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Background: Type 2M von Willebrand disease (VWD2M) is usually characterized by VWF:RCo/VWF:Ag<0.6 and normal multimeric profile; desmopressin (DDAVP) challenge test commonly shows poor response of VWF:RCo., Objective: We describe the bleeding tendency and the laboratory phenotype in a patient carrying two heterozygous mutations affecting VWF-A1 domain and VWF-A2 domain., Subjects/methods: A 12-year-old patient (O blood group) with severe hemorrhagic tendency was phenotypically and genotypically analyzed; his parents were also studied., Results: The proband showed decrease FVIII:C, VWF:RCo/VWF:Ag, and VWF:CB6/VWF:Ag ratios, but normal platelet count, VWF:CB1/VWF:Ag ratio, VWFpp and multimeric pattern, suggesting a VWD2M phenotype. The DDAVP challenge test, compared to controls (VWD2M patients with mutations in VWF-A1 domain), showed lower increase of FVIII:C and VWF:Ag than in heterozygous, but very similar to homozygous control. Two mutations were found in heterozygous and trans presentation: p.Pro1648fs*45 and a novel missense mutation, p.Arg1426Cys. The mother was p.Arg1426Cys heterozygous carrier, with few clinical symptoms. The father was asymptomatic, with no mutations. The p.Pro1648fs*45 was considered an apparent de novo mutation; proband's AS-PCR revealed mosaicism in the paternal allele. According to the predicted models, p.Arg1426Cys would not be affecting the binding of GPIbα to A1 domain, whereas p.Pro1648fs*45 seems to modify the folding of A2 domain, and in this way, it would affect the binding to GPIbα and type VI collagen. We believe that the combination of these two heterozygous mutations, in a child with O blood group, could result in a defective phenotype enhancer.

A prospective, cohort, clinical, observational study was performed in 14 Intensive Care Units (ICUs) to evaluate the contemporary epidemiology, morbi-mortality and determinants of outcome of the population with an infection on admission. All 3766 patients admitted during a consecutive 12-month period were screened. Their median age was 63 [26-83], 61.1% were male and 69.8% had significant comorbidities. On admission to the ICU 1652 patients (43.9%) had an infection, which was community acquired in 68.2% (one-fifth with healthcare-associated criteria) and ward-acquired in the others. Roughly half presented to the ICU with septic shock. As much as 488 patients with community-acquired infections were deemed stable enough to be first admitted to the ward, but had similar mortality to unstable patients directly admitted to the ICU (35.9% vs. 35.1%, p 0.78). Only 48.3% of this infected population had microbiological documentation and almost one-quarter received inappropriate initial antibiotic therapy. This, along with comorbidities, was a main determinant of mortality. Overall, infected patients on admission had higher mortality both in the ICU (28.0% vs. 19.9%, p <0.001) and in the hospital (38.2% vs. 27.5%, p <0.001) and even after being discharged to the ward (14.2% vs. 9.6%, p <0.001). Also, patients not infected on admission who acquired an infection in the ICU, had an increased risk of dying in the hospital (odds ratio 1.41 [1.12-1.83]). Consequently, infection, regardless of its place of acquisition, was associated with increased mortality. Improving the process of care, especially first-line antibiotic appropriateness, and preventing ICU-acquired infections, may lead to better outcomes., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

A prospective, multicentre, phase IIIb study with an exploratory, open-label design was conducted to evaluate efficacy and safety of anidulafungin for the treatment of candidaemia/invasive candidiasis (C/IC) in specific ICU patient populations. Adult ICU patients with confirmed C/IC meeting ≥ 1 of the following criteria were enrolled: post-abdominal surgery, solid tumour, renal/hepatic insufficiency, solid organ transplant, neutropaenia, and age ≥ 65 years. Patients received anidulafungin (200 mg on day 1, 100 mg/day thereafter) for 10-42 days, optionally followed by oral voriconazole/fluconazole. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Secondary endpoints included global response at the end of intravenous therapy (EOIVT) and at 2 and 6 weeks post-EOT, survival at day 90, and incidence of adverse events (AEs). The primary efficacy analysis was performed in the modified intent-to-treat (MITT) population, excluding unknown/missing responses. The safety and MITT populations consisted of 216 and 170 patients, respectively. The most common pathogens were Candida albicans (55.9%), C. glabrata (14.7%) and C. parapsilosis (10.0%). Global success was 69.5% (107/154; 95% CI, 61.6-76.6) at EOT, 70.7% (111/157) at EOIVT, 60.2% (77/128) at 2 weeks post-EOT, and 50.5% (55/109) at 6 weeks post-EOT. When unknown/missing responses were included as failures, the respective success rates were 62.9%, 65.3%, 45.3% and 32.4%. Survival at day 90 was 53.8%. Treatment-related AEs occurred in 33/216 (15.3%) patients, four (1.9%) of whom had serious AEs. Anidulafungin was effective, safe and well tolerated for the treatment of C/IC in selected groups of ICU patients., (© 2012 Pfizer Inc. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Dirofilaria immitis carries intracellular endosymbiotic bacteria of the genus Wolbachia, known to be vital for the worms and sensitive to tetracycline antibiotics. With the purpose of studying the interaction between D. immitis and the endosymbiont Wolbachia sp., heartworm naturally infected microfilaremic or antigenemic dogs were treated with doxycycline (10mg/kg/day of the drug in three cycles of 21 days each, with 6-month intervals). Blood samples were collected on days 0, 7 and 21 of each treatment as well as on day 111 after the beginning of each cycle. A final sample was collected on day 723 from the beginning of the first treatment. The samples were examined for the presence and number of microfilariae and the presence of antigen as well as the presences of D. immitis and Wolbachia sp. DNA using PCR (polymerase chain reaction). With this approach, an evaluation of the effect of doxycycline on antigenemia and on the presence of Wolbachia sp. DNA in dogs with heartworm infection was possible. Doxycycline treatment did not alter the detection of adult parasite antigens with the exception of two animals, though the number of animals carrying Wolbachia sp. DNA decreased, despite the presence of the microfilariae. The effect of the antibiotic therapy on the worms may have interfered with the transmission of heartworm disease because the population of microfilariae and the number of microfilaremic dogs were reduced and the microfilariae positive samples that were found did not test positive for Wolbachia sp. in many cases. These findings suggest that in areas were doxycycline is extensively used D. immitis transmission may be impaired by the reduction on the number of microfilariae and on the endosymbiotic bacteria in the larvae turning them incapable of completing development once they infected a new host., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Catheter-related infections constitute 10-15% of all nosocomial infections, and constitute a relevant and growing problem, with an impact that is far from irrelevant, especially in the intensive care unit. The most frequent pathogens implicated come from the skin flora; Gram-positive cocci are responsible for about two-thirds of the infections, and Candida has emerged as another important cause. Questions about drug, route of administration, dosage and duration of antibiotherapy for patients who have become apyretic and with no signs of sepsis after catheter removal are still under debate, and far from being definitively answered. Decisions regarding these questions are based on three main factors: namely, which is the microoorganism responsible for the infection, what was the time to response, and what kind of patient are we dealing with? However, the microorganism is clearly the main factor in making a decision. In summary, all catheter-related infections should be treated with appropriate antibiotics, regardless of the removal of the catheter, with parenteral drugs, using high doses and short courses, namely 1 week, and de-escalating to narrow-spectrum drugs on the basis of susceptibility tests as soon as possible. Staphylococcus aureus catheter-related infections constitute an exception, needing longer courses, as it is difficult to predict who will be high-risk patients.

Ventilator-associated pneumonia (VAP) is an important health problem that still generates great controversy. A consensus conference attended by 12 researchers from Europe and Latin America was held to discuss strategies for the diagnosis and treatment of VAP. Commonly asked questions concerning VAP management were selected for discussion by the participating researchers. Possible answers to the questions were presented to the researchers, who then recorded their preferences anonymously. This was followed by open discussion when the results were known. In general, peers thought that early microbiological examinations are warranted and contribute to improving the use of antibiotherapy. Nevertheless, no consensus was reached regarding choices of antimicrobial agents or the optimal duration of therapy. Piperacillin/tazobactam was the preferred choice for empiric therapy, followed by a cephalosporin with antipseudomonal activity and a carbapenem. All the peers agreed that the pathogens causing VAP and multiresistance patterns in their ICUs were substantially different from those reported in studies in the United States. Pathogens and multiresistance patterns also varied from researcher to researcher inside the group. Consensus was reached on the importance of local epidemiology surveillance programs and on the need for customized empiric antimicrobial choices to respond to local patterns of pathogens and susceptibilities.

Methods: From June 1989 to April 1991, 394 adolescents aged 10-18 years randomly selected upon admission at a state shelter in Belo Horizonte, Brazil underwent health history interview, physical examination, serology for HIV, hepatitis B, and syphilis, and stool examination. Participants were classified as street-based youths (n = 195) or home-based youths (n = 199). The age distribution was similar in both groups, although males were overrepresented among street-based youths (79.5% versus 62.3%)., Results: Compared with home-based youths, street-based youths reported earlier onset (p = 0.009) and higher rates of sexual activity (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4-3.3), sexual abuse (OR, 3.7; 95% CI, 1.2-10.1), and sexually transmitted diseases (OR, 2.9; 95% CI, 1.3-6.6). Overall condom use was low in both groups. Street-based youths were 7.8 times more likely to use drugs than home-based youths (95% CI, 4.9-12.7). Inhalants and marijuana were the more commonly used drugs. Intravenous drug use was low., Conclusions: Although chronic malnutrition and multiple parasitosis were common findings in both groups, street-based youths were more likely to present disorders related to trauma and poor hygienic conditions. Antibodies to HIV were detected in four (2%) street-based youths and in none of the home-based youths. This study confirms that street youths are at higher risk for HIV infection than their home-based peers and indicates a need for HIV prevention programs targeting this population.

The structural features and anticoagulant activity of heparins isolated from three species of molluscs (Anomalocardia brasiliana, Donnax striatus and Tivela mactroides) are reported. It is shown by chemical analyse, type of products formed by action of heparinase and heparitinase II, anticoagulant activity, 13C and 1H n.m.r. spectroscopy, that the mollusc heparins are virtually indistinguishable from heparins present in mammalian tissues. These data, taken as a whole, suggest that heparin has maintained its main structural features through evolution. The implications of these findings are discussed.

Six monoclonal antibodies raised against the human placental alkaline phosphatase (ALP) recognizing distinct antigenic determinants on the surface of this isozyme were used for immunohistochemical studies of adult and fetal human testes and testicular germ-cell tumors. ALP reacting with all six antibodies was defined as placental, whereas ALP reacting with some but not all antibodies was labeled as placental-like. ALP reacting with one of the monoclonal antibodies that recognizes a determinant common to intestinal and placental ALP was tentatively considered probably intestinal, unless it reacted with any other monoclonal placental specific antibody. Using this approach, the authors have identified placental ALP in 4 of 7 seminomas, 3 of 7 tumors composed in part or fully of embryonal carcinoma, and 1 yolk sac carcinoma. Placental-like ALP was identified in 2 additional seminomas and 4 embryonal carcinoma-containing tumors, whereas 1 seminoma and 1 benign teratoma were devoid of either placental or placental-like ALP. Trophoblastic giant cells in 2 seminomas and 3 teratocarcinomas expressed only the antigenic determinant common to placental and intestinal ALP. The authors thus show that testicular tumor cells may express either placental or placental-like ALP and that in some instances, the tumor isozyme is antigenically different from ALP found on either fetal or adult testicular germ cells.