Holistic Nursing Simulation: A Concept Analysis.

Simulation as a technology and holistic nursing care as a philosophy are two components within nursing programs that have merged during the process of knowledge and skill acquisition in the care of the patients as whole beings. Simulation provides opportunities to apply knowledge and skill through the use of simulators, standardized patients, and virtual settings. Concerns with simulation have been raised regarding the integration of the nursing process and recognizing the totality of the human being. Though simulation is useful as a technology, the nursing profession places importance on patient care, drawing on knowledge, theories, and expertise to administer patient care. There is a need to promptly and comprehensively define the concept of holistic nursing simulation to provide consistency and a basis for quality application within nursing curricula. This concept analysis uses Walker and Avant's approach to define holistic nursing simulation by defining antecedents, consequences, and empirical referents. The concept of holism and the practice of holistic nursing incorporated into simulation require an analysis of the concept of holistic nursing simulation by developing a language and model to provide direction for educators in design and development of holistic nursing simulation.

Clinical effects of non-invasive cerebellar magnetic stimulation treatment combined with neuromotor rehabilitation in traumatic brain injury. A single case study.

Multimodal treatments are emerging as effective approaches for motor recovery in traumatic brain injury (TBI). Various evidence has demonstrated that repetitive transcranial magnetic stimulation (rTMS) may improve outcomes in people with motor disorders. Behavioral gains from rTMS protocols may be maximized when brain stimulation is coupled with carefully designed occupational/physical therapy. We present the case of a 25-year-old man with chronic TBI (a bilateral corticosubcortical parieto-occipital lesion) who underwent three weeks of cerebellar intermittent theta burst stimulation (iTBS), a form of rTMS, combined with neurorehabilitation treatment. The Fugl-Meyer Assessment (FMA), Berg Balance Scale (BBS), Jebsen-Taylor Hand Function Test, and accelerometer gait analysis were administered before and after treatment. The results showed improvements in balance performance (BBS: T0=47; T1=53; +10.72%), motor recovery (FMA: T0=93/100; T1=96/100; +3.00%), step length (T0=50.4±7.2; T1=53.8±2.2 cm, p<0.001), and walking speed (T0=0.87±0.06; T1=0.91±0.04 m/sec,p<0.001). Combined cerebellar rTMS and neurore-Clinical effects of non-invasive cerebellar magnetic stimulation treatment combined with neuromotor rehabilitation in traumatic brain injury. A single case study. habilitation seems to be a promising treatment for motor and balance dysfunctions in TBI patients.

Blindfolded Balance Training in Patients with Parkinson's Disease: A Sensory-Motor Strategy to Improve the Gait.

Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson's Disease (PD) compared to patients treated with standard physical therapy (PT). Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage. Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups. Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient's rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications.

The ubiquitin ligase Smurf2 suppresses TGFß-induced epithelial-mesenchymal transition in a sumoylation-regulated manner.

Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-ß (TGFß) is a key inducer of EMT, but the mechanisms that regulate TGFß-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFß to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFß receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylation-regulated manner to suppress TGFß-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer.

θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect.

OBJECTIVE: Cortico-cortical circuits originating from the posterior parietal cortex (PPC) of the intact left hemisphere (LH) may become hyperexcitable in patients with hemispatial neglect due to a right hemispheric (RH) stroke. METHODS: In the current randomized, double-blind, sham-controlled study, we investigated safety and efficacy of continuous theta-burst stimulation (cTBS) in 10 sessions over 2 weeks applied over the intact PPC of the LH in subacute ischemic stroke patients. Severity of neglect was assessed through the standardized Behavioral Inattention Test (BIT). We also measured, by means of bifocal transcranial magnetic stimulation (TMS), how cTBS modified the excitability of the parieto-frontal functional connections in the intact LH. RESULTS: We found that 2 weeks of cTBS, but not sham cTBS, were effective in improving neglect symptoms as measured by BIT score. BIT scores improved by 16.3% after 2 weeks of cTBS and 22.6% at 1 month follow-up. We also found that hyperexcitability of LH parieto-frontal circuits was reduced following treatment with real but not sham cTBS. CONCLUSION: These findings suggest that a 2-week course of cTBS over the LH PPC may be a potential effective strategy in accelerating recovery from visuospatial neglect in subacute stroke patients, possibly counteracting the hyperexcitability of LH parieto-frontal circuits. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that left posterior parietal cortex theta-burst stimulation improves hemispatial neglect for up to 2 weeks after treatment.

SnoN: bridging neurobiology and cancer biology.

The transcriptional regulator SnoN has been the subject of growing interest due to its diverse functions in normal and pathological settings. A large body of evidence has established a fundamental role for SnoN as a modulator of signaling and responses by the transforming growth beta (TGFbeta) family of cytokines, though how SnoN regulates TGFbeta responses remains incompletely understood. In accordance with the critical and complex roles of TGFbeta in tumorigenesis and metastasis, SnoN may act as a tumor promoter or suppressor depending on the stage and type of cancer. Beyond its role in cancer, SnoN has also been implicated in the control of axon morphogenesis in postmitotic neurons in the mammalian brain. Remarkably, signaling pathways that control SnoN functions in the divergent cycling cells and postmitotic neurons appear to be conserved. Identification of novel SnoN regulatory and effector mechanisms holds the promise of advances at the interface of cancer biology and neurobiology.

Managing malignancy-associated hyperuricemia with rasburicase.

Along with hydration and urinary alkalinization, allopurinol has been the standard agent for the management of hyperuricemia in patients with a high tumor burden who are at risk for tumor lysis syndrome. However, this agent often fails to prevent and treat this complication effectively. Rasburicase, a recombinant urate oxidase, acts at the end of the purine catabolic pathway and, therefore, does not induce accumulation of xanthine or hypoxanthine, which can precipitate in the kidneys and lead to impaired renal function. Rasburicase may represent an effective alternative to allopurinol in rapidly reducing uric acid levels, improving patients' electrolyte status, and reversing renal insufficiency. The drug initially was studied in pediatric patients with acute lymphoblastic leukemia and aggressive non-Hodgkin lymphoma; data may suggest comparable benefit in adults with similar lymphoid malignancies. Current and future trials will evaluate alternate doses and schedules of rasburicase to maintain its efficacy while reducing its cost.

Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN.

Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation. SnoN is an important negative regulator of TGF-beta signaling that functions to maintain the repressed state of TGF-beta target genes in the absence of ligand. On TGF-beta stimulation, Smad3 and Smad2 translocate into the nucleus and induce a rapid degradation of SnoN, allowing activation of TGF-beta target genes. We show that Smad2- or Smad3-induced degradation of SnoN requires the ubiquitin-dependent proteasome and can be mediated by the anaphase-promoting complex (APC) and the UbcH5 family of ubiquitin-conjugating enzymes. Smad3 and to a lesser extent, Smad2, interact with both the APC and SnoN, resulting in the recruitment of the APC to SnoN and subsequent ubiquitination of SnoN in a destruction box (D box)-dependent manner. In addition to the D box, efficient ubiquitination and degradation of SnoN also requires the Smad3 binding site in SnoN as well as key lysine residues necessary for ubiquitin attachment. Mutation of either the Smad3 binding site or lysine residues results in stabilization of SnoN and in enhanced antagonism of TGF-beta signaling. Our studies elucidate an important mechanism and pathway for the degradation of SnoN and more importantly, reveal a novel role of the APC in the regulation of TGF-beta signaling.

TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation.

The receptor-regulated Smad proteins are essential intracellular mediators of signal transduction by the transforming growth factor-beta (TGF-beta) superfamily of growth factors and are also important as regulators of gene transcription. Here we describe a new role for TGF-beta-regulated Smad2 and Smad3 as components of a ubiquitin ligase complex. We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases. TGF-beta also induces the association of Smurf2 with the transcriptional co-repressor SnoN and we show that Smad2 can function to mediate this interaction. This allows Smurf2 HECT domain to target SnoN for ubiquitin-mediated degradation by the proteasome. Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.

Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.

Ubiquitin-mediated proteolysis regulates the activity of diverse receptor systems. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. IFN gamma, which stimulates expression of Smad7, induces Smad7-Smurf2 complex formation and increases TGF beta receptor turnover, which is stabilized by blocking Smad7 or Smurf2 expression. Furthermore, Smad7 mutants that interfere with recruitment of Smurf2 to the receptors are compromised in their inhibitory activity. These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation.