Cognitive control, goal maintenance, and prefrontal function in healthy aging

Cognitive control impairments in healthy older adults may partly reflect disturbances in the ability to actively maintain goal-relevant information, a function that depends on the engagement of lateral prefrontal cortex (PFC). In 2 functional magnetic resonance imaging studies, healthy young and older adults performed versions of a task in which contextual cues provide goal-relevant information used to bias processing of subsequent ambiguous probes. In Study 1, a blocked design and manipulation of the cue-probe delay interval revealed a generalized pattern of enhanced task-related brain activity in older adults but combined with a specific delay-related reduction of activity in lateral PFC regions. In Study 2, a combined blocked/event-related design revealed enhanced sustained (i.e., across-trial) activity but a reduction in transient trial-related activation in lateral PFC among older adults. Further analyses of within-trial activity dynamics indicated that, within these and other lateral PFC regions, older adults showed reduced activation during the cue and delay period but increased activation at the time of the probe, particularly on high-interference trials. These results are consistent with the hypothesis that age-related impairments in goal maintenance abilities cause a compensatory shift in older adults from a proactive (seen in young adults) to a reactive cognitive control strategy.     

Strength and voluntary activation of quadriceps femoris muscle in total knee arthroplasty with midvastus and subvastus approaches

To determine and compare the influence of 2 different approaches on quadriceps femoris muscle function in total knee arthroplasty (TKA), 20 patients (14 women, 6 men) with bilateral knee osteoarthritis underwent a 1-stage bilateral TKA. Surgical approaches (subvastus, midvastus) were performed by a random selection. Measurements of quadriceps voluntary activation and maximal voluntary contraction were estimated by a twitch interpolation technique before, 3 and 6 months after TKA. Knee pain was quantified by the Lewis Score. There was no difference between the 2 approaches at 3 and 6 months after TKA with regard to maximal voluntary contraction (P = 0.84, F = 0.041) and voluntary activation (P = .863, F = 0.031). In the subvastus group was a significantly higher knee pain until 6 months after surgery (P = .02). The subvastus approach for TKA does not provide any advantages compared with the midvastus approach with respect to the quadriceps femoris muscle strength in the early postoperative period. Furthermore, the subvastus approach caused significantly more pain postoperatively.     

Inhibition of porcine endogenous retrovirus in PK15 cell line by efficient multitargeting RNA interference

To effectively suppress porcine endogenous retroviruses (PERV)s, RNAi technique was utilized. RNAi is the up‐to‐date skill for gene knockdown which simultaneously multitargets both gag and pol genes critical for replication of PERVs. Previously, two of the most effective siRNAs (gag2, pol2) were found to reduce the expression of PERVs. Concurrent treatment of these two siRNAs (gag2+pol2) showed knockdown efficiency of up to 88% compared to negative control. However, despite the high initial knockdown efficiency 48 h after transfection caused by siRNA, it may only be a transient effect of suppressing PERVs. The multitargeting vector was designed, containing both gag and pol genes and making use of POL II miR Expression Vector, which allowed for persistent and multiple targeting. This is the latest shRNA system technique expressing and targeting like miRNA. Through antibiotics resistance characteristics utilizing this vector, miRNA‐transfected PK15 cells (gag2‐pol2) were selected during 10 days. An 88.1% reduction in the level of mRNA expression was found. In addition, we performed RT‐activity analysis and fluorescence in situ hybridization assay, and it demonstrated the highest knockdown efficiency in multitargeting (gag2+pol2) miRNA group. Therefore, according to the results above, gene knockdown system (siRNA and shRNA) through multitargeting strategy could effectively inhibit PERVs.     

Efficacy of poly(adenosine diphosphate-ribose) polymerase inhibition in extracorporeal shock wave-induced renal injury

Objectives: Extracorporeal shock wave lithotripsy (ESW) induces renal damage by excessive production of free oxygen radicals. Free Oxygen radicals cause cellular injury by inducing nicks in DNA. The enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) involved in the process of repair of DNA in damaged cells. However, its activation in damaged cells can lead to adenosine triphosphate depletion and death. Thus, we designed a study to evaluate the efficacy of 3-aminobenzamide (3-AB), a PARP inhibitor, against extracorporeal shock wave induced renal injury. Methods: Twenty-four Sprague-Dawley rats were divided into three groups: control, ESW, ESW?+?3-AB groups. All groups except control group were subjected to ESW procedure. ESW?+?3-AB group received 20?mg/kg/day 3-aminobenzamide intraperitoneally at 2?h before ESW and continued once a day for consecutive 3 days. The surviving animals were sacrificed at the 4th day and their kidneys were harvested for biochemical and histopathologic analysis. Blood samples from animals were also obtained. Results: Serum ALT and AST levels, serum neopterin and tissue oxidative stress parameters were increased in the ESW group and almost came to control values in the treatment group (p?p?Conclusion: Our data showed that PARP inhibition protected renal tissue against ESW induced renal injury. These findings suggest that it would be possible to improve the outcome of ESW induced renal injury by using PARP inhibitors as a preventive therapy.     

Proliferation of DU145 prostate cancer cells is inhibited by suppressing insulin-like growth factor binding protein-2

BACKGROUND: Insulin-like growth factor binding protein-2 (IGFBP-2) is expressed by all human prostate cancer cell lines and dramatically increases in the serum of prostate cancer patients. However, the role of IGFBP-2 in prostatic tumorigenesis is not known. The aim of the present study was to investigate the effects of IGFBP-2 on the proliferation of DU145 human prostate cancer cells in culture. METHODS: Using cell proliferation assays, we examined the effects of exogenously administered and endogenously modulated levels of IGFBP-2 on the proliferation of DU145 cells. RESULT: Cell growth was stimulated by exogenously administered IGFBP-2, but significantly retarded (P < 0.05) by its neutralizing antibody. Overexpression of IGFBP-2 by transfection also stimulated cell growth, which was significantly (P < 0.05) inhibited in transfectants expressing antisense mRNA to IGFBP-2. Furthermore, the proliferation of IGFBP-2 overexpressing cells was significantly dampened by exogenously administered IGFBP-2 antibody. CONCLUSIONS: IGFBP-2 is an autocrine growth factor for DU145 human prostate cancer cells and cell proliferation can be significantly retarded by neutralizing or inhibiting its synthesis. These findings provide a strong rationale for targeting IGFBP-2 in the testing of novel strategies to treat prostate cancer.     

Direction selectivity of neurons in the visual cortex is non‐linear and lamina‐dependent

Neurons in the visual cortex are generally selective to direction of movement of a stimulus. Although models of this direction selectivity (DS) assume linearity, experimental data show stronger degrees of DS than those predicted by linear models. Our current study was intended to determine the degree of non‐linearity of the DS mechanism for cells within different laminae of the cat's primary visual cortex. To do this, we analysed cells in our database by using neurophysiological and histological approaches to quantify non‐linear components of DS in four principal cortical laminae (layers 2/3, 4, 5, and 6). We used a DS index (DSI) to quantify degrees of DS in our sample. Our results showed laminar differences. In layer 4, the main thalamic input region, most neurons were of the simple type and showed high DSI values. For complex cells in layer 4, there was a broad distribution of DSI values. Similar features were observed in layer 2/3, but complex cells were dominant. In deeper layers (5 and 6), DSI value distributions were characterized by clear peaks at high values. Independently of specific lamina, high DSI values were accompanied by narrow orientation tuning widths. Differences in orientation tuning for non‐preferred vs. preferred directions were smallest in layer 4 and largest in layer 6. These results are consistent with a non‐linear process of intra‐cortical inhibition that enhances DS by selective suppression of neuronal firing for non‐preferred directions of stimulus motion in a lamina‐dependent manner. Other potential mechanisms are also considered.     

Characterization of a novel subtype of hippocampal interneurons that express corticotropin‐releasing hormone

A subset of corticotropin‐releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV‐Flex‐ChR2‐tdTomato reveal dense back‐projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. © 2015 Wiley Periodicals, Inc.     

Thrombotic Micro‐Angiopathy with Sirolimus‐Based Immunosuppression: Potentiation of Calcineurin‐Inhibitor‐Induced Endothelial Damage?

Thrombotic microangiopathy is a rare but important finding in the context of organ transplantation. Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes 'hemolytic uremic syndrome', can be associated with, or triggered by, conditions such as verocytotoxin-producing Escherichia coli, viral infections, malignant hypertension, scleroderma, allograft rejection, lupus erythematosus, pregnancy, and medications including mitomycin C, calcineurin inhibitors, and oral contraceptives. After renal transplantation, it can occur, as either a de novo episode, or recurrent disease. Calcineurin inhibitors have long been associated with post-transplantation thrombotic microangiopathy. Sirolimus has been used as a primary immunosuppressant in patients transplanted with a history of earlier hemolytic-uremic syndrome, and also as rescue therapy in patients with calcineurin-inhibitor-associated thrombotic microangiopathy. We describe four cases where there was significant thrombotic microangiopathy in the context of contemporaneous or contiguous calcineurin inhibitor and sirolimus usage. As the intrarenal cyclosporin concentration is thought to be significantly elevated when cyclosporin and sirolimus are used together, this may explain these findings, and mandates caution in their co-administration.     

Modified Two-Layer Preservation Method (M-Kyoto/PFC) Improves Islet Yields in Islet Isolation

Islet allotransplantation can achieve insulin independence in patients with type I diabetes. Recent reports show that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and UW solution, is superior to simple cold storage in UW for pancreas preservation in islet transplantation. However, UW solution has several disadvantages, including the inhibition of Liberase activity. In this study, we investigated the features of a new solution, designated M-Kyoto solution. M-Kyoto solution contains trehalose and ulinastatin as distinct components. Trehalose has a cytoprotective effect against stress, and ulinastatin inhibits trypsin. In porcine islet isolation, islet yield was significantly higher in the M-Kyoto/PFC group compared with the UW/PFC group. There was no significant difference in ATP content in the pancreas between the two groups, suggesting that different islet yields are not due to their differences as energy sources. Compared with UW solution, M-Kyoto solution significantly inhibited trypsin activity in the digestion step; moreover, M-Kyoto solution inhibited collagenase digestion less than UW solution. In conclusion, the advantages of M-Kyoto solution are trypsin inhibition and less collagenase inhibition. Based on these data, we now use M-Kyoto solution for clinical islet transplantation from nonheart-beating donor pancreata.