 hrs after CY i.p. injection respectively, no other changes were observed in any tissue, as compared with not CY treated mice. These results indicate that future treatment, combining the tumor localizing properties of endogenously formed porphyrins from ALA and antineoplasic drugs such as cyclophosphamide, should be encouraged.