Journal club: role of endoscopic third ventriculostomy and ventriculoperitoneal shunt in idiopathic normal pressure hydrocephalus: preliminary results of a randomized clinical trial.

1. Significance/Context and Importance of the Study: Idiopathic normal pressure hydrocephalus (INPH) was first defined by Hakim and colleagues in 19651, and its symptoms later classified by the clinical triad of gait dysfunction, urinary incontinence, and dementia. The exact pathophysiology of this disease is not well understood.2 Surgical options for the treatment of INPH are ventriculoperitoneal shunt (VPS) placement (most commonly with a programmable valve), and endoscopic third ventriculostomy (ETV). VPS is by far the most common method used to treat INPH worldwide. Debate exists as to the superiority between the two management options. Historically, VPS placement with a programmable valve has led to improved outcomes with INPH.3 More recent use of ETV has been reported in the form of retrospective data, demonstrating neurological improvement in up to 69% of patients.4 However, a cited limitation of this study is the less stringent diagnostic criteria that fails to discriminate secondary NPH from INPH. This is important because of the higher success rates of treatment in secondary NPH.2 This study by Pinto et al should be commended for its attempt to compare ETV to VPS with a nonprogrammable valve for patients with the diagnosis of INPH prospectively. Given that the natural history of VPS carries a significant rate of shunt revision, there have been no prior attempts to provide level I evidence demonstrating equivalence or superiority of ETV to VPS placement

Role of Dual PI3/Akt and mTOR Inhibition in Waldenstrom's Macroglobulinemia

Tumorigenesis occurs due to synergistic interactions from a complex of signal transduction processes, including multiple onco-proteins and tumor suppressors such as Ras, Myc, PI3K/Akt/mTOR, Her-2/Neu, p53 and PTEN. Specifically, the PI3K/Akt and mTOR pathways have been shown to play a pivotal role on the initiation and progression of malignancies, enhancing cell survival by stimulating cell proliferation, and inhibiting apoptosis. Therefore, it is critical to examine therapeutic agents that explicitly target both the PI3K/Akt and mTOR signaling cascades in diseases, such as Waldenstrom Macroglobulinemia (WM), that harbor activation of the PI3K/Akt pathway. We demonstrated that dual targeting of the PI3K and mTOR pathways by the novel inhibitor NVP-BEZ235, exhibited toxicity on WM cells by directly targeting the tumor clone and indirectly through an effect on the bone marrow milieu. These findings suggest that dual targeting of the PI3K and mTOR pathways is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR pathways, such as in WM

A biomechanical analysis of the stand-up paddle board stroke: A comparative study

Background: Stand-up paddle boarding (SUP) is a rapidly growing global aquatic sport, with increasing popularity among participants within recreation, competition and rehabilitation. To date, few scientific studies have focused on SUP. Further, there is no research examining the biomechanics of the SUP paddle stroke. The purpose of this study was to investigate whether variations in kinematics existed among experienced and inexperienced SUP participants using three-dimensional motion analysis. This data could be of significance to participants, researchers, coaches and health practitioners to improve performance and inform injury minimization strategies. Methods: A cross-sectional observational design study was performed with seven experienced and 19 inexperienced paddlers whereby whole-body kinematic data were acquired using a six-camera Vicon motion capture system. Participants paddled on a SUP ergometer while three-dimensional range of motion (ROM) and peak joint angles were calculated for the shoulders, elbows, hips and trunk. Mann-Whitney U tests were conducted on the non-normally distributed data to evaluate differences between level of expertise. Results: Significant differences in joint kinematics were found between experienced and inexperienced participants, with inexperienced participants using greater overall shoulder ROM (78.9° ± 24.9° vs 56.6° ± 17.3°, p = 0.010) and less hip ROM than the experienced participants (50.0° ± 18.5° vs 66.4° ± 11.8°, p = 0.035). Experienced participants demonstrated increased shoulder motion at the end of the paddle stoke compared to the inexperienced participants (74.9° ± 16.3° vs 35.2° ± 28.5°, p = 0.001 minimum shoulder flexion) and more extension at the elbow (6.0° ± 9.2° minimum elbow flexion vs 24.8° ± 13.5°, p = 0.000) than the inexperienced participants. Discussion: The results of this study indicate several significant kinematic differences between the experienced and inexperienced SUP participants. These variations in technique were noted in the shoulder, elbow and hip and are evident in other aquatic paddling sports where injury rates are higher in these joints. These finding may be valuable for coaches, therapists and participants needing to maximize performance and minimize injury risk during participation in SUP.Full Tex

Complications of Living Donor Hepatic Lobectomy–A Comprehensive Report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91208/1/j.1600-6143.2011.03972.x.pd

Thoracolumbar spine trauma: review of the evidence.

AIM: The aim of this paper was to provide a comprehensive review of literature regarding the classification systems and surgical management of thoracolumbar spine trauma. METHODS: A Pubmed search of thoracolumbar , spine , fracture was used on January 05, 2013. Exclusionary criteria included non-Human studies, case reports, and non-clinical papers. RESULTS. One thousand five hundred twenty manuscripts were initially returned for the combined search string; 150 were carefully reviewed, and 48 manuscripts were included in the review. DISCUSSION: Traumatic spinal cord injury (SCI) has a high prevalence in North America. The thoracolumbar junction is a point of high kinetic energy transfer and often results in thoracolumbar fractures. New classification systems for thoracolumbar spine fractures are being developed in an attempt to standardize evaluation, diagnosis, and treatment as well as reporting in the literature. Earlier classifications such as the Denis 3-column model emphasized anatomic divisions to guide surgical planning. More modern classification systems such as the Thoracolumbar injury classification system (TLICS) emphasize initial neurologic status and structural integrity of the posterior ligamentous complex as a guide for surgical decision making and have demonstrated a high intra- and interobserver reliability. Other systems such as the Load-Sharing Classification aid as a useful tool in planning the extent of instrumentation and fusion. CONCLUSION: There is still much controversy over the surgical management of various thoracolumbar fractures. Level I data exists supporting the nonsurgical management of thoracolumbar burst fractures without neurologic compromise. However, for the majority of fracture types in this region, more randomized controlled trials are necessary to establish standards of care

Candidate genes of Waldenström’s macroglobulinemia: current evidence and research

Waldenström’s macroglobulinemia (WM) is a relatively uncommon, indolent malignancy of immunoglobulin M-producing B cells. The World Health Organization classifies it as a lymphoplasmacytic lymphoma and patients typically present with anemia, hepatosplenomegaly and diffuse lymphadenopathies. Historically, the genetic characterization of the disease has been hampered by the relatively low proliferative rate of WM cells, thus making karyotyping challenging. The use of novel technologies such as fluorescence in situ hybridization, gene array, and whole genome sequencing has contributed greatly to establishing candidate genes in the pathophysiology of WM and to identifying potential treatment targets, such as L265P MYD88. The discovery of microRNAs and the recognition of epigenetics as a major modulatory mechanism of oncogene expression and/or oncosuppressor silencing have aided in further understanding the pathogenesis of WM. Once thought to closely resemble multiple myeloma, a cancer of terminally differentiated, immunoglobulin-secreting plasma cells, WM appears to genetically cluster with other indolent B-cell lymphomas such as chronic lymphocytic leukemia/small cell lymphoma. The relative high incidence of familial cases of WM and other B-cell malignancies has been helpful in identifying high-risk gene candidates. In this review, we focus on the established genes involved in the pathogenesis of WM, with special emphasis on the key role of derangement of the nuclear factor kappa B signaling pathway and epigenetic mechanisms

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs