A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome

Background: Cornelia de Lange syndrome (CdLS) is a rare and clinically variable syndrome characterized by growth impairment, multi-organ anomalies, and a typical set of facial dysmorphisms. Here we describe a 2-year-old female child harboring a novel de novo missense variant in HDAC8, whose phenotypical score, according to the recent consensus on CdLS clinical diagnostic criteria, allowed the diagnosis of a non-classic CdLS. Methods: Clinical exome sequencing was performed on the trio, identifying a de novo heterozygous variant in HDAC8 (NM_018486; c. 356C>G p.Thr119Arg). Molecular modeling was performed to evaluate putative functional consequence of the HDAC8 protein. Results: The variant HDAC8 c.356C>G is classified as pathogenic following the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines. By molecular modeling, we confirmed the deleterious effect of this variant, since the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function. Conclusion: We described a novel Thr119Arg mutation in HDAC8 in a patient displaying the major phenotypic traits of the CdLS. Our results suggest that a modest change outside an active site is capable of triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency

The paradoxical effects of somatostatin on the bioactivity and production of cytotoxins derived from human peripheral blood mononuclear cells.

Somatostatin (SMS), a naturally occurring peptide is known to inhibit the production of certain protein molecules and to diminish the ability of peripheral blood mononuclear cells to proliferate. We tested the effects of three forms of SMS on the bioactivity of both lymphotoxin (LT) and tumour necrosis factor (TNF). We also tested the effects of these agents on production of cytotoxins by peripheral blood mononuclear cells. We found the 28 amino acid form of SMS significantly enhanced the bioactivity of both LT and TNF (10(-9) M concentration) when tested in mouse L cells. The 14 amino acid form of SMS enhanced LT (10(-9) M concentration) activity but not TNF activity. The first 14 amino acid form of SMS-28 (amino terminal) did not affect bioactivity of the cytotoxin. In contrast, the naturally occurring 14 amino acid form of SMS (10(-8) M concentration) significantly diminished production of cytotoxin by human peripheral blood mononuclear cells. Cytotoxin produced by the latter was shown to be a combination of both LT and TNF. Similarly after SMS exposure, the cytotoxin produced remained a mixture of LT and TNF in roughly similar proportions. It thus appears that certain forms of SMS can enhance the bioactivity of cytotoxins, but at the same time decrease the production of these cytotoxins

Single center experience on talc poudrage morbidity: focus on high talc dosage

Malignant pleural effusion (MPE) is a common clinical problem of concern for most of the pneumologists and thoracic surgeons. A general consensus regarding the use of talc poudrage in treatment of MPE exists, but only few studies analyzed in detail talc insufflation related pulmonary morbidity. In particular, ARDS talc-related is caused by physical and chemical effects of the small talc particles (50% particle size <15 μm) and its occurrence is independent from the underlying disease, the quantity of talc used or the technique of talc instillation. In our series we observed 3 cases only (0.75%) of talc-related lung injury. This data strongly confirm the low rate of talc-related lung injury after talc poudrage in treatment of MPE regardless the amount of talc insufflated

Design, development and deployment of a hand/wrist exoskeleton for home-based rehabilitation after stroke - SCRIPT project

YesChanges in world-wide population trends have provided new demands for new technologies in areas such as care and rehabilitation. Recent developments in the the field of robotics for neurorehabilitation have shown a range of evidence regarding usefulness of these technologies as a tool to augment traditional physiotherapy. Part of the appeal for these technologies is the possibility to place a rehabilitative tool in one’s home, providing a chance for more frequent and accessible technologies for empowering individuals to be in charge of their therapy. Objective: this manuscript introduces the Supervised Care and Rehabilitation Involving Personal Tele-robotics (SCRIPT) project. The main goal is to demonstrate design and development steps involved in a complex intervention, while examining feasibility of using an instrumented orthotic device for home-based rehabilitation after stroke. Methods: the project uses a user-centred design methodology to develop a hand/wrist rehabilitation device for home-based therapy after stroke. The patient benefits from a dedicated user interface that allows them to receive feedback on exercise as well as communicating with the health-care professional. The health-care professional is able to use a dedicated interface to send/receive communications and remote-manage patient’s exercise routine using provided performance benchmarks. Patients were involved in a feasibility study (n=23) and were instructed to use the device and its interactive games for 180 min per week, around 30 min per day, for a period of 6 weeks, with a 2-months follow up. At the time of this study, only 12 of these patients have finished their 6 weeks trial plus 2 months follow up evaluation. Results: with the “use feasibility” as objective, our results indicate 2 patients dropping out due to technical difficulty or lack of personal interests to continue. Our frequency of use results indicate that on average, patients used the SCRIPT1 device around 14 min of self-administered therapy a day. The group average for the system usability scale was around 69% supporting system usability. Conclusions: based on the preliminary results, it is evident that stroke patients were able to use the system in their homes. An average of 14 min a day engagement mediated via three interactive games is promising, given the chronic stage of stroke. During the 2nd year of the project, 6 additional games with more functional relevance in their interaction have been designed to allow for a more variant context for interaction with the system, thus hoping to positively influence the exercise duration. The system usability was tested and provided supporting evidence for this parameter. Additional improvements to the system are planned based on formative feedback throughout the project and during the evaluations. These include a new orthosis that allows a more active control of the amount of assistance and resistance provided, thus aiming to provide a more challenging interaction.This work has been partially funded under Grant FP7-ICT-288698(SCRIPT) of the European Community Seventh Framework Programme

A Value-Based Approach to Increase Breast Cancer Screening and Health-Directed Behaviors among American Indian Women

American Indian/Alaska Native (AI/AN) women have the lowest cancer-screening rate of any ethnic or racial group; AI/AN women in all regions are less likely than non-Hispanic white women to be diagnosed with localized breast cancer; and those AI/AN women presenting with breast cancer have the lowest 5-year survival rate compared to other ethnic groups. This study found that cultural beliefs are more of a factor in mammography screening behavior than other barriers such as access; and that a more holistic educational intervention designed by AI/AN women prompted individual intent and actions to seek mammograms among AI/AN women >40 and to change unhealthy eating and sedentary lifestyles

In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

BACKGROUND: There is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report. METHODOLOGY: We performed contrast-enhanced CT (CECT) on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA), indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT. PRINCIPAL FINDINGS: In the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data. CONCLUSIONS: This study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is also suitable for longitudinal observation of the same animals

Warfarin Anticoagulation Exacerbates the Risk of Hemorrhagic Transformation after rt-PA Treatment in Experimental Stroke: Therapeutic Potential of PCC

Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke. Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h. Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001). Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option