Prevalence and clinical impact of VIral Respiratory tract infections in patients hospitalized for Community-Acquired Pneumonia: the VIRCAP study.

Prevalence and clinical impact of viral respiratory tract infections (VRTIs) on community-acquired pneumonia (CAP) has not been well defined so far. The aims of this study were to investigate the prevalence and the clinical impact of VRTIs in patients with CAP. Prospective study involving adult patients consecutively admitted at medical wards for CAP and tested for VRTIs by real-time PCR on pharyngeal swab. Patients' features were evaluated with regard to the presence of VRTI and aetiology of CAP. Clinical failure was a composite endpoint defined by worsening of signs and symptoms requiring escalation of antibiotic treatment or ICU admission or death within 30 days. 91 patients were enrolled, mean age 65.7 ± 10.6 years, 50.5% female. 62 patients (68.2%) had no viral co-infection while in 29 patients (31.8%) a VRTI was detected; influenza virus was the most frequently identified (41.9%). The two groups were similar in terms of baseline features. In presence of a VRTI, pneumonia severity index (PSI) was more frequently higher than 91 and patients had received less frequently pre-admission antibiotic therapy (adjusted OR 2.689, 95% CI 1.017-7.111, p = 0.046; adjusted OR 0.143, 95% CI 0.030-0.670, p = 0.014). Clinical failure and antibiotic therapy duration were similar with regards to the presence of VRTI and the aetiology of CAP. VRTIs can be detected in almost a third of adults with CAP; influenza virus is the most relevant one. VRTI was associated with higher PSI at admission, but it does not affect patients' outcome.

Serial monitoring of isavuconazole blood levels during prolonged antifungal therapy.

BACKGROUND: Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. OBJECTIVES: To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. METHODS: From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. RESULTS: A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64-8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023-0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity. CONCLUSIONS: Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Bariatric surgery is associated with increased risk of new-onset inflammatory bowel disease: case series and national database study.

BACKGROUND: Case series suggest a possible association between bariatric surgery and incident IBD. AIM: The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD. METHODS: We first conducted a multi-institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC. RESULTS: A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en-Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52). CONCLUSION: New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.

Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease.

BACKGROUND: Increased knowledge of pathways involved in the pathogenesis of IBD has led to the development of new treatment options for Crohn's disease (CD) and ulcerative colitis (UC). Two new biological agents have been recently approved for IBD: vedolizumab and ustekinumab. They have different therapeutic targets (α4 ß7 integrin for vedolizumab and interleukin-12/23 pathways for ustekinumab) than the primary biological class, anti-tumour necrosis factor alpha (anti-TNF) agents. As the armamentarium for IBD increases in coming years, it will become important to understand factors associated with response in order to best position and personalise therapy. AIM: To summarise the current data on predictors of response to vedolizumab and ustekinumab in IBD patients. METHODS: We conducted a comprehensive literature review. A PubMed search was performed using pre-defined key words and terms to identify relevant studies on predictors of response. RESULTS: Patients with severe disease (by clinical activity and inflammatory biomarkers), or prior anti-TNF exposure are less likely to respond to vedolizumab. Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD. Initial response seems to predict a better long-term maintenance in both therapies (P < 0.001). Contrary to anti-TNF therapies, immunogenicity appears to play less of a role in response. CONCLUSION: As the number of new biological therapies increase in IBD, identifying patients who are most likely to benefit from specific agents is of paramount importance to help best position IBD therapies.

Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation.

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.

Systematic review with meta-analysis: proximal disease extension in limited ulcerative colitis.

BACKGROUND: Disease extent in ulcerative colitis is one of the major factors determining prognosis over the long-term. Disease extent is dynamic and a proportion of patients presenting with limited disease progress to more extensive forms of disease over time. AIM: To perform a systematic review and meta-analysis of epidemiological studies reporting on extension of ulcerative colitis to determine frequency of disease extension in patients with limited ulcerative colitis at diagnosis. METHODS: We performed a systematic literature search to identify studies on disease extension of ulcerative colitis (UC) and predictors of disease progression. RESULTS: Overall, 41 studies were eligible for systematic review but only 30 for meta-analysis. The overall pooled frequency of UC extension was 22.8% with colonic extension being 17.8% at 5 years and 31% at 10 years. Extension was 17.8% (95% CI 11.2-27.3) from E1 to E3, 27.5% (95% CI 7.6-45.6) from E2 to E3 and 20.8% (95% CI 11.4-26.8) from E1 to E2. Rate of extension was significantly higher in patients younger than 18 years (29.2% (CI 6.4-71.3) compared to older patients (20.2% (CI 13.0-30.1) (P<.0001). Risk of extension was significantly higher in patients from North America (37.8%) than from Europe (19.6%) (P<.0001). CONCLUSIONS: In this meta-analysis, approximately one quarter of patients with limited UC extend over time with most extension occurring during the first 10 years. Rate of extension depends on age at diagnosis and geographic origin. Predicting those at high risk of disease extension from diagnosis could lead to personalised therapeutic strategies.

Soybean oil: a potentially new intravascular perfusate.

BACKGROUND: Given that micelles of lipids are colloids, the hypothesis was generated that the rapid administration of large volumes of soybean oil micelles would be an effective perfusion fluid. We also hypothesized that oxygen loading would be enhanced due to the greater solubility of oxygen in lipids compared to water. METHODS: A 100% lethal mouse model of blood loss was used to compare the ability of soybean oil micelles to that of Ringer's lactate, blood and other fluids, with respect to raising and maintaining the blood pressure for one hour. Oxygen on- and off-loading of various concentrations of soybean oil micelles was determined using mass spectroscopy. Nitric oxide uptake by micelles was also determined in a similar fashion. RESULTS: A 20% soybean oil emulsion was superior to Ringer's lactate in raising and maintaining blood pressure. A 20% soybean oil emulsion with 5% albumin added was superior to shed blood as well as solutions comprised of 5% albumin added to either normal saline or Ringer's lactate. There was a linear relationship between oxygen content and micelle concentration between 10% and 30%. Off-loading of oxygen from the micelles was nearly as fast as off-loading from water. Nitric oxide also loaded preferentially onto soybean oil micelles. CONCLUSIONS: (1) Soybean oil emulsions were superior to other fluids in restoring and maintaining the blood pressure; (2) oxygen-carrying ability of soybean oil micelles exceeds that of water and follows Henry's law between 10% and 30% w/v oil content; (3) nitric oxide was carried by the micelles; (4) animals receiving soybean oil micelles did not exhibit fat embolization; (5) colloids comprised of soybean oil-containing micelles may be used to replace blood loss and may be used to deliver oxygen and other potentially therapeutic gases such as nitric oxide to tissues.

Calixarene-based multivalent ligands.

Multivalency is a powerful concept which explains the strong binding observed in biological systems and guides the design and synthesis of ligands for self-assembly and molecular recognition in Chemistry. The phenol-formaldehyde cyclic oligomers, called calixarenes, have been used as scaffolds for the synthesis of multivalent ligands thanks to the fact that they have a variable number of reactive positions for attaching the ligating functions, well defined conformational properties and, in some cases, cavities of molecular dimensions eventually able to encapsulate guest species. This tutorial review illustrates the fundamental aspects of multivalency and the properties of calixarene-based multivalent ligands in lectin binding and inhibition, DNA condensation and cell transfection, protein surface recognition, self-assembly, crystal engineering, and nanofabrication.

Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure.

Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 10(7) particles (P<0.01), whereas the same recombinant vectors were ineffective at 10(8) particles and increased mortality at 10(9) particles. Improved survival after administration of 10(7) particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100-300 pg/g wet wt). In contrast, mortality after administration of 10(9) particles was associated with markedly elevated IL-10 expression, both in the lung (10000-70000 pg/g wet wt) and systemically (1000-3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFalpha). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.

New efficient calixarene amide ionophores for the selective removal of strontium ion from nuclear waste: synthesis, complexation, and extraction properties.

Three novel lower rim hexamide derivatives 5(6), 7(6), and 9(6) of p-hydroxycalix[6]arene and four octamides 5(8), 7(8)-9(8) derived from the corresponding p-hydroxycalix[8]arene were synthesized, and their potential as extractants in radioactive waste treatment was evaluated, in comparison with upper rim analogues 12(6) and 12(8) and other existing selective neutral ionophores currently used in radioactive waste treatment. Extraction of alkali and alkaline earth metal picrates from water to dichloromethane, and of the corresponding nitrates from acidic water solution simulating radioactive waste, to 2-nitrophenyl hexyl ether (NPHE), showed that the lower rim amides extract divalent cations much better than monovalent ones. The upper rim hexa-12(6) and octamide 12(8) are very inefficient ligands, hardly extracting any cation. In all cases, p-alkoxy octamides are more efficient and selective extractants than the corresponding hexamides. In the case of simulated waste solutions, the distribution coefficients for strontium removal by octamides (6.5 < D(Sr) < 30) are much higher than the corresponding value (D(Sr)) found for dicyclohexyl-18-crown-6 (DC18C6), and the same applies for the strontium/sodium selectivity, which is 6500 < D(Sr)/D(Na) < 30 000 for octamides and 47 for DC18C6. ESI-MS, UV-vis, and X-ray crystal structure studies give consistent results and indicate the formation of 2:1 (cation/ligand) strontium complexes for all octamides tested. Stability constants were determined in homogeneous methanol solution for alkali metal (log beta(11) < or = 2), calcium (4.3 < or = log beta(11) < or = 6.0; 9.4 < or = log beta(21) < or = 12.0), and strontium (5.6 < or = log beta(11) < or = 12.3) ions using a UV-vis competition method with 1-(2-pyridylazo)-2-naphthol (PAN). They confirm the high efficiency and high divalent/monovalent selectivity found in metal ion extraction experiments for the new octamide ligands. Evidence for a positive cooperative effect between the two metal ion binding sites was obtained in the case of the Ca(2+) complex of octamide 1(8).

Catalysis of acyl group transfer by a double-displacement mechanism: the cleavage of aryl esters catalyzed by calixcrown-Ba2+ complexes

The scope of the barium salt of p-tert-butylcalix[4]arene-crown-5 as a transacylation catalyst has been defined by evaluating its efficiency in the methanolysis of a series of aryl acetates at 25.0 degrees C in MeCN/MeOH 9:1 (v/v) under slightly basic conditions. In this system a phenolic hydroxyl is the acyl-receiving and -releasing unit in a double-displacement mechanism. The complexed barium ion acts both as a nucleophile carrier and a built-in Lewis acid in providing electrophilic assistance to the ester carbonyl both in the acylation and deacylation step (nucleophilic-electrophilic catalysis). Turnover capability is ensured by the acylated intermediate reacting with the solvent more rapidly than the original ester, but a serious drawback derives from the incursion of back-acylation of the liberated phenol. A gradual shift from rate-determining deacylation (p-nitrophenyl acetate) to rate-determining acylation (phenyl acetate) is observed along the investigated series. It is shown that the scope of the catalyst is restricted to acetate esters whose reactivity lies in the range approximately defined by the phenyl acetate-p-nitrophenyl acetate pair, with a maximum efficiency for p-chlorophenyl acetate. Moreover, the catalyst effectively promotes ester interchange between phenols, showing that its activity is not limited to solvolysis reactions. The very high sensitivity of the rate of acylation of the catalyst to leaving group basicity has been interpreted as due to rate-determining decomposition of the tetrahedral intermediate, which is believed to arise from the presumably low basicity of the metal ion stabilized nucleophile. The turnover frequency was in the range of 3.8 x 10(-4) min(-1) for phenyl acetate to 7.4 x 10(-3) min(-1) for p-nitrophenyl acetate ([ArOAc]0=4.0 mM]). A first attempt to enhance the rate of acylation of the catalyst through intramolecular general acid catalysis is also described.

Silicate pneumoconiosis in hens.

Thirteen cases of silicate pneumoconiosis in 3- to 4-year-old hens are described. Ten of the birds were raised in the suburbs of a city near several chalk quarries and two cement-works; the remaining three hens (aged 3 years) had lived in an environment with high particulate pollution from a nearby brick-works in which large amounts of clay were used daily. Silicotic granulomas composed of dust-laden macrophages were scattered over the lungs. They were located mainly in the infundibula and atria of tertiary bronchi and around vessels; more rarely they occurred in the lamina propria mucosae of primary and secondary bronchi. Energy dispersive x-ray microanalysis coupled with both transmission and scanning electron microscopy revealed that the dust was composed mainly of silicon, aluminium, calcium, iron and potassium. Titanium, sulphur, magnesium, zinc, copper and chlorine were also found. It is concluded that animals raised in polluted environmental conditions may serve as an important indicator of risks to human health and pathogenetic mechanisms. Thirteen cases of silicate pneumoconiosis in 3- to 4-year-old hens are described. Ten of the birds were raised in the suburbs of a city near several chalk quarries and two cement-works; the remaining three hens (aged 3 years) had lived in an environment with high particulate pollution from a nearby brick-works in which large amounts of clay were used daily. Silicotic granulomas composed of dust-laden macrophages were scattered over the lungs. They were located mainly in the infundibula and atria of tertiary bronchi and around vessels; more rarely they occurred in the lamina propria mucosae of primary and secondary bronchi. Energy dispersive x-ray microanalysis coupled with both transmission and scanning electron microscopy revealed that the dust was composed mainly of silicon, aluminium, calcium, iron and potassium. Titanium, sulphur, magnesium, zinc, copper and chlorine were also found. It is concluded that animals raised in polluted environmental conditions may serve as an important indicator of risks to human health and pathogenetic mechanisms.

2,2'-bipyridine lariat calixcrowns: a new class of encapsulating ligands forming highly luminescent Eu3+ and Tb3+ complexes

A new class of calix[4]arene crown ethers with one or two bipyridines appended to the polyether ring (lariat calixcrowns) have been designed and synthesized; the luminescence properties of their Eu3+ and Tb3+ complexes have been studied in acetonitrile. In this solvent, long lifetimes for the metal emitting states and high metal-luminescence intensities obtained upon ligand excitation have been observed in both Eu3+ and Tb3+ complexes. The association constants in methanol have been determined for some of the complexes studied.

Recognition of cationic species with synthetic receptors.

In the past year progress in the study of cationic species has been made, particularly in our understanding of the factors which control the selective recognition of biologically important cations such as ammonium, alkali and alkaline earth metal ions, and of metal ions used in biomedicine such as lanthanides and iron(III). Based on this knowledge, several new hosts with improved transport, photophysical and biological properties have been designed.

A family history study of schizophrenia-related personality disorders.

This study examined whether the family history method can be used to detect cases of schizophrenia-related personality disorder in the families of schizophrenic patients. After proposing specific family history criteria for this diagnosis, the authors applied these criteria in a blind family history study and found that schizophrenia-related personality disorders were significantly more common in the first-degree relatives of schizophrenic patients than in the relatives of medically ill controls.