A general strategy for absolute stereochemical control in enone-olefin [2+2] photocycloaddition reactions.
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Alkenes↗
Biomedical subjects
V Chang
Publications and source records attributed to V Chang.
G Protein beta subunit types differentially interact with a muscarinic receptor but not adenylyl cyclase type II or phospholipase C-beta 2/3.
In comparison with the alpha subunit of G proteins, the role of the beta subunit in signaling is less well understood. During the regulation of effectors by the betagamma complex, it is known that the beta subunit contacts effectors directly, whereas the role of the beta subunit is undefined in receptor-G protein interaction. Among the five G protein beta subunits known, the beta(4) subunit type is the least studied. We compared the ability of betagamma complexes containing beta(4) and the well characterized beta(1) to stimulate three different effectors: phospholipase C-beta2, phospholipase C-beta3, and adenylyl cyclase type II. beta(4)gamma(2) and beta(1)gamma(2) activated all three of these effectors with equal efficacy. However, nucleotide exchange in a G protein constituting alpha(o)beta(4)gamma(2) was stimulated significantly more by the M2 muscarinic receptor compared with alpha(o)beta(1)gamma(2). Because alpha(o) forms heterotrimers with beta(4)gamma(2) and beta(1)gamma(2) equally well, these results show that the beta subunit type plays a direct role in the receptor activation of a G protein.
Adenylyl Cyclases↗
Survival of patients who had salvage castration after failure on bicalutamide monotherapy for stage (D2) prostate cancer.
Patients with hormone-naive stage D2 prostate cancer often benefit from castration. This treatment, however, frequently produces many unacceptable physical and psychological side effects, especially in younger and sexually active patients. Bicalutamide is an oral antiandrogen with excellent tolerance and preservation of sexual function. Three institutions participated in phase II and III trials of bicalutamide monotherapy (50 mg daily) as primary therapy in hormone-naive patients with stage D2 prostate cancer. Upon bicalutamide failure, all patients underwent castration and were followed until death. Fifty-four patients received bicalutamide 50 mg orally once a day. One patient (2%) had complete response, 9 patients (17%) had partial response, and 27 patients (50%) had stable disease. Seventeen patients (31%) had progressive disease. The median time to bicalutamide failure was 47.4 weeks, 70.5 weeks for the responders vs. 25.4 weeks for the nonresponders (p < 0.001). The median survival time after the sequential use of bicalutamide and castration was 119.2 weeks for all 54 patients, 162.0 weeks for the responders, and 73.5 weeks for nonresponders (p < 0.0001). The median survival time after initiation of castration was 71.1 weeks for all 54 patients, 91.4 weeks for bicalutamide responders, and 42.1 weeks for nonresponders (p < 0.01). In hormone-naive patients with stage D2 prostate cancer, sequential treatment with bicalutamide monotherapy followed by castration upon failure may produce survival time within the range reported for initial treatment with castration. Thus, considering the favorable quality of life profile of bicalutamide, further studies are needed to define the role of sequential hormonal therapy in younger sexually active patients.
Aged↗
Medial arch strain after medial displacement calcaneal osteotomy: an in vitro study.
Posterior tibial tendon dysfunction with concomitant progressive flatfoot deformity is associated with ligamentous failure along the medial arch. Medial displacement calcaneal osteotomy is being used alone and in combination with other procedures, with the expectation that it contributes to maintaining the arch. The objective of this study was to examine the effect of osteotomy on reducing medial arch strain. Whole cadaver feet were subjected to vertical loads while plantigrade. Spring ligament length was monitored using liquid metal displacement gauges. Two outcomes were examined: the length of the ligament under one-half body weight and the change in length of the ligament per unit of applied load. The medial displacement calcaneal osteotomy allowed elongation of the ligament with weightbearing, but at a shorter ligament length. This afforded the spring ligament protection from the levels of force experienced in the intact and lateral column-lengthened conditions.
Biomechanical Phenomena↗
Ganglion cysts of the lower extremity: an analysis of 54 cases and review of the literature.
This article reviews 54 consecutive patients with lower extremity ganglion cysts that were surgically removed and histologically confirmed at the Hospital for Special Surgery from 1981 to 1993. Lower extremity ganglia were more common among women. Patients' ages ranged from 13 to 80 years, with the fifth and sixth decades being the most common. Size of the cysts ranged from 3 cm to 10 cm (average: 2.9 cm). Thirty-six (67%) patients had ganglion cysts of the foot and ankle, and 18 (33%) patients had ganglion cysts of the knee area. Four (7%) patients had intraosseous ganglia located in the proximal tibia, patella, and the first metatarsal head. Follow-up data of 40 (74%) patients at an average of 5.9 years (range: 1 to 12.5 years) were obtained. Satisfaction was reported by 83% of patients. Recurrence was seen in 10% of patients, and a report of no or mild pain was given by 86% of the group. Patients who underwent revision ganglion excision had inferior results. Only 25% reported satisfaction and 50% reported no or mild pain. Patients who underwent curettage of an intraosseous ganglion appeared to have superior results. All patients reported satisfaction and no or mild pain. The performance of a concomitant surgical procedure, the anatomic region of the ganglion, or type of postoperative immobilization did not appear to affect the outcome.
Adolescent↗
Regional distribution and time-course of calpain activation following kainate-induced seizure activity in adult rat brain.
Systemic injection of kainic acid (KA) in adult rat elicits a pattern of neuronal pathology which exhibits several features of human temporal lobe epilepsy. KA-induced seizure activity is accompanied by the activation of the calcium-dependent protease calpain in limbic structures. In the present study, we evaluated the spatio-temporal activation of calpain after the onset of seizure activity by immunohistochemistry using an antibody for the spectrin breakdown product (sbdp) generated by calpain-mediated spectrin proteolysis. In addition, we compared the changes in sbdp immunoreactivity with those in immunoreactivity to subunits of the Glu/AMPA receptors (GluR1 and GluR2/3). One hour after seizure onset, sbdp accumulation was observed in selected interneurons in stratum oriens and in the hilus of the dentate gyrus. By 4 h, sbdp immunoreactivity was prominent in dendritic fields of the hippocampus as well as in neurons in thalamus and piriform cortex. By 8 h, sbdp immunoreactivity had disappeared from interneurons but was localized in pyramidal cell bodies in hippocampus. Intense labeling of cell bodies and dendritic fields persisted until 5 days following KA treatment. Changes in GluR subunit immunoreactivity were mirror images of those seen for sbdp. In general, increased sbdp immunoreactivity in dendritic fields was associated with decreased GluR1 immunoreactivity. However, increased sbdp immunoreactivity in neuronal perikarya was also associated with increased GluR immunoreactivity. These results indicate that calpain activation following seizure onset exhibits a specific spatio-temporal pattern, with activation in restricted interneurons preceding widespread activation in pyramidal neurons. Calpain activation also precedes neuronal pathology and could thus represent an initial trigger for neuronal pathology. Finally, the results suggest that calpain activation produces rapid alterations in GluR subunit properties which could be involved in the hyperexcitability observed following seizure activity.
Animals↗
Prospective, randomized trial of 5-fluorouracil, leucovorin, doxorubicin, and cyclophosphamide chemotherapy in combination with the interleukin-3/granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein (PIXY321) versus GM-CSF in patients with advanced breast cancer.
We conducted a prospective randomized trial to evaluate the ability of the interleukin-3/granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein, PIXY321, to ameliorate cumulative thrombocytopenia after multiple cycles of 5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide (FLAC) chemotherapy compared with GM-CSF in patients with advanced breast cancer. Fifty-three patients were randomized to receive either PIXY321. 375 microg/m2 twice a day subcutaneously, or GM-CSF, 250 microg/m2 daily subcutaneously after FLAC chemotherapy. PIXY321 was less well tolerated than GM-CSF, with more patients developing chills and local skin reactions and more patients stopping PIXY321 due to intolerance. While no difference in the neutrophil nadirs was seen with the two cytokines, the duration of the absolute neutrophil count less than 1,000/muL for all cycles was significantly longer with PIXY321 than with GM-CSF. Fifty percent of patients treated with multiple cycles of FLAC chemotherapy on both study arms developed dose-limiting thrombocytopenia. No differences in platelet nadirs, duration of thrombocytopenia, or need for platelet transfusions were observed with PIXY321 versus GM-CSF. The average delivered doses of FLAC chemotherapy were somewhat higher in the GM-CSF study arm. PIXY321 was not superior to GM-CSF in ameliorating the cumulative thrombocytopenia observed with multiple cycles of FLAC chemotherapy and was less well tolerated.
Antineoplastic Combined Chemotherapy Protocols↗
Preliminary results for positron emission mammography: real-time functional breast imaging in a conventional mammography gantry.
In order to optimally integrate radiotracer breast imaging within the breast clinic, anatomy and pathology should be easily correlated with functional nuclear medicine breast images. As a first step in the development of a hybrid functional/anatomic breast imaging platform with biopsy capability, a conventional X-ray mammography gantry was modified to image the compressed breast with positron emitters. Phantom studies with the positron emission mammography (PEM) device showed that a 1-cc hot spot could be detected within 5 min. A preliminary clinical trial demonstrated in vivo visualization of primary breast cancer within 4 min. For sites where positron-emitting radionuclides are available, PEM promises to achieve low-cost directed functional examination of breast abnormalities, with the potential for achieving X-ray correlation and image-guided biopsy.
Breast↗
The C-terminal domain of glutamate receptor subunit 1 is a target for calpain-mediated proteolysis.
The AMPA receptors are glutamate-gated ion channels mediating synaptic transmission at the majority of excitatory synapses in the mammalian CNS. They are composed of four subunits (GluR1-4) which exist in two alternatively spliced variants (flip and flop) and are generally considered to form pentameric receptors. The transmembrane structure of the receptors remains a matter of controversy as some data suggest a transmembrane topology consisting of five, four, or three membrane spanning regions. Some receptor properties have been shown to be regulated by phosphorylation processes as well as by the phospholipid environment. More recently, we have shown that calcium treatment of thin (10 microns) frozen-thawed brain sections resulted in profound modifications of the immunochemical properties of the AMPA receptors. More specifically, immunolabelling of the AMPA receptors with antibodies directed against the C-terminal domain of GluR1 and GluR2/3 was markedly decreased in dendritic fields following such treatment at 35 degrees C. This effect was temperature-dependent and completely blocked by inhibitors of the calcium-dependent proteases calpains, and we suggested that calpains are involved in the regulation of AMPA receptor properties. The results of the present study demonstrate that calpain activation produces a partial proteolysis in the C-terminal domain of the receptors and generates a new receptor species with an apparent molecular weight of 103,000 mol. wt. Sequence analysis of the GluR1 C-terminal domain suggests a couple of cleavage sites for calpains. These results are of particular interest considering the body of evidence implicating calpains and changes in excitatory amino acid receptors in mechanisms of synaptic plasticity as well as in neurodegenerative processes.
Blotting, Western↗
Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration.
BACKGROUND: This survey documents the strategies used by pain control physicians in the selection of opioid drugs and routes of administration in the management of inpatients referred to a cancer pain service. METHODS: The following approaches were prospectively evaluated during the treatment of 100 consecutive inpatients: 1) the influence of the evaluation of the goals of care on decision making, 2) selection of opioid drugs, 3) indications for changing opioid drugs and the frequency with which this strategy is used, and 4) selection of route of administration. RESULTS: Eighty of the 100 patients underwent a total of 182 changes in drug, route, or both drug and route before discharge or death. The major reasons for change were to improve the convenience of treatment regimen in the setting of adequate pain relief (31.4%), diminish side effects in the setting of controlled pain (25.0%), reduce the invasiveness of therapy in the setting of controlled pain (19.3%), and simultaneously improve pain control and reduce opioid toxicity (17.7%). When opioid toxicity was the reason for change, physicians changed the opioid drug in 71% of cases and the route in 29%. When convenience or invasiveness were targeted, the physicians changed the route in 61% of cases and the opioid in 39%. Forty-four patients required one or more change in the opioid, and 20 required 2 or more changes (range, 2-6 changes). At the time of discharge (n = 82), morphine was more commonly selected than hydromorphone or fentanyl (39% vs. 23% vs. 17%) and the routes of administration were oral (57%), transdermal (18%), intravenous (18%), subcutaneous (5%), and intraspinal (4%). Therapeutic changes were associated with improvement in physician-recorded pain intensity and a lower prevalence of cognitive impairment, hallucinations, nausea and vomiting, and myoclonus among patients who were discharged from the hospital. CONCLUSIONS: These data illustrate the application of strategies for selections of opioid drugs and their route of administration that are recommended in current guidelines for the management of cancer pain.
Adult↗
Substance P innervation of lumbar spine facet joints.
Sixteen adult human lumbar spine facet joints were harvested from patients undergoing various lumbar spine procedures. Diagnoses included degenerative disc disease, adult spinal deformity, facet joint degenerative arthritis, and degenerative spondylolisthesis. Facet joints were processed for routine hematoxylin and eosin staining. Immunohistochemical analysis was performed using a monoclonal antibody to substance P. All facets grossly exhibited evidence of degenerative disease, including cartilage surface irregularity and fibrillation. Histological examination of facets obtained from patients with degenerative spinal conditions demonstrated erosion channels extending through the subchondral bone and calcified cartilage into the articular cartilage. Immunostaining showed the presence of substance P-positive nerve fibers within these erosion channels, and also within marrow spaces. The presence of substance P nerve fibers within subchondral bone of degenerative lumbar facet joints implicates this type of joint in the etiology of low back pain.
Adult↗
Myosin light chain gene expression associated with disease states of the human heart.
During development of the human heart, the atrial isoform of alkali myosin light chain (MLC1A) is expressed in the ventricle. With maturation of the heart, MLC1A expression is completely replaced by that of the adult ventricular myosin light chain, MLC1V. We have evaluated the re-expression of MLC1A as a marker of different disease states of the human ventricle. RNA was isolated from the ventricles of patients with idiopathic dilated cardiomyopathy (CM) and severe congenital cardiac defects (CCD). Northern blot analysis was used to measure the mRNA levels of MLC1A and MLC1V in these samples. As a control, the level of regulatory MLC2V mRNA was also measured. We find that the level of MLC2V mRNA per microgram total ventricular RNA is very similar in CM, CCD and normal human samples. In contrast, we find that MLC1V mRNA levels tend to be reduced in both CM and CCD samples. In the case of the CCD samples, this apparent drop in MLC1V is compensated by expression of the developmental MLC1A isoform. However, in CM patients in end-stage failure, expression of MLC1A is barely detectable. The expression of MLC1A in CCD samples may reflect an adaptive mechanism in response to cardiac overload. The failure to detect substantial MLC1A expression in the CM samples may reflect the failure of such an adaptive mechanism.
Adult↗
[Surgical treatment with aortic valve homograft harvested from heart transplant recipients or donors].
From March 1988 to November 1991, 24 patients underwent aortic valve replacement or aortic root replacement with an aortic homograft harvested from a heart transplant recipient or donor that was not suitable for heart transplantation. Those patients were followed from 2 to 34 months (mean 12.6 months). The mean age was 44 years (range 19 to 77 years). The main lesion was aortic stenosis in 8 patients, aortic regurgitation in eight, mixed lesion in eight, annulo-aortic ectasia in two, active prosthetic valve endocarditis in two, and recurrent LVOTO in one. Cardiac status before operation was NYHA class II in one patient, III in nineteen, IV in four. Aortic valve replacement was performed in 17 patients, and aortic root replacement in seven. There was no early or late death. No structural deterioration was found. Surgical technical error resulted in moderate aortic regurgitation in one patient and mild paravalvular leak in another patient immediately after operation. All patients except one were not given anticoagulants postoperatively, but the entire group was free from thromboembolism. All patients returned to NYHA class I. Most homografts in this series were cryopreserved without antibiotic sterilization immediately after harvest, but homograft valve endocarditis did not occur. The results in this series suggested that homografts from heart transplant recipients or donors were encouraging, but more long-term follow-up was required to be determined whether homografts from heart transplant recipients without antibiotic sterilization were superior to homografts prepared in ordinary manner.
Adolescent↗
Ethinyl estradiol and norethindrone radioimmunoassay following Sephadex LH-20 column chromatography.
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Chromatography, Ion Exchange↗
Lipoprotein (a) is a substrate for factor XIIIa and tissue transglutaminase.
The mechanisms which mediate deposition of lipoprotein (a) (Lp(a)), an atherogenic lipoprotein particle, onto the vessel wall and cell surfaces are unknown. An irreversible deposition of Lp(a) may require the presence of enzymes that catalyze its binding to surface-oriented structures. Transglutaminases catalyze cross-linking of proteins as well as incorporation of primary amines into protein substrates. We studied whether tissue transglutaminase and/or activated Factor XIII (plasma derived or recombinant FXIIIa) incorporate primary amines into Lp(a). In the presence of Ca2+, Factor XIIIa and tissue transglutaminase catalyze incorporation of monodansylcadaverine or [14C]putrescine into purified Lp(a) in a specific and time-dependent manner. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that monodansylcadaverine became incorporated into the apo(a) portion of Lp(a). Lp(a) purified from five different donors showing different apo(a) phenotypes were substrates for tissue transglutaminases (TG). Western blot analysis confirmed that apo(a) was the major monodansylcadaverine carrying protein moiety of Lp(a). Tissue TG also extensively cross-linked the apo(a) portion of the Lp(a) particle. Characterization of the specificity of tissue TG showed that fibronectin, alpha 2-plasmin inhibitor, and apo(a) could be readily labeled with monodansylcadaverine by tissue TG, but other proteins including low density lipoprotein, IgG, alpha 1-proteinase inhibitor, and albumin showed poor or no reactivity. Direct comparison of Lp(a) with low density lipoprotein showed that apoB 100 was a poor substrate for transglutaminases. Recombinant apolipoprotein (a) proved to be an excellent substrate for TGs in that 1 mol of recombinant apolipoprotein (a) incorporated as much as 15 mol of [14C]putrescine, which corresponded to five times the amount of amine incorporated into Lp(a). The susceptibility of Lp(a) to transglutaminases suggests a mechanism whereby the interaction of Lp(a) with surface receptors and other surface oriented structures could be enzymatically altered.
Animals↗
Absence of particle-induced coronary vasoconstriction during cardioplegic infusion: is it desirable to use a microfilter in the infusion line?
Many cardiac surgical units now use a microfilter in the infusion line for delivery of crystalloid cardioplegic solution to protect against the potential hazards of particulate contamination of cardioplegic solution. The aim of this group of studies was to determine the effects of particulate contamination of cardioplegic solutions, in order to establish whether a microfilter is needed in the infusion line. Total particle counts performed on two commercial cardioplegic solutions were low, but there were sufficient particles greater than 10 microns in diameter to cause coronary vasoconstriction. In isolated rat hearts a 20-minute infusion of St. Thomas' Hospital cardioplegic solution produced a progressive reduction in coronary flow, which was not prevented by the inclusion of a 0.8 micron filter in the infusion line. Two studies were performed on canine hearts to determine the effects of unfiltered cardioplegic solution on coronary vascular resistance. In the first, cardioplegic solution at 20 degrees C was infused for 20 minutes at a constant pressure of 50 mm Hg and flow rate was measured. In the second, the same solution at 4 degrees C was infused at a constant flow rate for 2 1/2 minutes and the infusion pressure was measured. In neither study did coronary vascular resistance rise. A final clinical study involving patients undergoing coronary bypass surgery compared the effects on coronary resistance of infusion at a constant flow of filtered versus unfiltered cardioplegic solution (n = 10 in each group). There was a similar rise in coronary perfusion pressure in both groups during the infusion. We conclude that there is insufficient evidence of particle-induced coronary vasoconstriction to justify the expense of a microfilter in the cardioplegic infusion line.
Animals↗
Antinuclear antibodies in sera of patients with recurrent pregnancy wastage.
Four groups of women were studied to determine whether low-level antinuclear antibody titers are associated with a higher risk for pregnancy loss. Group A consisted of 30 patients with a history of unexplained fetal losses. Group B consisted of 30 women with "explained" fetal losses (e.g., uterine septum or luteal phase defect). Ages and number of losses were comparable between the women in groups A and B. Group C consisted of 61 healthy pregnant women. Group D involved 61 healthy nonpregnant women of reproductive age. In groups A and B, 40% and 53.3% of the respective patients had antinuclear antibody titers greater than or equal to 1:40. In groups C and D the frequencies of positive antinuclear antibody titers were 8.2% and 5.6%, respectively. This study demonstrates a high prevalence of low-titer antinuclear antibody-positive serum in patients with explained and unexplained pregnancy losses.
Abortion, Habitual↗
Immediate postexcision mammography for occult noncalcified breast lesions.
To evaluate completeness of surgical excision, we studied the use of film screen mammography done immediately after excision of occult noncalcified breast lesions in 11 patients. The postoperative mammograms were well tolerated, and allowed high quality films to be obtained. Complete excision was documented in ten patients, and one patient had small artifacts that resolved on follow-up studies. Roentgenograms of the surgical specimen from ten patients showed a discrete lesion in only three. Histologic analysis revealed malignancy in two patients and benign changes in nine. These findings indicate that mammography done immediately after excision of occult noncalcified lesions is more reliable than roentgenograms of the specimen and may be a useful method for confirming extent of excision. This method may also eliminate the present delay of four to six weeks before adequate postoperative follow-up films can be obtained to evaluate excision.
Adult↗