Comparison of circadian rhythm characteristics of blood pressure and heart rate in patients before and after elective coronary artery bypass surgery

Coronary artery bypass grafting surgery (CABGS) is done to reperfuse the ischemic myocardium of coronary disease patients. This study was designed to analyze the circadian rhythm characteristics of blood pressure (BP) and heart rate (HR) of patients before and after CABGS. Fifty-one patients undergoing elective CABGS were studied; 21 patients received one, 12 two and 18 three or more grafts. BP was monitored for 24h before and after CABGS while patients were recumbent in the hospital. Systolic (S) and diastolic (D) BP and HR were assessed every 30 min. Of the 51 patients, 37 (73%) had nondipper 24h BP patterns (nocturnal decline in BP < 10% of daytime mean level) in the preoperative baseline assessment. The peak and MESOR (rhythm-adjusted 24h mean) values of the circadian rhythm in SBP, DBP, and pulse pressure (PP) significantly declined following surgery, while HR and rate-pressure product (RPP = SBP x HR) markedly increased. The double amplitude (peak-to-trough variation) of the circadian rhythm in SBP and DBP was significantly reduced postoperatively, and that of the rhythm in HR and RPP significantly increased. The slopes of the morning rise and evening dip in the 24h SBP profile were reduced significantly after bypass grafting. The corresponding slopes of the HR profile, in contrast, were markedly increased.     

Insulin resistance is an intrinsic defect independent of fat mass in women with Turner's syndrome

BACKGROUND/AIMS: Turner's syndrome (TS) is associated with increased insulin resistance and adiposity, which might be associated with type 2 diabetes in later life. We aimed to determine whether the defect in insulin sensitivity is a primary intrinsic defect in TS or dependent on variation in body composition. METHODS: Sixteen women with TS not on growth hormone replacement but receiving oestrogen replacement therapy [age (mean +/- SD): 30.2 +/- 8.5 years; height-corrected fat-free mass: 26.1 +/- 3.1 kg/height] and a control group of 16 normal healthy women (age: 30.1 +/- 8.2 years; height-corrected fat-free mass: 25.9 +/- 2.4 kg/height) were studied. Fasting blood samples were obtained for measurement of glucose, insulin, IGF-I, IGFBP-1, IGFBP-3 and lipid levels. The hyperinsulinaemic euglycaemic clamp was performed to assess peripheral insulin sensitivity (M value), and the Homeostasis Model Assessment (HOMA-S) was used to estimate fasting insulin sensitivity. Body composition was assessed using a dual-energy X-ray absorptiometry scan. RESULTS: Fasting insulin sensitivity (HOMA-S 103.2 +/- 78.6 vs. 193.9 +/- 93.5, p = 0.006) was lower in TS subjects compared to controls as was whole-body insulin sensitivity (M value 2.9 +/- 1.9 vs. 5.5 +/- 2.6 mg/kg/min, p = 0.003). In a multiple regression analysis the Turner karyotype was significantly related to insulin sensitivity (p = 0.008) independent of any differences in fat-free mass and percent whole-body fat mass. CONCLUSION: The increased insulin resistance in women with TS is independent of measures of body composition and may represent an intrinsic defect related to their chromosomal abnormality.     

Wee1 Inhibition by MK-1775 Leads to Tumor Inhibition and Enhances Efficacy of Gemcitabine in Human Sarcomas

Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10–20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible and new agents are needed. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by MK1775 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas. In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo both alone and in combination with gemcitabine, which is frequently used in the treatment of sarcomas. Our data demonstrate that MK1775 treatment as a single agent at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. Additionally, MK1775 significantly enhances the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status. In patient-derived bone and soft tissue sarcoma samples we showed that MK1775 alone and in combination with gemcitabine causes significant apoptotic cell death. Magnetic resonance imaging (MRI) and histopathologic studies showed that MK1775 induces significant cell death and terminal differentiation in a patient-derived xenograft mouse model of osteosarcoma in vivo. Our results together with the high safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients.     

Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy

In the present study, the effect of systemically administered vasoactive intestinal peptide (VIP) (25 ng/kg i.p.) was investigated on drug-induced rotational behavior, extra-cellular dopamine levels and histology of corpus striatum in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. After 15 days of 6-OHDA lesion, apomorphine-induced (0.05 mg/kg s.c.) rotational behavior of the animals significantly increased and extra-cellular dopamine levels of corpus striatum were significantly reduced. VIP reversed the rotational deficits but did not alter the decrease in striatal dopamine levels. On the other hand, histological data indicate that VIP significantly reduced neuronal death and demyelination. Electron microscopic appearance of mast cells showed ultra-structural variety between VIP-treated and 6-OHDA lesioned groups. VIP activates mast cells without any evidence of typical exocytosis, and possibly mast cells could participate in neuroprotection. Our results suggest that systemically administered VIP can attenuate the motor response changes, neuronal cell death, and myelin sheet loss characteristically associated with 12 microg 6-OHDA administration into the rat striatum. Brain mast cells seem to participate in neuronal protection. Possibly, protective cues could be produced by brain mast cells.     

Study protocol to examine the effects of spaceflight and a spaceflight analog on neurocognitive performance: extent,longevity, and neural bases

Background

Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether spaceflight also affects other central nervous system functions such as cognition is yet largely unknown, but of importance in consideration of the health and performance of crewmembers both in- and post-flight. We are therefore conducting a controlled prospective longitudinal study to investigate the effects of spaceflight on the extent, longevity and neural bases of sensorimotor and cognitive performance changes. Here we present the protocol of our study.

Methods/design

This study includes three groups (astronauts, bed rest subjects, ground-based control subjects) for which each the design is single group with repeated measures. The effects of spaceflight on the brain will be investigated in astronauts who will be assessed at two time points pre-, at three time points during-, and at four time points following a spaceflight mission of six months. To parse out the effect of microgravity from the overall effects of spaceflight, we investigate the effects of seventy days head-down tilted bed rest. Bed rest subjects will be assessed at two time points before-, two time points during-, and three time points post-bed rest. A third group of ground based controls will be measured at four time points to assess reliability of our measures over time. For all participants and at all time points, except in flight, measures of neurocognitive performance, fine motor control, gait, balance, structural MRI (T1, DTI), task fMRI, and functional connectivity MRI will be obtained. In flight, astronauts will complete some of the tasks that they complete pre- and post flight, including tasks measuring spatial working memory, sensorimotor adaptation, and fine motor performance. Potential changes over time and associations between cognition, motor-behavior, and brain structure and function will be analyzed.

Discussion

This study explores how spaceflight induced brain changes impact functional performance. This understanding could aid in the design of targeted countermeasures to mitigate the negative effects of long-duration spaceflight.

     

Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells

During bone formation, multipotential mesenchymal cells proliferate and differentiate into osteoblasts, and subsequently many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors. Furthermore, the effects of PTH and PTHrP on apoptosis were dramatically dependent on cell status. In preconfluent C3H10T1/2 and MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced reduction in cell viability, which was dependent on cAMP activation. Conversely, PTH and PTHrP resulted in reduced cell viability in postconfluent cells, which was also dependent on cAMP activation. Further, the proapoptotic-like effects were associated with an inhibition of Akt phosphorylation. These data suggest that parathyroid hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at least in part via the protein kinase A pathway.     

End-to-end linkage (EEL) clustering algorithm: a study on the distribution of Meissner corpuscles in the skin

A novel hierarchical clustering algorithm was applied to the distribution of Meissner corpuscles in the skin of mammals. This method, called end-to-end linkage (EEL), is useful for grouping data that consists of chain-like contingencies in the multivariable space. Unlike the traditional techniques which uncover hyperspherical clusters (e.g. single linkage), EEL considers the shortest distance between the predefined end pairs of the two clusters as an inter-group distance. This scheme allows characterizing the internal structure of data better than other hierarchical techniques. The anatomical data used in the case study is important for studying the sense of touch. The results show a substantial improvement over the traditional single-linkage method. On average, the number of correctly classified corpuscles is increased to twice the number identified by the single-linkage method. EEL can also be used for analyzing other sensory modalities where geometric relationships need to be explored. In addition, the report contains corpuscle density and epidermal-ridge width data obtained from several species.     

Transglutaminase 2: a molecular Swiss army knife

Transglutaminase 2 (TG2) is the most widely distributed member of the transglutaminase family with almost all cell types in the body expressing TG2 to varying extents. In addition to being widely expressed, TG2 is an extremely versatile protein exhibiting transamidating, protein disulphide isomerase and guanine and adenine nucleotide binding and hydrolyzing activities. TG2 can also act as a protein scaffold or linker. This unique protein also undergoes extreme conformational changes and exhibits localization diversity. Being mainly a cytosolic protein; it is also found in the nucleus, associated with the cell membrane (inner and outer side) and with the mitochondria, and also in the extracellular matrix. These different activities, conformations and localization need to be carefully considered while assessing the role of TG2 in physiological and pathological processes. For example, it is becoming evident that the role of TG2 in cell death processes is dependent upon the cell type, stimuli, subcellular localization and conformational state of the protein. In this review we discuss in depth the conformational and functional diversity of TG2 in the context of its role in numerous cellular processes. In particular, we have highlighted how differential localization, conformation and activities of TG2 may distinctly mediate cell death processes.