Multiple drug delivery hydrogel system for spinal cord injury repair strategies

The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion.     

MLL-MLLT10 fusion in acute monoblastic leukemia: variant complex rearrangements and 11q proximal breakpoint heterogeneity

Cytogenetic studies of acute monoblastic leukemia cases presenting MLL-MLLT10 (alias MLL-AF10) fusion show a broad heterogeneity of chromosomal breakpoints. We present two new pediatric cases (French-American-British type M5) with MLL-MLLT10 fusion, which we studied with fluorescence in situ hybridization. In both we detected a paracentric inversion of the 11q region that translocated onto chromosome 10p12; one case displayed a variant complex pattern. We review the cytogenetic molecular data concerning the proximal inversion breakpoint of 11q and confirm its heterogeneity.     

In systemic sclerosis macrovascular damage of hands digital arteries correlates with microvascular damage

Objective

To assess morphology and blood flow of the proper palmar digital arteries (PPDA) by Color Doppler Ultrasonography (CDUS) and its relationship with nailfold videocapillaroscopy (NVC), skin blood perfusion and digital arteries pulsatility of hands in SSc patients and healthy controls.

Methods

CDUS, NVC, Laser Doppler Perfusion Imaging (LDPI) and photoplethysmography (PPG) were performed in 36 systemic sclerosis (SSc) patients and 20 healthy controls.

Results

CDUS was pathologic in 69% of patients with SSc and in none of healthy controls (p < 0.0001). SSc patients with low vascular damage (early capillaroscopic pattern) have a normal morphology of PPDA, but the blood flow, evaluated by peak systolic velocity (PSV) and end diastolic velocity (EDV), is reduced and vascular resistance, measured by resistive index (RI) and pulsatility index (PI), increased. At this stage the LDPI mean perfusion and digital artery pulsatility, evaluated by PPG, were reduced. The US changes appear with microvasculare damage progression (active and late capillaroscopic patterns), while the PPDA blood flow progressively decreases (PSV and EDV decreased, RI and PI increased). The macrovascular damage correlates with disease duration. Anti-topoisomerase I represents an independent predictive factor for macrovascular damage. We not observed any association between digital ulcer history, pulmonary fibrosis and US findings.

Conclusion

PPDA blood flow dysfunction is already present in early disease. Structural macrovascular damage progresses with worsening of SSc microangiopathy.     

Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.     

US-guided percutaneous radiofrequency thermal ablation for the treatment of solid benign hyperfunctioning or compressive thyroid nodules

The aim of the study was to define the effectiveness and safety of ultrasound-guided percutaneous radiofrequency (RF) thermal ablation in the treatment of compressive solid benign thyroid nodules. Thirty-one patients not eligible for surgery or radioiodine (¹³¹I) treatment underwent RF ablation for benign nodules; a total of 33 nodules were treated (2 patients had 2 nodules treated in the same session): 10 cold nodules and 23 hyperfunctioning. Fourteen patients complained of compressive symptoms. Nodule volume, thyroid function and compressive symptoms were evaluated before treatment and at 1, 3 and 6 mo. Ultrasound-guided RF ablation was performed using a Starbust RITA^® needle, with nine expandable prongs; total exposure time was 6 to 10 min at 95° C in one area or more of the nodule. Baseline volume (measured at the time of RF ablation) was 27.7 ± 21.5 mL (mean ± SD), but significantly decreased during follow-up: 19.2 ± 16.2 at 1 mo (–32.7%; p < 0.001), 15.9 ± 14.1 mL at 3 mo (–46.4 %; p < 0.001) and 14.6 ± 12.6 mL at 6 mo (–50.7%; p < 0.001). After treatment, all patients with cold nodules remained euthyroid: five patients with hot nodules normalized thyroid function, and the remaining sixteen showed a partial remission of hyperthyroidism. Besides a sensation of heat and mild swelling of the neck, no major complications were observed. Improvement in compressive symptoms was reported by 13 patients, with a reduction on severity scale from 6.1 ± 1.4 to 2.2 ± 1.9 (p < 0.0001). Radiofrequency was effective and safe in reducing volume by about 50% and compressive symptoms in large benign nodules. Hyperfunction was fully controlled in 24% of patients and partially reduced in the others. (E-mail: mdeandrea@libero.it)     

Prognostic Stratification by Conventional Echocardiography of Patients with Aortic Stenosis: The “CAIMAN‐ECHO Score”

Background and Aim: Surgery is not recommended in asymptomatic patients with aortic stenosis (AS). However, prognosis of these patients is worse than retained. We built a simple score (named by the acronym “CAIMAN”) for stratifying asymptomatic patients with AS according to the different risk for cardiovascular events. Material and Methods: Data from 141 patients with moderate‐to‐severe AS followed up for 36 months were analyzed. The end point “outcome” was defined as death of all causes or aortic valve replacement imposed by symptoms or hospital admission for myocardial infarction and/or heart failure. The score was validated in 143 patients prospectively recruited in 2 different centers. Results: The 40 events occurred in the original cohort were associated with higher aortic transvalvular peak jet velocity, calcium score, and observed/predicted left ventricular (LV) mass ratio. Based on the hazard ratios of Cox analysis, the score was calculated as follows: calcium score 1–3 = 1 point, 4 = 6 points; transvalvular peak jet velocity ≤3.6 m/sec = 1 point, 3.6 m/sec = 3 points, observed/predicted LV mass ratio ≤110% = 1 point, >110% = 3 points. After a mean period of 28 ± 18 months, event‐free survival was 18%, 42%, 91%, and 96% in the 4 quartiles of echo score. The accuracy of the score in predicting events was 84% and 77% (P = 0.09) in the original and validation cohort, respectively. Conclusions: The CAIMAN‐ECHO score is a simple and feasible tool useful for an accurate prognostic stratification of patients with asymptomatic moderate‐to‐severe AS.     

Sativex-induced neurobehavioral effects: causal or concausal? A practical advice!

Nabiximols (Sativex) is an oromucosal spray, containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), used as treatment for unresponsive spasticity in multiple sclerosis (MS) patients. Sativex is thought to not affect cognition or induce any psychiatric problem at the doses generally used. Nonetheless, it is known that the concomitant use of more than one muscle-relaxant drugs can result in additive neuropsychiatric effects. Herein we describe a case of a woman affected by MS and treated with baclofen and methylprednisolone, who developed important behavioral changes, including suicidal ideation, after 4 weeks of Sativex administration. We are not completely able to state if Sativex alone was responsible for our patient’s psychiatric symptoms, in reason of the concomitant use of the other drugs.In conclusion, physicians should pay more attention when prescribing drugs to MS patients affected by spasticity, including Sativex, since neurobehavioral side effects may emerge especially in predisposed individuals.     

Validity and reliability of the Unified Classification System applied to periprosthetic femur fractures: a comparison with the Vancouver system

Abstract

Objective: The Unified Classification System (UCS) presents itself as an evolution of the Vancouver Classification (VCS) for the evaluation of periprosthetic fractures of the proximal femur (PPF). The aim of our study was to highlight any loss of reproducibility or validity of the new classification system, compared to the previous one.

Material and methods: We tested the interobserver and intraobserver agreement using 40 PPF clinical cases. Each classifying subtype of the UCS and VCS was present in at least two cases. Six experienced hip surgeons (Senior Surgeon, SS) and 5 surgeons in training (Junior Surgeon, JS) classified the clinical cases, using VCS and UCS. The validity of both classifications was then tested with intraoperative surveys.

Results: The mean κ value for interobserver agreement for the VCS in the JS group was 0.65 and 0.81 for the SS group. The mean κ value for interobserver agreement for the UCS in the JS group was 0.63 and 0.65 for the SS group. The mean κ value for intraobserver agreement for the VCS in the JS group was 0.71 and 0.73 for the SS group. The mean κ value for intraobserver agreement for the UCS in the JS group was 0.72 and 0.7 for the SS group. Validity analysis showed a moderate agreement for the VCS and a good agreement for the UCS.

Conclusion: The UCS completes the Vancouver classification, expanding it. It is reliable, despite the increase in classification categories and number of parameters to evaluate, with a slightly higher validity.