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Mobile applications, wearables, in-home medical devices and other peripherals are reshaping consumer participation in healthcare. While much research has focused on patient facing mobile technologies, there remains limited evidence of the implications of technologies on models of care and health service delivery. In this paper, we present an evaluation of the clinician experiences of using a bidirectional healthcare platform, Activate TKR, for orthopaedic patients undergoing a Total Knee Replacement (TKR). The platform provides mobile-enabled media rich content to support patients through their journey, while facilitating data sharing and remote monitoring by clinicians. Results show that physiotherapists experienced the greatest enhancements in care delivery through access to patient generated information which improved appointments, status and progress discussion, and tailoring of physiotherapy. Surgeons found value in the mobile-enabled information patients accessed in preparation for surgery, enhancing their overall TKR experience.

Dengue virus, the causative agent for the dengue fever, infects approximately 50-100 million people worldwide per year. The high incidence of dengue fever, along with its potential to develop into a severe, life-threatening form, resulted in great interest in the discovery of an antiviral against it. In this study, we constructed a DENV2-EGFP infectious clone, established a fluorescence-based, high-throughput screening platform, and conducted a screen for anti-DENV compounds on a flavonoid-derivative library, Amongst the hits identified, ST081006 was found to be a strong inhibitor of the DENV replication. Time-course studies suggest that the presence of ST081006 is necessary to inhibit successive rounds of virus replication. Further investigations demonstrated that ST081006 affects the synthesis of both viral protein and viral RNA, and one anti-DENV mechanism is the direct inhibition of viral protein synthesis. The replication of all dengue serotypes, along with that of the enterovirus EV-A71, was shown to be affected by ST081006. Attempts to generate ST081006-resistant DENV were unsuccessful, and thus hints at host factors as potential drug target. Together, these results suggest that ST081006 affect DENV replication, likely by acting on a target involved in the viral protein and/or RNA synthesis pathway.

Purpose: Endometrioid endometrial carcinoma (EEC) is the major histologic type of endometrial cancer, the most prevalent gynecologic malignancy in the United States. EEC recurrence or metastasis is associated with a poor prognosis. Early-stage EEC is generally curable, but a subset has high risk of recurrence or metastasis. Prognosis estimation for early-stage EEC mainly relies on clinicopathologic characteristics, but is unreliable. We aimed to identify patients with high-risk early-stage EEC who are most likely to benefit from more extensive surgery and adjuvant therapy by building a prognostic model that integrates clinical variables and protein markers. Experimental Design: We used two large, independent early-stage EEC datasets as training (n = 183) and validation cohorts (n = 333), and generated the levels of 186 proteins and phosphoproteins using reverse-phase protein arrays. By applying an initial filtering and the elastic net to the training samples, we developed a prognostic model for overall survival containing two clinical variables and 18 protein markers and optimized the risk group classification. Results: The Kaplan–Meier survival analyses in the validation cohort confirmed an improved discriminating power of our prognostic model for patients with early-stage EEC over key clinical variables (log-rank test, P = 0.565 for disease stage, 0.567 for tumor grade, and 1.3 × 10−4 for the integrative model). Compared with clinical variables (stage, grade, and patient age), only the risk groups defined by the integrative model were consistently significant in both univariate and multivariate analyses across both cohorts. Conclusions: Our prognostic model is potentially of high clinical value for stratifying patients with early-stage EEC and improving their treatment strategies. Clin Cancer Res; 22(2); 513–23. ©2015 AACR.

Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3‐kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse‐phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P

Many statisticians and policy researchers are interested in using data generated through the normal delivery of health care services, rather than carefully designed and implemented population-representative surveys, to estimate disease prevalence. These larger databases allow for the estimation of smaller geographies, for example, states, at potentially lower expense. However, these health care records frequently do not cover all of the population of interest and may not collect some covariates that are important for accurate estimation. In a recent paper, the authors have described how to adjust for the incomplete coverage of administrative claims data and electronic health records at the state or local level. This article illustrates how to adjust and combine multiple data sets, namely, national surveys, state-level surveys, claims data, and electronic health record data, to improve estimates of diabetes and prediabetes prevalence, along with the estimates of the method's accuracy. We demonstrate and validate the method using data from three jurisdictions (Alabama, California, and New York City). This method can be applied more generally to other areas and other data sources.

PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α–dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor–expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PRcre/+Ptenf/f mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer. Cancer Res; 74(24); 7371–82. ©2014 AACR.

Object The development of minimally invasive surgical techniques is driven by the quest for better patient outcomes. There is some evidence for the use of minimally invasive surgery for degenerative lumbar spine stenosis (LSS), but there are currently no studies comparing outcomes with matched controls. The object of this study was to compare outcomes following minimally invasive unilateral laminectomy for bilateral decompression (ULBD) to a standard “open” laminectomy for LSS. Methods The authors conducted a prospective, 1:1 randomized trial comparing ULBD to open laminectomy for degenerative LSS. The study enrolled 79 patients between 2007 and 2009, and adequate data for analysis were available in 54 patients (27 in each arm of the study). Patient demographic characteristics and clinical characteristics were recorded and clinical outcomes were obtained using pre- and postoperative Oswestry Disability Index (ODI) scores, visual analog scale (VAS) scores for leg pain, patient satisfaction index scores, and postoperative 12-Item Short Form Health Survey (SF-12) scores. Results Significant improvements were observed in ODI and VAS scores for both open and ULBD interventions (p < 0.001 for both groups using either score). In addition, the ULBD-treated patients had a significantly better mean improvement in the VAS scores (p = 0.013) but not the ODI scores (p = 0.055) compared with patients in the open-surgery group. ULBD-treated patients had a significantly shorter length of postoperative hospital stay (55.1 vs 100.8 hours, p = 0.0041) and time to mobilization (15.6 vs 33.3 hours, p < 0.001) and were more likely to not use opioids for postoperative pain (51.9% vs 15.4%, p = 0.046). Conclusions Based on short-term follow-up, microscopic ULBD is as effective as open decompression in improving function (ODI score), with the additional benefits of a significantly greater decrease in pain (VAS score), postoperative recovery time, time to mobilization, and opioid use.

Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors. Cancer Res; 74(1); 15–23. ©2013 AACR.

Background Mycophenolate mofetil (MMF) has enjoyed increasing popularity as an emerging immunosuppressant treatment for various autoimmune dermatologic conditions, including pyoderma gangrenosum (PG). Objective The aim of this study was to examine the efficacy and safety of MMF as used in PG. Methods A retrospective chart review was conducted for all patients with PG treated with MMF at our institution (Victoria, Australia) for the past 11 years (2001-2012). Results We identified 26 patients, 14 female and 12 male. Nine patients (34.6%) had associated systemic conditions. All patients received prednisolone. MMF was used as a first-line steroid-sparing agent in 11 patients (42.3%), second-line in 14 (53.8%), and third-line in 1 (3.85%). The average duration of treatment was 12.1 months. Fourteen patients experienced side effects (53.8%), although most were mild (26.9%). One patient died after a sigmoid colon perforation (3.85%). Overall 22 patients demonstrated clinical improvement during MMF treatment (84.6%). Thirteen patients achieved complete ulcer healing (50%), 10 while taking MMF and 3 after ceasing it. Limitations This is a retrospective study based on a single-center cohort. Conclusion Our experience suggests that MMF is highly efficacious in PG together with prednisolone, or as part of combination therapy with other immunosuppressants.

The authors describe a hybrid technique that involves a combination of open decompression and posterior lumbar interbody fusion (PLIF) and percutaneously inserted pedicle screws. This technique allows performance of PLIF and decompression via a midline incision and approach without compromising operative time and visualization. Furthermore, compared to standard open decompression, this approach reduces post-operative wound pain because the small midline incision significantly reduces muscle trauma by obviating the need to dissect the paraspinal muscles off the facet joint complex and by avoiding posterolateral fusion, thus requiring limited lateral muscle dissection off the transverse processes. A series of patients with Grade I-II spondylolisthesis at L4-5 and moderate-severe canal/foraminal stenosis underwent midline PLIF at L4-5, with closure of the midline incision. Percutaneous pedicle screws were inserted, thereby minimizing local muscle trauma, reduction of the spondylolisthesis being performed by using a pedicle screw construct. Rods were inserted percutaneously to link the L4 and L5 pedicle screws. Image intensification was used to confirmed satisfactory screw placement and reduction of spondylolisthesis. The results of a prospective study comparing a standard open decompression and fusion technique for spondylolisthesis versus the minimally invasive hybrid technique are discussed. The minimally invasive technique resulted in shorter hospital stay, earlier mobilization and reduced postoperative narcotic usage. The long-term clinical outcomes were equivalent in the two groups.

Mycophenolate use in dermatology is growing due to its reputation as a steroid-sparing agent with a favourable side-effect profile. However, there are limited data on the efficacy and tolerability of mycophenolate for many dermatological indications. We conducted a retrospective clinical audit in 33 dermatology patients who had received mycophenolate at our institution between April 2010 and January 2012. The top indication was pyoderma gangrenosum (14 patients) followed by atopic dermatitis (seven patients). Overall 70 per cent of patients showed some benefit from mycophenolate treatment, with 12 per cent failing to respond. Side-effects were experienced by 45 per cent of patients, two of whom had serious side-effects. Female sex appears to be a risk factor for adverse effects. We conclude that although mycophenolate is a promising agent across a variety of dermatological conditions, further randomised controlled trials are required.

Introduction : Commonwealth Scientific & Industrial Research Organisation (CSIRO) of Australia was tasked to lead a National Telehealth Trial for chronic disease in the community to investigate models of care, health service utilization and economic impact on the Australian health system. Chronic and aged care accounted for over 70% of Australia’s $155bn expenditure on healthcare during 2013–14, and is projected to dramatically increase into the future. Australia’s hospital-centric public health system is unnecessarily burdened by the management of chronic disease, which should occur in home and community settings. Telehealth services delivered through home Telemonitoring have been demonstrated to deliver cost effective, timely and improved access to quality care. They also reduce social dislocation and enhance the quality of life within communities and their sustainability by allowing chronically ill and aged members to stay in their homes and communities longer. The development of a robust business case and business models for large scale commercial deployment of Telehealth services based on solid economic evidence is essential if these services are to be scaled up nationally to have any impact on the escalating costs of health service delivery and the increasing deficit in clinical work force. Description of practice change : Trial was designed with the aim of demonstrating how Telehealth services for chronic disease management in the community can be deployed nationally in a range of hospital and community settings, by piloting services in six different locations across five Australian states with a range of health service provider’s, including a hospital, Local Health Districts, Medicare Locals and aged care organisation. The intervention was the provision of Telemonitoring equipment for the collection of vital signs and the administration of questionnaires. Control patients received normal care. In this trial we analysed and compared the performance, across four distinct groups with one hospital site, two community based services, two GP managed Medicare Local coordinated services and one Aged Care focused service. Key Findings : Based on a before and after control intervention (BACI) case matched design this trial evaluated health outcomes, impact of workplace culture and capacity for organizational change management. The project recruited 113 chronically ill patients with multiple co-morbidities and remotely monitored using Telehealth. These patients were compared with 174 patients acting as matched controls who were tracked for periods 6-18 months with at home telemonitoring of vital signs and clinical symptoms. Telehealth monitored patients’ demonstrated: a. Reduction in health services utilisation observed towards the later part of the trial (after 8-9 months) by reduced number of GP visits, specialist consultations, laboratory tests and procedures performed. b. Reduction in primary healthcare costs were demonstrated by the reduction of Medicare benefit costs by more than AUD600/year/patient and pharmaceutical dispensing cost by more than $300/year/patient at end of trial. c. Reduction in hospital length of stay by more than 7 days d. Reduction in rate of hospitalisations by 1 less event e. There were improved Quality of life metrics/Human factors /Useability and acceptability to patients and clinicians Highlights : At all trial sites the Telehealth technology was well accepted by patients. The key barriers were related to integration of Telemonitoring into existing models of care was at the services provider level. These barriers included the capacity to implement/participate in new programs within health organisations and one of our trial sites had to be decommissioned. Main highlight was the continuation of Telemonitoring at three sites post-trial, offering Telehealth as a mainstream service for chronic disease management of patients in their home. This is a big win from the trial where three health service providers have integrated Telehealth as an ongoing sustainable service for chronic disease management in the community. Conclusions : Telemonitoring can be deployed for management of chronic disease in the community as a cost effective alternative. From the experience throughout the trial has demonstrated that successful deployment of remote Telemonitoring of chronic disease requires the following success factors: − Importance of a new Clinical Care Coordination role to centrally coordinate optimal response to caregivers as demonstrated in this trial − Strong support and leadership from the health service management team and the formation of strong clinical governance for the service − Strong alignment of workplace culture and values with the objectives of Telemonitoring. This will often require the implementation of extensive training and education programs − A clear “ownership” and engagement not only with the patient, but with the patient’s carers who may include relatives, neighbours, community nurses and GPs. − Clear governance protocols and lines of communication between the clinical care coordinator and the patient’s care team, in particular the patient’s GP. − Support for Telemonitoring services through automated risk stratification protocols that can identify with high probability patients who are demonstrating an exacerbation of their condition and may require immediate attention to avoid an unnecessary hospitalisation.

Mutation of PPP2R1A has been observed at high frequency in endometrial serous carcinomas but at low frequency in ovarian clear cell carcinoma. However, the biological role of mutation of PPP2R1A in ovarian and endometrial cancer progression remains unclear. In this study, we found that PPP2R1A expression is elevated in high-grade primary tumor patients with papillary serous tumors of the ovary. To determine whether increased levels or mutation of PPP2R1A might contribute to cancer progression, the effects of overexpression or mutation of PPP2R1A on cell proliferation, migration, and PP2A phosphatase activity were investigated using ovarian and endometrial cancer cell lines. Among the mutations, PPP2R1A-W257G enhanced cell migration in vitro through activating SRC-JNK-c-Jun pathway. Overexpression of wild type (WT) PPP2R1A increased its binding ability with B56 regulatory subunits, whereas PPP2R1A-mutations lost the ability to bind to most B56 subunits except B56δ. Total PP2A activity and PPP2R1A-associated PP2Ac activity were significantly increased in cells overexpressing PPP2R1A-WT. In addition, overexpression of PPP2R1A-WT increased cell proliferation in vitro and tumor growth in vivo.

Chordomas are rare, malignant, low grade, primary bone tumours arising from notochord remnants. They are rarely located in the lumbar spine and consequently, the literature is lacking about the condition. There are very few case reports on the technical aspects of resection of extensive lesions such as our case. Treatment can be potentially curative only if aggressive surgical resection is utilised. We describe a case of an extensive lumbar chordoma, and demonstrate the possibility of performing a staged anterior and posterior total tumour resection with planned transgression in conjunction with an expandable cage, vascularised rib, fibula and latissimus dorsi grafts for the treatment and reconstruction of extensive spinal disease with this condition.

Alopecia areata (AA) is a T-cell-mediated hair loss disorder but the exact cause is unknown. In this report we describe patterns of onset, regrowth and relapse in AA and propose potential underlying mechanisms. We believe that these aspects of AA require integration into modern theories of AA pathogenesis.

Raman microspectroscopy was first used to determine the composition of a calcified plaque located at the pterygium-excision site of a 51-year-old female patient's left nasal sclera after surgery. It was unexpectedly found that the Raman spectrum of the calcified sample at 1149, 1108, 1049, 756, 517, 376 and 352/cm was similar to the Raman spectrum of monoclinic form of calcium pyrophosphate dihydrate (CPPD) crystal, but differed from the Raman spectrum of triclinic form of CPPD. An additional peak at 958/cm was also observed in the Raman spectrum of the calcified plaque, which was identical to the characteristic peak at 958/cm of hydroxyapatite (HA). This is the first study to report the spectral biodiagnosis of both monoclinic CPPD and HA co-deposited in the calcified plaque of a patient with sclera dystrophic calcification using Raman microspectroscopy.

The molecular mechanisms leading to neurodegeneration in Parkinson disease (PD) remain elusive, although many lines of evidence have indicated that alpha-synuclein and DJ-1, two critical proteins in PD pathogenesis, interact with each other functionally. The investigation on whether alpha-synuclein directly interacts with DJ-1 has been controversial. In the current study, we analyzed proteins associated with alpha-synuclein and/or DJ-1 with a robust proteomics technique called stable isotope labeling by amino acids in cell culture (SILAC) in dopaminergic MES cells exposed to rotenone versus controls. We identified 324 and 306 proteins in the alpha-synuclein- and DJ-1-associated protein complexes, respectively. Among alpha-synuclein-associated proteins, 141 proteins displayed significant changes in the relative abundance (increase or decrease) after rotenone treatment; among DJ-1-associated proteins, 119 proteins displayed significant changes in the relative abundance after rotenone treatment. Although no direct interaction was observed between alpha-synuclein and DJ-1, whether analyzed by affinity purification followed by mass spectrometry or subsequent direct co-immunoprecipitation, 144 proteins were seen in association with both alpha-synuclein and DJ-1. Of those, 114 proteins displayed significant changes in the relative abundance in the complexes associated with alpha-synuclein, DJ-1, or both after rotenone treatment. A subset of these proteins (mortalin, nucleolin, grp94, calnexin, and clathrin) was further validated for their association with both alpha-synuclein and DJ-1 using confocal microscopy, Western blot, and/or immunoprecipitation. Thus, we not only confirmed that there was no direct interaction between alpha-synuclein and DJ-1 but also, for the first time, report these five novel proteins to be associating with both alpha-synuclein and DJ-1. Further characterization of these docking proteins will likely shed more light on the mechanisms by which DJ-1 modulates the function of alpha-synuclein, and vice versa, in the setting of PD.

Calcinosis cutis is characterized by the deposition of calcium salts in the subcutaneous tissues. Both Fourier transform infrared (FTIR) and Raman microspectroscopic analysis have been applied to easily get the chemical compositions of the skin calcified deposit (SCD), which was surgically excised from a female patient. This SCD was cut into two parts for histopathological (HE stain) examination and vibrational microspectroscopic study. The result indicates that the whole SCD in the skin lesion was found to be a well-developed, mature and hard mass. Several FTIR absorption bands at 873, 961 and 1,031 cm(-1) [the stretching modes of carbonate and phosphate of hydroxyapatite (HA)], 1,547 and 1,658 cm(-1) (the amide I and II bands of collagen) were detected in the IR spectrum of SCD. The Raman spectral bands at 1,665 and 1,450 cm(-1) (collagen); 1,519 and 1,156 cm(-1) (beta-carotene); and 1,072 and 958 cm(-1) (HA) were also obtained. To our knowledge, this is the first report using FTIR and Raman microspectroscopies to quickly identify and quantify three predominant components, collagen, beta-carotene and type B carbonated HA, in the SCD of a patient.

The aim of this study was to quickly and quantitatively detect the chemical composition of the calcified deposit on the surface of a surgically excised cornea by using vibrational microspectroscopy.Both attenuated total reflection (ATR)/Fourier transform infrared (FTIR) and confocal Raman microspectroscopies were used to evaluate the chemical composition of the excised corneal calcified opaque deposit of a 50-year-old male patient. Hydroxyapatite (HA) was used as a reference.Microscopic observations indicated that a whitish-grayish opaque plaquelike deposit was observed. A peak at 1020 cm(-1) assigned to the stretching vibration of phosphate of the poorly crystalline, immature and nonstoichiometric HA was observed from the IR spectrum of the corneal calcified deposit, as compared with the peak at 1030 cm(-1) of the mature, crystalline and stoichiometric HA reference sample. Higher contents of two IR spectral peaks at 871 cm(-1) due to the type-B carbonated apatite and at 866 cm(-1) corresponded to a labile carbonate were also evidenced in the corneal calcified deposit. The predominate peak at 959 cm(-1) due to the stretching mode of phosphate was also found in the Raman spectrum of corneal calcified deposit.The corneal calcified deposit was evidenced to contain much poor crystalline and immature HA having higher content of the type-B carbonated apatite within the corneal collagen matrix. The process of corneal calcification still proceeds on the surface of this cornea.

An 82-year-old woman on long-term prednisolone for chronic obstructive airways disease presented with a 2-month history of nodules on her left forearm. This occurred 10 years after nodules on her right forearm caused by a culture-proven Mycobacterium marinum infection. Histopathological examination, polymerase chain reaction and culture of biopsy specimens were positive for M. chelonae. To our knowledge this is the first case of metachronous nontuberculous mycobacterial skin infection reported, and it highlights the diagnostic and therapeutic challenges of such infections.

Background: The Stanford BCNU protocol (carmustine, etoposide and cyclophosphamide) is a high-dose conditioning regimen widely used prior to autologous stem cell transplantation. While acute renal failure requiring renal replacement therapy is a known but rare complication of autologous stem cell transplantation, acute nephrotoxicity following carmustine and etoposide has not yet been reported. Case: We present the first case of carmustine-induced acute kidney injury in the setting of autologous stem cell transplantation and perform a review of the literature. Renal failure was associated with a sharp rise in serum creatinine, oliguria and trace proteinuria. Urgent haemodialysis was required; however, renal failure resolved after 7 days. Con clusion: Although a rare complication, its severity mandates close monitoring of renal function as early recognition and treatment may limit long-term sequelae.

The CSIRO has received funding from the National Telehealth Pilot Program to undertake a study of telehealth for the management of the chronically ill in the community. This study is being carried out at six locations in five states, ranging from community-based, nurse-led programs to a hospitalfocused, chronic-disease management program supported by highly trained doctors and specialist nurses and seeks to investigate all aspects of using at home telehealth services to better manage chronic disease. The study will introduce telehealth services and observe how each test site integrates these into their established models of care. Based on an Intervention-Control design, 150 chronically ill patients with multiple co-morbidities will be monitored with an additional 300 patients acting as controls. Healthcare outcomes, changes in patterns of utilisation of GP and other healthcare services, socio-economic costs of delivering care, impact on clinical workforce, patient and clinician acceptance of the service and the organisational change management that was required to influence and change established workplace culture will be studied. The CSIRO study is finishing at the end of December of 2014. Preliminary data will be presented together with a number of examples where at home tele-monitoring of vital signs identified early signs of an exacerbation in the patients’ condition and led to the timely orchestration of care which avoided unnecessary hospitalisation. World Congress on Integrated Care 2014, Sydney, November 23-26, 2014. International Journal of Integrated Care – Volume 14, 8 December – URN:NBN:NL:UI:10-1-116582– http://www.ijic.org/ CSIRO is also developing a sophisticated risk stratification and decision support system which identifies statistically significant changes in patients’ vital signs and questionnaire responses giving clinical care coordinators the opportunity to focus their attention to those patients most at risk of hospitalisation. Advanced data analytics together with clinical decision support will allow telehealth to be deployed in very large numbers nationally without placing an excessive workload on the monitoring facility or the patient's own clinicians. Outcomes from this trial will contribute to government policy frameworks and lead to funding mechanisms which will assist in finally progressing large-scale national deployment of telehealth services in Australia.

A highly efficient Fourier transform infrared (FT-IR) microscopy was used to determine the biophysical structure of anagen scalp hair roots of neonates suffering from congenital hypothyroidism (CH) due to ectopic thyroid. The present results indicate that the lower composition near 1,053 cm- 1 (also assigned to the aromatic iodide stretching band) in the infrared (IR) spectra of the hair roots for CH patients was directly associated with the lower serum level of T 4 and fT 4, and the elevated TSH levels determined by RIA method. This strongly implies the lower evidence of the aromatic iodide stretching band in the IR spectra of hair roots. These findings suggest that FT-IR microscopy has the potential to become a good diagnostic tool and that hair can be useful as a genetic marker.

Hair analysis can be used as a screening tool in the diagnosis of genetic diseases. The scalp hair roots of 67 normal neonates and 39 neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency were analysed using Fourier transform infrared (FT-IR) microspectroscopy to differentiate the stages of the hair growth cycle and to diagnose the genetic disorder on the basis of spectral differences. We have demonstrated that FT-IR microspectroscopy is a rapid and effective noninvasive diagnostic method to differentiate scalp hair roots of normal neonates into the anagen, catagen or telogen phases of the hair growth cycle, using IR spectral differences within the 3000-2800 cm(-1) region and the IR peak area ratio of 2854 cm(-1)/2873 cm(-1) or 1084 cm(-1)/amide II band (p0.001). Moreover, G6PD-deficient neonates could be accurately diagnosed from telogen phase hair roots owing to significant differences in IR peak area ratios of 2854 cm(-1)/2873(-1) or 1084 cm(-1)/amide II band compared to normal values in healthy neonates. The result suggests that the application of FT-IR microspectroscopy may be capable not only of differentiating the hair growth cycle into anagen, categen or telogen phases but also of detecting G6PD deficiency. Hair root analysis promises to be a useful complement to serum and urine analysis in the diagnosis of genetic diseases.

Previous study has supposed a possible mechanism of exacerbating cataract formation in cataractous human lens capsules induced by hypertension or glaucoma. To clarify the glaucoma-induced cataract formation of the eyes lens, changes in the human lens lipid and protein structures of immature cataractous patients with or without glaucoma were investigated. Two normal lenses, ten immature cataractous lenses without any complication and four immature cataractous lenses with glaucoma were used after surgical operation. Each de-capsulated human lens sample was sliced with a number 15 surgical blade. The intact nuclear lens regions were used for non-destructive analysis. The lens lipid and protein structures, as well as compositions of these lens samples, were determined using a Fourier transform infrared (FTIR) microspectroscopy with second-derivative, de-convolution and curve-fitting methods. The results indicate that the IR spectrum of glaucomatous lenses appeared as a shoulder only at 2853 cm −1 , thus the composition of the symmetric CH 2 stretching band at 2853 (2852) cm −1 decreased more significantly in glaucomatous lens to only one half of that in normal and immature cataractous lenses. The composition of the asymmetric CH 3 stretching band at 2965 cm −1 for normal lens decreases markedly from 32 to 20% for immature cataractous lenses with or without glaucoma. The compositional ratio of component at 2965 cm −1 to component at 2928 (2930) cm −1 for normal lenses was about 0.702, and that ratio for cataractous lenses without glaucoma was 0.382 but for glaucomatous lenses was 0.377. The maximum peak position of amide I band for IR spectra of the normal lens, immature cataractous lenses without complications or glaucomatous lenses appeared respectively at 1632, 1630 or 1622 cm −1 , assigned to β sheet structure. A marked difference in peak intensity of amide I band for the normal lenses and immature cataractous human lenses with or without glaucoma was observed. The peak intensity ratio of amide I /amide II (1632/1545 cm −1 ) for normal lenses was in the range of 2.20–2.33, whereas in the spectra of immature cataractous lenses without glaucoma this ratio (1630/1545 cm −1 ) was 1.28–1.41 but was 1.04–1.13 for glaucomatous lens in the intensity ratio of 1622/1545 cm −1 . The intensity of the glycogen bands in the wavenumber region 1135–1076 and 1069–1032 cm −1 was found to increase for the immature cataractous lenses with or without glaucoma, as compared with the normal ones. The peaks ranging from 1633 to 1610 cm −1 assigned to β -sheet structure also exhibited a pronounced compositional difference, particularly in glaucomatous lenses. The human lens lipid and protein secondary structures were more affected by glaucoma. Higher protein side chains and reduced lipid content contributed predominantly to the CH stretching vibrations of normal lens structure, whereas high lipid content and less protein side chains dominated the CH stretching vibrations of cataractous lenses with or without glaucoma. Decrease α -helix and random coil structures but enhanced β -sheet structure in the immature cataractous human lens induced by glaucoma might result from the formation of intermolecular hydrogen-bonding insoluble protein aggregates that modify the secondary structure of protein in lenses.

Objective: To illustrate a hybrid technique that involves a combination of open decompression and Posterior Lumbar Interbody Fusion (PLIF) and percutaneously placed pedicle screws. This technique allows for PLIF via a midline incision and approach, and decompression without compromise in operative time and visualisation. Furthermore, this approach is proposed to reduce post-operative wound pain by: smaller midline incision, significantly reduced muscle trauma by not dissecting the paraspinal muscles off the facet joint complex, avoidance of a posterolateral fusion to facilitate limited lateral muscle dissection off the transverse processes. Summary of background data: PLIF fusion rates are comparable to posterolateral fusion rates, as well as providing greater sagittal and coronal balance. There is positive evidence that degenerative spondylolisthesis with canal and/or foraminal stenosis requires stabilisation when decompressed via laminectomy. Methods: Patients with Grade I-II spondylolisthesis at L4/5 with moderate - severe canal/foraminal stenosis undergo a midline PLIF at L4/5, with closure of the midline incision. Percutaneous pedicle screws are inserted, therefore minimising local muscle trauma, with reduction of the spondylolisthesis performed using the pedicle screw construct. Rods are inserted percutaneously to link the L4 and L5 pedicle screws. Image intensification is used to confirmed satisfactory screw placement and reduction of the spondylolisthesis. Conclusion: Percutaneous lumbar pedicle screws can be combined with a standard midline PLIF to reduce postoperative wound pain while allowing for satisfactory screw placement.

Objectives On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. Methods Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and 18 F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. Results Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9months and 4.5months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5months, and another patient with a PIK3CA mutation had stable disease (SD) for 4months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with 18 F-FDG-PET responses. Conclusions Patients tolerated perifosine 150mg PO daily plus docetaxel at 75mg/m 2 every 4weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

Idiopathic calcinosis cutis (CC) is a rare disease in a child. The chemical composition of the calcified deposits in idiopathic CC was first qualitatively and quantitatively examined using vibrational microspectroscopy via spectral diagnosis. The combined application of the Fourier transform infrared (FT-IR) and Raman microscopic techniques was used to detect and identify the nature of the components of the calcified deposits in idiopathic CC and to compare the results with histopathological findings. Two major components of type B carbonated apatite and β-carotene interspersing subcutaneous tissue were clearly evidenced to make up the calcified deposits in idiopathic CC in our pediatric patient. Moreover, the calcified deposits of idiopathic CC contained a relatively larger amount of type B carbonated apatite and a smaller amount of type A carbonated apatite than the calcified deposits analyzed in dystrophic CC. This is the first report on the chemical composition of calcified deposits in idiopathic CC established by spectral analysis. The combination of FT-IR and Raman microscopic techniques was very useful for simultaneous assessment of the intact components of the calcified deposits in idiopathic CC.

Objective. To establish the correlations among the mineral components, progressive calcification process and clinical symptoms of calcific tendonitis. Methods. The morphology of the calcified deposits on the shoulders of 28 patients with calcific tendonitis was determined by high-resolution ultrasonography. The calcified deposit from each patient was aspirated and determined by the Fourier transform infrared and Raman microspectroscopies. The curve-fitting program was applied to estimate the chemical component in the calcified deposits of calcific tendonitis. Results. The morphology of calcified deposits for 28 patients was classified into four shapes: arc shape (7 patients), fragmented/punctuate shape (4 patients), nodular shape (13 patients) and cystic shape (4 patients). These classified shapes markedly correlated with the pain levels in patients. The infrared spectra of all the calcified deposits for 28 patients were easily classified into three types in the blind study and corresponded to the formative, resting and resorptive phases in the progressive calcification process of calcific tendonitis. With the progressive calcification, the IR wavenumber at 1018 cm � 1 assigned to poorly crystalline, non-stoichiometric apatite for the formative phase was shifted to 1028 cm � 1 for the resting phase and then to 1031 cm � 1 due to matured crystalline stoichiometric apatite for the resorptive phase. The curve-fitted results revealed that calcified deposits in calcific tendonitis were composed of different quantities of A-type and B-type carbonated apatites in the three phases. A significant difference was found in carbonated apatite content among the three phases (P < 0.001). Conclusions. The different quantities of A-type and B-type carbonated apatites determined by vibrational microspectroscopy in calcified deposits were well correlated with those of the four shapes of morphologic classification, with the three phases in the progressive calcification process and with the clinical symptoms of calcific tendonitis.

A case of urinary vessel calcification was detected incidentally in pelvic cavity of a 59-year-old man by computed tomography. The silver reticulin, actin, and hematoxylin and eosin stains were applied to diagnose the feature of vessel and confirmed that the vessel was the vesical artery. To our knowledge, this is the first report to find out the obliteration of superior vesical artery caused by calcified deposit. The calcified deposit in superior vesical artery was qualitatively identified to consist of hydroxyapatite, cholesterol and beta-carotene by Fourier transform infrared and Raman microspectroscopies, in which A-type carbonated apatite was a predominate component.

Although much has been learned in the last few decades concerning the molecular mechanisms and pathways associated with the development of familial as well as sporadic Parkinson disease (PD), the precise mechanisms and specific proteins responsible for mediating these effects remain to be elucidated. Thus, the identification and biological evaluation of novel proteins involved in these pathways is critical to providing a more comprehensive understanding of PD pathogenesis. Previously, in a cellular model of PD, we identified nucleolin as a protein interacting with alpha-synuclein and DJ-1, two critical proteins involved in PD pathogenesis. In our current study, we found the expression levels of nucleolin were dramatically reduced in the substantia nigra pars compacta of human PD subjects, compared with controls. Furthermore, manipulation of nucleolin in an in vitro model of PD resulted in significant alterations in the generation of oxidative stress as well as proteasomal inhibition following rotenone exposure. Interestingly, nucleolin expression did not influence mitochondrial complex I activity, suggesting a selective specificity for oxidative stress and proteasomal pathways.

Fourier transform infrared (FT-IR) and Raman vibrational microspectroscopies used for biomedical diagnosis of human tissues are reviewed from basic principle to biological applications. The advantages and disadvantages of both vibrational microspectroscopies are compared to highlight their efficiency and adaptability for noninvasively investigating the chemical compositions of ultrastructual human tissues at different disease states. Biochemical fingerprints applied to the biological samples by using FT-IR and Raman microspectroscopies are illustrated. The spectral biodiagnoses of several diseased human tissues such as ophthalmic disorders (risk factors-induced cataractous lens capsules and lens, lens and corneal calcifications, opacification and contamination of intraocular lens, vitreous asteroid bodies), alcohol-disordered human gastric mucosa, skin disorders (cancer and calcification), brain tumors (pituitary adenomas and astrocytomas), genetic hair roots disorder (glucose-6-phosphate dehydrogenase deficiency, phenylketonuria and congenital hypothyroidism), benign prostatic hyperplasia, and interstitial cystitis investigated by both vibrational microspectroscopies in our laboratory are introduced.

The Virtual Critical Care Unit, (ViCCU®) is a telemedicine system that allows a specialist at a major referral hospital to direct a team in a rural hospital. ViCC® allows remote consultation to take place based on the transmission of multiple channels of real-time video/audio information of the patient, the clinical team, x-ray/paper documents and patient vital signs from the remote site to the specialist. This paper explores clinicians' experience of presence in a telemedicine application. In this study we used a modified version of the Slater-Usoh-Steed (SUS) presence questionnaire to measure clinicians' sense of presence when using ViCC®. We also explored the relationship between presence felt when using ViCCU® and personal, usability and media factors. Initial results indicate that in this context, personal factors influenced clinicians experience of presence and that there was a positive relationship between presence and both usability and media factors. Reflection on some of the challenges in conducting this study in an emergency department and the appropriateness of the SUS presence measure in this real setting are also included.

Endometrial cancer is the most common cancer of the female reproductive system. PTEN is mutated or absent in more than half of human endometrial cancers. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. Mig-6 suppresses estrogen signaling. Here, we show the significance of MIG-6 in human endometrial cancer through sample analysis, where MIG-6 expression is inversely associated with ERK phosphorylation; this relationship is tightly correlated with endometrial cancer progression. To determine the tumor suppressor function of Mig-6 in the development of endometrial cancer, we generated Mig-6 conditional overexpression mice (R26Mig-6LSL). To assess the effects of Mig-6 on the PTEN/PI3K/AKT signaling pathway in uterine tumorigenesis, mice with Pten floxed (Ptenf/f) and R26Mig-6LSL were bred to the PRCre mouse model to generate overexpression of Mig-6 and ablation of Pten in the uterus (PRcre/+ R26Mig-6LSL Ptenf/f). PRcre/+ R26Mig-6LSL Ptenf/f showed significantly increased survival time and uterine weight compared to PRcre/+ Ptenf/f mice. Gross morphology and histological analysis displayed dramatically suppressed development of endometrial cancer in double mutant mice compared to ablation of Pten alone. Immunohistochemical analysis showed significantly increased apoptosis and decreased proliferation in epithelial cells of PRcre/+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice. Interestingly, the expression of pERK1/2 was significantly decreased in PRcre/+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice. To examine whether inhibition of ERK phosphorylation suppresses tumor progression in endometrial cancer, PRcre/+Ptenf/f mice were treated with U0126, an effective inhibitor of MAPK/ERK kinase. PRcre/+Ptenf/f mice treated with U0126 exhibited a significant reduction in uterine weight. Histopathological analysis of the entire animal cohort showed that inhibition of ERK phosphorylation suppressed endometrial cancer progression in PRcre/+ Ptenf/f mice, as reflected by the arrest of tumors at the hyperplastic or normal stage, whereas tumors from PRcre/+Ptenf/f mice treated with vehicle advanced to endometrial cancer. These results demonstrate that activation of ERK signaling is critical for endometrial cancer development and progression in Pten mutation. Our findings highlight a crucial tumor suppressor role for MIG-6 in progression of PTEN-null endometrial cancer by inhibiting ERK phosphorylation. As MIG-6 is a mediator of progesterone signaling, the activity of which can suppress unopposed-estrogen signaling, our studies provide a potential new drug target for the intervention of metastatic human endometrial cancer. (This work was supported by NIH, U54 HD007495 to J.P.L, NIH, R01 HD057873 and American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.) Citation Format: Jung-Yoon Yoo, Tae Hoon Kim, Hong Im Kim, Jane Li, Gordon B. Mills, Russell R. Broaddus, John P. Lydon, Ho-Geun Yoon, Jae-Wook Jeong. Mig-6 suppresses development and progression of endometrial cancer by inhibiting ERK2 phosphorylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 60. doi:10.1158/1538-7445.AM2014-60

In order to investigate the conformational structure of isolated human gastric mucus gel pretreated with or without ethanol, gel samples were determined by attenuated total reflection/Fourier transform-infra-red (ATR/FT-IR) microspectroscopy. The result indicates that the secondary structure-dependent amide I band and the glycoprotein region were significantly different in the gastric mucus gels pretreated with and without 40% ethanol. The structural composition of β-sheet structure (1640-1600 cm -1 ) increased from 38.48 to 55.08% (+ 16.6%) after 6-hour pretreatment with 40% ethanol, but the β-turn structure, (1660-1700 cm -1 ) decreased from 41.38 to 24.29% (-17.05%). The peak area ranging from 1180 to 1000 cm -1, assigned to the glycoprotein region, was also different after pretreatment with ethanol for 6 h. The higher peak area of the carbohydrate band was obtained in the frequency region between 1000 and 1040 cm -1 and 1100 and 1180 cm ' for mucus gel pretreated with 40% ethanol. However, the peak area ranging from 1100 to 1040 cm -1 mainly due to the symmetric phosphate stretching mode of proteins was somewhat lower for the ethanol-pretreated mucus gel than the native mucus gel. This result strongly reveals that ethanol significantly modified the conformational structure of proteins and carbohydrates of gastric mucus gel. We propose that the dehydration and interference of hydrophobic interactions in the isolated mucus gel after pretreatment with ethanol might be responsible for this conformational change.

To clarify the role of the lens capsule in cataract formation, changes in the protein conformational structure of immature cataractous lens capsules from patients with systemic hypertension or glaucoma have been investigated, as compared to normal lens capsules. The protein secondary structure and composition of these capsular samples were determined using Fourier transform infrared microspectroscopy with second-derivative, deconvolution and curve-fitting methods. We found that the composition of both random coil and beta-type (beta-sheet and beta-turn) structures in the immature cataractous human lens capsules was increasingly induced by systemic hypertension or glaucoma, but alpha-helix content clearly decreased, leading to the alteration of protein conformational structures in lens capsules. A possible pathway of cataract formation exacerbated by systemic hypertension or glaucoma is discussed. According to the results, we propose that systemic hypertension or glaucoma induce changes in the protein conformational structures of the lens capsule, then cause alteration of membrane transport and permeability for ions, and finally increase intraocular pressure, resulting in the exacerbation of cataract formation. The effect on the conformational structure of cataractous human lens capsules is more pronounced for systemic hypertension than for glaucoma. The present study implies that systemic hypertension or glaucoma can exacerbate cataract formation in senile patients by modifying the protein secondary structures in the lens capsule.

Endometrial cancer remains the most common gynecologic malignancy in the United States with an estimated 43,000 cases annually. Limited options exist for patients with recurrent endometrial cancer after tumor progression following platinum/taxane combinations, and newer therapies are needed. Endometrial cancers have among the highest rates of oncogenic aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway with frequencies approaching 75%, and clinical trials targeting components on the PI3K pathway are ongoing. Despite the clinical observation that many responses to PI3K inhibitors are short lived an understanding of the molecular mechanisms of resistance is lacking. We have derived endometrial cancer cell lines resistant to a panel of PI3K/AKT/mTOR inhibitors in clinical development in an effort to understand molecular mechanisms and signaling changes underlying resistance to PI3K-targeted therapy. All lines have previously undergone mutational analysis of the PI3K and RAS-ERK pathways. Representative compounds inhibiting each node in the canonical class I PI3K signaling cascade have been chosen. These agents have been synthesized base on the published structures and include a pan-p110 inhibitor, an allosteric AKT inhibitor, a dual p110-mTOR, and a MEK inhibitor. Using parallel high-throughput intracellular phospho-kinase and phospho-receptor tyrosine kinase (RTK) arrays for screening we have identified candidate common resistance mechanisms to inhibition of signaling nodes in the PI3K pathway. The phospho-screening approach has highlighted the interplay between PI3K/AKT/mTOR signaling and the Ras/Raf/MEK/ERK pathways in the development of resistance. We have begun to validate ERK upregulation as an activated escape pathway in patient samples from an AKT inhibitor clinical trial. Conserved resistance profiles may ultimately be used to define a subset of endometrial cancer patients unlikely to respond to PI3K/Akt/mTOR inhibitors and may inform more rational early phase combination strategies. Citation Format: Samuel J. Klempner, Andrea P. Myers, Jane Li, Gordon Mills, Lewis C. Cantley. Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2013-4265

Corneal neovascularization (NV) is usually associated with inflammatory or infectious disorders of the ocular surface and often accompanied by stromal edema, lipid deposits, keratitis, or scarring. All of which frequently results in vision impairment or blindness. Pathological angiogenesis is also thought to predispose to the reflection of corneal allografts by facilitating the exposure of antigens in the donor cornea to the immune system. Many medical and surgical treatments, including angiostatic steroid, nonsteroidal anti-inflammatory agent, argon laser photocoagulation, photodynamic therapy, and limbal stem cell transplantation have been effective in animal or human models in inhibition of corneal neovascularization. However, anti-angiogenic therapy needed to be further investigated for effective treatment against actively growing and established corneal neovascularization.

ESR1 is one of the most important oncogenes and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and favorable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insight into how ESR1 is regulated by NR2E3 and clinical relevance of NR2E3 in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2011-356