Effects of Posterior Tibial Slope on a Posterior Cruciate Retaining Total Knee Arthroplasty Kinematics and Kinetics

BackgroundIt has been hypothesized that increasing posterior tibial slope can influence condylar rollback and play a role in increasing knee flexion. However, the effects of tibial slope on knee kinematics are not well studied. The objective of this study is to assess the effects of tibial slope on femorotibial kinematics and kinetics for a posterior cruciate retaining total knee arthroplasty design.MethodsA validated forward solution model of the knee was implemented to predict the femorotibial biomechanics of a posterior cruciate retaining total knee arthroplasty with varied posterior slopes of 0°-8° at 2° intervals. All analyses were conducted on a weight-bearing deep knee bend activity.ResultsIncreasing the tibial slope shifted the femoral component posteriorly at full extension but decreased the overall femoral rollback throughout flexion. With no tibial slope, the lateral condyle contacted the polyethylene 6 mm posterior of the midline, but as the slope increased to 8°, the femur shifted an extra 5 mm, to 11 mm posterior of the tibial midline. Similar shifts were observed for the medial condyle, ranging from 7 mm posterior to 13 mm posterior, respectively. Increasing posterior slope decreased the posterior cruciate ligament tension and femorotibial contact force.ConclusionThe results of this study revealed that, although increasing the tibial slope shifted the femur posteriorly at full extension and maximum flexion, it reduced the amount of femoral rollback. Despite the lack of rollback, a more posterior location of condyles suggests lower chances of bearing impingement of the posterior femur and may explain why increasing slope may lead to higher knee flexion.     

HOXB7: a key factor for tumor-associated angiogenic switch

We had demonstrated previously a functional bridge between altered homebox (HOX) gene expression and tumor progression through HOXB7 transactivation of basic fibroblast growth factor. Here, we have studied whether HOXB7, in addition to basic fibroblast growth factor, may induce other genes directly or indirectly related to neoangiogenesis and tumor invasion. Parental, beta-galactosidase-transduced, and HOXB7-transduced SkBr3 cell lines were examined for the expression of several growth factors and growth factor receptors involved in the proliferative and angiogenic processes. Vascular endothelial growth factor, melanoma growth-stimulatory activity/growth-related oncogenene alpha, interleukin-8, and angiopoietin-2 were up-regulated by HOXB7 transduction. The exception was angiopoietin-1 expression that was abrogated. Additional analyses included the expression levels of enzymes such as matrix metalloprotease (MMP)-2 and MMP-9 and heparanase, capable of proteolytic degradation of extracellular matrix and basement membranes. Results showed an induction of only MMP-9. The functional implication of such a finding was tested using an in vitro coculture assay in a three-dimensional matrix. A delay of differentiation with persistent nests of proliferating cells was found in endothelial cells cocultured with HOXB7-transduced SkBr3 cells. Tumorigenicity of these cells has been evaluated in vivo. Xenograft into athymic nude mice showed that SkBr3/HOXB7 cells developed tumors in mice, either irradiated or not, whereas parental SkBr3 cells did not show any tumor take unless mice were sublethally irradiated. Comparison of tumor nodules for vascularization by CD-31 and CD-34 immunostaining revealed an increased number of blood vessels in tumors expressing HOXB7. Together, the results indicate HOXB7 as a key factor up-regulating a variety of proangiogenic stimuli. Thus, HOXB7 gene or protein is a target to aim at to inhibit tumor-associated neoangiogenesis, considering the number and the redundancy of proangiogenic molecules that should be targeted one by one to theoretically achieve the same effect.     

Early detection of neurological involvement in IDDM and NIDDM. Multimodal evoked potentials versus metabolic control

Clarification of the extent and mechanisms of damage to the central nervous system in diabetes is a frontier of current neurological research. Our aim was to obtain ample electrophysiological documentation of possible neurological abnormalities in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients with a short duration of disease and without overt complications, taking into account metabolic control. Group 1 comprised 11 IDDM patients, and group 2 included 14 NIDDM patients treated with diet alone; the duration of disease was less than 4 yr, and no concomitant clinical complications were present. Age- and sex-matched normal subjects formed groups 3 and 4. Pattern visual evoked potentials (VEP), brain stem auditory evoked potentials (BAEP), and somatosensory evoked potentials (SEP; after the stimulation of both median and tibial nerves) were recorded in all subjects, and metabolic control was evaluated in terms of glycemia and glycosylated hemoglobin. In group 1, significant abnormalities were found in the latency values of VEP, median SEP, and tibial SEP compared with control subjects. Similar latency abnormalities were shown in group 2 for VEP, median SEP, and tibial SEP values and for wave I latency of BAEP. Glycosylated hemoglobin values were correlated with BAEP and SEP abnormalities in many patients in both groups. Furthermore, in group 2, glycemic values correlated with SEP abnormalities. We therefore conclude that neurophysiological abnormalities are present at different levels in IDDM and NIDDM patients only a few years after clinical diagnosis and before the appearance of overt complications, and these abnormalities seem to be correlated with metabolic control status.     

Effects of the Medial Plateau Bearing Insert Conformity on Mid-Flexion Paradoxical Motion in a Posterior-Stabilized Total Knee Arthroplasty Design

BackgroundOne of the most common kinematic abnormalities reported for posterior-stabilized (PS) total knee arthroplasty (TKA) design is paradoxical anterior sliding during early and mid-flexion. PS TKAs have been designed such that the cam-post mechanism does not engage until later in flexion, making these implants vulnerable to anterior sliding during early and mid-flexion. The objective of this study is to investigate the biomechanical effect of increasing bearing conformity on a PS TKA.MethodsUsing a validated computational model of the knee joint, the sagittal conformity of the medial plateau of a PS TKA design was altered. Three scenarios were created and evaluated for mechanics: (1) baseline conformity, (2) increased conformity, and (3) decreased conformity.ResultsFrom full extension to approximately 70° of knee flexion, the medial condyle demonstrated minimal anterior sliding for the increased medial conformity design but revealed anterior sliding of 2 and 4 mm for the baseline and decreased conformity designs, respectively. After cam-post engagement, the medial condyle consistently rolled back for all 3 designs. The lateral condyle experienced consistent rollback throughout the entire flexion range for all 3 designs. However, femorotibial contact force was higher for the increased conformity design, peaking at 3.13 times body weight (×BW) compared to 3.0 × BW contact force for other 2 designs.ConclusionIncreasing medial conformity of the bearing insert appears to reduce mid-flexion sliding for PS TKA designs, although this comes at the expense of increased femorotibial forces. This could be due to kinematic conflicts that may be introduced with highly constraining designs.     

Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABA_A receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABA_A antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABA_A antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABA_A antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.

     

Enforced expression of HOXB7 promotes hematopoietic stem cell proliferation and myeloid-restricted progenitor differentiation

Hematopoietic progenitor/stem cells (HPCs/HSCs) purified from human adult peripheral blood (PB) were triggered into cycling, retrovirally transduced with HOXB7 and then functionally assayed in vitro. HPCs were assayed in multi- and unilineage differentiation cultures in either liquid phase or semisolid medium, primitive HPCs in the high proliferative potential colony-forming cell (HPP-CFC) evaluation system and putative HSCs in Dexter type long-term culture (LTC) as LTC initiating cells (LTC-ICs). Control experiments ensured that the exogenous HOXB7 gene was constantly expressed, while the endogenous one was barely or not transcribed. Enforced expression of the gene markedly modulated the proliferation/differentiation program of the entire HSC/HPC population. Enforced HOXB7 expression exerted a potent stimulatory effect on the proliferation of the primitive HPC and putative HSC subsets, assayed as HPP-CFCs and LTC-ICs respectively. While not modifying the total number of HPCs, exogenous HOXB7 induced an increase of the number of granulo-monocytic (GM) HPCs [colony-forming unit GM (CFU-GM) CFU-GM, CFU-G and CFU-M, as evaluated by clonogenic assays] and markedly amplified the progeny of both CFU-G and CFU-M, which showed a sustained proliferation through at least 1-2 months (as evaluated in liquid suspension culture). The prolonged proliferative stimulus induced by HOXB7 transfer into LTC, primitive and GM oriented HPC culture was characterized by persistent proliferation of a discrete population of blast cells and a large pool of differentiated myeloid precursors. Altogether, these results suggest the hypothesis that the proliferative stimulus exerted by exogenous HOXB7 in primitive and GM-oriented HPCs may represent a preleukemic immortalization step. Consistent with the functional role of HOXB7 in the initial ontogenetic phase, these studies indicate that ectopic HOXB7 expression in early HPCs and HSCs from adult PB stimulates their self renewal, sustained proliferation and myeloid differentiation.