Model-based development of neuroprostheses for restoring proximal arm function.

Neuroprostheses with the use of functional neuromuscular stimulation (FNS) have the potential to restore elbow and shoulder function lost to paralysis because of spinal cord injury (SCI). The human shoulder is highly flexible and thus provides a large range of motion to the arm and hand, although at the expense of precarious stability of the articulations. The complexity of the shoulder has prevented widespread use of FNS at this joint. However, musculoskeletal modeling of the elbow and shoulder has the potential to significantly speed the development of neuroprostheses by allowing many mechanical issues to be resolved in simulation prior to implementation in human subjects. This paper describes our rationale for the use of musculoskeletal modeling, the model we are using, and several practical applications of the model to study the potential use of shoulder and elbow muscle FNS to restore function following cervical SCI.     

Uteroglobin: physiological role in normal glomerular function uncovered by targeted disruption of the uteroglobin gene in mice

Blastokinin or uteroglobin (UG) is an evolutionarilly conserved, steroid-inducible, homodimeric, multifunctional, secreted protein with potent Immunomodulatory/antiinflammatory properties. Recently, a UG-receptor expressed on several malignant and normal cell types has been characterized. Although the biochemistry, structural, and molecular biology of UG have been extensively studied, its physiological function(s), until recently, remained unknown. By generating UG-null (UG-/-) mice, we determined that an essential role of UG is to prevent severe renal disease caused by an abnormal deposition of predominantly multimeric fibronectin (Fn) and collagen in the glomerulus. The molecular mechanisms by which UG prevents this disease in control (UG+/+) mice, at least in part, is attributable to its high-affinity binding to Fn and the formation of Fn-UG heteromers, which counteract both Fn-Fn and Fn-collagen interactions, required for abnormal tissue deposition. In addition, by inhibiting secretory phospholipase A2 (sPLA2) activity and decreasing the level of lysophosphatidic acid (LPA), UG may indirectly prevent the activation of integrins (eg, alpha5beta1) that enhance abnormal tissue deposition of Fn. The mechanism(s) of UG action is likely to be even more complex, because it also functions through a receptor-mediated pathway that has not yet been clearly defined. Nevertheless, the UG gene-knockout mice provide a valuable animal model for investigation of human glomerulopathies in general and familial Fn-deposit glomerulopathy in particular.     

Biological properties of a recombinant human immunoglobulin epsilon-chain fragment.

A recombinant human immunoglobulin epsilon-chain gene expression product (rFc epsilon) was compared with a human E myeloma protein in the affinity for epsilon-chain Fc fragment receptors (Fc epsilon R) on cultured human basophils. The association-dissociation kinetics of the rFc epsilon-Fc epsilon R interaction are indistinguishable from that of E myeloma protein, indicating that rFc epsilon and IgE have identical affinity for the receptors. The recombinant gene product sensitizes cultured basophils for anti-IgE-induced histamine release. A dose-response curve of histamine release indicates that the gene product is equally efficient in transducing the signal for degranulation as the natural IgE. Both the rFc epsilon and IgE lost the affinity for Fc epsilon R by heating at 56 degrees C. Upon renaturation by passage through a solution of 6 M guanidine hydrochloride, rFc epsilon recovered both the affinity for Fc epsilon R and the original CD spectra. On the other hand, renaturation of heat-denatured IgE largely restored optical activity above 250 nm but restored neither the affinity for Fc epsilon R nor the CD spectrum below 220 nm. The results suggest that either the amino acid sequence or the carbohydrate present in the myeloma protein, but not the rFc epsilon, may interfere with refolding of the receptor-binding structures.     

Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.     

The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load

OBJECTIVE: To compare the rate of disease progression according to viral load and CD4 cell count in patients receiving or not receiving highly active antiretroviral therapy (HAART), defined as protease inhibitor-containing regimens. DESIGN: An observational study, with prospectively collected data. METHODS: All patients attending the HIV Outpatient clinic as of 1 January 1995 (n = 2083) were included. Follow-up was until the first AIDS-defining event or death. Associations between viral load or CD4 cell count and disease progression were assessed using a person-years approach. Event rates were compared using Poisson regression analysis; a multivariate model was used to assess the independent effects of CD4, viral load and treatment group on event rates and to consider interactions between these variables. RESULTS: The event rates increased with lower CD4 cell count and higher viral load for both treatment groups and were generally lower in the HAART group. In a multivariate analysis, lower CD4 cell counts and higher viral loads remained significantly associated with disease progression, irrespective of treatment group. However, the event rate was significantly lower for the HAART group compared with the control group (relative rate 0.53, P < 0.001). CONCLUSIONS: HAART-treated patients with high viral loads and CD4 cell counts experienced reduced disease progression compared with individuals with the same CD4 cell count and viral load not receiving HAART. Consequently, the short-term prognosis associated with viral load levels and CD4 cell counts may differ in patients on HAART. Whether this effect will be observed with non-protease-inhibitor-containing HAART is not known at this time.     

Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits

BACKGROUND & AIMS: Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha-hydroxylase in rabbits. The aim of this study was to explore the mechanism. METHODS: Twenty male New Zealand white rabbits were fed regular chow with and without 2% cholesterol for 10 days followed by 7 days of bile drainage. The activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase that control bile acid synthesis in classic and alternative pathways were related to the size and composition of bile acid pool. RESULTS: After feeding cholesterol, plasma and hepatic cholesterol concentrations increased, the bile acid pool doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7 alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool and stimulated down- regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected. CONCLUSIONS: Feeding cholesterol increased hepatic cholesterol and stimulated sterol 27- hydroxylase and alternative bile acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool. (Gastroenterology 1997 Dec;113(6):1958-65)     

Computerassistierte Point of Care Dokumentation der Schockraumversorgung

The documentation of severely injured patients in the emergency room (ER) has to meet all standards and laws concerning of medical record keeping. More importantly ER documentation has to transmit all keyinformation for the further inhospital treatment. In addition it is often intended to establish the data basis for an extensive quality management system as a decisive factor in optimizing the treatment of patients with major trauma. This can be achieved by participating in the trauma registry of the German Society of Trauma Surgery (DGU) in combination with internal, hospital specific evaluations. Usually the data processing is performed by computer systems. In this process retrospective entering of data from primarily handwritten patient files has to be avoided: it is time consuming and a source of unnecessary errors. The following paper provides a review of current concepts in computer assisted point of care ER documentation: 1) Scanners which grasp coded information on paper specially designed for ER records directly after the primary and secondary survey, 2) audio or video documentation of the ER treatment, 3) Personal Digital Assistant (PDA – Palm^® or Windows Mobile^®) based solutions, 4) PC solutions with conventional hardware for data acquisition, pen-computer/tablet-PCs or automated speech recognition systems, 5) digital pen/digital paper systems. Specific advantages and disadvantages of the presented technologies are explained in detail. Presently, however, most of the systems are developed and used in single hospitals or departments, solitarily. This situation could be improved by developing a modular standardized ER documentation system. It should meet the following profile: 1) the fundamental basis should be a standardized "National Dataset Emergency Room"; 2) based on this dataset a nationwide accepted ER patient file, like the German DIVI – Emergency Medical Service Protocol, has to be developed; 3) the third and last step will be the development of a computer assisted ER documentation system.