Intracellular messengers and the control of protein synthesis

The molecular events responsible for controlling cell growth and development, as well as their coordinate interaction is only beginning to be revealed. At the basis of these controlling events are hormones, growth factors and mitogens which, through transmembrane signalling trigger an array of cellular responses, initiated by receptor-associated tyrosine kinases, which in turn either directly or indirectly mediate their effects through serine/threonine protein kinases. Utilizing the obligatory response of activation of protein synthesis in cell growth and development, we describe efforts to work backwards along the regulatory pathway to the receptor, identifying those molecular components involved in modulating the rate of translation. We begin by describing the components and steps of protein synthesis and then discuss in detail the regulatory pathways involved in the mitogenic response of eukaryotic cells and during meiotic maturation of oocytes. Finally we discuss possible future work which will further our understanding of these systems.     

The 2006 Henry N. Wagner Lecture: Of mice and men (and positrons)--advances in PET imaging technology.

There have been major advances in PET technology that cumulatively have helped improve image quality, increased the range of applications for PET, and contributed to the more widespread use of PET. Examples of these technologic advances include whole-body imaging, 3-dimensional imaging, new scintillator materials, iterative reconstruction algorithms, combined PET/CT, and preclinical PET. New advances on the immediate horizon include the reintroduction of time-of-flight PET, which takes advantage of the favorable timing properties of newer scintillators; the integration of PET and MRI scanners into a dual-modality imaging system; and the possibility of further significant improvements in spatial resolution in preclinical PET systems. Sensitivity remains a limiting factor in many PET studies. Although, conceptually, huge gains in sensitivity are still possible, realizing these gains is thwarted largely by economic rather than scientific concerns. Predicting the future is fraught with difficulty; nonetheless, it is apparent that ample opportunities remain for new development and innovation in PET technology that will be driven by the demands of molecular medicine, notably sensitive and specific molecular diagnostic tools and the ability to quantitatively monitor therapeutic entities that include small molecules, peptides, antibodies, nanoparticles, DNA/RNA, and cells.     

Precision grip function after free toe transfer in children with hypoplastic digits.

Although toe-to-hand transfer has a defined role in the management of congenital hand deformities, it remains unclear how well children integrate the transferred digits into physiological grasping. We analysed fingertip forces in the precision grip of 13 patients when lifting a test object more than three years after free toe transfer for absent or hypoplastic digits. Clinically, most patients showed normal sensibility of transferred digits, but active motion and pinch strength were limited as compared to the normal hand. For the control of fingertip forces, two key features of the normal two-digit opposition grip were seen in all operated hands: adaptation of grip force to object weight and parallel coordination of lift and grip forces. These physiological grasping strategies developed independently of the patients' age at the time of operation, which ranged from one to 13 years. In four patients, we observed increased tangential load forces with the operated hand due to misalignments in the application of fingertips on the grasp surfaces. Such forces lead to increased grip force requirements on both fingers that may overload transferred digits with limited motor function. The need for optimal alignment of the grip axis during toe-transfer surgery is emphasised.     

Myocardial perfusion SPECT reconstruction: Receiver operating characteristic comparison of CAD detection accuracy of filtered backprojection reconstruction with all of the clinical imaging information available to readers and solely stress slices iteratively reconstructed with combined compensation

BACKGROUND: Past receiver operating characteristic (ROC) studies have demonstrated that single photon emission computed tomography (SPECT) perfusion imaging by use of iterative reconstruction with combined compensation for attenuation, scatter, and detector response leads to higher area under the ROC curve (A(z)) values for detection of coronary artery disease (CAD) in comparison to the use of filtered backprojection (FBP) with no compensations. A new ROC study was conducted to investigate whether this improvement still holds for iterative reconstruction when observers have available all of the imaging information normally presented to clinical interpreters when reading FBP SPECT perfusion slices. METHODS AND RESULTS: A total of 87 patient studies including 50 patients referred for angiography and 37 patients with a lower than 5% likelihood for CAD were included in the ROC study. The images from the two methods were read by 4 cardiology fellows and 3 attending nuclear cardiologists. Presented for the FBP readings were the short-axis, horizontal long-axis, and vertical long-axis slices for both the stress and rest images; cine images of both the stress and rest projection data; cine images of selected cardiac-gated slices; the CEQUAL-generated stress and rest polar maps; and an indication of patient gender. This was compared with reading solely the iterative reconstructed stress slices with combined compensation for attenuation, scatter, and resolution. With A(z) as the criterion, a 2-way analysis of variance showed a significant improvement in detection accuracy for CAD for the 7 observers (P = .018) for iterative reconstruction with combined compensation (A(z) of 0.895 +/- 0.016) over FBP even with the additional imaging information provided to the observers when scoring the FBP slices (A(z) of 0.869 +/- 0.030). When the groups of 3 attending physicians or 4 cardiology fellows were compared separately, the iterative technique was not statistically significantly better; however, the A(z) for each of the 7 observers individually was larger for iterative reconstruction than for FBP. Compared with results from our previous studies, the additional imaging information did increase the diagnostic accuracy of FBP for CAD but not enough to undo the statistically significantly higher diagnostic accuracy of iterative reconstruction with combined compensation. CONCLUSIONS: We have determined through an ROC investigation that included two classes of observers (experienced attending physicians and cardiology fellows in training) that iterative reconstruction with combined compensation provides statistically significantly better detection accuracy (larger A(z)) for CAD than FBP reconstructions even when the FBP studies were read with all of the extra clinical nuclear imaging information normally available.     

Emphysematous pyelonephritis successfully treated with laparoscopic nephrectomy

Emphysematous pyelonephritis is a severe life-threatening infection which continues to carry significant morbidity and mortality. We present a case recently managed at our institution by laparoscopic nephrectomy. The patient survived, and in comparison to some of the more conventionally managed patients in the literature, made an extremely speedy recovery. We would advocate this option to be seriously considered when patients are suitable and appropriately trained surgeons are available.     

Sonographic diagnosis of early recurrence after inguinal herniorrhaphy: Potential pitfalls

Three patients who presented with scrotal swelling within a few days of inguinal herniorrhaphy are reported. Ultrasonography scans performed in these patients all demonstrated features suspicious of recurrence of hernia. One patient underwent surgical exploration, which revealed only a scrotal haematoma without evidence of recurrent hernia. The other two patients were managed conservatively because clinically the swellings were regarded to be more compatible with haematoma. Both patients had subsequent resolution of the scrotal swelling with no clinical evidence of recurrence of hernia on follow‐up. It is concluded that sonographic diagnosis of recurrence of hernia shortly after inguinal herniorrhaphy can occasionally be misleading.     

Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.

Phospholipidosis (PLD) is characterized by an intracellular accumulation of phospholipids in lysosomes and the concurrent development of concentric lamellar bodies. Recently, H. Sawada et al. (2005, Toxicol. Sci. 83, 282-292) identified 17 genes as potential biomarkers of PLD in HepG2 cells. The present study was undertaken to determine if this set of genes measured by quantitative PCR could be validated in the same cell line. The objective was also to investigate the dose-response relationship to further validate the assay and to select the concentrations to use for screening activities. In a first experiment (one concentration tested), out of the 17 genes, the best gene biomarkers of PLD (i.e., 11 genes) were selected for practical screening reasons. Based on these genes, 91.6% (i.e., 11 of 12) of the compounds known to induce PLD were identified as positive and all the negative compounds (i.e., five of five) were also confirmed. When the data obtained in the first experiment were compared to the data by Sawada et al., (2005) the coefficient of correlation calculated was slightly higher than 75%. In the second experiment (26 compounds [all 17 compounds from the first experiment plus 9 other compounds] tested at a minimum of three concentrations), 93.3% (14/15) of the compounds known to induce PLD were identified as such and all the negative controls (six compounds) were also confirmed. Three compounds likely to induce PLD were identified as positive in our assay. Finally, two compounds for which no data are available were also tested. When both experiments 1 and 2 were compared, the coefficient of correlation for 16 compounds tested at the same concentrations reached 87.7%. In conclusion, the present study further confirms the utility of gene expression in HepG2 cells to identify a potential to induce PLD. Finally, based on the data presented, researchers are encouraged to use a range of minimum three concentrations (e.g., 12.5, 25, and 50 microM) to screen for PLD in the human HepG2 cell line.