Real-time in vivo loading in the lumbar spine: part 1. Interbody implant: load cell design and preliminary results

STUDY DESIGN: Instrumented interbody implants were placed into the disc space of a motion segment in two baboons. During the animal's activities, implants directly measured in vivo loads in the lumbar spine by telemetry transmitter. OBJECTIVES: Develop and test an interbody implant-load cell and use the implant to measure directly loads imposed on the lumbar spine of the baboon, a semiupright animal. SUMMARY OF BACKGROUND DATA: In vivo forces in the lumbar spine have been estimated using body weight calculations, moment arm models, dynamic chain models, electromyogram measurements, and intervertebral disc pressure measurements. METHODS: An analytical model was used to determine the force-strain relation in a customized interbody implant. After validation by finite element modeling, strain gauges were mounted onto the implant and connected to a telemetry transmitter. Implants were placed surgically into the L4-L5 disc space of skeletally mature baboons and the transmitter in the flank. After surgery, load data were collected from the animals during activities. Radiographs were taken monthly to assess fusion. RESULTS: The implant-load cell is sufficiently sensitive to monitor dynamic changes in strain and load. During extreme activity, highest measurable strain values were indicative of loads in excess of 2.8 times body weight. CONCLUSIONS: The study technique and technology are efficacious for measuring real-time in vivo loads in the spine. Measuring load on an intradiscal implant over the course of healing provides key information about the mechanics of this process. Loads may be used to indicate performance demands on the intervertebral disc and interbody implants for subsequent implant design.     

Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines: toward tolerance induction across discordant xenogeneic barriers

BACKGROUND: Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination. METHODS: Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic/severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks. RESULTS: Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation. CONCLUSIONS: These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations.     

Intragraft events preceding chronic renal allograft rejection in a modified tolerance protocol

BACKGROUND: Inbred miniature swine treated for 12 days with high-dose cyclosporine A develop tolerance to histocompatibility complex (MHC) class I-mismatched renal allografts. When this protocol was modified by adding thymectomy before transplant, all animals developed acute rejection. Thereafter, by day 100, one half developed chronic rejection (progression group) and the other half recovered (recovery group). This provides an excellent experimental model to identify the mechanisms of chronic rejection as well as the early changes that may predict chronic rejection. METHODS: We assessed the cellular infiltration, immune activation, humoral immunity, and cell- and antibody-mediated graft injury in the progression and the recovery groups. In addition, we also examined circulating donor reactive cytotoxic T lymphocyte (CTL) and antidonor antibody in both groups. RESULTS: From days 8 to 18 after transplantation, the two groups were indistinguishable. Both showed acute rejection with endarteritis (type II); had IgG and IgM deposition in glomeruli and small vessels; had an infiltrate with similar numbers of T cells, proliferating (PCNA+) and activated (interleukin-2 receptor+) cells; and had a similar degree of parenchymal cell apoptosis [in situ DNA nick-end labeling (TUNEL)+]. However, by days 30 to 60, the two groups could be distinguished by several intragraft features. The recovery group became tolerant and had diminished T-cell infiltration, activation and proliferation, and no detectable antibody deposition. The number of TUNEL+-injured parenchymal cells decreased. In contrast, the progression group showed persistent cell infiltration with activation and proliferation. Significantly prominent TUNEL+ apoptotic parenchymal cells in tubules, glomeruli, peritubular capillaries and arteries were seen from day 30 to day 100. Circulating donor reactive CTL and antidonor class I IgG were detected in the progression group at higher levels than in the recovery group from days 30 to 60. CONCLUSION: In tolerance-induction protocols, unstable tolerance induction is associated with the persistent immunologic activation that mediates immunologic destruction of graft parenchymal cells and chronic rejection. Certain of the described immunopathologic findings (activation, proliferation, apoptosis, and antibody deposition) may be useful in distinguishing the type of rejection, that is, whether the allograft will progress to chronic rejection or recovery.     

Treating nondementia illnesses in patients with dementia

Physicians increasingly are called on to provide primary care for the growing population of people with Alzheimer-type dementia. However, little attention has been paid to the care of nondementia illnesses in this group of patients. To illustrate how presence of dementia can alter the risk-benefit ratio of treatment of a common medical problem, we present a case study in which a patient with dementia developed disastrous adverse effects to a drug commonly used to treat osteoporosis. This case and 2 composite vignettes illuminate how presence of dementia should influence the decision-making process for treatment of nondementia illnesses. We address issues such as decreased decision-making capacity, problems with reporting adverse effects, decreased cognition leading to problems with treatment adherence, and the role of screening and basic questions about acceptable burdens of treatments in patients with limited prognosis. We suggest ways to improve communication with patients with dementia in an effort to minimize complications and improve care, as well as policy changes to include patients with dementia in clinical trials. JAMA. 2000;283:3230-3235     

Underprediction of visibly complex chromosome aberrations by a recombinational-repair ('one-hit') model

PURPOSE: Published low-LET FISH data were used to test two models of chromosome aberration production based on breakage-and-reunion or recombinational repair. MATERIALS AND METHODS: Randomness of DNA double strand break induction and misrejoining is analyzed comprehensively and adopted as a working hypothesis. Proximity effects are approximated by using interaction sites. Model results are calculated using CAS (chromosome aberration simulator) Monte Carlo computer software with two adjustable parameters. CAS can emulate the specifics of any experimental painting protocol, allowing very detailed tests of the models. RESULTS: To reasonable approximation, breakage-and-reunion model predictions are consistent with low-LET FISH results, including two large, elaborate, one-paint data sets. An explicitly specified version of the recombinational-repair model severely underpredicts the frequency of the visibly complex aberration patterns most commonly observed with one-paint FISH, and is inconsistent with some observed multi-paint patterns. When high-dose effects (distortion and saturation) are taken into account quantitatively, a dose-response relation for apparently simple interchanges slightly favours the breakage-and-reunion model over the recombinational-repair model, despite being approximately linear over the dose range 2-6 Gy. CONCLUSIONS: The random breakage-and-reunion model gives comprehensive baseline predictions that are sufficiently accurate for the organization of experimental results. The data speak against complex aberrations being formed by the random recombinational repair pathway discussed here.     

Dysphoria from a transnosological perspective

The objective of our psychopathological analyses is to shed light on the position of irritable mood (dysphoria) in psychiatric diagnostics and nosology. In today's most commonly applied classification systems, the ICD-10 and the DSM-IV, dysphoria is mentioned mostly in the context of diagnostic criteria of personality and affective disorders. Other authors have emphasized the importance of dysphoric states in organic psychoses and delusional disorders. Summarizing the various publications on the nosological position, dysphoria is a nosological nonspecific syndrome which may occur in the course of all psychiatric disorders and illnesses. According to the results of our psychopathological analyses, the pathogenesis of dysphoria has to be considered as a multidimensional circular process in which various mental, physical and social factors act as predisposing, triggering and disorder-maintaining factors. Stressors induced by particular experiences and perceptions and by impaired health may lead to a dysphoric state if adequate coping mechanisms are missing. Dysphoria itself usually leads to a deterioration in the mental and physical state of the patient, and shows a clear impact on the patient's social network. The reactions of people close to the patient combined with the impaired mental and physical conditions of the patient cause the circle to restart. As contemporary diagnostic entities do not refer to pathogenesis, classical categorical diagnostics cannot provide the basis for effective pathogenesis-oriented therapy. A change of paradigm in diagnostics from a categorical to a dimensional approach thus becomes necessary. Following a dimensional diagnostic approach based on a dynamic model of vulnerability, a precise differential diagnosis of the complex constellation of conditions and their interactions becomes necessary in order to develop effective treatment strategies. Disorder-maintaining factors determine the treatment of the acute symptomatology, whereas predisposing and triggering factors serve as the basis for the prophylactic treatment.