Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human platelets independent of integrin alphaIIb beta3

Low density lipoprotein (LDL) is known to sensitize platelets to agonists via integrin mediated outside-in signaling (Hackeng, C. M., Huigsloot, M., Pladet, M. W., Nieuwenhuis, H. K., Rijn, H. J. M. v., and Akkerman, J. W. N. (1999) Arterioscler. Thromb. Vasc. Biol., in press). As outside in signaling is associated with phosphorylation of p125(FAK), the effect of LDL on p125(FAK) phosphorylation in platelets was investigated. LDL induced p125(FAK) phosphorylation in a dose- and time- dependent manner. The phosphorylation was independent of ligand binding to integrin alphaIIbbeta3 and aggregation, such in contrast to alpha-thrombin-induced p125(FAK) phosphorylation, that critically depended on platelet aggregation. Platelets from patients with Glanzmann's thrombastenia showed the same LDL- induced phos- phorylation of p125(FAK) as control platelets, whereas alpha-thrombin completely failed to phosphorylate the kinase in the patients platelets. LDL signaling to p125(FAK) was independent of integrin alpha2 beta1, the FcgammaRII receptor, and the lysophosphatidic acid receptor and not affected by inhibitors of cyclooxygenase, protein kinase C, ERK1/2 or p38(MAPK). Phosphorylation of p125(FAK) by LDL was strongly inhibited by cyclic AMP. These observations indicate that LDL is a unique platelet agonist, as it phosphorylates p125(FAK) in platelet suspensions, under unstirred conditions and independent of integrin alphaIIb beta3.     

Theoretical prediction of the hemodynamic performance of slow resorbing polyester protein impregnated arterial prostheses after implantation: a plea for fast resorption of the coating

OBJECTIVE: Although age-related mortality after intensive care unit (ICU) admission has been studied, functional recovery for different age groups following ICU admission is not well characterized. We hypothesized that compared with younger age groups, fewer patients older than age 65 admitted to an ICU would regain their full prehospitalization functional ability and that their recovery would be slower than that of younger patients. DESIGN: A prospective observational cohort study with convenience sampling. SETTING: Intensive care units of an urban university-affiliated Veterans Administration Medical Center. PARTICIPANTS: A total of 222 patients during the first 72 hours after entry to a medical or surgical ICU at the Denver Veteran's Administration Medical Center between September 1991 and July 1992. MEASUREMENTS: We collected baseline data on patient demographics and on the severity of acute illness using the Acute Physiology and Chronic Health Evaluation (APACHE II), Acute Physiology Score (APS), and functional status (highest level of physical activity level 1 month before admission). We recorded survival and patient-perceived global functional status at 6 weeks and 6 months after admission. Post-ICU function was adjusted for baseline function, age, APACHE II, and APS using multiple regression. RESULTS: Average patient age was 62+/-.74 years (mean +/- SEM). Fifty-two percent of the entire cohort returned to baseline function at 6 months. Although baseline function was better for younger people, there was no difference in recovery at 6 weeks in older compared with younger patients. Most functional recovery occurred by 6 weeks, with maintenance of this recovery at 6 months. Baseline function was the major determinant of both 6 week recovery (P < .001) and 6 month recovery (P = .002), whereas APACHE II was not (P = .3). Age predicted recovery significantly (P = .04) at 6 months but not at 6 weeks (P = .26). APACHE II (P < .001) and baseline function (P = .03) predicted mortality. CONCLUSIONS: Older people had worse functional ability at ICU admission, but the proportion of older people who recovered and their rate of recovery was the same as for younger people. Baseline functional status, rather than abnormal physiologic status (as measured by APACHE II) on admission, was the major determinant of recovery, whereas APACHE II was the main correlate of mortality. Together, baseline function and physiologic status provide valuable complementary information for clinically relevant outcomes following an ICU admission.     

Protective cytotoxic T lymphocyte responses against paramyxoviruses induced by epitope-based DNA vaccines: involvement of IFN-gamma

Plasmid DNA vectors have been constructed with minigenes encoding a single cytotoxic T lymphocyte (CTL) epitope from either the M2 protein of respiratory syncytial virus (RSV) or from the nucleoprotein of measles virus (MV) with or without a signal sequence (also called secretory or leader sequence). Following intradermal immunization, plasmids in which the CTL epitopes were expressed in-frame with the signal sequence were more effective at inducing peptide- and virus-specific CTL responses than plasmids expressing CTL epitopes without the signal sequence. This immunization resulted in protection against MV-induced encephalitis and a significant reduction in viral load following RSV challenge. The reduction of viral load following RSV challenge was abrogated by prior injection with anti-IFN-gamma antibodies. These results highlight the ability of epitope-based DNA immunization to induce protective immune responses to well-defined epitopes and indicate the potential of this approach for the development of vaccines against infectious diseases.     

Changes in the aortic endothelium and plasma von Willebrand factor levels during the onset and progression of insulin-dependent diabetes in BB rats

The superior volume maintenance of membranous over endochondral bone has been shown in several studies and provides the basis for its preferred clinical use as an onlay grafting material in the craniofacial skeleton. The scientific rationale for this seeming embryologic advantage, however, has never been proven. Our hypothesis is that the pattern of onlay bone graft resorption is primarily determined by a graft's micro-architecture (relative cortical and cancellous composition) rather than its embryologic origin (membranous versus endochondral). Twenty-five adult New Zealand, White rabbits were used for this study. Eight animals were killed at 3 weeks, eight animals at 8 weeks, and nine animals at 16 weeks. Three graft types were placed onto each rabbit cranium: cortical bone graft of membranous origin and cortical and cancellous bone graft of endochondral origin. Fluorochrome markers were injected into all living rabbits at 1, 6, and 14 weeks. Microcomputed tomography scanning was performed on all of the bone grafts to determine postsacrifice volumes and to obtain detailed information regarding the bone graft's trabecular architecture. In addition, specimens were examined histologically. Volume analysis showed a statistically greater resorption rate in the cancellous endochondral bone graft than in either the endochondral or membranous cortical bone grafts (p < 0.05) for all time points. In addition there was no significant difference in the resorption rates between the endochondral and membranous cortical bone grafts. A post-test power analysis (alpha = 5 percent) of the volume data comparing the two types of cortical bone grafts showed that a difference in resorption of 8.9 percent would be detected with a 90-percent probability. Previous studies, which have shown a seeming superiority of membranous over endochondral bone grafts, used composite grafts composed of both cortical and cancellous portions. By separating these components, we have shown that cortical bone grafts maintain their volumes significantly better than cancellous bone grafts. In addition, we found no statistical difference in the resorption rates between the two cortical onlay bone grafts of different embryologic origins, a finding that has never been previously published. From our results, we believe cortical bone to be a superior onlay grafting material, independent of its embryologic origin. We believe these results challenge the currently accepted theories of bone graft dynamics and may lead to a change in the way clinicians approach bone graft selections for craniofacial surgery.     

Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease

Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.     

Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.     

The misrepresentation of the human pelvis

A representative series of illustrations of the human bony pelvis dating from the sixteenth century to the present is used to demonstrate the persistent misrepresentation in the orientation of the pelvis and in the nomenclature. Early erroneous concepts were probably strongly reinforced by publications of the Belgian anatomist Vesalius in the sixteenth century. In mounting the vertebrae on a vertical iron rod, he erased much of the sacral curvature and, as a consequence, the orientation of the rest of the pelvis was distorted. True versions of the pelvis were executed by Leonardo da Vinci before the time of Vesalius but these drawings were apparently among those that were lost for many years. A relatively small number of similarly accurate depictions of the bony pelvis have appeared down through the centuries and some of these are also included. A persistent error in many anatomical textbooks used today presents a modified inferior view of the pelvis as the "front view" and a nearly accurate front view as a "view from above." No definitive conclusion can be reached concerning the reason(s) for the remarkably long persistence of this error. The figures referenced are presented in the Gallery immediately following this article.