In vitro reversion of amphotericin B resistance in Leishmania donovani by poloxamer 188

A micellar formulation of amphotericin B (AmB) solubilized with poloxamer 188 was evaluated against an AmB Leishmania donovani-resistant line. A concave isobologram showed a synergistic effect of this association against promastigotes. This result was confirmed with amastigotes since the 50% effective concentration of the new formulation was 100 times less than that of the control AmB formulation

Evolution of coronary atherosclerosis in patients with mild coronary artery disease studied by serial quantitative coronary angiography at 2 and 4 years follow up

AIMS: Angiographic studies on the natural course of both focal and diffuse coronary atherosclerosis have not been performed before, but can both be assessed by quantitative coronary angiography. The objective of this study was to describe the natural course of focal and diffuse coronary atherosclerosis over time. METHODS AND RESULTS: In 129 patients with mild coronary artery disease, but not on lipid-lowering medication, three coronary angiograms were made each 2 years apart. Nine hundred and sixty five angiographically diseased and non-diseased segments were analysed by quantitative coronary angiography. Mean lumen diameter and minimal lumen diameter were used as measures of diffuse and focal coronary atherosclerosis. Mean lumen diameter and minimum lumen diameter decreased by 0.02 and 0.03 mm per year. The rate of progression was similar in the angiographically non-diseased, as in the mildly and moderately diseased segments. Progression of diffuse coronary atherosclerosis was largest in severely stenosed lesions (percentage diameter stenosis > or = 50%) and in the right coronary artery with a loss of 0.19 mm and 0.16 mm in mean lumen diameter. Progression of focal disease was most prominent in new and mild lesions and the right coronary artery, with a decrease in minimum lumen diameter of 0.34 mm and 0.22 mm. In most subgroups, progression occurred gradually over time. On a per segment level, progression and the occurrence of new lesions occurred in 4.4% and 4.2%. Regression and disappearance of a lesions was found in 2.3% and 1.9%. On a per patient level, 36% were progressors, 12% had a mixed response, 36% were stable, and 16% were regressors. CONCLUSION: Diffuse and focal coronary atherosclerosis progressed at the same rate in the first and second 2 years in stenosed and non-stenosed segments. The rate of coronary atherosclerosis progression was small, but was higher for focal than for diffuse disease. A minority of lesions progressed and spontaneous regression was rare

Deux cas d’adénite cervicale à mycobactéries non tuberculeuses chez l’enfant

BACKGROUND: Cervical lymphadenitis is the most common manifestation of infection with nontuberculous mycobacteria (NTM) in immunocompetent children. Nevertheless, it is poorly known by dermatologists. Its incidence, which is currently increasing since the cessation of BCG vaccination in 2007, raises several issues regarding its pathophysiology, diagnosis and management. PATIENTS AND METHODS: We report two cases of NTM adenitis: one in a 2-year-old girl vaccinated with BCG and one in an unvaccinated 22-month-old boy, in whom a misleading presentation led to delayed diagnosis. The condition progressed to fistula formation and the diagnosis was finally made on systematic cultures of lymph node samples. The time to diagnosis was 2 and 4months, respectively. The girl was treated with erythromycin for 3 weeks and with clarithromycin for 3 weeks; the boy received clarithromycin for 7 weeks and underwent complete surgical excision. DISCUSSION: NTM adenitis preferentially affects girls under 4 years and occurs more frequently in winter and spring. First, the other differential diagnoses, including tuberculosis, must be ruled out by chest radiography. The diagnosis is oriented by the clinical picture, a positive TST and resistance to conventional antibiotics. However, it is only certified by systematic culture or PCR of lymph node biopsies, with screening for atypical mycobacteria being specified. The decrease in child protection by BCG vaccination coincides with the current increase in NTM infections, of which the most frequent is Mycobacterium avium complex (MAC) for cervical adenitis. The reference treatment is surgery. However, alternative treatments (incomplete excision, antibiotics, watchful waiting, etc.) should be considered where surgery fails or there is excessive risk of injury to a branch of the facial nerve. CONCLUSION: Atypical mycobacterial adenitis in immunocompetent children has become an increasingly common infection since the abandonment of BCG vaccination. Improved knowledge of this disease would result in complete surgical excision at an early stage with a lower rate of aesthetic sequelae

Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice

Objective: To study the toxicity and activity of two new amphotericin B formulations: poly(ε-caprolactone) nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM). Materials and methods: The toxicity of these formulations was evaluated in erythrocytes, J774.2 macrophages and LLCPK1 renal cells, as well as in mice. Activity was determined in clinical isolates and in neutropenic mice. Mice were made neutropenic with 5-fluorouracil, infected with Candida albicans and treated with the antifungal formulations for three consecutive days. AmB association in cells and accumulation in kidneys and liver of animals was quantified by HPLC. Results: Both formulations decreased between 8- and 10-fold the MIC of the polyene against clinical isolates of C. albicans. However, their activity was lower than or equal to that of AmB-deoxycholate when it was assessed against C. albicans-infected macrophages. When given as a single intravenous dose in mice, AmB-MM and AmB-NP had an LD50 of 9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmBdeoxycholate. Comparison of residual infection burdens in the liver and kidneys showed that AmB-deoxycholate (0.5 mg/kg) was more effective and faster in eradicating yeast cells than polymeric formulations. This fact can be related to a lower AmB accumulation inside macrophages and in liver and kidneys (about 1.5 mg drug/g tissue) of mice, compared with those detected for AmB-deoxycholate (4 mg drug/g). Overall, the efficacy of these formulations at 2 mg/kg was equal to that of AmB-deoxycholate at 0.5 mg/kg. Conclusions: AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher concentrations were therefore necessary to obtain a similar therapeutic effect. However, these higher concentrations were achievable owing to the reduced toxicity of these formulations

Perspective:Moving Toward Desirable Linoleic Acid Content in Infant Formula

Infant formula should provide the appropriate nutrients and adequate energy to facilitate healthy infant growth and development. If conclusive data on quantitative nutrient requirements are not available, the composition of human milk (HM) can provide some initial guidance on the infant formula composition. This paper provides a narrative review of the current knowledge, unresolved questions, and future research needs in the area of HM fatty acid (FA) composition, with a particular focus on exploring appropriate intake levels of the essential FA linoleic acid (LA) in infant formula. The paper highlights a clear gap in clinical evidence as to the impact of LA levels in HM or formula on infant outcomes, such as growth, development, and long-term health. The available preclinical information suggests potential disadvantages of high LA intake in the early postnatal period. We recommend performing well-designed clinical intervention trials to create clarity on optimal levels of LA to achieve positive impacts on both short-term growth and development and long-term functional health outcomes

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

BACKGROUND: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. METHODS: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. RESULTS: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). CONCLUSIONS: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015

Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance

Monoclonal gammopathies of undetermined significance (MGUS) have been shown to be associated with an increased risk of fractures. This study describes prospectively the bone status of MGUS patients and determines the factors associated with vertebral fracture. We included prospectively 201 patients with MGUS, incidentally discovered, and with no known history of osteoporosis: mean age 66.6±12.5 years, 48.3% women, 51.7% immunoglobulin G (IgG), 33.3% IgM and 10.4% IgA. Light chain was kappa in 64.2% patients. All patients had spinal radiographs and bone mineral density measurement in addition to gammopathy assessment. At least one prevalent non-traumatic vertebral fracture was discovered in 18.4% patients and equally distributed between men and women. Fractured patients were older, had a lower bone density and had also more frequently a lambda light chain isotype. Compared with patients with κ light chain, the odds ratio of being fractured for patients with λ light chain was 4.32 (95% confidence interval 1.80-11.16; P=0.002). These results suggest a high prevalence of non-traumatic vertebral fractures in MGUS associated with lambda light chain isotype and not only explained by low bone density

TB hackathon : development and comparison of five models to predict subnational tuberculosis prevalence in Pakistan

Pakistan's national tuberculosis control programme (NTP) is among the many programmes worldwide that value the importance of subnational tuberculosis (TB) burden estimates to support disease control efforts, but do not have reliable estimates. A hackathon was thus organised to solicit the development and comparison of several models for small area estimation of TB. The TB hackathon was launched in April 2019. Participating teams were requested to produce district-level estimates of bacteriologically positive TB prevalence among adults (over 15 years of age) for 2018. The NTP provided case-based data from their 2010-2011 TB prevalence survey, along with data relating to TB screening, testing and treatment for the period between 2010-2011 and 2018. Five teams submitted district-level TB prevalence estimates, methodological details and programming code. Although the geographical distribution of TB prevalence varied considerably across models, we identified several districts with consistently low notification-to-prevalence ratios. The hackathon highlighted the challenges of generating granular spatiotemporal TB prevalence forecasts based on a cross-sectional prevalence survey data and other data sources. Nevertheless, it provided a range of approaches to subnational disease modelling. The NTP's use and plans for these outputs shows that, limitations notwithstanding, they can be valuable for programme planning