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Biomedical subjects

S L Cheng

Publications and source records attributed to S L Cheng.

At least 37 records · Page 2Linked to original sources
PubMed2000

Differential regulation of cadherins by dexamethasone in human osteoblastic cells.

Human osteoblasts express a repertoire of cadherins, including N-cadherin (N-cad), cadherin-11 (C11), and cadherin-4 (C4). We have previously shown that direct cell-cell adhesion via cadherins is critical for BMP-2-induced osteoblast differentiation. In this study, we have analyzed the regulation of cadherin expression in normal human trabecular bone osteoblasts (HOB), and osteoprogenitor marrow stromal cells (BMC), during exposure to dexamethasone, another inducer of human bone cell differentiation. Dexamethasone inhibited the expression of both C11 and N-cad mRNA in both BMC and HOB, although the effect was much more pronounced on N-cad than on C11. This action of the steroid was dose dependent, was maximal at 10(-7) M concentration, and occurred as early as after 1 day of incubation. By contrast, expression of C4 mRNA and protein was strongly induced by dexamethasone in BMC and was stimulated in HOB. This stimulatory effect lasted for at least 2 weeks of incubation. A cadherin inhibitor, HAV-containing decapeptide only partially ( approximately 50%) prevented dexamethasone-induced stimulation of alkaline phosphatase activity by BMC, which instead was not altered by incubation with a neutralizing antibody against C4. Therefore, the pattern of cadherin regulation by dexamethasone radically differs form that observed with BMP-2. Dexamethasone effects on certain osteoblast differentiated features, such as induction of alkaline phosphatase activity are not strictly dependent on cadherin function.

Alkaline Phosphatase↗
PubMed2000

A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

Animals↗
PubMed2000

Sensory recovery and Meissner corpuscle number after toe-to-hand transplantation.

This study investigated the possible relationship between sensory recovery and receptor number after toe-to-hand transplantation. Moving two-point discrimination was measured after a course of sensory re-education. Meissner corpuscle number was then quantified by light microscopic examination of multiple sections of glabrous skin obtained at pulp reduction and from site-matched normal toe and fingertip skin. Meissner corpuscle number per millimeter was 0.94 in normal toe skin (n = 4), and 0.37 after toe-to-hand transplantation (n = 34). A significant correlation existed between moving two-point discrimination and Meissner corpuscle number (r = -0.62; p < 0.001). No significant relationship was found between moving two-point discrimination and patient age or interval from injury to reconstruction. The results suggest that despite sensory re-education, there may be a level of receptor reinnervation below which good sensory recovery may not be obtained.

Adolescent↗
PubMed2000

Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced thymocyte apoptosis.

Sepsis induces extensive lymphocyte cell death that may contribute to immune depression and morbidity/mortality in the disorder. bcl-2 is a member of a new class of oncogenes that prevents cell death from an array of noxious stimuli. Transgenic mice that overexpress BCL-2 in T lymphocytes are resistant to sepsis-induced T cell apoptosis, and mortality was decreased in sepsis. The purpose of this study was to identify key initiator and executioner "caspases" involved in sepsis-induced lymphocyte apoptosis and to determine if BCL-2 acts prior to caspase activation. Thymi were removed 5-22 h post-cecal ligation and puncture (CLP) or sham surgery. Apoptosis was evaluated in thymocytes by annexin-V FITC labeling and flow cytometry. Caspase-1 activity was determined by western blot analysis of the procaspase protein and p20 subunit of the activated caspase; activities of caspases -2, -6, and -9 were determined by colorimetric assays using specific substrates conjugated to a color reporter molecule. Caspase-3 activity was determined both by western blot and by a fluorogenic assay in which a fluorescent compound was generated. Thymocytes from CLP mice had markedly increased apoptosis and activation of caspases -2, -3, -6, and -9 in comparison with thymocytes of sham-operated mice. Caspase-1 was not activated. BCL-2 prevented sepsis-induced thymocyte apoptosis and inhibited activation of all caspases. We conclude that sepsis causes activation of multiple caspases and that BCL-2 acts upstream as an inhibitor of caspase activation. The pattern of caspase activation suggests a mitochondrial mediated pathway.

Animals↗
PubMed2000

Treatment of the mobile, painful arthritic elbow by distraction interposition arthroplasty.

Between 1986 and 1994, 13 patients with mobile painful arthritic elbows were treated by distraction interposition arthroplasty using fascia lata. The mean period of follow-up was 63 months. An elbow distractor/fixator was applied for three to four weeks to separate the articular surfaces and to protect the fascial graft. Nine of the 13 patients (69%) had satisfactory relief from pain; eight (62%) had an excellent or good result by the objective criteria of the Mayo Elbow Performance score. Four have required revision to total elbow arthroplasty at a mean of 30 months with good results to date. Instability of the elbow, both before and after surgery, was found to be associated with unsatisfactory results. The rate of success when the procedure was performed for inflammatory arthritis was similar to that for post-traumatic arthritis, about 67%. Eight complications occurred in six patients, all in the group with post-traumatic arthritis. Two of these required further surgical procedures such as transposition of the ulnar nerve or repair of hernia of the fascia lata. Although less reliable than prosthetic replacement, distraction interposition arthroplasty is a useful option in the treatment of young, high-demand patients with arthritis of the elbow. It is rarely indicated in the presence of generalised inflammatory arthritis, but may be of value in those patients in whom the disease is limited primarily to the elbow.

Adult↗
PubMed2000

A dominant negative cadherin inhibits osteoblast differentiation.

We have previously indicated that human osteoblasts express a repertoire of cadherins and that perturbation of cadherin-mediated cell-cell interaction reduces bone morphogenetic protein 2 (BMP-2) stimulation of alkaline phosphatase activity. To test whether inhibition of cadherin function interferes with osteoblast function, we expressed a truncated N-cadherin mutant (NCaddeltaC) with dominant negative action in MC3T3-E1 osteoblastic cells. In stably transfected clones, calcium-dependent cell-cell adhesion was decreased by 50%. Analysis of matrix protein expression during a 4-week culture period revealed that bone sialoprotein, osteocalcin, and type I collagen were substantially inhibited with time in culture, whereas osteopontin transiently increased. Basal alkaline phosphatase activity declined in cells expressing NCaddeltaC, relative to control cells, after 3 weeks in culture, and their cell proliferation rate was reduced moderately (17%). Finally, 45Ca uptake, an index of matrix mineralization, was decreased by 35% in NCaddeltaC-expressing cells compared with control cultures after 4 weeks in medium containing ascorbic acid and beta-glycerophosphate. Similarly, BMP-2 stimulation of alkaline phosphatase activity and bone sialoprotein and osteopontin expression also were curtailed in NCaddeltaC cells. Therefore, expression of dominant negative cadherin results in decreased cell-cell adhesion associated with altered bone matrix protein expression and decreased matrix mineralization. Cadherin-mediated cell-cell adhesion is involved in regulating the function of bone-forming cells.

Alkaline Phosphatase↗
PubMed1999

Insulin activates caspase-3 by a phosphatidylinositol 3'-kinase-dependent pathway.

Activation of the caspase proteases by c-Jun N-terminal kinase 1 (JNK1) has been proposed as a mechanism of apoptotic cell death. Here we report that insulin activates caspase-3 by a pathway requiring phosphatidylinositol 3'-kinase (PI3-kinase). JNK1 assays demonstrated that insulin treatment of myeloma cells induced 3-fold activation of JNK1. Inhibition of PI3-kinase with wortmannin and LY294002 blocked insulin-dependent activation of JNK1. Caspase assays demonstrated that insulin increased caspase-3 activity 3-fold and that inhibition of PI3-kinase blocked this effect. Cell death was doubled by insulin and was due to a 3-fold increase in apoptosis of cells in the G1/G0 phase of the cell cycle. Inhibition of PI3-kinase completely blocked this effect. Finally, inhibition of caspase-3 with benzyloxycarbonyl-Asp-2,6-dichlorobenzoyloxymethylketone blocked cell death due to insulin. Taken together, these findings indicate that insulin activates caspase-3 by a PI3-kinase-dependent pathway resulting in increased apoptosis and cell death.

Apoptosis↗
PubMed1999

Toe transplantation for isolated index finger amputations distal to the proximal interphalangeal joint.

Functional deficit following single distal index finger amputations has been considered insignificant, and reconstruction is usually not recommended. Herein, 19 cases of second toe transplantation for reconstruction of isolated index finger amputation distal to the proximal interphalangeal joint are presented with long-term functional results. There are 14 men and 5 women. The average age was 26 years. The toe transplantations were performed either as a primary procedure (5 patients) while the wounds were still open or as a secondary procedure (14 patients) after the wounds healed. In 11 patients, the dominant hand was involved. All toes survived completely, although re-exploration was required in three cases (16 percent). The functional evaluation included (1) sensory recovery, where the average static and moving two-point discrimination were 8 mm (range 4 to 15 mm) and 6 mm (range 2 to 15 mm); (2) motor function, where the average of index-thumb pulp-to-pulp pinch compared with the normal hand was 67.5 percent (range 36 to 96 percent); (3) average range of motion in index finger joints (extension/flexion), where metacarpophalangeal joint was 14/90, proximal interphalangeal joint was 0/94, and distal interphalangeal joint was 19/38; and (4) functional and cosmetic results, where percentage of involvement in daily activities and functional capacity of the reconstructed index were 69 percent and 70.5 in average, respectively, over a total score of 100. Average scores of aesthetic appearance and acceptability of donor-site deformity were 74 and 87.5 over a total score of 100, respectively. Toe transplantation for distal index finger amputations improved hand function when performed in selected patients with specific job requirements or high motivation.

Adolescent↗
PubMed1999

Free fibula osteoseptocutaneous-pedicled pectoralis major myocutaneous flap combination in reconstruction of extensive composite mandibular defects.

Lateral composite mandibular defects resulting from excision of advanced oral carcinoma often require mandible, intra-oral lining, external face, and soft-tissue bulk reconstruction. Ignorance of importance soft-tissue deficit in those patients may cause significant morbidity and functional loss. Such defects, therefore, can be reconstructed best with a double free flap technique. However, this procedure may not be feasible for every patient or surgeon. An alternative procedure is a free fibula osteoseptocutaneous flap combined with a pedicled pectoralis major myocutaneous flap. This combination was used in reconstruction of extensive composite mandibular defects in 14 patients with T3/T4 oral squamous cell carcinoma. All patients were men, and the average age was 54.3 years. The septocutaneous paddle of the fibula flap was used for the mucosal lining of the defects while the bony part established the rigid mandibular continuity. The pectoralis major flap then covered the external skin defect in the face and cheek, and the dead spaces left by the extirpated masticator muscles, buccal fat, and parotid gland. One free fibula flap failed totally, and one pectoralis major flap developed marginal necrosis. At the time of final evaluation, nine patients (64.3 percent) were alive, surviving an average of 25.7 months. All patients eventually regained their oral continence and an acceptable cosmetic appearance. In conclusion, the fibula osteoseptocutaneous flap plus regional myocutaneous flap choice is a successful and technically less demanding alternative to the double free flap procedures in reconstruction of extensive lateral mandibular defects.

Adult↗
PubMed1999

Reconstruction of bilateral metacarpal hands with multiple-toe transplantations.

Bilateral metacarpal hands, if not treated properly, leave a patient without prehensile ability in both hands. Since 1990, six patients with bilateral metacarpal hands caused by accidents have undergone reconstruction with multiple-toe transplantations. Four or five toes were used for each patient, with a total of 27 toes transplanted to the hands. There was no toe loss. One nonunion in a middle-finger reconstruction was treated successfully with bone grafting. Secondary operations for functional improvement included one joint fusion and one flexor tendon tenolysis. Only one patient required excision of a plantar callus 42 months postoperatively, whereas the other five patients reported no major donor-site problems in an average 57 months of follow-up time. The six patients continue all their daily activities independently. Although their jobs were changed, all adult male patients were able to return to regular work. Principles of reconstruction to achieve satisfying prehensile function combined with minor donor-site morbidity in bilateral metacarpal hands include an adequate soft-tissue coverage before toe transplantations, selection of digits to be reconstructed based on functional and individual requirements, selection of toes and number of toes to be harvested based on consideration of usefulness for the hands and of foot morbidity, and consideration of thenar function in planning the sequence of transplantations. In conclusion, given thorough planning, multiple toe-to-hand transplantations can provide adequate prehensile function in reconstructed bilateral metacarpal hands with acceptable donor-site morbidity.

Adult↗
PubMed1999

Effect of injection rate of contrast medium on pancreatic and hepatic helical CT.

PURPOSE: To assess the effect of the injection rate of contrast medium on pancreatic and hepatic enhancement at abdominal helical computed tomography (CT). MATERIALS AND METHODS: Sixty-four contrast medium-enhanced abdominal helical CT scans (64 adult patients) were obtained with 150 mL of contrast medium. The injection rate was 2.5 mL/sec for the first 32 scans and 5.0 mL/sec for the remaining 32. Scans were obtained at 5-sec intervals, with an intermediate 8-sec breathing interval. Hepatic and pancreatic enhancement levels were measured and averaged, and time-attenuation curves were plotted for both groups. Differences in weight, age, time to peak pancreatic and hepatic enhancement, and peak enhancement were assessed with the Student t test. RESULTS: Both peak enhancement and time to peak enhancement were significantly different between the two injection rates (P < or = .002), with faster, more intense hepatic and pancreatic enhancement at the higher rate. At 2.5 mL/sec, the pancreas reached a peak attenuation level of 65 HU at 69 sec, and the liver reached a peak of 58 HU at 87 sec. At 5.0 mL/sec, the pancreas reached a peak attenuation of 84 HU at 43 sec, and the liver reached a peak of 75 HU at 63 sec.

Adult↗
PubMed1999

Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss.

It is well documented that glucocorticoid excess causes bone loss, but the mechanisms of these effects remain poorly defined. To understand further the mechanisms of glucocorticoid-induced osteoporosis, we investigated the effects of glucocorticoids on bone formation and bone resorption by examining the proliferation, functional activities, and cytokine secretion of cultured human bone marrow stromal cells (hBMSC). Treatment with dexamethasone for 24 h at the concentration of 10(-8) M significantly suppressed [(3)H]thymidine incorporation and further inhibition was observed with longer treatment (8 days) or higher concentration (10(-7) M). Alkaline phosphatase activity of hBMSC was markedly stimulated with addition of dexamethasone (10(-8) M), to 191 +/- 22% (after 4 days) and 317 +/- 46% (after 7 days) of control. Dexamethasone (10(-8) M) treatment for 48 h decreased the incorporation of [(3)H]proline into collagenase-digestible protein (CDP; 43.7+/-7.9% of control) and non-collagen protein (65.2+/-8.4% of control), with a greater effect on CDP. Northern blot analysis indicated that alpha1(I)-collagen mRNA level was decreased by dexamethasone to 27.6 +/- 9.0% of the control value after 1 day of exposure, and to 55.2 +/- 6.2% after 7 days. Dexamethasone markedly suppressed basal production of interleukin (IL)-6 and IL-11 and that stimulated by parathyroid hormone (PTH), IL-1alpha, or tumour necrosis factor-alpha in a dose-dependent manner. These results suggest that the glucocorticoid-induced bone loss is derived at least in part via inhibition of bone formation, which includes the suppression of osteoblast proliferation and collagen synthesis. As both basal and PTH-stimulated production of IL-6 and IL-11 are decreased by dexamethasone, the increased bone resorption observed in glucocorticoid-induced osteopenia does not appear to be mediated by IL-6 or IL-11.

Alkaline Phosphatase↗
PubMed1998

Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone.

Glucocorticoids inhibit the proliferation, but induce the differentiation, of bone marrow stromal cells into osteoblast-like cells. The mechanisms, however, are still conjectural. Since insulin-like growth factors (IGFs) have profound effects on osteoblast growth and differentiation, it is possible that glucocorticoids exert their effects on bone marrow stromal cells in part via regulation of IGFs. Therefore, we analyzed the effects of dexamethasone (Dex) on the expression of IGF I and IGF II in cultured preosteoblastic normal human bone marrow stromal cells (HBMSC). Whereas Dex decreased the concentration of IGF I in the conditioned medium since early in the treatment, the concentration of IGF II was increased progressively as culture period lengthened. As the activities of IGF I and IGF II are regulated by the IGF binding proteins (IGFBPs), we analyzed the effects of Dex on the expression of IGFBPs. Dex increased IGFBP-2 in a time-dependent manner. The increase in IGFBP-2, however, was only to the same extent as that of IGF II at most, depending on the length of treatment. Therefore, the increase in IGFBP-2 would dampen, but not eliminate, the increased IGF II activities. By contrast, Dex decreased IGFBP-3 levels, the latter increasing the bioavailability of IGF II. Although IGFBP-4 mRNA levels were stimulated by Dex, IGFBP-4 concentration in the conditioned medium was unchanged as measured by RIA. IGFBP-5 and IGFBP-6 mRNA levels were decreased by Dex in a time-dependent fashion. IGFBP-5 protein level was also decreased 1-4 days after Dex treatment. IGFBP-1 mRNA was not detectable in HBMSC. These accumulated data indicate that Dex regulates IGF I and IGF II and their binding proteins differentially in normal human bone marrow stromal cells. The progressive increase in IGF II may contribute to Dex-induced cell differentiation.

Blotting, Northern↗
PubMed1998

Clinical evaluation of C7 spinal nerve transection: 21 patients with at least 2 years' follow-up.

We have performed C7 spinal nerve transfer to treat root injury of the brachial plexus since 1989. Out of a total of 43 patients, 21 have been followed up for at least 2 years. Evaluation of the effect of C7 transection included clinical examination, intraoperative C7 stimulation, LIDO Workset machine and electrophysiological studies to test C7 innervated muscles, and histochemical analysis of the anterior and posterior division of the upper trunk using acetylcholinesterase stain. Nearly half of the study group (48%) reported no significant sensory changes and most patients (81%) did not notice any weakness of the limb following C7 transection. Some patients did experience sensory and motor abnormalities which were most frequent during the first postoperative month, improved during the 2nd month and in most cases resolved in the 3rd postoperative month. The only longer persistent abnormality was the triceps reflex, which becomes weak or absent. We also found that intraoperative C7 stimulation was a useful predictor of possible post-transection morbidity. Subclinical deficits, detected by the LIDO workset machine and by electro-physiological studies, were quite common. Histochemical analysis revealed that the posterior division of C7 had more motor fibres than the anterior division.

Adolescent↗
PubMed1998

Gap junctional communication modulates gene expression in osteoblastic cells.

Bone-forming cells are organized in a multicellular network interconnected by gap junctions. In these cells, gap junctions are formed by connexin43 (Cx43) and connexin45 (Cx45). Cx43 gap junctions form pores that are more permeable to negatively charged dyes such as Lucifer yellow and calcein than are Cx45 pores. We studied whether altering gap junctional communication by manipulating the relative expression of Cx43 and Cx45 affects the osteoblast phenotype. Transfection of Cx45 in cells that express primarily Cx43 (ROS 17/2.8 and MC3T3-E1) decreased both dye transfer and expression of osteocalcin (OC) and bone sialoprotein (BSP), genes pivotal to bone matrix formation and calcification. Conversely, transfection of Cx43 into cells that express predominantly Cx45 (UMR 106-01) increased both cell coupling and expression of OC and BSP. Transient cotransfection of promoter-luciferase constructs and connexin expression vectors demonstrated that OC and BSP gene transcription was down-regulated by Cx45 cotransfection in ROS 17/2. 8 and MC3T3-E1 cells, in association with a decrease in dye coupling. Conversely, cotransfection of Cx43 in UMR 106-01 cells up-regulated OC and BSP gene transcription. Activity of other less specific osteoblast promoters, such as osteopontin and osteonectin, was less sensitive to changes in gap junctional communication. Thus, altering gap junctional permeability by manipulating the expression of Cx43 and Cx45 in osteoblastic cells alters transcriptional activity of osteoblast-specific promoters, presumably via modulation of signals that can diffuse from cell to cell. A communicating intercellular network is required for the full elaboration of a differentiated osteoblastic phenotype.

Animals↗
PubMed1998

Successful replantation of an avulsed middle finger.

In avulsion amputations of the digits, soft-tissue injuries are extensive and often require tendon, nerve, and vessel transfers or grafts. The functional results of such digital replantations are frequently less than ideal. Therefore, avulsion amputation of a single digit proximal to the insertion of the flexor digitorum superficialis has been a contraindication to replantation, because the anticipated poor functional result may interfere with overall hand function, and is not worth the sacrifice of a tendon, nerve, or vessel from another digit or transfer. The authors report a patient with avulsion amputation of the middle finger at the proximal interphalangeal joint. The digit was replanted successfully without any tissue transfers other than a radial digital artery from the ring finger. The functional results were good, and the authors believe that good functional and cosmetic results can be achieved in select patients with isolated digital avulsions, provided that an experienced hand microsurgeon and a skillful hand therapist are available for a compliant patient.

Amputation, Traumatic↗