In vivo and in vitro effects of 42-hydroxy-palytoxin on mouse skeletal muscle: Structural and functional impairment

Palytoxins (PLTXs) are known seafood contaminants and their entrance into the food chain raises concern about possible effects on human health. The increasing number of analogs being identified in edible marine organisms complicates the estimation of the real hazard associated with the presence of PLTX-like compounds. So far, 42-OH-PLTX is one of the few congeners available, and the study of its toxicity represents an important step toward a better comprehension of the mechanism of action of this family of compounds. From this perspective, the aim of this work was to investigate the in vivo and in vitro effect of 42-OH-PLTX on skeletal muscle, one of the most sensitive targets for PLTXs. Our results demonstrate that 42-OH-PLTX causes damage at the skeletal muscle level with a cytotoxic potency similar to that of PLTX. 42-OH-PLTX induces cytotoxicity and cell swelling in a Na⁺-dependent manner similar to the parent compound. However, the limited Ca²⁺-dependence of the toxic insult induced by 42-OH-PLTX suggests a specific mechanism of action for this analog. Our results also suggest an impaired response to the physiological agonist acetylcholine and altered cell elasticity.     

A Case of Compound Mutations in the MYBPC3 Gene Associated with Biventricular Hypertrophy and Neonatal Death

Hypertrophic cardiomyopathy (HCM) is a familial, genetically determined, primary cardiomyopathy caused by mutations in genes coding for proteins of the sarcomere, or, less frequently, genes involved in storage diseases. In pediatric settings, pure HCM has an estimated incidence of 4.7 per million children. The disease is often sub-clinical and goes unrecognized mainly because most patients with HCM have only mild symptoms, if any. However, sudden cardiac death, the most dramatic clinical occurrence and the primary concern for patients and physicians alike, may be the first manifestation of the disease. We describe a case of compound heterozygosity in the MYBPC3 gene (p.Glu258Lys and IVS25-1G>A) associated with biventricular hypertrophy, atrial enlargement and subsequent neonatal death 33 days postpartum. Other studies have reported compound and/or double heterozygosis in the same or different sarcomeric genes during childhood and adulthood, and neonatal presentations have also been described. Our observations show that the combination of a missense (p.Glu258Lys) and a splice-site mutation (IVS25-1G>A) profoundly affects the clinical course. In families in which parental mutations are known, preimplantation (where ethically and legally feasible) or prenatal genetic screening should be adopted because: (1) neonatal HCM in genetic heterozygosity is potentially lethal and (2) heart disease is the most common developmental malformation and the leading cause of neonatal mortality and morbidity.     

Effectiveness of cast immobilization in comparison to the gold-standard self-removal orthotic intervention for closed mallet fingers: A randomized clinical trial

Study designRandomized clinical trial.IntroductionAlthough orthotic immobilization has become the preferable treatment choice for closed mallet injuries, it is unclear whether orthosis self-removal has an impact on the final outcome.PurposeTo evaluate the treatment efficacy of cast immobilization of closed mallet fingers using Quickcast^® (QC) compared to a removable, lever-type thermoplastic orthosis (LTTP).Methods57 subjects were randomized in 2 groups. DIPj extensor lag and the Gaberman success scale were used as primary outcomes.ResultsLTTP subjects resulted in greater extensor lag than QC subjects (x = 5°; p = 0.05) at 12 weeks from baseline, and high edema and older age negatively affected DIPj extensor lag. No other differences were found between groups.ConclusionCast immobilization seems to be slightly more effective than the traditional approach probably for its greater capacity to reduce edema.Level of evidence1B.     

A technical concept of a computer game for patients with Parkinson's disease – a new form of PC-based physiotherapy

Background: At present, there are no meaningful and sophisticated computer games that simultaneously allow the treatment of movement disorders such as Parkinson's syndrome. In particular, there are no systems to consider the severity of the disease and the physical skills of the patient.

Methods: A computer game using the Microsoft Kinect as markerless sensor for the 3?D recognition of the patient’s movement was developed to support the rehabilitation. The scenario of a basketball game was created after determining that the movement like throwing a ball and the correct posture of the body are important. A study based on system usability was performed with 15 patients to evaluate the system.

Results: The technical feasibility of a computer-assisted training system for supporting patients with Parkinson‘s disease has been demonstrated. No markers on the patient are required for movement detection and allow a user-friendly handling. Regarding the usability study, the patients were accepting of such a system and its at-home use and symptoms like ‘freezing’ and the Pisa syndrome can be treated.

Conclusions: The physiotherapist can be assisted by the developed rehabilitation system. An objective measurement of the patient’s training progress delivers valuable information to adjust the training sessions for every patient individually. Due to its modular character, the system can also be applied to other diseases or sports injuries and offers the basis for further development.     

Dedifferentiated endometrial cancer: an atypical case diagnosed from cerebellar and adrenal metastasis: case presentation and review of literature

Dedifferentiated endometrial cancer (DEC) is microscopically characterized by the presence of high-grade areas emerging from low-grade tumour. DEC is an aggressive tumour even when the dedifferentiated component represents only 20% of the entire neoplasm. A proper histological diagnosis is essential to define the most appropriate therapeutic approach for these tumors, since they are characterized by a particularly aggressive trend and by an extremely poor prognosis. We report a single case of DEC associated with dedifferentiated and adrenal metastasis, for which the patient underwent both abdominal-pelvic and cerebellar surgery. Dedifferentiated carcinoma of the endometrium is a poorly recognized neoplasm since they have not been clearly defined the histological features discriminating this neoplasm from high-grade endometrioid adenocarcinoma. Revising existing literature we found 79 described cases of central nervous system secondary involvement and 13 cases where the onset of the disease was characterized by neurological signs and symptoms. We could only find two reported cases of adrenal metastases originating from endometrial neoplasia but in no case of dedifferentiated endometrial carcinoma previously described has been reported the concomitant adrenal-cerebellar involvement.     

A relaxometric method for the assessment of intestinal permeability based on the oral administration of gadolinium‐based MRI contrast agents

Herein, a new relaxometric method for the assessment of intestinal permeability based on the oral administration of clinically approved gadolinium (Gd)‐based MRI contrast agents (CAs) is proposed. The fast, easily performed and cheap measurement of the longitudinal water proton relaxation rate (R₁) in urine reports the amount of paramagnetic probe that has escaped the gastrointestinal tract. The proposed method appears to be a compelling alternative to the available methods for the assessment of intestinal permeability. The method was tested on the murine model of dextran sulfate sodium (DSS)‐induced colitis in comparison with healthy mice. Three CAs were tested, namely ProHance®, MultiHance® and Magnevist®. Urine was collected for 24 h after the oral ingestion of the Gd‐containing CA at day 3–4 (severe damage stage) and day 8–9 (recovery stage) after treatment with DSS. The Gd content in urine measured by ¹H relaxometry was confirmed by inductively coupled plasma‐mass spectrometry (ICP‐MS). The extent of urinary excretion was given as a percentage of excreted Gd over the total ingested dose. The method was validated by comparing the results obtained with the established methodology based on the lactulose/mannitol and sucralose tests. For ProHance and Magnevist, the excreted amounts in the severe stage of damage were 2.5–3 times higher than in control mice. At the recovery stage, no significant differences were observed with respect to healthy mice. Overall, a very good correlation with the lactulose/mannitol and sucralose results was obtained. In the case of MultiHance, the percentage of excreted Gd complex was not significantly different from that of control mice in either the severe or recovery stages. The difference from ProHance and Magnevist was explained on the basis of the (known) partial biliary excretion of MultiHance in mice. Copyright © 2016 John Wiley & Sons, Ltd.     

Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specifc cell-permeable peptide inhibitor

Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identifcation of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efcacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.