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PubMed1997

A receptor-G protein coupling-independent step in the internalization of the thyrotropin-releasing hormone receptor.

To determine whether functional receptor-G protein coupling or signaling are required for internalization of the thyrotropin-releasing hormone receptor (TRHR), we compared the endocytosis of Gq-coupled and uncoupled receptors. A hemagglutinin epitope-tagged TRHR (HA-TRHR) was in the Gq-coupled state when bound to the agonist, MeTRH, and in a nonsignaling state when bound to the HA antibody (12CA5). 12CA5 did not induce an increase in [Ca2+]i or inositol phosphates and did not inhibit [3H]MeTRH binding or MeTRH-induced production of second messengers. Both agonist- and antibody-bound HA-TRHRs were rapidly internalized via the same pathway; internalization was sensitive to hypertonic shock, and both types of internalized receptors were sorted into lysosomes. In addition, the amino acid sequence CNC (positions 335-337) in the C-terminal tail of the TRHR, which is important in ligand-induced receptor internalization as determined by deletion mutagenesis (Nussenzveig, D. R., Heinflink, M., and Gershengorn, M. C. (1993) J. Biol. Chem. 268, 2389-2392), was also important for 12CA5-induced internalization. We expressed two truncated receptors, HA-K338STOP and HA-C335STOP, in GH12C1 pituitary cells. Both HA-TRHR and HA-K338STOP were localized at the plasma membrane of untreated cells and were translocated to intracellular vesicles after MeTRH or 12CA5 binding; however, HA-C335STOP was internalized and recycled constitutively. The intracellular localization of HA-C335STOP was not altered by MeTRH; however, 12CA5 binding induced the disappearance of internalized HA-C335STOP and caused its localization at the plasma membrane, indicating that constitutively cycling HA-C335STOP cannot be reinternalized after antibody binding. Thus, amino acids 335-337, which are important for the internalization of Gq-coupled TRHRs, are also required for the sequestration of functionally uncoupled TRHRs, and in addition, they act as an inhibitory signal that prevents constitutive receptor internalization. Specifically, the Cys residues at positions 335 and 337 are important for preventing constitutive TRHR internalization, because a mutant HA-C335S/C337S receptor was sequestered constitutively. We conclude that release from a negative regulatory internalization sequence or domain is important for HA-TRHR internalization and that the role of the CNC sequence in internalization is independent of functional TRHR-Gq coupling.

Animals↗
PubMed2001

Internalization rates of murine and ovine gonadotropin-releasing hormone receptors.

Rates of internalization of the murine GnRH receptor fused via its C-terminus to green fluorescent protein (GnRH-R-GFP) were examined in Chinese hamster ovary cells (CHO cells) and compared to those of native murine GnRH-R in a clonal murine gonadotroph cell line (LbetaT2 cells). The resulting rates of internalization of murine receptors were then compared with those of sheep GnRH-R in ovine gonadotrophs. Cells were incubated with radioiodinated [D-Ala6]GnRH on ice for 4 h to allow binding of the ligand to GnRH-R, then cells were warmed to 37 degrees C to permit internalization. Surface-bound radioligand began to decrease as soon as the cells were warmed and had decreased significantly within 20 min. A steady-state level of surface-bound radioligand was achieved after 60 min in both CHO cells and LbetaT2 cells (38% and 41%, respectively, of initial value; P < 0.05). Internalization of radioligand began immediately after warming the cells to 37 degrees C, and a significant proportion of surface ligand had been internalized by 20 min. A steady-state maximum of internalization was reached after 60 min in both CHO cells and LbetaT2 cells (29% and 28%, respectively, of total cell-associated ligand; P < 0.05). Changes in surface-bound radioligand and internalized radioligand in sheep pituitary cells were similar to those in CHO cells and LbetaT2 cells, but the amount of radioligand internalized after 60 min (40% of total cell-associated ligand) was 1.4 times higher than in CHO cells and LbetaT2 cells (P < 0.05). In a separate experiment, the effect of estradiol on the rate of internalization of GnRH-R in ovine pituitary cells was examined. Although treatment of ovine pituitary cells with estradiol approximately doubled the number of GnRH receptors, it did not alter either the rate or extent of receptor internalization. These results show that rates of internalization of recombinant murine GnRH-R-GFP in CHO cells and native murine and ovine GnRH-R in LbetaT2 cells and in sheep pituitary cells, respectively, are similar, but amounts of ovine GnRH-R internalized are greater than those for murine GnRH-R. Further, the rate of internalization of occupied receptor is similar in gonadotroph and nongonadotroph cells, and the addition of GFP to the C-terminus of the murine GnRH-R does not alter the rate of internalization.

Animals↗
PubMed1983

Cell surface receptor-mediated internalization of interferon: its relation to the antiviral activity of interferon.

The binding of [3H]leucine-labelled pure human interferon alpha from Namalwa cells to human FL and Daudi cells was studied, and evidence obtained to indicate receptor-mediated internalization of interferon. Cell surface-bound and internalized interferons were quantified separately as trypsin-released and unreleased radioactivities, respectively. At 37 degrees C, surface-bound interferon reached a maximum after 1 h and then decreased, while internalized interferon reached a maximum after 2 h. At 21 degrees C, in contrast, surface-bound interferon reached a maximum after 2 h and did not decrease thereafter; no internalization was observed. The same was true at 37 degrees C in the presence of NaF, indicating dependence of internalization on temperature and energy. In control cultures at 37 degrees C, internalized interferon, after reaching a maximum, decreased after prolonged incubation, and concomitantly acid-soluble radioactivity appeared in the culture medium. The decrease in internalized interferon and the emergence of degraded interferon were inhibited by the lysosomotropic agents, ammonium chloride and chloroquine. The fate of labelled interferon, bound to the cell surface of FL cells at 21 degrees C was studied at 37 degrees C, and the results indicated that trypsin-unreleased interferon was derived from the surface-bound interferon, and was secreted in part into the culture fluid in a degraded form upon prolonged incubation. The relation of internalization of interferon to its biological activity was studied in three ways. In FL cells, the antiviral activity was not induced when internalization of interferon was entirely blocked (at 21 degrees C or in the presence of NaF at 37 degrees C). In Daudi cells, both 2'-5'-oligoadenylate (2-5A) synthetase induction by interferon and internalization of interferon were inhibited completely by diethyldithiocarbamate (DDC), whereas in the case of FL cells, DDC inhibited neither 2-5A synthetase induction nor internalization of interferon. Raji cells, which have an interferon-specific binding site on the cell surface but are insensitive to interferon, were found not to internalize interferon, whereas other Burkitt's lymphoma cells, Daudi and Namalwa, which are sensitive to interferon, did internalize it. These findings suggest (but do not prove) that internalization is required for the establishment of interferon activity.

Biological Transport↗
PubMed1989

Catastrophic consequences of internal mammary artery hypoperfusion.

Inappropriate use of the internal mammary artery for complex coronary artery bypass operations may have disastrous yet avoidable consequences. In 712 consecutive coronary artery bypass operations performed between January 1985 and September 1986, five patients had an intraoperative course suggesting internal mammary artery hypoperfusion. In three, coronary artery bypass was performed as a reoperative procedure. The following similarities were noted in all five patients: a technically satisfactory internal mammary artery anastomosis, a left anterior descending coronary artery having critical proximal stenosis (greater than or equal to 90%), a distal artery at least 2.0 mm diameter free of disease, satisfactory left ventricular function, a catastrophic clinical outcome (death in three, cardiac transplantation in one, 3-month hospitalization in one), and all patients could be weaned from cardiopulmonary bypass only after insertion of a saphenous vein graft distal to the internal mammary artery graft. Bilateral internal mammary grafts were used in four of five patients. In both patients without prior coronary artery bypass, there was a discrepancy in internal mammary artery flow and myocardial demand: cardiac hypertrophy, large (2.5 mm) distal left anterior descending supplied by a small (less than 2.0 mm) internal mammary artery, and sequentially grafted arteries. All three patients having reoperative coronary artery bypass had normal anterior wall motion, and in two of the three patients, the left anterior descending-saphenous vein graft was arteriographically normal and the sole source of blood to the anterior, septum, and inferior myocardium. In two patients the normal left anterior descending-saphenous vein graft supply a large left anterior descending (greater than 2.0 mm) was replaced with a small left internal mammary artery. Internal mammary artery hypoperfusion typically occurred 30 to 40 minutes after discontinuation of cardiopulmonary bypass but was also seen in the intensive care unit. The condition may be confused with internal mammary artery or coronary artery spasm. It may be avoided by careful prebypass planning of the operation, intraoperative assessment of internal mammary artery flow and size with prudent use of sequential internal mammary artery grafting, avoiding use of the terminal left anterior descending (unless large), retaining nonobstructed saphenous vein grafts when the internal mammary artery has marginal flow or size, and placement of a saphenous vein graft distal to the left internal mammary artery when size or flow in the latter is small.

Aged↗
PubMed2005

Behavior problems and mental health referrals of international adoptees: a meta-analysis.

CONTEXT: International adoption involves more than 40,000 children a year moving among more than 100 countries. Before adoption, international adoptees often experience insufficient medical care, malnutrition, maternal separation, and neglect and abuse in orphanages. OBJECTIVE: To estimate the effects of international adoption on behavioral problems and mental health referrals. DATA SOURCES: We searched MEDLINE, PsychLit, and ERIC from 1950 to January 2005 using the terms adopt* combined with (behavior) problem, disorder, (mal)adjustment, (behavioral) development, clinical or psychiatric (referral), or mental health; conducted a manual search of the references of articles, books, book chapters, and reports; and consulted experts for relevant studies. The search was not limited to English-language publications. STUDY SELECTION: Studies that provided sufficient data to compute differences between adoptees (in all age ranges) and nonadopted controls were selected, resulting in 34 articles on mental health referrals and 64 articles on behavior problems. DATA EXTRACTION: Data on international adoption, preadoption adversity, and other moderators were extracted from each study and inserted in the program Comprehensive Meta-analysis (CMA). Effect sizes (d) for the overall differences between adoptees and controls regarding internalizing, externalizing, total behavior problems, and use of mental health services were computed. Homogeneity across studies was tested with the Q statistic. DATA SYNTHESIS: Among 25,281 cases and 80,260 controls, adoptees (both within and between countries) presented more behavior problems, but effect sizes were small (d, 0.16-0.24). Adoptees (5092 cases) were overrepresented in mental health services and this effect size was large (d, 0.72). Among 15,790 cases and 30,450 controls, international adoptees showed more behavior problems than nonadopted controls, but effect sizes were small (d, 0.07-0.11). International adoptees showed fewer total, externalizing and internalizing behavior problems than domestic adoptees. Also, international adoptees were less often referred to mental health services (d, 0.37) than domestic adoptees (d, 0.81). International adoptees with preadoption adversity showed more total problems and externalizing problems than international adoptees without evidence of extreme deprivation. CONCLUSIONS: Most international adoptees are well-adjusted although they are referred to mental health services more often than nonadopted controls. However, international adoptees present fewer behavior problems and are less often referred to mental health services than domestic adoptees.

Adolescent↗
PubMed2004

Radiation safety standards and their application: international policies and current issues.

This paper briefly describes the current policies of the United Nations Scientific Committee on the Effects of Atomic Radiation and the International Commission on Radiological Protection and how these policies are converted into international radiation safety standards by the International Atomic Energy Agency, which is the only global organization-within the United Nations family of international agencies-with a statutory mandate not only to establish such standards but also to provide for their application. It also summarizes the current status of the established corpus of such international standards, and of it foreseeable evolution, as well as of legally binding undertakings by countries around the world that are linked to these standards. Moreover, this paper also reviews some major current global issues related to the application of international standards, including the following: strengthening of national infrastructures for radiation safety, including technical cooperation programs for assisting developing countries; occupational radiation safety challenges, including the protection of pregnant workers and their unborn children, dealing with working environments with high natural radiation levels, and occupational attributability of health effects (probability of occupational causation); restricting discharges of radioactive substances into the environment: reviewing current international policies vis-a-vis the growing concern on the radiation protection of the "environment;" radiological protection of patients undergoing radiodiagnostic and radiotherapeutic procedures: the current International Action Plan; safety and security of radiation sources: post-11 September developments; preparedness and response to radiation emergencies: enhancing the international network; safe transport of radioactive materials: new apprehensions; safety of radioactive waste management: concerns and connections with radiation protection; and radioactive residues remaining after the termination of activities: radiation protection response to the forthcoming wave of decommissioning of installations with radioactive materials. The ultimate aim of this paper is to encourage information exchange, cooperation, and collaboration within the radiation protection professional community. In particular, the paper tries to facilitate consolidation of the growing international regime on radiation safety, including the expansion of legally binding undertakings by countries, the strengthening of the current corpus of international radiation safety standards, and the development of international provisions for ensuring the proper worldwide application of these standards, such as a system of international appraisals by peer review.

Government Agencies↗
PubMed1992

A quantitative study of postoperative luminal narrowing of the internal thoracic artery graft in coronary artery bypass surgery.

We used quantitative angiography to determine the postoperative diameter of the internal thoracic artery graft at the point close to the anastomosed site in 147 patients who received the graft for the left anterior descending coronary artery. We performed generalized multiple linear regression analysis (Type I quantification method) to assess the effects of the following factors on the internal thoracic artery graft diameter: age, gender, time of angiography, laterality of the internal thoracic artery used, presence of an undivided major side branch of the internal thoracic artery, presence of a saphenous vein graft having blood flow competition with an internal thoracic artery graft, presence of distal stenosis of the recipient left anterior descending coronary artery, severity of postoperative left anterior descending coronary artery stenosis, and presence of coronary risk factors. The standardized category scores for 25% left anterior descending coronary artery stenosis, 50% left anterior descending coronary artery stenosis, and presence of a saphenous vein graft having blood flow competition with an internal thoracic artery graft were -1.418, -0.767 and -0.622, respectively. Thus, the internal thoracic artery diameter was smaller in patients with well-preserved flow of the recipient coronary artery. The internal thoracic artery diameter had a particularly strong correlation with the degree of left anterior descending coronary artery stenosis (partial correlation coefficient: 0.670). The other factors seemed to have little or no correlation with the postoperative internal thoracic artery diameter. With the criterion that the internal thoracic artery diameter below 1.0 mm represents the "string sign" of internal thoracic artery graft, this phenomenon was observed in nine patients (6.1%). In all of these patients, left anterior descending coronary artery flow was well-preserved, and no ischemia was disclosed in the left anterior descending coronary artery-perfused area. These results indicate that internal thoracic artery grafts have flow adaptability responding to the flow demand of the recipient coronary artery and that the string sign of internal thoracic artery grafts is mainly an outcome of its physiologic characteristics.

Adult↗
PubMed1998

International health training in family practice residency programs.

BACKGROUND AND OBJECTIVES: This survey determined the extent of involvement in and support of international health training by family practice residency programs. METHODS: We mailed a 17-item survey about four areas of international health training (curriculum, faculty, financial support, and international health sites) to the 192 family practice residency programs that answered affirmatively to the American Academy of Family Physicians (AAFP) 1996 survey question, "Does your program offer or encourage an elective in an international setting?" RESULTS: Of the surveyed programs, 75% (144/192) responded. Fifty-four percent of programs offered some form of international health curriculum, and 15.3% (22/144) provided significant support for resident involvement in international health, defined as having 1) an international health curriculum, 2) funding support (other than paid salary while away), and 3) at least one faculty member who had done health care work in a developing country in the past 2 years. Of the responding programs, 24.3% (35/144) had none of the three criteria. The number of residents who worked in developing countries most strongly correlated with the number of faculty who have done such work in the past 2 years. Logistic regression suggested that the factors associated with a program having residents who have worked in developing countries in the past 2 years included the number of faculty who worked in developing countries in the past 2 years, the number of months of salary paid while on an international health elective, the length of time a program had offered an international health experience, and paid living expenses while at the international site. CONCLUSIONS: A wide range of support is offered for international health education by programs that are self-identified as offering or encouraging international health rotations. This survey begins to clarify the specific factors associated with placing residents in international training opportunities.

Curriculum↗
PubMed2004

Internal target volume determined with expansion margins beyond composite gross tumor volume in three-dimensional conformal radiotherapy for lung cancer.

PURPOSE: Gross tumor volume (GTV) of lung cancer defined by fast helical CT scan represents an image of moving tumor captured at a point in active respiratory movement. However, the method for defining internal margins beyond GTV to account for its expected physiologic movement and all variations in size and shape during the administration of radiation has not been established. The goal of this study was to determine the internal margins with expansion margins beyond individual GTVs defined with (1) fast scan at shallow free breathing, (2) breath-hold scans at the end of tidal volume inspiration and expiration, and (3) 4-s slow scan to approximate the composite GTV of all scans. METHODS AND MATERIALS: A series of sequential CT scans were acquired with (1) a fast helical scan at shallow free breathing and (2) breath-hold scans at the end of tidal volume expiration and inspiration for the first 6 patients, and (3) a 4-s slow scan at quiet free breathing, which was added for the latter 7 patients. We fused breath-hold scans and the 4-s slow scan to the fast scan at shallow free breathing to generate the composite GTV. Margins necessary to encompass the composite GTV beyond individual GTVs defined by either fast scan at quiet free breathing, breath-hold scans, or the 4-s slow scan at quiet free breathing were defined as expansion or internal margins and termed the internal target volumes. The centroid of the tumor volume was also used as another reference for tumor movement. RESULTS: Thirteen patients with 14 tumors were enrolled into the study. Substantial tumor movement was noted by either the extent of internal margins beyond each GTV or the movement of the centroid. Internal margins varied significantly according to the method of CT scanning for determination of GTV. Even for tumors in the same lobe of the lung, a wide range of internal margins and significant variation in the centroid movement in all directions (x, y, and z) were observed. The GTV of a single fast helical scan at free breathing (n = 14) required the largest internal margin (mean, 3.5 mm; maximum, 18 mm; standard deviation [SD], 4.2 mm) to match the composite GTV, compared with those of the 4-s slow scan (mean 2.7 mm, maximum 14 mm, SD 3.5 mm) or combined breath-hold scans (mean 1.1 mm, maximum 9 mm, SD 1.9 mm). Internal margins (expansion margins) required to approximate the composite GTV in 95% of cases were 13 mm, 10 mm, and 5 mm for the GTVs of a single fast scan, 4-s slow scan, and breath-hold scans at the end of tidal volume inspiration and expiration, respectively. CONCLUSIONS: The internal margins required to account for the internal tumor motion in three-dimensional conformal radiotherapy are substantial. For the use of symmetric and population-based margins to account for internal tumor motion, GTV defined with breath-hold scans at the end of tidal volume inspiration and expiration has a narrower range of internal margins in all directions than that of either a single fast scan or 4-s slow scan.

Aged↗
PubMed2004

Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessel coronary artery bypass grafting: effects on mortality and event-free survival.

BACKGROUND: The issue of superiority of single internal thoracic artery grafting versus bilateral internal thoracic artery grafting remains unresolved. The aim of this study was to compare the long-term outcome of single and bilateral internal thoracic artery grafting with concomitant saphenous vein grafting for multivessel coronary artery bypass grafting. METHODS: Between March 1985 and April 1995, 6650 patients underwent primary isolated coronary artery bypass grafting with internal thoracic artery grafts, including 4382 patients with multivessel bypass grafting requiring at least 3 grafts. Outcomes of patients undergoing single internal thoracic artery plus saphenous vein grafting (n = 2547) and bilateral internal thoracic artery plus saphenous vein grafting (n = 1835) were obtained at a mean follow-up of 11 +/- 3 years. RESULTS: Patients with bilateral internal thoracic artery grafting were younger, were mostly male, and had less diabetes, hypertension, unstable angina, and recent myocardial infarction than patients undergoing single internal thoracic artery grafting. Thirty-day mortality was 2.3% for the group undergoing single internal thoracic artery grafting versus 1.2% for those undergoing bilateral internal thoracic artery grafting (P =.007). Survival probability at 10 years was 88% for the single-graft group compared with 93% for the bilateral-graft group (P <.001). Multivariate analysis with propensity scoring showed that bilateral internal thoracic artery grafting decreased the risk of death (hazard ratio, 0.74; 95% confidence interval, 0.60-0.90), myocardial infarction (hazard ratio, 0.79; 95% confidence interval, 0.67-0.93), and coronary reoperation (hazard ratio, 0.41; 95% confidence interval, 0.21-0.80) throughout the follow-up period. Other significant predictors of death were diabetes, prior myocardial infarction, need for intra-aortic balloon pump, chronic heart failure, and peripheral vascular disease. CONCLUSION: Patients undergoing bilateral internal thoracic plus saphenous vein grafting appear to have a significantly better long-term clinical outcome than patients undergoing single internal thoracic artery plus saphenous vein grafting for multivessel coronary artery bypass grafting.

Coronary Artery Bypass↗
PubMed2001

Affinity and location of an internal K+ ion binding site in shaker K channels.

We have examined the interaction between TEA and K+ ions in the pore of Shaker potassium channels. We found that the ability of external TEA to antagonize block of Shaker channels by internal TEA depended on internal K+ ions. In contrast, this antagonism was independent of external K+ concentrations between 0.2 and 40 mM. The external TEA antagonism of internal TEA block increased linearly with the concentration of internal K+ ions. In addition, block by external TEA was significantly enhanced by increases in the internal K+ concentration. These results suggested that external TEA ions do not directly antagonize internal TEA, but rather promote increased occupancy of an internal K+ site by inhibiting the emptying of that site to the external side of the pore. We found this mechanism to be quantitatively consistent with the results and revealed an intrinsic affinity of the site for K+ ions near 65 mM located approximately 7% into the membrane electric field from the internal end of the pore. We also found that the voltage dependence of block by internal TEA was influenced by internal K+ ions. The TEA site (at 0 internal K+) appeared to sense approximately 5% of the field from the internal end of the pore (essentially colocalized with the internal K+ site). These results lead to a refined picture of the number and location of ion binding sites at the inner end of the pore in Shaker K channels.

Animals↗
PubMed2004

Internal impingement of the shoulder in flexion.

Contact of the rotator cuff to the superior glenoid with the arm in flexion has been described and postulated to be a source of rotator cuff disease. The goals of the current study were to document the existence of internal impingement in flexion arthroscopically and to determine its prevalence in patients with various diseases. Also, we attempted to determine the clinical significance of internal impingement in flexion by investigating the associations between internal impingement in flexion and the preoperative and intraoperative findings. A consecutive case series of 376 patients having arthroscopy of the shoulder were entered prospectively into this study. During arthroscopy, intraarticular lesions were evaluated and the presence of contact of the rotator cuff to the superior glenoid and the degree of flexion making the contact were noted. Statistical analysis was done with two dependent variables defined: the presence of internal impingement in flexion and the flexion degree making internal impingement in flexion. Of the 376 patients, 277 (74%) had internal impingement in flexion and 99 (26%) did not have internal impingement in flexion. There were no statistically significant differences in the prevalence of internal impingement in flexion according to the primary diagnoses. Statistical analysis revealed that the presence of internal impingement in flexion was associated with Type II superior labrum anterior posterior (SLAP) lesions and the presence of internal impingement of the rotator cuff to the superior glenoid in abduction and external rotation. There was a significant relationship between rotator cuff disease and decreasing angle of contact for internal impingement in flexion. This study showed that internal impingement in flexion is common in a cohort of patients having shoulder surgery, with an overall prevalence of 74%, and that internal impingement in flexion may contribute to the development of Type II SLAP lesions and rotator cuff disease.

Adolescent↗
PubMed1986

Insulin internalization into monocytes is decreased in patients with type II diabetes mellitus.

We studied the internalization of [125I]insulin into circulating human monocytes, a cell type widely used for insulin binding studies. The internalization of [125I]insulin was assessed by both an acid extraction technique, which removes surface-bound insulin but not intracellular insulin, and by a trypsinization technique, which removes cell surface-bound hormone. After 5 h of incubation at 22 C, over 40% of the total cell-associated [125I]insulin was internalized into monocytes of normal subjects. This internalization was temperature dependent; the fraction of internalized hormone was progressively decreased when the incubation temperature was reduced from 37 to 4 C. Treatment of monocytes with increasing concentrations of 2,4-dinitrophenol also decreased [125I]insulin internalization, whereas dansylcadaverine, an inhibitor of transglutaminase, had no effect. Analysis by gel filtration of the internalized labeled hormone after 4 h of incubation at 22 C indicated that 50-60% of the label was degraded insulin, but detectable intact insulin was still present. Internalization of insulin was then studied in monocytes from eight obese patients (161% of ideal body weight) with type II diabetes mellitus. After 4 h of incubation at 22 C, the specific total monocyte-associated [125I]insulin was decreased compared to that in cells from 7 normal subjects [6.02 +/- 0.38% (+/- SE) vs. 3.91 +/- 0.31% of the total; P less than 0.001]. Moreover, the percentage of hormone that was internalized was also decreased from 41.4 +/- 1.2% of the total to 28.9 +/- 1.8% (P less than 0.001). In 20 nondiabetic obese subjects, specific cell-associated [125I]insulin was reduced to 3.9 +/- 0.3% (P less than 0.001). However, compared to that in normal subjects, the percentage of hormone that was internalized was not decreased (39.7 +/- 3.51% of the total). The present findings indicate that human circulating monocytes internalize [125I]insulin; this process is temperature and energy dependent; and monocytes from obese type II diabetic patients have a significantly decreased ability to internalize insulin. This decreased internalization may play a role in the cellular resistance to insulin that occurs in these patients.

Adult↗
PubMed2005

Planning of the internal mammary field based on lymphoscintigraphy localization before postoperative radiotherapy of breast cancer.

BACKGROUND: Internal mammary irradiation is still an issue of great debate. Although treatment of internal mammary lymph nodes was routinely given in the majority of randomized trials, data in its value are still limited. The aim of this study is to determine the variability of position of the internal mammary lymph nodes using lymphoscintigraphy and to compare the dose of radiation that reaches these lymph nodes, the heart and lungs if only tangential fields are used. MATERIAL AND METHODS: This is a prospective study that included 30 breast cancer patients treated in the department of radiation oncology of the Egyptian National Cancer Institute, Cairo University, planned for postoperative radiotherapy. Lymphoscintigraphy was done for all patients for detection of the exact site of the internal mammary lymph nodes. Dose volume histogram (DVH) was done to measure the dose to the heart using CT planning. Two plans were done for each patient, the first with internal mammary field (plan I), and the second without but with contralateral crossing of the midline by 1cm (plan II). RESULTS: The mean percentage of the internal mammary lymph nodes included in the internal mammary field (plan I) was 70.03% while in plan II it was 3.05%. The mean dose percentage reaching the heart in plan I was 54.5% of total dose, while in plan II it was 9.16% of total dose with significant p value<0.001. The mean dose to the heart decreased as the heart volume increased, this significant difference between the 2 plans was maintained for the different heart volumes. Also, the radiation dose to the heart in plan I varied significantly (p: 0.001) between the right side vs the left side with a mean dose of 48.02% and 63.5%, respectively. The mean dose percentage reaching the lungs in plan I and plan II was 46.53% and 24.5% respectively, with significant p value<0.001. CONCLUSION: If irradiation of internal mammary chain is intended, then a direct internal mammary field should be used. The planning of internal mammary field should be adjusted according to lymphoscintigraphy so as to include most of the draining internal mammary lymph nodes. The risk of late cardiac and pulmonary complications will increase when using direct internal mammary field, but the risk of cardiac complications will be less in irradiation of right side internal mammary lymph nodes compared to that of irradiation of the left side.

Adult↗
PubMed2004

The effect of bilateral internal thoracic artery grafting on survival during 20 postoperative years.

BACKGROUND: To compare survival of patients receiving bilateral internal thoracic artery grafts and single internal thoracic artery grafts more than 20 postoperative years, assess magnitude of benefit, and identify predictors of benefit. METHODS: From cohorts of 8123 patients receiving single internal thoracic artery grafts and 2001 receiving bilateral internal thoracic artery grafts during primary isolated bypass operations for multivessel coronary disease between 1971 and 1989, we identified 1152 propensity-matched pairs. Mean follow-up of survivors was 16.5 years, with 51 patients followed for 20 years or more. Hazard function methodology was used to identify risk factors for mortality, compare survival, and assess magnitude of benefit. RESULTS: Comparison of the matched pairs showed survival of the bilateral internal thoracic artery and single internal thoracic artery groups at 7, 10, 15, and 20 years was 89% versus 87%, 81% versus 78%, 67% versus 58%, and 50% versus 37%, respectively (p < 0.0001). Divergence of bilateral internal thoracic artery and single internal thoracic artery hazard function curves continued to widen through 20 postoperative years. At 20 years, bilateral internal thoracic artery grafting was predicted to produce worse survival in 2.8% of patients, a survival advantage of less than 5% in 12.9%, greater than 10% in 52%, and greater than 15% in 7.6%. Combinations of cardiac and noncardiac descriptors were used to define higher and lower risk patient subsets. Advanced age, abnormal left ventricular function and noncardiac risk factors decreased overall survival but the incremental benefit of bilateral internal thoracic artery grafting persisted. CONCLUSIONS: Bilateral internal thoracic artery grafting produces improved survival compared with single internal thoracic artery grafting during the second postoperative decade, and the magnitude of that benefit increases through 20 postoperative years.

Coronary Disease↗
PubMedDate not supplied

'Non-lethal' weapons and international law: three perspectives on the future.

Literature on 'non-lethal' weapons (NLWs) frequently contains assertions that more robust NLW development and use are needed because of the changing nature of military operations. These assertions are in opposition to international legal analysis of NLWs, which show international law restricting NLW development and use. This article examines this tension by briefly analyzing the restrictive impact that international law has on NLWs and by elaborating three perspectives on what the relationship between NLWs and international law should be. The article outlines the moral foundations for existing international law on the use of force and armed conflict and then sketches international law's current impact on NLW development and use. Next, the article explores the compliance, selective and radical change perspectives that emerge from discourse about international law and NLWs. The compliance perspective insists that NLWs comply with existing rules of international law. The selective change perspective seeks limited changes in international law to allow more robust use of NLWs. The radical change perspective sees in NLWs the potential to reform radically international law on the use of force and armed conflict. Identifying the three perspectives helps clarify future choices NLWs may present in international law and suggests that the future relationship between NLWs and international law will be more complex, controversial and dangerous than people may realize.

Forecasting↗
PubMed1985

Twelve-year experience with internal mammary artery for coronary artery bypass.

From Feb. 1, 1972, to Jan. 30, 1984, 1,000 patients had isolated coronary bypass with at least one internal mammary artery, and 103 of them had bilateral internal mammary artery grafts. There were 1,395 associated vein grafts and 1,158 internal mammary artery anastomoses, for a total of 2,556 grafts (2.5 per patient). Patients were followed up for 1 to 12 years (mean 6.3 years) and 77 patients were lost to follow-up at a mean of 4.0 years. Operative mortality was 1.4%, with 11 of 14 deaths in the first 240 patients (4.6%) and eight of 14 in the 103 patients with bilateral internal mammary artery grafts. There were 93 late deaths, with an actuarial survival rate of 93% at 5 years and 84% at 10 years. Angina occurred at a mean rate of 6.2% +/- 1.2% per year. Perioperative infarction was detected in 37 patients (3.7%). Late infarction occurred in 75 patients, for a mean rate of 1.5% +/- 0.3% per year. Reoperation (or percutaneous transluminal coronary angioplasty) was necessary in 35 patients, for a mean rate of 0.85% +/- 0.28% per year. Graft patency was assessed by 1,029 follow-up catheterizations in 519 patients. The patency rate of the left internal mammary artery was 96.4% at 1 year, 88.1% at 5 years, and 88.1% at 10 years. That of the right internal mammary artery was 92.8% (p = NS) at 1 year, 84.6% (p = NS) at 5 years, and at 10 years the numbers were too small to be meaningful. Comparison of patency rates for all internal mammary artery grafts with vein grafts gave 1 year graft patency rates of 95.7% versus 93.4% (p less than 0.025), 5 year rates of 87.9% versus 74.0% (p less than 0.001), and 10 year rates of 83.0% versus 41.0% (p less than 0.001). Included in these patency data are 20 free internal mammary artery grafts; 16 were studied (mean 2.3 years) and 12 of these 16 (75%) were patent. Of the 58 sequential internal mammary artery grafts, 18 were studied by catheterization (mean interval 2.0 years); 35 of 36 anastomoses were patent and one end-to-side anastomosis was closed. Morbidity and mortality for patients having internal mammary artery grafting are comparable to those of patients having saphenous vein bypass only. The demonstrated superior patency for internal mammary artery grafts supports the routine use of bilateral internal mammary artery grafting.

Actuarial Analysis↗
PubMed1991

T cell receptor/CD3 complex internalization following activation of a cytolytic T cell clone: evidence for a protein kinase C-independent staurosporine-sensitive step.

The fate of the T cell receptor (TcR)/CD3 complex was examined on a cytotoxic T lymphocyte (CTL) clone (KB5.C20) activated either via binding of an anti-TcR monoclonal antibody (mAb) or by a Ca2+ ionophore and phorbol 12-myristate 13-acetate (PMA). After binding of the anti-TcR mAb, electron microscopy revealed internalization through coated vesicles followed by slow degradation of the antibody as shown by use of radiolabeled mAb. The influence of activation on TcR/CD3 internalization was analyzed. The Ca2+ ionophore alone had no effect on internalization, whereas PMA induced an accelerated internalization of anti-TcR mAb. PMA-induced internalization was dependent on protein kinase C (PKC) as shown by its absence in PKC-depleted cells or in the presence of the PKC inhibitor staurosporine. Anti-TcR mAb-induced internalization was maintained in PKC-depleted cells, but unexpectedly remained sensitive to inhibition by staurosporine. The monovalent anti-TcR mAb Fab fragment is non-stimulatory for the CTL. It was poorly internalized but its internalization was induced by PMA. Surprisingly, on PKC-depleted cells, the Fab was internalized more readily than in untreated cells and this internalization was sensitive to inhibition by staurosporine. Inhibition of PMA-induced phosphorylation of gamma and epsilon subunits of CD3 was demonstrated after depletion of PKC or in the presence of staurosporine, confirming that PKC function was inhibited in those conditions. Cross-linking of the TcR via plastic-coated anti-TcR mAb led to phosphorylation of CD3 gamma and epsilon and also of zeta, known to be phosphorylated on tyrosines. All of these phosphorylation events were inhibited by treatment with staurosporine. Our results indicate that staurosporine inhibits the receptor internalization induced by anti-TcR mAb by means other than inhibition of PKC, suggesting that other kinases may control a step of this internalization process.

Alkaloids↗