MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles.

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood-brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.

Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels.

Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer.

When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cancer cell death directly, and enhance the release of exosome-like particles containing tumor-associated antigens, which boosts the anti-tumor immune response. In this study, we have examined whether delivery of an early region 1 (E1)-deleted, replication-defective Ad vector encoding the reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein can provide therapeutic efficacy in an immunocompetent mouse tumor model. A high multiplicity of infection of AdFAST is required to induce cell fusion in mouse mammary carcinoma 4T1 cells in vitro, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect.

Comparison of black, green and rooibos tea on osteoblast activity.

Globally, tea is the second most consumed beverage after water. Habitual tea intake has been associated with higher bone mineral density, particularly in postmenopausal women. This association may be due to its polyphenols and resulting protective antioxidant effects. While in vivo studies have shown improved bone outcomes with a consumption of individual purified tea polyphenols, it is unclear if a particular tea - due to its different profiles of polyphenols - is more beneficial than others. Therefore, we compared three different types of commercially available teas on osteoblasts: green, black and rooibos tea. Tea was normalized to 1 or 10 µg per mL gallic acid equivalents to assess differences in outcomes based on tea profiles rather than the quantity of polyphenol naturally present. The lower level of polyphenols (1 µg per mL gallic acid equivalents) - regardless of tea type and thus polyphenol profile - resulted in greater mineral content as well as cellular and alkaline phosphatase activity in Saos2 cells. Moreover, this was associated with higher markers of differentiation (osteopontin, sclerostin) and reduced cellular toxicity and pro-inflammatory markers (IL6, TNFα). Green, black and rooibos tea improved osteoblast activity at the low level and support epidemiological evidence suggesting tea consumption may benefit bone heath.

Solvent stimulated actuation of polyurethane-based shape memory polymer foams using dimethyl sulfoxide and ethanol.

Solvent exposure has been investigated to trigger actuation of shape memory polymers (SMPs) as an alternative to direct heating. This study aimed to investigate the feasibility of using dimethyl sulfoxide (DMSO) and ethanol (EtOH) to stimulate polyurethane-based SMP foam actuation and the required solvent concentrations in water for rapid actuation of hydrophobic SMP foams. SMP foams exhibited decreased Tg when submerged in DMSO and EtOH when compared to water submersion. Kinetic DMA experiments showed minimal or no relaxation for all SMP foams in water within 30 min, while SMP foams submerged in EtOH exhibited rapid relaxation within 1 min of submersion. SMP foams expanded rapidly in high concentrations of DMSO and EtOH solutions, where complete recovery over 30 min was observed in DMSO concentrations greater than 90% and in EtOH concentrations greater than 20%. This study demonstrates that both DMSO and EtOH are effective at triggering volume recovery of polyurethane-based SMP foams, including in aqueous environments, and provides promise for use of this actuation technique in various applications.

Impact of emergency access targets on admissions to general medicine: a retrospective cohort study.

BACKGROUND: Emergency access targets have been implemented Australia-wide following recent retrospective cohort studies linking emergency department (ED) overcrowding and excess mortality. AIM: To examine the impact of ED access targets on the characteristics and health service utilisation of general medicine (GM) inpatients at the Royal Melbourne Hospital. METHODS: A retrospective cohort study was conducted on all patient episodes admitted from ED to GM units from January 2009 to December 2012 (n = 15562), compared in two cohorts for 24 months before (n = 7393) and after (n = 8169) the implementation of the '4-h rule'. The main outcome measures were age, comorbidity, clinical urgency at presentation (Australasian Triage Score), ED and inpatient length of stay, diagnosis at discharge, and in-hospital complications. RESULTS: After the implementation of the '4-h rule', there was an increased proportion of younger patients aged ≤50 years (7.7-9.1%), urgent Australasian Triage Scale 3 (45.6-49.7%) and semi-urgent Australasian Triage Scale 4 (21.8-27.6%) patients admitted to GM. On average, GM patients had fewer comorbid conditions (proportion with Charlson score ≥6 decreased from 14.2% to 11.9%), and higher proportions (21.8-24.7%) were admitted for less than 48 h. CONCLUSION: Implementation of a 4-h access target has been associated with changes to the characteristics of patients admitted to GM, including higher proportions of younger patients, with fewer comorbid conditions and lower clinical urgency at presentation, although the latter may be explained by a coincidental change in the way that ED patients were triaged, as well as a greater number of these patients presenting to ED overall.

Functional categories and syntactic operations in (Ab)normal language acquisition.

This article argues in favor of the hypothesis that computational complexity determines order of acquisition of functional categories by normal children and patterns of impairment vs. relative preservation of these categories in children with Specific Language Impairment. Complexity is defined in terms of the properties of functional categories of the language the (ab)normal child is acquiring. The results of a study on present/past tense production and comprehension, carried out with children with and without Specific Language Impairment confirm the predictions of the computational complexity hypothesis. It is shown that it is easier to compute kernel functional categories than those that introduce further semantic modifications in the sentence.

Variables influencing the origins of diverse abnormal behaviors in a large sample of captive chimpanzees (Pan troglodytes).

The developmental origin of abnormal behaviors is generally associated with early rearing environments that lack sufficient physical and sensory stimulation. However, other factors should also be considered. A large sample of captive chimpanzees (128 males and 140 females) was surveyed for the presence or absence of 18 abnormal behaviors. Origin variables included the subject's source (zoo, pet, performer, or laboratory), rearing (mother- or hand-reared), and sex. Animals were assessed while held at the Primate Foundation of Arizona, University of Texas M. D. Anderson Cancer Center, or White Sands Research Center. There was a confound among origin variables; more hand-reared animals than expected were from laboratories. Logistic regression tested the relationship of rearing and source, with sex as a secondary predictor variable, to each of the abnormal behaviors. There was no clear association between any abnormal behavior and source. However, for coprophagy, relative to animals from the laboratory, zoo animals tended to show a higher prevalence, while performers tended to show a lower prevalence (when rearing and sex were controlled). Rocking and self-sucking were significantly more likely in hand-reared animals. Coprophagy and depilation of self were significantly more likely in mother-reared animals. When rearing and source were statistically controlled, the only significant sex difference was a higher prevalence of coprophagy in females and a higher prevalence of rocking in males. In a second, smaller sample of 25 males and 33 females from Southwest Foundation for Biomedical Research, no significant sex association was found for coprophagy, urophagy, rocking, or self-depilation. In this second sample, coprophagy was also significantly more likely in mother-reared than hand-reared subjects. The association of some abnormal behaviors with mother-rearing suggests that some form of social learning may be involved in the origin of some of these behavior patterns. This indicates that some abnormal behaviors may not be always be indicative of reduced psychological well-being in captive chimpanzees.

Nonselective debridement and antimicrobial cleansing of a venting ductal breast carcinoma.

A woman with a moderately differentiated carcinoma that erupted through the skin and amputated her breast was treated with whirlpool, topical antimicrobials, radiation, and chemotherapy. The draining, necrotic, and septic wound was treated for 5 months with a whirlpool containing dilute povidone-iodine solution and intravenous chemotherapy. Wet bandages, necrotic tissue, and softened eschar were removed by whirlpool agitation or mechanically debrided. To start treatment the wound was dressed with Debrisan crystals and sterile gauze for 1 week. Afterwards, wet-to-dry dressings wetted with Dakin's solution were applied. Tissue ingrowth at the wound margin started after 2 weeks, with whirlpool treatments effecting a tissue-reddening hyperemia. Wound drainage ceased after 2 months, with granulation and revascularization resulting. Eleven months later the wound was closed, aseptic, and undergoing dry flaking. The patient was cancer free with a completely healed wound 2 years after treatment. In this case, nonspecific debridement using whirlpool and topical antimicrobials promoted healing of an open fungating wound from a breast carcinoma.

In vitro formation by reverse dialysis of collagen gels containing highly oriented arrays of fibrils.

Acid extracts of rat tail tendon were subjected to reverse dialysis against 0.5% PEG at 4 degrees C in an attempt to induce liquid crystallization. After 48 h, gel and fibril formation were initiated by continuing dialysis at 20 degrees C against the same PEG solution adjusted to pH 7.4. The inclusion of calcium- or magnesium chloride (final concentration 0.3-33 mM) in the collagen solution before dialysis resulted in strongly birefringent gels that showed a progressive rotation of the slow axis of birefringence with increasing distance from the lateral margin of the gel. The gels contained fibers running predominantly in the plane of the flattened gel and crossing at angles of between 55 degrees and 90 degrees. We suggest that liquid crystallization is responsible for this phenomenon and that it might be possible to exploit this to produce materials for tissue engineering.

The delusion of infection with HIV.

OBJECTIVE: This article briefly describes the consultation-liaison service of the HIV/AIDS service of the Royal North Shore Hospital, and reviews three men who had the delusional belief of being infected with HIV. METHOD: Twenty-three consecutive referrals from the HIV/AIDS unit to consultation-liaison psychiatry were reviewed. Three of these patients persistently believed that they were infected with HIV despite low risk factors and negative blood tests. RESULTS: These three men had a major depression. Two of the three patients were offered treatment with psychotherapy and antidepressant medication. The third declined psychiatric follow-up. CONCLUSION: The presentation of a patient for HIV testing, with an atypical history, should raise the interviewer's concern that there may be an underlying mental illness, in particular a depressive disorder.

Characterization of the desulfurization genes from Rhodococcus sp. strain IGTS8.

Rhodococcus sp. strain IGTS8 possesses an enzymatic pathway that can remove covalently bound sulfur from dibenzothiophene (DBT) without breaking carbon-carbon bonds. The DNA sequence of a 4.0-kb BstBI-BsiWI fragment that carries the genes for this pathway was determined. Frameshift and deletion mutations established that three open reading frames were required for DBT desulfurization, and the genes were designated soxABC (for sulfur oxidation). Each sox gene was subcloned independently and expressed in Escherichia coli MZ1 under control of the inducible lambda pL promoter with a lambda cII ribosomal binding site. SoxC is an approximately 45-kDa protein that oxidizes DBT to DBT-5,5'-dioxide. SoxA is an approximately 50-kDa protein responsible for metabolizing DBT-5,5'-dioxide to an unidentified intermediate. SoxB is an approximately 40-kDa protein that, together with the SoxA protein, completes the desulfurization of DBT-5,5'-dioxide to 2-hydroxybiphenyl. Protein sequence comparisons revealed that the predicted SoxC protein is similar to members of the acyl coenzyme A dehydrogenase family but that the SoxA and SoxB proteins have no significant identities to other known proteins. The sox genes are plasmidborne and appear to be expressed as an operon in Rhodococcus sp. strain IGTS8 and in E. coli.