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BACKGROUND: Concentration of microorganisms in blood is low in bacteremia from extravascular sources. The best yield from blood cultures is achieved by culturing a minimum of 10-20 ml, although in some processing blood culture systems such as Bactec NR-860, smaller volume is used. The objectives of the present study were to establish the frequency in which inadequate small blood volumes are employed for culturing and to analyze the relation between the cultured blood volume in Bactec 6A bottles and the yield achieved. MATERIAL AND METHODS: We weighed 2000 Bactec 6A bottles pertaining to consecutive blood cultures obtained from untreated patients with clinical suspicion of Infection. The cultured blood volume was estimated subtracting the mean empty bottle weight. RESULTS: Microorganisms were recovered from 251 bottles (12.5%). One hundred and thirty one (6.8%) isolates were considered as clinically significant and 115 (5.7%) as contaminant. The inoculated blood volume in both significant (5.532 +/- 1.587 ml) and non-significant (5.471 +/- 1.563 ml) recoveries was superior than that of bottles without microbiologic growth (5.209 +/- 1.575 ml, p = 0.016 and p = 0.06, respectively). A linear positive trend was found between the cultivated blood volume and the rate of recoveries (p = 0.008). Within the range of 1 up to 10 ml, the rate of recoveries increased 2.28% for each additional ml of cultivated blood (r = 0.953, p < 0.0001). Out of the 2,000 weighed bottles 127 (6.3%) contained less than 3 ml of blood and 576 (29%) between 3 and 5 ml. CONCLUSIONS: We have proved that the rate of recoveries from Bactec 6A bottles increased with the volume of cultured blood. In untreated patients, this increase is maintained up to volumes of 7 to 10 ml.

International audience; OBJECTIVE: The aims of this study were to evaluate the therapeutic outcome and morbidity associated with management of squamous cell carcinoma (SCC) T3-T4 of the floor of the mouth. PATIENTS AND METHODS: This was a retrospective study (1993 and 2005). Inclusion criteria were: 1) Presence of a locally advanced (T3-T4) lesion of the floor of the mouth; 2) Pathological confirmation of SCC; 3) No previous treatment of the floor of the mouth; 4) Absence of any synchronous lesions at the primary endoscopic work-up; 5) Absence of distant metastasis outside the aero-digestive tract; 6) Karnofsky performance index > 70. All patients were treated by surgery and adjuvant radiotherapy. The statistical analysis was conducted using the stat-view software; categorical variables were compared using the Fisher's exact test; analysis of recurrence-free survival rate was done following the Kaplan-Meier method, and the log-rank test was used for the comparison of survival graphs. RESULTS: Fourty-seven patients were included in this study (42 men), of a mean age of 53.3 years. The majority of patients (93.6%) presented with a stage IVa tumour and no clinical evidence of cervical lymphadenopathy in 60% of cases. All patients underwent bilateral neck dissection adapted to the cervical lymph node status. Forty-one (87%) patients underwent partial mandibulectomy with fibula free-flap reconstruction in 32 cases (78%). Early local complication rate was of 32%. The mean duration of hospitalization was 34 days. Late local complication rate was of 17%. The immediate post-operative death rate was 2%. The rate of survival and recurrence free survival was of 47.5% and 47% respectively. The 3 survival-influencing factors were age (p = 0.02), margins of surgical resection (p = 0.002), and histologic cervical lymph node status (p = 0.03). CONCLUSION: T3-T4 tumours of the floor of the mouth are managed by surgical resection and adjuvant radiotherapy. There is a high rate of treatment-associated complications. The prognosis of locally advanced tumours of the floor of the mouth remains humble.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.

Levofloxacin is a useful quinolone for patients infected with osteomyelitis or tuberculosis. There is little information on the tolerance and safety of levofloxacin in long-term treatment. Fifteen patients (10 men and 5 women) with prosthetic joint infection or chronic osteomyelitis were analyzed. The treatment was levofloxacin (500 mg/d) and rifampicin (600 mg/d). Controls were performed monthly during the treatment, and after that every six months. Problems that were likely related to medication were noted by medical interview. Analyses of hepatic and renal function were performed at each visit. The mean age was 64 years. Ten patients had prosthetic joint infection, two chronic osteomyelitis, two osteosynthetic device infection and one silicone graft infection. Staphylococcus aureus was isolated in eight cases, staphylococcus coagulase being negative in five, and the cultures negative in two cases. The mean duration of treatment was 3.6 months (range 2-6 months). No adverse reactions were observed in seven patients (46%). Occasional digestive symptoms were reported in six patients (40%), and two cases (13%) presented light diarrhea. These patients also took antiinflammatory treatment. Sleeplessness was observed in one patient (6%). Tendinitis or alterations in hepatic function were not observed. In no case was the treatment changed due to adverse reactions. It was concluded that levofloxacin is well tolerated and safe and could be an option for infections that require long-term treatment.

Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5% of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69%) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90%). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48%). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality.

An approach of daily or 5 days per week treatment as maintenance therapy is mandatory among HIV patients with CMV retinitis. We evaluate the efficacy and tolerance of thrice weekly maintenance therapy for CMV retinitis in AIDS patients.Sixty nine consecutive patients with CMV disease were eligible for a prospective open clinical trial. Thirty three completed the induction treatment of CMV retinitis, agreed on maintenance thrice weekly and were included. Twenty nine received Ganciclovir (10 mg/kg/day) and 4 foscarnet (100 mg/kg/day) thrice weekly.The mean age was 34 years. Twenty nine of the 33 (87%) were males and 13 (39%) drug addicts. Mean CD4+ lymphocyte count at inclusion was 44 cells per relapsed and 22 (66%) died. The median time to relapse, survival free of CMV retinitis and the median survival was 18, 14 and 34 weeks respectively.Since the outcome of our patients with thrice weekly maintenance therapy was similar to historical controls our study at least provides the rational for this hypothesis to be tested in a future randomised trial.

The objectives of this study were to analyze the changes in the incidence of cryptococcal disease in the last 10 years (1987-1997) and to assess the factors of poor prognosis in HIV-1 infected patients.Clinical records of HIV-1 infected patients diagnosed with cryptococcal infection from June 1987 to December 1997 at Hospital Clinic i Provincial in Barcelona, Spain, were examined. An univariate and multivariate analysis of the predictors of poor outcome was performed.Sixty clinical records were analyzed. The number of cases per 100 exposed patients per year decreased from 1991 to 1993 and, afterwards, decreased again from 1996. Fifty patients had a resolution of clinical symptoms, 17 out of this 50 patients (34%) had a relapse. Factors associated with a higher risk of relapse were a positive blood culture and cryptococcal antigen title in cerebrospinal fluid above 1/1.024.The decrease in the number of cases of cryptococcal infection coincides with the broad use of triazole antifungal drugs for oral candidiasis (1990-1991) and, afterwards, with the initiation of highly active antiretroviral therapy (1996). The best predictors of relapse are a positive blood cryptococcal culture and a high titter of cryptococcal antigen.

Infections are the most common medical complications in drug addicts. Some studies suggest that heroin itself could facilitate them by altering the polymorphonuclear leukocyte (PMNL) function of these patients. The aim of this study was to analyze the heroin effect on the chemotaxis, the phagocytosis and the bactericidal oxidative metabolic activity on PMNL from 10 healthy adults.Three samples of 20 ml of blood were obtained from each donor, separating the leukocytes later. The first sample was used as control (A group); heroin was added to the blood of the second sample before PMNL separation (1 mg of heroin into 20 ml of blood)(B group) and to the third sample after PMNL separation (0.05 mg of heroin in 1 ml of PMNL suspension)(C group). The concentration of heroin used was 50 microliters/ml of blood (this concentration was higher than the lethal concentration found in the blood of drug addicts who die from heroin overdose). The PMNL functions studied in vitro were the chemotaxis of PMNL applying the under agarosa gel method, and for the phagocytosis and the intracellular oxidative metabolic activity the following two tests were used: the ingestion of bacto-latex particles combined with nitroblue tetrazolium (NBT) reduction test and the chemoluminiscence method. The statistical analysis was done using parametric and non-parametric tests.There were no differences between the three groups studied (A, B or C) regarding chemotaxis, the ingestion of bacto-latex particles and the NBT reduction test. Concerning chemoluminiscence, it was inferior in the C group (with PMNL directly incubated with heroin) compared with A group (control) and B group (with PMNL from blood with heroin)(p0.05). However, there were no statistically significant differences between A and B groups.In this study, heroin did not have any in vitro significative effect of chemotaxis, phagocytosis and oxidative metabolic activity on the human PMNL.

Paragonimiasis (infestation by the Paragonimus species) in Spain is a very infrequent entity within the group of imported infectious diseases. A native, resident of Equatorial Guinea who was affected by pulmonary and probably extrapulmonary paragonimiasis together with active pulmonary tuberculosis is described. This association is relatively common and may complicate the diagnostic process. The identification of the parasite was established from samples of pulmonary secretion obtained by natural expulsion and by fiber bronchoscopy in which Kinyoun carbonfucsine dye, Giemsa dye and argentic impregnation were used. The possibility of neurological disease existing (medullar and cerebral) produced by the same parasite is also discussed. Antituberculous treatment and the use of praziquantel satisfactorily control both infections.

Clinical aspects of 10 consecutive patients hospitalized for acute human leptospirosis, confirmed by serology using the microscopic agglutination test (MAT), between 1975 and 1988 in a 1000 beds Teaching Hospital are retrospectively analyzed. All of them were male, mean age of 55, presenting a suggestive epidemiological data to be at risk for Leptospira infection. Leptospira icterohaemorrhagiae was responsible for 8 cases and Leptospira canicola for 2. 7 patients were treated, after 3-4 days of admittance, with penicillin. 5 patients died. Cause of death was gastrointestinal haemorrhage in 3 and cardiogenic shock in 2. We discuss the clinical, biochemical, pathological and therapeutic aspects of the acute human leptospirosis.

[Background]: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood., [Results]: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes., [Conclusions]: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders., Major financial support for this research was received from Spanish “Ministerio de Ciencia, Innovación y Universidades.” Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish “Ministerio de Ciencia, Innovación y Universidades”). S.M. was first supported by a contract with the “Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,” and later by “Centro de Investigación Biomédica en Red de Enfermedades Raras” (CIBERER). N.F.C. is also under contract by CIBERER.

[Background] Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells., [Results] Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees., [Conclusions] This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases., This work was supported by National Institute of Mental Health by the following awards: U01MH106874, U01MH106876, U01MH106883, U01MH106882, U01MH106884, U01MH106891, U01MH106892, U01MH106893, U01MH108898.

Key Points Question Is receipt of tumor necrosis factor (TNF) inhibitor monotherapy at the time of COVID-19 diagnosis associated with adverse COVID-19 outcomes compared with other treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs)? Findings In this cohort study of 6077 patients with IMIDs and COVID-19, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, or Janus kinase inhibitor monotherapy were each associated with significantly higher odds of hospitalization or death compared with TNF inhibitor monotherapy. Meaning This study’s findings support the continued use of TNF inhibitor monotherapy among individuals with IMIDs during the pandemic., Importance Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19–associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures The main outcome was COVID-19–associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P, This cohort study uses data from 3 international registries to examine the association between the receipt of tumor necrosis factor monotherapy and the risk of COVID-19–associated hospitalization or death among adult patients with immune-mediated inflammatory diseases.

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE. © 2015 Elsevier Inc.

The use of Y chromosome haplotypes, important for the detection of sexual crimes in forensics, has gained prominence with the use of databases that incorporate these genetic profiles in their system. Here, we optimized and validated an amplification protocol for Y chromosome profile retrieval in reference samples using lesser materials than those in commercial kits. FTA(®) cards (Flinders Technology Associates) were used to support the oral cells of male individuals, which were amplified directly using the SwabSolution reagent (Promega). First, we optimized and validated the process to define the volume and cycling conditions. Three reference samples and nineteen 1.2 mm-diameter perforated discs were used per sample. Amplification of one or two discs (samples) with the PowerPlex(®) Y23 kit (Promega) was performed using 25, 26, and 27 thermal cycles. Twenty percent, 32%, and 100% reagent volumes, one disc, and 26 cycles were used for the control per sample. Thereafter, all samples (N = 270) were amplified using 27 cycles, one disc, and 32% reagents (optimized conditions). Data was analyzed using a study of equilibrium values between fluorophore colors. In the samples analyzed with 20% volume, an imbalance was observed in peak heights, both inside and in-between each dye. In samples amplified with 32% reagents, the values obtained for the intra-color and inter-color standard balance calculations for verification of the quality of the analyzed peaks were similar to those of samples amplified with 100% of the recommended volume. The quality of the profiles obtained with 32% reagents was suitable for insertion into databases.

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 = 68.2 nm ), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6% at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4% cell viability at 1000 μm), affording good neuroprotection against toxic insults such as Aβ1-40, Aβ1-42, H2O2, and oligomycin A/rotenone on SH-SY5Y cells, at 1 μm. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.