Effectiveness of bone marrow aspirate concentrate (BMAC) as adjuvant therapy in the surgical treatment of congenital pseudoarthrosis of the tibia: a retrospective comparative study.

Congenital pseudoarthrosis of the tibia (CPT) is a rare disease characterised by the onset of bone anomalies or fractures, leading to deformities in paediatric patients. The aetiology of this pathology is unknown. The main theories include the presence of hamartomatous tissue related to Neurofibromatosis type 1, vascularisation deficit of the periosteum and alterations in the numbers and functions of the osteoblasts and osteoclasts in loco. Surgical treatment generally requires multiple operations during the patient's childhood and adolescence. The best outcomes seem to occur when using intramedullary nailing, vascularised fibular transplant and external fixation with the Ilizarov technique. The purpose of this paper is to evaluate the effectiveness of in-situ injections of Bone Marrow Aspirate Concentrate (BMAC) as an adjuvant therapy for congenital pseudoarthrosis of the tibia in patients treated with external fixation and that of radiographic healing over time compared to external fixation treatment alone. We performed a retrospective review of clinical and radiographic records of patients affected by CPT and treated in the Paediatric Orthopaedics and Traumatology Department of the Gaetano Pini Orthopaedic Institute with in-situ injections of bone marrow aspirate concentrate (BMAC) on the pseudoarthrosis site, in addition to pseudoarthrosis site excision and application of circular external fixator frame in compression (Group A). The time needed to reach the radiological consolidation of the resection site was recorded and compared to that needed for patients treated with only pseudoarthrosis site excision and application of circular external fixator frame in compression (Group B). There is a statistically relevant improvement of healing time in patients affected by congenital pseudoarthrosis of the tibia treated with external fixation and bone marrow aspirate concentrate compared to patients affected by the same pathology treated with external fixation only. Injection of MSC in the pseudoarthrosis site after focus removal in combination with circular external fixation achieves faster bone healing compared with external fixation only, and the lower refracture percentage may be associated with the better quality and structure of the new bone. However, it would be desirable to have a longer followup to determine if the results of the BMC as adjuvant therapy will hold up over time.

Histological changes of the meniscus following an osteochondral lesion.

In the last few years, different tissue engineering strategies have been developed for the repair of osteochondral lesions. When the osteochondral scaffold is implanted on the femoral condyle, the meniscus might be affected by the implant and might undergo a progressive degeneration. The aim of our study is to analyze the morphological changes of the meniscus following an osteochondral lesion and the implant of a biphasic scaffold. A critical osteochondral defect was generated in the medial femoral condyle of mature sheep. Three defects were left untreated, the remaining lesions were divided into three groups and treated with a biphasic substituted formed by collagen type I and Wollastonite or Wollastonite/Hydroxyapatite. Animals were sacrificed after 6 months and menisci were isolated and analyzed by arthro-CT, macroscopic evaluation and histology. The results demonstrated that the osteochondral lesion negatively affects meniscus morphology and that the osteochondral substitute only partially mitigates the meniscus degeneration.

What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion.

Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient.

The physical phenotype of frailty for risk stratification of older medical inpatients.

OBJECTIVES: To determine the usefulness of physical phenotype of frailty, cognitive impairment, and serum albumin for risk stratification of elderly medical impatients. DESIGN: Prospective, observational cohort study. SETTING: A general internal medicine unit of a university hospital in Italy. PARTICIPANTS: Inpatients with an average age of 80.8 ± 7.5 yr (N = 470). MEASUREMENTS: Frailty was defined using the Study of Osteoporotic Fractures Index, a parsimonious version of the physical phenotype (two of the following markers: weight loss, inability to rise five times from a chair, and exhaustion). Two frailty markers from non-physical dimensions were also evaluated: cognitive impairment (Mini-Cog score < 3) and low serum albumin on ward admission (< 3,5 gr/dl). Logistic regression adjusted for preadmission and admission-related confounders was used to investigate whether the physical phenotype of frailty and the two non-physical markers were associated with ward length of stay and unfavorable discharge (death plus any other ward discharge disposition different from direct return home). Areas Under the receiver operating characteristic Curve (AUCs) and Likelihood Ratios (LRs) were used for evaluation of discriminatory ability and clinical usefulness of significant predictors. RESULTS: The physical phenotype of frailty was associated with both study outcomes (p < 0.010) but the association was mainly mediated by chair standing ability. Non-physical markers were associated only with unfavourable discharge (p < 0.001). All of these predictors, either alone or in combination, had poor discriminatory ability (AUCs < 0.70) and poor clinical usefulness (+LRs near 1) for the study outcomes. CONCLUSIONS: The physical phenotype of frailty appears of limited clinical use for risk stratification of older medical inpatients. Combination with markers from non-physical dimensions does not improve its prognostic abilities.

First Report of Rust Caused by Puccinia psidii on Eucalyptus dunnii in Uruguay.

Eucalypt rust caused by Puccinia psidii Winter represents a major disease affecting eucalypt production in South America, and is threatening myrtaceous hosts worldwide. In Uruguay, it was first detected infecting Eucalyptus globulus in 2001 (4) and later on E. grandis, Myrrhinium atropurpureum, and Myrcianthes pungens, two myrtaceae hosts native to Uruguay (3). Over the summer 2013, bright orange-yellowish pustules were detected on stock plants of E. dunnii in a nursery located in western Uruguay, province of Paysandú. A severe and explosive epidemic was readily observed. Affected leaves were taken to the laboratory and examined under the microscope. Uredinia and urediniospores were similar with those described previously in Uruguay on other hosts (3,4). Uredioniospores were 18 to 25 × 15 to 21 µm, yellow, unicellular, spherical to elliptical, base truncate, finely and uniformly echinulate with spines up to 1 µm long, with an evident bald patch without spines. To confirm identity of this fungus, genomic DNA was extracted from single-pustule urediniospores, and ITS region was amplified using primers PR1 and PR2 (1) with PCR conditions previously described (3). Forward and reverse sequences from three single pustules were obtained, assembled, and compared with those available in GenBank using BLAST searches. Obtained sequences showed to be identical to those analyzed by Pérez et al. (2011) collected from E. grandis and E. globulus, with no variation found in the analyzed region. A 100% identity was found with isolates UY1374 and UY1375 obtained from E. globulus, and with isolate UY1731 obtained from E. grandis (FJ710805, FJ710806, and FJ710807, respectively). Sequences were deposited in GenBank with accession numbers KM083129, KM083130, and KM083131. Even though this pathogen is known to occur in a wide variety of myrtaceous species, to our knowledge, this is the first natural infection record of P. psidii on E. dunnii in Uruguay and worldwide. This report confirms previous studies that indicated the susceptibility of E. dunnii when inoculated under controlled conditions (2,5). E. dunnii is being widely planted in Uruguay, eastern Argentina, and southern Brazil, with increasing significance to the pulp industry. Although the consequences of this finding have yet to be realized, scouting plantations is essential to estimate the real impact of this pathogen on this tree species. Our study contributes to expand the host range known for this globally important pathogen. References: (1) S. R. H. Langrell et al. Plant Pathol. 57:687, 2008. (2) L. Morin et al. PLoS ONE 7:e35434, 2012. (3) C. A. Pérez et al. Mycol. Progress 10:273, 2011. (4) N. Telechea et al. Plant Pathol. 52:427, 2003. (5) E. A. V. Zauza et al. Australas. Plant Pathol. 39:406, 2010.

Upper limb evaluation with robotic exoskeleton. Normative values for indices of accuracy, speed and smoothness.

BACKGROUND: Robotic rehabilitation devices for upper limb function (ULF) provide global indicators of a patient's ability, but the temporal evolution of motion related to motor control is disregarded. OBJECTIVE: To determine normative values for indices of accuracy, speed and smoothness in the evaluation of upper limb function. METHODS: Twenty-five healthy individuals performed the Armeo®Spring device "Vertical Capture" task. Custom stand-alone software was developed to provide the following indices: global Hand Path Ratio (HPR), local HPR in the target area (locHPR), vertical and horizontal overshoot (vertOS, horOS), maximum and mean velocity (maxVel, meanVel), mean/maximum velocity, number of peaks in velocity profiles (NVelPeaks) and normalized jerk (NormJerk). The dependence of indices on task characteristics was analyzed by an ANCOVA test. Indices inner relationships were assessed by a correlation and a factor analysis. Normative values were then provided. RESULTS: 4,268 single reaching movements were analyzed. Four indices were not affected by movement direction. Indices were minimally influenced by the difficulty level. Based upon correlation and factor analysis indices and can be grouped into three assessment fields, dealing with precision, velocity and smoothness. CONCLUSIONS: We have developed a tool to assess ULF in dynamic condition. Normative values were obtained to be used as references in assessing patients.

Variation of B-type natriuretic peptide concentrations and intrauterine growth restriction: mother, fetus and newborn.

To evaluate maternal, fetal, neonatal B-type natriuretic peptide (BNP) concentrations related to Intra Uterine Growth Restriction (IUGR). BNP concentrations in 43 IUGR and 35 healthy, Appropriate for Gestational Age (AGA) infants/paired mothers have been compared, from delivery/birth to first month of life. Maternal and IUGR cord BNP concentrations were coupled to fetal ultrasonography. Neonatal echocardiography was performed too. On delivery BNP was higher in all IUGR mothers, suffering or not from gestational hypertension, than in AGA (median 37.14 vs 11.1 pg/ml p=0.002). Maternal BNP was not associated to cord/neonatal BNP or fetal ultrasonographic parameters. Cord BNP was higher in IUGR than AGA newborns (median 23.9 vs 11.4 pg/ml p=0.0007) independently of gestational age, while varied with amniotic fluid (p=0.0044) and umbilical artery flowmetry (p=0.0121). Earlier drop of BNP on day 3 was reported in IUGR neonates (p=0.0001).Ventricular mass change/body weight varied positively in AGA newborns (p<0.001), while declined in IUGR ones (p=0.003). Carrying IUGR fetus is a stress factor resulting in high maternal BNP concentration. Altered fetal ultrasonographic parameters in IUGR newborns lead to higher BNP cord levels. A rapid BNP drop and probable ventricular mass adjustment of IUGR newborns may indicate earlier post-natal cardiovascular adaptation than AGA infants.

Effect of drug chirality on the skin permeability of ibuprofen.

The in vitro passive diffusion of S-ibuprofen (S-IB) and RS-ibuprofen (RS-IB) through human epidermis was determined to study the effects of drug chirality. S-IB has a lower melting point (T(m)=54 degrees C) than RS-IB (T(m)=77 degrees C) and, therefore, a greater solubility (S-IB: 127+/-1 microg/mL; RS-IB: 81+/-1 microg/mL). Supersaturated plasters were prepared by using a poly(dimethylsiloxane) adhesive and Eugragit RL and propylene glycol as antinucleant agents. The in vitro skin permeation profiles were determined by Franz cells and human epidermis obtained from three different donors. The permeation profiles of S-IB from saturated solutions resulted statistically higher than those of RS-IB (p<0.002). When plasters were used, no differences were noticeable between the enantiomer and racemate (p>0.17). The latter unexpected results could be explained considering that the RS-IB or S-IB in vitro release rate constants, determined using 3% w/w or 6% w/w loaded plasters, were not statistically different, suggesting that the drug diffusivity within the adhesive matrix represented the rate limiting step to the skin absorption.

Palliative sedation therapy does not hasten death: results from a prospective multicenter study.

BACKGROUND: Palliative sedation therapy (PST) is indicated for and used to control refractory symptoms in cancer patients undergoing palliative care. We aimed to evaluate whether PST has a detrimental effect on survival in terminally ill patients. METHODS: This multicenter, observational, prospective, nonrandomized population-based study evaluated overall survival in two cohorts of hospice patients, one submitted to palliative sedation (A) and the other managed as per routine hospice practice (B). Cohorts were matched for age class, gender, reason for hospice admission, and Karnofsky performance status. RESULTS: Of the 518 patients enrolled, 267 formed cohort A and 251 cohort B. In total, 25.1% of patients admitted to the participating hospices received PST. Mean and median duration of sedation was 4 (standard deviation 6.0) and 2 days (range 0-43), respectively. Median survival of arm A was 12 days [90% confidence interval (CI) 10-14], while that of arm B was 9 days (90% CI 8-10) (log rank = 0.95, P = 0.330) (unadjusted hazard ratio = 0.92, 90% CI 0.80-1.06). CONCLUSION: PST does not shorten life when used to relieve refractory symptoms and does not need the doctrine of double effect to justify its use from an ethical point of view.

Feasibility and reliability of Doppler flow recordings in the fetal aortic isthmus: a multicenter evaluation.

OBJECTIVES: To evaluate the performance of three different centers with respect to their ability to identify the fetal aortic isthmus (AoI) adequately and place a Doppler sample volume in the AoI correctly, and to address the reproducibility of the isthmic flow index (IFI) calculated from Doppler waveforms recorded in the three centers. METHODS: The three collaborating centers sent several ultrasonographic recordings taken at random over a 6-week period to the Saint-Justine Fetal Cardiology Unit (StJ-FCU). A performance quotient ((number of total readings - number of unsatisfactory results)/number of total readings) was calculated for each center by each of three judges, who were experienced fetal cardiologists, to assess the ability of each center to identify the isthmus and to place the Doppler sample volume (DSV) adequately. Intraclass correlation coefficients (ICC) were computed to quantify the variability of IFI measurements ((systolic + diastolic)/systolic flow velocity integrals). RESULTS: Fifty-five recordings were available for this study. Concerning isthmus identification, there was 100% agreement between the three judges from StJ-FCU and the performance quotients of Centers A, B and C were: 0.90, 0.95 and 1.00, respectively. For DSV positioning, agreement between the judges varied; for Judge 1 vs. Judge 2, kappa = 0.836 (95% CI, 0.651-1.000); for Judge 1 vs. Judge 3, kappa = 0.773 (95% CI, 0.557-1.000); for Judge 2 vs. Judge 3, kappa = 0.941 (95% CI, 0.805-1.000). The performance quotients of the three centers for DSV positioning were consistently lower than were those for identification of the isthmus, being 0.85, 0.76 and 0.92, respectively. The ICC between the first and second measurements of the IFI by Rater 1 was 0.96 (95% CI, 0.93-0.98, P < 0.001) and that between Raters 1 and 2 was 0.97 (95% CI, 0.95-0.99, P < 0.001). CONCLUSION: Adequate imaging of the fetal AoI can be achieved easily by a trained sonographer, while DSV positioning is challenging. The intra- and interrater variability of the IFI are low.

Drug use and pregnancy - challenges for public health.

Involving pregnant drug users in drug treatment is likely to decrease the chances of pre- and perinatal complications related to drug use and to increase access to prenatal care. Timely medical intervention can effectively prevent vertical transmission of human immunodeficiency virus, hepatitis B virus as well as certain other sexually transmitted diseases, and would allow newborns infected with hepatitis C virus during birth to receive immediate treatment.

Occurrence of fungi in water used at a haemodialysis centre.

AIMS: The aim of this study was to identify and determine the diversity, occurrence and distribution of fungi in water used at a haemodialysis centre. METHODS AND RESULTS: Samples in the hydraulic circuit for the distribution of the water, dialysate samples and samples of sterilization solution from dialysers were collected over a 3-month period, and 500 ml of each sample was filtered through membranes. All together 116 isolates of fungi were recovered from 89% of all water samples collected inside the haemodialysis unit, with prevalence of moulds in tap water samples and of yeasts in dialysate samples. Fusarium spp. was the most abundant genus found, whereas Candida parapsilosis was the predominant yeast species. CONCLUSIONS: This study demonstrated that various fungi were present in the water system. These data suggest the inclusion of the detection and quantification of fungi in the water of haemodialysis. SIGNIFICANCE AND IMPACT OF THE STUDY: The recovery of fungi from aqueous haemodialysis environments implies a potential risk for haemodialysis patients and indicates the need for continuous maintenance and monitoring. Further studies on fungi in haemodialysis water systems are required to investigate the organism ability to persist, their role in biofilm formation and their clinical significance.

Prevalence of undiagnosed autoimmune rheumatic diseases in the first trimester of pregnancy. Results of a two-steps strategy using a self-administered questionnaire and autoantibody testing.

OBJECTIVE: To evaluate the prevalence of undiagnosed rheumatic diseases in the first trimester of pregnancy. DESIGN: We screened for rheumatic diseases in 1210 consecutive pregnant women during the first trimester of pregnancy using a 10-item questionnaire. SETTING: A university hospital in northern Italy. POPULATION: One hundred and thirty-seven (11.3%) women who answered positively to at least one question constituted the cases and were compared with 107 negative controls. METHODS: Cases and controls were tested for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibody, anti-beta2-glycoprotein I antibodies and lupus anticoagulant) and were evaluated by a rheumatologist for a definite diagnosis of rheumatic disease. MAIN OUTCOME MEASURES: Prevalence of undiagnosed rheumatic disease in the first trimester of pregnancy. RESULTS: The overall rate of positivity to the antibodies tested was 43.1% (59/137) among cases and 9.3% (10/107) in the controls (P < 0.001). A definitive diagnosis of rheumatic disease was made in 35 cases (25.5%) and in none of the controls (P <0.001). In stepwise logistic regression analysis, photosensitivity (adjusted OR 5.72; 95% CI 2.38-13.8), erythema or malar rash (adjusted OR 3.91; 95% CI 1.53-10) and history of two or more miscarriages (adjusted OR 5.6; 95% CI 1.55-20.6) were independent predictors of a definitive diagnosis of rheumatic disease (area under receiving operator curve = 0.814; 95% CI 0.76-0.86). Birthweight was lower (3180 g +/- 475 compared with 3340 g +/- 452, P= 0.008), and overall serious pregnancy complications (miscarriage, fetal growth restriction, delivery before 34 weeks of pregnancy and severe pre-eclampsia) were higher among cases (12/137) than controls (2/107) (adjusted OR 5.60; 95% CI 1.29-24.3; P= 0.021). CONCLUSIONS: A two-step screening process with a self-administered questionnaire proved to be a useful method to screen for undiagnosed rheumatic diseases during the first trimester of pregnancy.

Evaluation of skin permeability of sesquiterpenes of an innovative supercritical carbon dioxide Arnica extract by HPLC/DAD/MS.

Recently, a supercritical carbon dioxide dried extract of Amica flower, with a very high sesquiterpene content was developed. In view of using this extract in formulations for cutaneous application, the ability of sesquiterpenes to permeate the skin was evaluated by HPLC/DAD/MS using the following permeation enhancers: oleic acid (OA), dimethylsulfoxide (DMSO), lauroglycol, isopropyl myristate and Tween 80. A skin permeation study was performed using a modified Franz diffusion cell and the human stratum corneum and epidermis as membrane. Solutions of the enhancers were directly analysed after dilution with methanol or DMSO. A simple RP-HPLC-DAD-MS method for the quantification of the sesquiterpenes was developed and the method showed no interference with the other substances extracted from the skin and the permeation enhancers. The study evidenced that among the selected skin permeation enhancers, DMSO and OA canbe considered as good candidates to be used in preparations for cutaneous application.

Poly(lactide-co-glycolide) microspheres containing bupivacaine: comparison between gamma and beta irradiation effects.

The beta- and gamma-irradiation effects on stability of microspheres made of poly(lactide-co-glycolide) 50:50 copolymer (PLGA) containing bupivacaine (BU) were studied. Microspheres containing 10, 25, and 40% w/w, respectively, of BU were prepared by spray drying and irradiated in air with beta- and gamma-irradiation at a dose of 25 kGy. Morphology (atomic force microscopy, particle-size analysis), physico-chemical characteristics (DSC and FT-IR spectroscopy), drug content and in vitro dissolution profile of microspheres were all determined; the stability of irradiated microspheres was evaluated over a 9-month period. The decrease of BU content in gamma-irradiated microspheres was almost always constant independent of the amount of BU per sample, therefore it was in inverse proportion to drug loading (range between 5 and 15%). BU release rate increased immediately after irradiation and increased slightly until 90 days of storage. As far as beta-irradiated microspheres are concerned, BU content decreased in a significant way (approximately 3%) only in microspheres containing 10% w/w of BU. Immediately after irradiation, drug release rate in beta-irradiated microspheres increased less than in the corresponding gamma-irradiated microspheres, and it did not change further over the following storage period. BU-loaded microspheres have been shown to be more stable against beta- than gamma-irradiation. AFM revealed that the surface roughness of the irradiated microspheres increases depending on irradiation. As such, if a parameter is quantifiable, it is proposed as a marker of degradation due to ionizing radiation.

Formulation study and anti-inflammatory efficacy of topical semi-solids containing a nitro ester of flurbiprofen.

A new nitro-oxybutylester of flurbiprofen (NO-FP) is a promising anti-inflammatory drug in the treatment of dermatological disorders, and the feasibility of its cutaneous administration was evaluated. Four different semi-solid formulations were evaluated in order to assess the influence of the composition on the drug amount retained in the stratum corneum and epidermis (SCE). The lipophilic ointment induced the highest NO-FP amount retained in the SCE and, therefore, skin permeation enhancers (Transcutol), Lauroglycol), oleic acid and isopropyl myristate) were added to this formulation. The in vitro NO-FP amounts retained in the SCE were correlated with the solubility parameters, and a good linear correlation was found (r(2) = 0.925). The formulation of the lipophilic ointment was optimized, and the activity of this preparation was verified in methyl-nicotinate-induced contact urticaria and UV-induced erythema obtaining good results in terms of efficacy and safety.