Insights into the preparation of zein nanoparticles by continuous membrane nanoprecipitation.

Nanoparticles (NPs) preparation is limited to an exclusive use in batch processes and small-scale formulations. The use of membranes as high-performance micromixers is expected to open new scenarios to overcome limitations of conventional nanoprecipitation system such as stirred tank (ST) nanoprecipitation. The ability of the porous membrane to add uniformly one phase to another and govern their mixing at the membrane interface seems to be an important parameter for obtaining uniform NPs. Inorganic membranes (pore size of 1 µm) were used to carry out membrane nanoprecipitation (MN) to form Zein nanoparticles (ZNPs) at pores level by non-solvent induced phase separation. A systematic study of the preparation of ZNPs in the ST and MN systems was carried out to establish the Ouzo diagram. The influence of zein concentration and solvent to non-solvent ratio on the size and size distribution of ZNPs was also investigated. A wider stable Ouzo zone was obtained with MN than with the ST process. ZNPs size increased from 100 nm up to 700 nm, while maintaining low polydispersity index (PDI < 0.2). The results demonstrate the suitability of MN for the continuous production of ZNPs and open the possibility of scaling up the nanoprecipitation process.

Declining mortality due to severe sepsis and septic shock in Spanish intensive care units: A two-cohort study in 2005 and 2011 / Disminución de la mortalidad de la sepsis grave y shock séptico en las ucis españolas: un estudio de dos cohortes en 2005 y 2011

OBJECTIVE: To analyze the evolution of sepsis-related mortality in Spanish Intensive Care Units (ICUs) following introduction of the Surviving Sepsis Campaign (SSC) guidelines and the relationship with sepsis process-of-care. DESIGN: A prospective cohort study was carried out, with the inclusion of all consecutive patients presenting severe sepsis or septic shock admitted to 41 Spanish ICUs during two time periods: 2005 (Edusepsis study pre-intervention group) and 2011 (ABISS-Edusepsis study pre-intervention group). Scope: Patients with severe sepsis or septic shock admitted to Spanish ICUs. PATIENTS: All ICU admissions from the emergency department or wards and all ICU patients with a diagnosis of severe sepsis or septic shock. A total of 1348 patients were included: 630 in the 2005 group and 718 in the 2011 group. Intervention: None. Primary endpoints: ICU mortality, 28-day mortality and Hospital mortality, hospital length of stay, ICU length of stay and compliance with the resuscitation bundle. RESULTS: Compliance with the resuscitation bundle was significantly greater in the 2011 group (5.7% vs. 9.9%; p = 0.005), and was associated to lower mortality (OR 0.602 [0.365-0.994]; p = 0.048). The 2011 group had lower absolute in-hospital mortality (44.0% vs. 32.6%; p = 0.01), 28-day mortality (36.5% vs. 23.0%; p = 0.01), and adjusted mortality (OR 0.64 [0.49-0.83], p = 0.001). CONCLUSIONS: Mortality related to severe sepsis or septic shock in Spain decreased between two patient cohorts in 2005 and 2011, and was attributable to earliness and improvement in sepsis care

OBJETIVO: Analizar la evolución de la mortalidad relacionada con la sepsis en las unidades de cuidados intensivos (UCI) españolas desde la introducción de las directrices Surviving Sepsis Campaing y la relación con el proceso de atención de la sepsis. DISEÑO: Estudio prospectivo de cohortes. Se incluyeron de manera consecutiva, todos los pacientes con sepsis grave o shock séptico ingresados en 41 UCI españolas durante 2 periodos de tiempo: en 2005 (grupo pre-intervención en el estudio Edusepsis) y en 2011 (grupo pre-intervención en el estudio ABISS-Edusepsis). Ámbito: Pacientes con sepsis grave o shock séptico ingresados en las UCI españolas. PACIENTES: Todos los ingresos en UCI procedentes de Urgencias o planta y todos los pacientes de UCI con diagnóstico de sepsis grave/shock séptico. Se incluyeron 1348 pacientes: 630 del grupo de 2005 y 718 del grupo de 2011. Intervención: Ninguna. Variables de interés principal: Mortalidad en UCI, a 28 días y hospitalaria, estancia en la UCI y en el hospital y cumplimiento con el bundle de reanimación. RESULTADOS: El cumplimiento del bundle de reanimación fue significativamente mayor en el grupo de 2011 (5,7 frente a 9,9%, p = 0,005) y se asoció con una menor mortalidad (OR 0,602 [0,365 a 0,994], p = 0,048). El grupo de 2011 tuvo una menor mortalidad absoluta hospitalaria (44,0 frente a 32,6%, p = 0,01), mortalidad a los 28 días (36,5 frente a 23,0%, p = 0,01) y mortalidad ajustada (OR 0,64 [0,49 a 0,83], p = 0,001). CONCLUSIONES: La mortalidad relacionada con la sepsis grave y el shock séptico en España disminuyó entre las 2 cohortes de pacientes de 2005 y 2011, atribuible a la precocidad y las mejoras en la atención de la sepsis

Declining mortality due to severe sepsis and septic shock in Spanish intensive care units: A two-cohort study in 2005 and 2011.

OBJECTIVE: To analyze the evolution of sepsis-related mortality in Spanish Intensive Care Units (ICUs) following introduction of the Surviving Sepsis Campaign (SSC) guidelines and the relationship with sepsis process-of-care. DESIGN: A prospective cohort study was carried out, with the inclusion of all consecutive patients presenting severe sepsis or septic shock admitted to 41 Spanish ICUs during two time periods: 2005 (Edusepsis study pre-intervention group) and 2011 (ABISS-Edusepsis study pre-intervention group). SCOPE: Patients with severe sepsis or septic shock admitted to Spanish ICUs. PATIENTS: All ICU admissions from the emergency department or wards and all ICU patients with a diagnosis of severe sepsis or septic shock. A total of 1348 patients were included: 630 in the 2005 group and 718 in the 2011 group. INTERVENTION: None. PRIMARY ENDPOINTS: ICU mortality, 28-day mortality and Hospital mortality, hospital length of stay, ICU length of stay and compliance with the resuscitation bundle. RESULTS: Compliance with the resuscitation bundle was significantly greater in the 2011 group (5.7% vs. 9.9%; p=0.005), and was associated to lower mortality (OR 0.602 [0.365-0.994]; p=0.048). The 2011 group had lower absolute in-hospital mortality (44.0% vs. 32.6%; p=0.01), 28-day mortality (36.5% vs. 23.0%; p=0.01), and adjusted mortality (OR 0.64 [0.49-0.83], p=0.001). CONCLUSIONS: Mortality related to severe sepsis or septic shock in Spain decreased between two patient cohorts in 2005 and 2011, and was attributable to earliness and improvement in sepsis care.

La administración precoz y adecuada de la antibioticoterapia empírica en la sepsis salva vidas; pero ¿cómo hacerlo? / Early and adequate empirical antibiotic treatment in sepsis saves lives, but how should it be provided?

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Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes.

Co-encapsulation of drugs in the same carrier, as well as the development of microencapsulation processes for biomolecules using mild operating conditions, and the production of particles with tailored size and uniformity are major challenges for encapsulation technologies. In the present work, a suitable method consisting of the combination of membrane emulsification with solvent diffusion is reported for the production of multi-core matrix particles with tailored size and potential application in multi-therapies. In the emulsification step, the production of a W/O/W emulsion was carried out using a batch Dispersion Cell for formulation testing and subsequently a continuous azimuthally oscillating membrane emulsification system for the scaling-up of the process to higher capacities. In both cases precise and gentle control of droplet size and uniformity of the W/O/W emulsion was achieved, preserving the encapsulation of the drug model within the droplet. Multi-core matrix particles were produced in a post emulsification step using solvent diffusion. The compartmentalized structure of the multicore-matrix particle combined with the different chemical properties of polycaprolactone (matrix material) and fish gelatin (core material) was tested for the simultaneous encapsulation of hydrophilic (copper ions) and hydrophobic (α-tocopherol) test components. The best operating conditions for the solidification of the particles to achieve the highest encapsulation efficiency of copper ions and α-tocopherol of 99 (± 4)% and 93(± 6)% respectively were found. The multi-core matrix particle produced in this work demonstrates good potential as a co-loaded delivery system.

Micro and nano polycaprolactone particles preparation by pulsed back-and-forward cross-flow batch membrane emulsification for parenteral administration.

In the pharmaceutical field, manufacturing processes which are able to make products with tailored size at suitable shear stress conditions and high productivity are important requirements for their industrial application. Cross-flow and premix membrane emulsification are the membrane-based processes generally used for particles preparation at large scale, however some disadvantages still limit their applicability for the production of fragile products. In this work, we investigated, for the first time, the preparation of micro and nano polymeric particles in a size range between 2.35 (±0.14)µm and 210 (±10)nm by using pulsed back-and-forward membrane emulsification for the application in pharmaceutical field. The suitability of the method to produce tailored particles by applying mild shear conditions has been demonstrated. The optimized fluid-dynamic conditions studied allowed the production of particles with target size by selecting the appropriate pore size of the membrane (1 µm and 0.1 µm). The uniformity of the particles could be obtained with an axial velocity of 0.5 ms(-1) (corresponding to a shear stress of 4.1 Pa) that is 9 times lower than the maximum cross flow velocity reported in literature (4.5 ms(-1)).

Sepsis grave y shock séptico: Todo hecho, todo por hacer / Severe sepsis and septic shock: everything done, everything to be done

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Serotonin toxicity: a short review of the literature and two case reports involving citalopram.

The serotonin toxicity (ST) is a potentially life-threatening adverse drug reaction results from therapeutic drug use, intentional self-poisoning, or inadvertent interactions between drugs. ST can be caused by a single or a combination of drugs with serotonergic activity due to excessive serotonergic agonism on central nervous system and peripheral serotonergic receptors (monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, opiate analgesics, over-the-counter cough medicines, antibiotics, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse, H2-antagonist and herbal products). The serotonin toxicity is often described as a clinical triad of mental-status changes (agitation and excitement with confusion), autonomic hyperactivity (diaphoresis, fever, tachycardia, and tachypnea), neuromuscular abnormalities (tremor, clonus, myoclonus, and hyperreflexia) and, in the advanced stage, spasticity; not all of these findings are consistently present. In this article, we describe two cases of ST due to interaction between Citalopram and two CYP2D6 inhibitors: Cimetidine and Topiramate and their clinical resolution after treatment discontinuation.

Treatment of rhinosinusitis: the role of surgery.

The treatment of rhinosinusitis in children is mostly medical. Surgery is indicated in few but important exceptions: orbital or intracranial complications of acute rhinosinusitis not responding to medical therapy, chronic rhinosinusitis (CRS) with persisting sinonasal infection and purulent discharge, cystic fibrosis, ciliary diskinesia, dacryocystitis due to sinusitis and resistant to medical treatment, fungal rhinosinusitis. According to recent data, 50 percent of ENT specialist perform an adenoidectomy to manage CRS before endoscopic sinus surgery (ESS). ESS techniques introduced in mid 90s, has significantly modified the treatment of complications of acute rhinosinusitis and of selected cases of chronic recurrent infections. ESS consists of minimally invasive surgical procedure as middle meatal antrostomy and anterior ethmoidectomy. Evidence suggests that adenoidectomy and ESS are the most frequent surgical procedure performed in RS management.

Chronic rhinosinusitis and allergy.

The role of allergic sensitization in chronic sinusitis in childhood is currently unclear, as contrasting results were reported in the studies thus far available. In fact, some surveys found prevalence of atopy up to 60% in subjects with chronic sinusitis, while other failed to confirm any association between the two conditions. The data we obtained in a cross-sectional study on a large population of children should help in better defining such issue. Among 2200 children referring for evaluation of chronic respiratory symptoms, subjects satisfying at least two of major criteria for the definition of chronic sinusitis were recruited, and underwent to allergen sensitization workup by skin prick test with common inhalant allergens and total IgE measurement. Patients were stratified according to age lower than 3 years (group 1), age between 3 and 6 years (group 2), and age above 6 years (group 3). In all, 351 children (217 boys, 134 girls, mean age 5.23+/-2.11 years, range 1.5-15 years) were available for evaluation and formed three groups (27 in group 1, 261 in group 2 and 63 in group 3). Prevalence of both sensitization to at least one inhalant allergen by skin test and of high total IgE was 29.9%, with significant difference for the former across age groups, with a value of 7.4% in group 1, 31.4% in group 2 and 33.3% in group 3 (p=0.028), but after adjusting for age, sinusitis and aeroallergen sensitization were not significantly correlated. The difference across groups for high total IgE did not reach statistical significance, with respective prevalence of 22.7%, 30.1% and 32.1%. It is possible to conclude that the prevalence of sensitization to aeroallergens in children with chronic sinusitis is comparable with that of the general paediatric population, as assessed in the Italian arm of the ISAAC study and this does not account for routine investigation for allergy in children with chronic sinusitis.

Sinusitis and Eustachian tube dysfunction in children.

Because of its anatomic and functional connections, middle ear disorders frequently occur in sinusitis. Its prevalence, however, is likely to be underestimated. We evaluated the prevalence of Eustachian tube dysfunction in children with chronic sinusitis, in a large group of patients with chronic respiratory symptoms and its possible relationship with respiratory allergy. From a population of 1810 children with respiratory symptoms referred to our Pediatric Allergy Center, subjects with chronic sinusitis diagnosed by clinical criteria were selected. The children underwent testing of Eustachian tube function by tympanometry and of allergy by skin tests with common environmental allergens. Patients were divided into three groups according to age: group 1, <3 yr; group 2, between 3 and 6 yr, group 3, older than 6 yr. Overall 402 children (22.2%) had clinical diagnosis of chronic sinusitis according to the established criteria. Thirty-three patients were in group 1, 299 in group 2, and 70 in group 3. Altered middle ear pressure was found in 69.1% of patients, with a significantly higher rate of altered tympanograms in younger children (p=0.001). A positive skin-prick test was found in 29.8% of children, with a significantly higher rate of positivity in older children (p=0.015). The decrease in the rate of Eustachian tube dysfunction with age is likely to be associated with the anatomic development of the upper airways, while the presence of atopy does not seem to play a role in their occurrence.

Chronic sinusitis and atopy: a cross-sectional study.

BACKGROUND: The role of allergic sensitization in chronic sinusitis in childhood is currently unclear, as contrasting results were reported in the studies thus far available. OBJECTIVE: We evaluated by a cross-sectional study the prevalence of sensitization to common inhalant allergens in children with chronic sinusitis. METHODS: Among 2200 children referring to our Paediatric out-patient Unit for evaluation of chronic respiratory symptoms, subjects satisfying at least two of major criteria for the definition of chronic sinusitis were recruited, and underwent to allergen sensitization workup by skin prick test (SPT) with common inhalant allergens and total IgE determination. Participants were stratified according to age inferior to three years (Group 1), age between three and six years (Group 2), and age above six years (Group 3) for the purpose of evaluation. RESULTS: In all, 351 children (217 boys, 134 girls, mean age 5.23 ? 2.11 years, range 4-15 years) were available for evaluation and were stratified (27 in Group 1, 261 in Group 2 and 63 in Group 3). Prevalence of both sensitization to at least one inhalant allergen by SPT and of high total IgE was 29.9%. Prevalence of SPT sensitization was significantly different across age groups, with a value of 7.4% in Group 1, 31.4% in Group 2 and 33.3% in Group 3 (p = 0.028), but after adjusting for age, sinusitis and aeroallergen sensitization did not correlate significantly. The difference across groups for high total IgE did not reach statistical significance, with 22.7%, 30.1% and 32.1% for each group respectively. CONCLUSIONS: The prevalence of sensitization to aeroallergens in children with chronic sinusitis is comparable to that of the general paediatric population, as assessed in the Italian arm of the ISAAC study. This does not account for routine investigation for allergy in children diagnosed with such disease.

Papel de la microcirculación en el desarrollo de la lesión pulmonar aguda inducida por la ventilación mecánica / Role of microvasculature in the development of acute lung injury induced by mechanical ventilation

La presión capilar pulmonar es uno de los determinantes de la formación de edema pulmonar y además favorece el desarrollo de lesión pulmonar inducida por la ventilación mecánica (VILI). En consecuencia, en los enfermos críticos sometidos a ventilación mecánica (VM), la determinación ajustada de la presión capilar cobra mayor relevancia. El flujo vascular también es un factor determinante de la lesión pulmonar aguda, cuyo incremento favorece una mayor lesión pulmonar. El aumento de estas variables fisiológicas determina un incremento del estrés mecánico sobre las células del endotelio capilar pulmonar, lo que puede inducir una respuesta inflamatoria endotelial y favorecer la aparición o el empeoramiento de la lesión pulmonar aguda. En consecuencia, reducir el estrés vascular pulmonar puede disminuir la lesión pulmonar aguda en modelos experimentales

Pulmonary wedge pressure is one of the determinants of pulmonary edema and in addition favors the development of pulmonary injury induced by mechanical ventilation (PIMV). Accordingly, in the critically ill patients subject to mechanical ventilation (MV), the precise determination of pulmonary wedge pressure gain in importance. Vascular flow is also a decisive factor in acute pulmonary injury, and its increase favors a more intense pulmonary injury. The increase of these physiological variables determines an increment in mechanical stress on the cells of pulmonary capillary endothelium, and this stress can induce an endothelial inflammatory response with appearance or worsening of acute pulmonary injury. Accordingly, reducing pulmonary vascular stress can diminish acute lung injury in experimental models

Growth in the first two years of uninfected children born to HIV-1 seropositive mothers.

OBJECTIVE: To assess the growth curves of uninfected infants born to type 1 human immunodeficiency virus (HIV-1) seropositive mothers by means of standardised anthropometric indices. METHODS: The z scores (National Center for Health Statistics-World Health Organization data) of weight for age, length for age, and weight for length of 92 uninfected full term infants born to HIV positive mothers were compared with those of 65 bottle fed full term infants born to healthy mothers at 0, 1, 2, 3, 4, 6, 9, 12, 18, and (in a subgroup) 24 months of age. Confounders were also recorded. RESULTS: The study population had a lower length for age z score at birth (95% confidence intervals (CI): 0.02, -0.58) and higher weight for length z scores at 1 (95% CI: 0.21, 0.63), 2 (95% CI: 0.25, 0.66), and 3 (95% CI: 0.0, 0.48) months compared with the reference group. After a temporary recovery, the length for age z score difference increased progressively from the 4th month onwards and was significant at 18 (95% CI: -0.31, -1.05) and 24 (95% CI: -0.02, -0.91) months. The difference between the length for age z scores at birth was associated with maternal covariates, but the between group difference at 18 months was apparent even after adjustment for covariates. CONCLUSION: Uninfected infants born to HIV positive mothers have a rapid weight gain immediately after birth. A decrease in length progression during the second year might be a result of the social risk connected with the family environment and an unfavourable programming related to the maternal HIV status.

Activities of oral antibiotics on Providencia strains isolated from institutionalized elderly patients with urinary tract infections.

More than 250 Providencia strains isolated from the urine of institutionalized elderly patients were tested against cefaclor, cefuroxime, cefetamet, cefpodoxime, ciprofloxacin, and amoxicillin-clavulanic acid. Our results confirm the strong activities of expanded-spectrum oral cephalosporins against Providencia isolates, f1p4ell as the marked differences in susceptibilities among accurately identified Providencia species.

Persistence of human T cell lymphotropic virus type 1 (HTLV-1) sequences in peripheral blood mononuclear cells from patients with mycosis fungoides.

Mycosis fungoides (MF) is a rare form of cutaneous T cell lymphoma suspected of having a viral etiology. As in adult T cell leukemia, the virus involved may be human T lymphotropic virus type 1 (HTLV-1). We cultured the peripheral blood mononuclear cells (PBMC) of 29 patients with MF HTLV-1 seronegative by enzyme-linked immunosorbent assay and Western blot. The presence of reverse transcriptase (RT) and p24 antigen was investigated in the concentrate supernatant of the culture. The DNA of all studied patients was submitted to polymerase chain reaction and Southern blot analysis using primers and probes recognizing the tax region of HTLV-1/2 and the pol region of HTLV-1. 10 of 29 patients were found positive to HTLV-1, whereas they were always negative to RT and p24. The same results were confirmed in double blind after 6 mo. Our findings suggest HTLV-1 may be involved in the etiology of MF, at least in certain cases.

In vitro activity of cefpirome (HR 810) against enterococci and staphylococci.

The inhibitory activity of cefpirome (HR 810), a new cephalosporin derivative for parenteral use, was tested by agar dilution methods against Enterococcus faecalis (100 strains), Staphylococcus aureus (40 strains) and coagulase-negative staphylococcal species (60 strains) in comparison with other beta-lactam antibiotics. For E. faecalis, the cefpirome minimum inhibitory concentration (MIC) range was 2-128 micrograms/ml, with an MIC50 of 8 micrograms/ml, and an MIC90 of 64 micrograms/ml. The optimal bactericidal activity against strains with MICs of < or = 8 micrograms/ml occurred at 2-4 times the MIC, and the reduction in the initial inoculum was 99.9-99.7% after 24 h incubation at these concentrations. Mec gene-negative staphylococci (both S. aureus and coagulase-negative species) had cefpirome MICs of 0.25-2 micrograms/ml (MIC50 0.5 microgram/ml, MIC90 1 microgram/ml). Mec gene-positive strains had MICs of 0.5-128 micrograms/ml (MIC50 2 micrograms/ml, MIC90 32 micrograms/ml). Strains with borderline resistance to oxacillin which did not harbor the mec gene and which were susceptible to cefpirome maintained their susceptibility even when high-density inocula were used and after several passages in media containing the antibiotic. These studies present some potential advantages of cefpirome over other cephalosporins in the inhibitory activity against Gram-positive cocci.