Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation.

The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.

Anti-proliferative effects of mesenchymal stem cells (MSCs) derived from multiple sources on ovarian cancer cell lines: an in-vitro experimental study.

Mesenchymal stem cells (MSCs) have surfaced as ideal candidates for treatment of different therapeutically challenging diseases however their effect on cancer cells is not well determined. In this study, we investigated the effect of MSCs derived from human bone marrow (BM), adipose tissue (AT), and umbilical cord derived MSCs (UC-MSCs) on ovarian cancer.Measurements of ovarian tumor marker proteins were computed by ELISA. Proliferative, apoptosis and anti-inflammatory effects of the MSCs were measured by Flow cytometry (FCM). MMPs expression was measured by RT-PCR.The co-culture of cancer cell lines OVCAR3, CAOV3, IGROV3 and SKOV3 with the conditioned media of MSCs (CM-MSC) and MSCs showed an increase in cellular apoptosis, along with a reduction in the level of CA-125 and a decline of LDH and beta-hCG. A decrease in CD24 of the cancer cell lines in co-culture with the CM-MSCs showed a reduction of the cancer tumorigenicity. In addition, the invasion and aggressiveness of cancer cell lines was significantly decreased by CM-MSC; this was translated by a decrease in MMP-2, MMP-9, and CA-125 mRNA expression, and an increase in TIMP 1, 2, and 3 mRNA expression. An increase in IL-4 and IL-10 cytokines, and a decrease in GM-CSF, IL-6, and IL-9, were also noted.In conclusion, mesenchymal stem cells derived from different sources and their conditioned media appear to have a major role in inhibition of cancer aggressiveness and might be considered as a potential therapeutic tool in ovarian cancer.

Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era.

BACKGROUND: The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. METHODS: Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in pre- and post-KAS periods. RESULTS: The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20-29 y and 13% vs 18% in age group 30-39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50-59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). CONCLUSIONS: The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.

Income, egalitarianism and attitudes towards healthcare policy: a study on public attitudes in 29 countries.

OBJECTIVES: To evaluate the relationship between income and egalitarian values and attitudes towards healthcare policy. STUDY DESIGN: Cross-sectional and cross-national study. METHODS: Data for 29 countries from the International Social Survey Programme (ISSP) 2011 were used. The dependent variables are a general attitude towards government involvement in healthcare provision and two attitudes regarding specific policies (taxes and public funding). Income and egalitarianism were also measured by using ISSP. Data were analysed using regression models that account for individual and country-level characteristics, and country-fixed effects. RESULTS: The effect of income is small and non-significant for attitudes towards government involvement and public funding. For willingness to pay (WTP) taxes to improve healthcare services, we find a positive association with income. Results for egalitarianism suggest a positive association with government involvement in healthcare provision and significant interactions with WTP taxes. CONCLUSIONS: The distinction of dimensions and mechanisms underlying policy attitudes appears as relevant. Citizens across socioeconomic groups are motivated to support state-funded healthcare, favouring the design of non-selfish policies. These findings suggest that there is space for policymakers who seek to increase healthcare spending encouraging either policies for specific groups or broader institutional changes.

Coloduodenovesical Fistula After Simultaneous Pancreas-Kidney Transplant: Case Report and Review of the Literature.

BACKGROUND: Complicated diverticulitis after transplantation occurs in as many as 3.5% of cases and carries a 25% mortality rate. Diagnosis of complicated diverticulitis in this population can be challenging because of abnormal presentations caused by immunosuppression. Only 4 cases of fistulization after kidney transplantation are described in the literature; none occurred after simultaneous pancreas-kidney transplant. METHODS: We present a first case of a coloduodenovesical fistula in a patient 9 years after simultaneous pancreas-kidney transplant. The patient presented with intermittent episodes of elevated creatinine and recurrent urinary tract infection. The presence of fistula was strongly suspected in cystoscopy, but, despite extensive investigation, a fistula tract could not be identified. RESULTS: The patient ultimately underwent surgical exploration for positive cystoscopy examination, continuation of urinary complaints, and presence of multiple colonic diverticula in computed tomography scan. At surgical exploration, a fistula track was identified between the sigmoid colon and duodenal stump of the pancreas allograft. Subsequently, sigmoidectomy, bladder repair, and enteric conversion of the pancreas transplant were performed. CONCLUSIONS: Complications of diverticulitis should be considered in organ transplant recipients presenting with recurrent urinary infection and elevated creatinine, and surgical exploration might be indicated even if unable to well-define the fistula tract.

Echocardiographic assessment of myocardial infarction: comparison of a rat model in two strains.

The purpose of this study was to induce myocardial infarction (MI) and compare the echocardiographic parameters and mortality ratio of Lewis inbred and Wistar outbred strain before and after the procedure to help choose the best one for MI studies. In this study MI was induced in 46 Lewis and 34 Wistar by occlusion of left anterior descending artery (LAD). Doppler, two-dimensional (2-D) and 2-D guided M-mode images were recorded from parasternal long-axis and parasternal short-axis and apical four-chamber views. The following parameters were acquired. Interventricular septum diastolic and systolic dimension (IVSd, s), diastolic and systolic left ventricular internal diameter (LVIDd, s), diastolic and systolic left ventricular posterior wall dimension (LVPWd, s), ejection fraction (EF), and fractional shortening (FS). The significant changes were observed in systolic IVS, LVID and EF and FS before and after MI and no significant difference was detected between Lewis and Wistar. The high mortality rate of 51% was seen in the procedure, including anesthesia in Lewis compared to 34% in Wistar. As a conclusion the echocardiographic parameters of these two strains were similar, but according to mortality rate and more cardiac anatomic variation in Lewis rats, Wistar is better for MI studies.

Landscape of Kidney Transplantation in Patients With Compensated Liver Disease: Results of a Survey of Transplant Surgeons in the United States.

BACKGROUND: The therapeutic options that provide the best long-term outcome for patients who have a combination of end-stage renal disease and compensated cirrhosis are unknown. METHODS: Given the paucity of data and the lack of clinical guidance in this area, a national survey was conducted in the form of an e-mail-based questionnaire addressed to the transplantation surgeons registered with the American Society of Transplant Surgeons. RESULTS: Of the 818 surgeons invited to participate in the survey, 167 (20%) responded. Twenty-one (12.6%) respondents indicated that their program performed <50 kidney transplantations per year, 49 (29.3%) reported performing 50 to 100 kidney transplantations per year, and the majority, 97 (58.1%) of respondents, performed >100 kidney transplantations per year. The majority, 116 (69.5%), believed that compensated cirrhotic patients with end-stage renal disease could be considered for renal transplantation alone, 45 (26.9%) respondents believed that compensated cirrhotic patients on dialysis could only be considered for simultaneous liver-kidney transplantation, and 6 (3.6%) believed that this population of patients was not suitable for kidney transplantation alone. CONCLUSIONS: Our findings suggest that there is a substantial heterogeneity of opinion among transplantation surgeons towards transplantation options for compensated cirrhotic patients. Further data is needed to define best practices and clinical guidelines.

Successful Robotic Cystogastrostomy after Failed Endoscopic Drainage for Infected Pancreatic Fluid Collection Post Distal Pancreatectomy.

We are presenting the management of an infected pancreatic fluid collection that occurred six months after distal pancreatectomy in the setting of a radical resection for adrenal carcinoma. Progressive increase in size of the cyst and failure of endoscopic drainage represented the surgical indications for cystogastrostomy. The procedure was facilitated by robotic approach with da Vinci Surgical System. Though as per current literature the endoscopic drainage has largely been accepted for this pathology due to its high rate of success and a low rate of complications, in this particular case, surgical drainage by the minimally invasive robotic approach was successful after endoscopic approach has failed.

Instrument for evaluating the electrical resistance and wavelength-resolved transparency of stretchable electronics during strain.

A complete analysis of strain tolerance in a stretchable transparent conductor (TC) should include tracking of both electrical conductivity and transparency during strain; however, transparency is generally neglected in contemporary analyses. In this paper, we describe an apparatus that tracks both parameters while TCs of arbitrary composition are deformed under stretching-mode strain. We demonstrate the tool by recording the electrical resistance and light transmission spectra for indium tin oxide-coated plastic substrates under both linearly increasing strain and complex cyclic strain processes. The optics are sensitive across the visible spectrum and into the near-infrared region (∼400-900 nm), and without specifically optimizing for sampling speed, we achieve a time resolution of ∼200 ms. In our automated analysis routine, we include a calculation of a common TC figure of merit (FOM), and because solar cell electrodes represent a key TC application, we also weigh both our transparency and FOM results against the solar power spectrum to determine "solar transparency" and "solar FOM." Finally, we demonstrate how the apparatus may be adapted to measure the basic performance metrics for complete solar cells under uniaxial strain.

Pancreaticobronchial Fistula Diagnosed by MDCT.

Pancreatic duct disruption is a serious complication of acute or chronic pancreatitis. These ruptures may cause collections of pancreatic secretion leading to ascites but also to pleural or mediastinal effusions. Rupture into the bronchial tree, resulting in a pancreaticobronchial fistula, is also possible, but it is a rare complication. It should be considered if a patient with pancreatitis develops respiratory symptoms and requires cross-sectional imaging to identify pancreaticobronchial fistulae.

Wavelength interrogation of fiber Bragg grating sensors using tapered hollow Bragg waveguides.

We describe an integrated system for wavelength interrogation, which uses tapered hollow Bragg waveguides coupled to an image sensor. Spectral shifts are extracted from the wavelength dependence of the light radiated at mode cutoff. Wavelength shifts as small as ~10 pm were resolved by employing a simple peak detection algorithm. Si/SiO2-based cladding mirrors enable a potential operational range of several hundred nanometers in the 1550 nm wavelength region for a taper length of ~1 mm. Interrogation of a strain-tuned grating was accomplished using a broadband amplified spontaneous emission (ASE) source, and potential for single-chip interrogation of multiplexed sensor arrays is demonstrated.

Bioimpedance phase angle predicts muscle function, quality of life and clinical outcome in maintenance hemodialysis patients.

BACKGROUND/OBJECTIVES: The association of bioimpedance phase angle (PA), as a measure of nutritional status, with muscle function, health-related quality of life (QoL) and subsequent clinical outcomes in maintenance hemodialysis (MHD) patients. SUBJECTS/METHODS: A 2-year prospective observational study on 250 MHD outpatients (36.8% women) with a mean age of 68.7±13.6 years. Prospective all-cause and cardiovascular (CV) hospitalization and mortality, malnutrition-inflammation score (MIS), handgrip strength (HGS), bioimpedance and short form 36 (SF-36) QoL scores were the study's measurements. RESULTS: Across the three PA tertile groups, HGS was incrementally higher in the higher PA tertiles (P<0.001), maintaining this order in both male (r=0.38, P<0.001) and female patients (r=0.36, P<0.001). Better self-reported QoL was noted with higher PA values. This trend was prominent in total score (P<0.001), mental health (P=0.005) and physical health (P<0.001) dimensions, and in most of the SF-36 scales. For each 1° increase in baseline PA, the first hospitalization hazard ratio (HR) was 0.79 (95% confidence interval (CI), 0.68-0.91) and first CV event HR was 0.70 (95% CI, 0.52-0.95); all-cause death HR was 0.63 (95% CI, 0.48-0.81) and CV death HR was 0.64 (95% CI, 0.44-0.91). Associations between PA and morbidity risk continued to be significant after adjustments for various confounders, but the association between PA and mortality risk was abolished after adding MIS to the multivariable model. CONCLUSIONS: For the MHD population, PA emerged as a useful predictor for impaired muscle function, health-related Qol, upcoming hospitalizations and mortality.

Trigeminal melanoma metastasis.

We present the case of a 70-year-old patient presented to our institution for paresthesia of the right hemiface associated with dysarthria in aggravation since 1 year. He was diagnosed with right trigeminal melanoma metastasis. This case is characterized by a thickening of the right trigeminal nerve from his cisternal segment to his mandibular branch V3. MRI demonstrated an intensive perineural spread by a melanotic melanoma.

Advantages of multiplex proteomics in clinical immunology: the case of rheumatoid arthritis: novel IgXPLEX™: planar microarray diagnosis.

Clinical multiplex diagnostic proteomics is the application of proteomic technologies to improve a patient's clinical outcomes. The future holds impact potential for testing prognosis, diagnosis, and drug therapy, while monitoring efficacious treatment with qualitative and quantitative data. Multiplex clinical diagnostic use of novel biomarkers in body fluids to confirm presence and severity of clinical disease states, holds great promise for clinical use. Challenges for diagnostic clinics include awareness of proteome complexity in clinical samples, the effects of high-abundance proteins, such as albumin, that could mask detection of other and low abundance disease proteins or biomarkers. Standardized approaches to sample collection and preparation, new analytical techniques and novel algorithms for bio-statistical analysis will facilitate release of the great potential of clinical multiplex diagnostic proteomics. A sensitive RA assay has been developed for the simultaneous measurement of the three rheumatoid factors (RFs), RF-IgA, IgG, and IgM, with the option to simultaneously measure anti-cyclic citrullinated peptide (anti-CCP) IgG antibodies using IgXPLEX™: technology. Testing 10-µL serum samples, SQI's multiplex microarray rheumatoid arthritis assay provides both positive/negative as well as qualitative/semi-quantitative results for anti-CCP IgG, RF-IgA, IgG, and IgM in each sample well on a 96-well microtiter-formatted microarray plate. Signal detection uses sensitive fluorescent-tagged markers captured onto planar microarray spots and read in a microarray scanner. Each result is verified with confidence confirmation technology and validating quality controls in every sample well. For an 80-RA positive patient cohort, the 4-PLEX profile sensitivity was determined at 82.5%. The specificity for the 44 RA healthy control cohort was determined at 97.7%. The multiplex data also demonstrated that a patients' severity of disease profile, mild to severe, correlates the status of RA biomarkers to disease status.

Callus culture of Echium italicum L. towards production of a shikonin derivative.

Callus induction and proliferation of Echium italicum L. (Boraginaceae) were investigated using cotyledon, hypocotyl and root explants. Calli were initiated and established using B5, LS, 1/2LS and White media supplemented with different auxins, including 2,4-dichlorophenoxyacetic acid (2,4-D), indole-3-acetic acid (IAA) and 1-naphthaleneacetic acid (NAA) in combination with kinetin. The maximum pigmented callus induction (100%) was observed in the White medium. The n-hexane extract of proliferated callus tissues were analysed by TLC and HPLC. The major secondary metabolite was separated by preparative HPLC and its structure was elucidated by UV, ¹H and ¹³C-NMR spectroscopy. As a result, shikonin acetate was identified by various spectroscopic methods from callus culture of E. italicum. These findings highlight the shikonin production potential of the E. italicum callus, which may be considered as a new source for the production of shikonin and its derivatives for industrial use.

Pioglitazone attenuates ischemia/reperfusion-induced liver injury in rats.

INTRODUCTION: Hepatic ischemia/reperfusion (I/R) injury leads to free radical generation and acute inflammatory responses that cause liver damage, an important problem for liver transplantation. Pioglitazone is known to protect I/R injury in various tissues; however, the mechanism of cytoprotection is not well understood. This study investigated the effects of pioglitazone administration in a warm hepatic I/R model on tumor necrosis factor (TNF)-alpha level, tissue injury, and antioxidant enzyme activity. MATERIALS AND METHODS: Eighty wistar strain rats were divided into 4 groups (n = 20): Group 1 sham hosts; Group 2 hepatic I/R; Group 3 hepatic I/R + pioglitazone (10 mg/kg); and Group 4 hepatic I/R + vehicle. Rat livers were subjected to 30 minutes of ischemia followed by 6 hours of reperfusion. After reperfusion rats were humanely killed to obtain liver tissue to study glutathione peroxidase (GPx), superoxide dysmutase (SOD), malondialdehyde (MDA) levels and for histopathologic assessment. TNF-alpha, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in serum. RESULTS: Pioglitazone pretreatment significantly reduced liver enzyme content (ALT, 176.80 +/- 13.75 vs 235.28 +/- 31.92 and AST, 748.20 +/- 79.29 vs 944.85 +/- 101.87) and TNF-alpha level (9:8.60 +/- 8.67 vs 138.28 +/- 9.99) after I/R compared with the control group. MDA level (3.02 +/- 0.37 vs 4.36 +/- 0.38) and hepatocytic degeneration were reduced in the pioglitazone-treated group. GPx (2.40 +/- 0.25 vs 1.36 +/- 0.31) and SOD activity (2.22 +/- 0.30 vs 1.40 +/- 0.35) were significantly higher in the pioglitazone-treated group compared with the control group. CONCLUSION: The present study showed that pioglitazone administration improved hepatic I/R injury that was associated with enhanced antioxidant enzyme activities and suppression of TNF-alpha, ALT, and AST levels. Because peroxisome proliferator-activated receptor-gamma agonists are widely used to treat diabetic patients, it may be relatively easy to expand their clinical indication. However, further investigations will be required to delineate protective mechanisms by which pioglitazone attenuates hepatic tissue injury after I/R.