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C D Scott

Publications and source records attributed to C D Scott.

At least 37 records · Page 2Linked to original sources
PubMed1994

Regulation of the acid-labile subunit of the insulin-like growth factor complex in cultured rat hepatocytes.

The acid-labile subunit (ALS) is a glycoprotein that forms a ternary complex in serum with insulin-like growth factors and insulin-like growth factor-binding protein-3. This study investigates the regulation of ALS production, measured by RIA, and messenger RNA (mRNA) content, measured by Northern analysis, in primary rat hepatocyte monolayer cultures. Hepatocytes produced ALS at a linear rate over 48 h. Exposure to human GH (30 ng/ml) caused a maximum 2.2-fold stimulation of ALS production compared to that in control cultures, giving a rate of 200 ng/10(6) cells.48 h. ALS mRNA appeared as a predominant 2-kilobase band and increased 4-fold by administration of 30 ng/ml GH. Both dexamethasone and epidermal growth factor (EGF) inhibited ALS production, with maximal effects at 100 nM dexamethasone and 50 ng/ml EGF (both approximately 50% inhibition). ALS mRNA levels measured 24 or 48 h after dexamethasone addition were decreased 75-80% compared to the control value. A similar decrease in ALS mRNA was observed 24 h after EGF addition, but a second addition of EGF at 24 h was required to maintain this decrease for 48 h. This study demonstrates that rat hepatocytes secrete immunoreactive ALS under GH regulation, and that EGF and corticosteroid inhibit ALS production and mRNA levels. The quantitative discrepancies between ALS production rates and mRNA levels suggest that posttranscriptional events may have a role in ALS regulation.

Acids↗
PubMed1993

Upper gastrointestinal dysmotility in heart-lung transplant recipients.

Recipient pneumonectomy and the necessity for meticulous hemostasis in heart-lung transplantation can result in injury to the vagus nerves as they course through the posterior mediastinum, with consequent delay in gastric emptying. This has been reported to lead to chronic aspiration and associated pulmonary sequelae. To study the association between delayed gastric emptying, bronchiectasis, and bronchiolitis obliterans after heart-lung transplantation, we performed esophageal manometry, 24-hour pH monitoring, and radioisotopic gastric emptying in 10 patients who underwent heart-lung transplantation. Three patients had grossly delayed liquid and solid emptying that was compatible with complete vagotomy. Six other patients had delayed liquid but normal solid emptying--an unexplained finding that is the reverse of what one would expect from vagal injury. Two of these 9 patients had esophageal dysmotility, but none demonstrated gastroesophageal reflux. One remaining patient had faster than normal gastric emptying for both solids and liquids. Of the 10, 2 patients have radiologic changes of bronchiectasis and 3 have biopsy evidence of obliterative bronchiolitis. There is no relationship between these sequelae and the occurrence of esophageal dysmotility, gastroesophageal reflux, or vagotomy. We conclude that gastric emptying abnormalities can occur after heart-lung transplantation, but such abnormalities are not associated with gastroesophageal reflux and the development of pulmonary sequelae, as previously reported.

Adult↗
PubMed1993

Heart rate and late mortality in cardiac transplant recipients.

There are currently 104 patients at this centre who have survived at least 3 months after orthotopic cardiac transplantation. Seven of these long-term survivors have subsequently died and in three cases death was sudden and unexpected. All three of these patients had been noted to have inappropriately high resting heart rates (> 130 b.min-1). The rhythm was sinus tachycardia, supraventricular tachycardia or both intermittently. The heart rates of all 104 long-term survivors were recorded from ECGs taken at routine follow-up visits every 3 months for one year and annually thereafter. The overall mean heart rate was 100 +/- 13.2 b.min-1. Four patients, including the three identified above, had mean heart rates greater than the 95th centile. The mortality rate in this group is 75%. Four deaths have occurred in the remaining 100 patients (P < 0.001). In our series, an inappropriately high resting heart rate due to sinus tachycardia or supraventricular tachycardia in long-term survivors of cardiac transplantation, is an adverse prognostic sign.

Adult↗
PubMed1993

Morphology of the cardiac conduction system in patients with electrophysiologically proven dual atrioventricular nodal pathways.

INTRODUCTION: Although the electrophysiologic criteria for dual atrioventricular nodal pathways are well established, the anatomical substrate is still unclear. METHODS AND RESULTS: We examined the hearts from 10 patients who had been studied electrophysiologically prior to cardiac transplantation. All 10 patients were male, aged 22 to 60 years. Nine of the 10 patients had dual atrioventricular nodal pathways according to accepted criteria. Histologic studies of the atrioventricular conduction system showed normal structure of the atrioventricular node in all 10 hearts, with minor variations within the node in 3 cases, within the penetrating bundle in 3 cases, and within the nonbranching bundle in 3 cases. The atrial approaches to the atrioventricular node were generally scanty in 6 hearts. The solitary case that was shown electrophysiologically to lack dual pathways had no obvious difference in the structure of the nodal area other than sparsity of transitional cells. We were unable to locate any extranodal atrial tracts as described by other investigators. CONCLUSION: The anatomical substrate for conduction over dual pathways may be too subtle to be detected by gross morphologic studies. Since dual pathways were unmasked in all patients but one during electrophysiologic studies, it may be that the potential for these pathways is ubiquitous.

Adult↗
PubMed1993

Permanent pacing after cardiac transplantation.

OBJECTIVE: To determine the need for long-term pacing and optimum mode of pacing in cardiac transplant recipients. DESIGN: (a) A retrospective review of patient records. (b) A prospective study of pacemaker use by 24 hour ambulatory electrocardiography before and after reprogramming to minimise use of pacemakers. SETTING: Outpatient clinic, supra-regional cardiopulmonary transplant unit. PATIENTS: All 21 patients at this centre who had received permanent pacemakers after cardiac transplantation. 18 of 19 survivors completed the prospective part of the study. MAIN OUTCOME MEASURE: The presence of pacing during a 24 hour ambulatory electrocardiographic recording (programming: 50 beats/min, rate sensor inactivated). RESULTS: 21 of 191 (11%) recipients surviving one month or more received permanent pacemakers. The indication was sinus node dysfunction in 13 (62%) and atrioventricular (AV) block in eight (38%). Patients who paced on follow up 12 lead electrocardiograms declined from 38% at three months to 10% at three years after transplantation. After programming to 50 beats/min only five of 18 (28%) patients paced during a 24 hour ambulatory recording. Four of 11 (36%) recipients who received pacemakers for sinus node dysfunction paced compared with one of seven patients (14%) paced for AV block. No patient who had a pacemaker before the 16th day after operation continued to pace whereas five of nine implanted later were used long-term. CONCLUSION: Only five of 18 (28%) patients with pacemakers continued to pace long-term. Continued pacing was more common in those with persistent sinus node dysfunction after the second week after operation but the need for long-term pacing was not predictable.

Cardiac Pacing, Artificial↗
PubMed1992

Arrhythmias after cardiac transplantation.

The etiology and clinical significance of sustained arrhythmias, and atrial and ventricular premature complexes (APCs and VPCs, respectively) after heart transplantation are controversial. Fifty adult recipients surviving > 2 weeks were studied by continuous telemetry while in the hospital and by ambulatory electrocardiographic monitoring at 2, 4, 6, 12 and 24 weeks after transplantation. The median APC frequency was greater among subjects who experienced allograft rejection in the early postoperative period (0.7/hour, range 0 to 23) than among those who did not (0.2/hour, range 0 to 10.4) (p = 0.04). The APC frequency in all subjects decreased from 0.25/hour (range 0 to 23) early to 0/hour (0 to 14) later (p = 0.04). Atrial flutter was the most frequent sustained arrhythmia; it was recorded in 5 of 21 rejectors and in 1 of 29 nonrejectors (p = 0.04), and 11 of 16 episodes (69%) were related to acute rejection temporally. VPCs were recorded in all patients early after transplantation, but the median frequency subsequently decreased from 4.6/hour (range 0.5 to 470) early to 1.25/hour (range 0 to 225) later (p < 0.001). VPC frequency was unrelated to rejection. Sustained ventricular tachycardia was recorded once and was caused by the proarrhythmic effect of flecainide. Thus, APCs and VPCs occur frequently after transplantation. Frequent APCs are associated with rejection, whereas the main determinant of VPC frequency is time after transplantation. Atrial flutter is closely associated with rejection and should be regarded as an indication for endomyocardial biopsy. Ventricular tachycardia occurs seldom, and in this study was due to proarrhythmic drug effects.

Adult↗
PubMed1992

Determinants of graft arteriosclerosis after heart transplantation.

Accelerated graft coronary artery disease (TxCAD) is now the most common complication limiting long-term survival after heart transplantation. This study examines its association with several potentially causative factors. The study population comprised all 73 transplants recipients at this centre between May 1985 and June 1989 who survived at least 2 years. Coronary angiography was performed in every patient at 2 years after transplantation and annually thereafter. All angiograms were retrospectively examined for any evidence of TxCAD. The number of rejection episodes and history of cytomegalovirus (CMV) infection were determined from patient records. Fasting serum triglycerides, and total and HDL cholesterol were measured at between 18 and 60 months after transplantation. Patients with advanced TxCAD (> 70% stenoses) had a mean of 1.4 +/- 1.4 rejection episodes in the first year compared with 0.5 +/- 0.8 episodes in those without TxCAD (P < 0.05). The mean number of episodes in all patients with any evidence of TxCAD was 0.8 +/- 1.1 which was not significantly different from those without TxCAD. There were no association between exposure to CMV infection and TxCAD or between hyperlipidaemia and TxCAD. We conclude that frequent episodes of allograft rejection are associated with the development of advanced TxCAD. Hyperlipidaemia is not associated with the development of TxCAD in the first 5 years after transplantation. A history of exposure to CMV is not associated with TxCAD in our patients possibly because of our routine use of anti-CMV hyperimmune globulin in CMV-mismatched patients.

Adult↗
PubMed1992

Paediatric cardiac transplantation with steroid-sparing maintenance immunosuppression.

In order to determine the results of steroid-sparing maintenance immunosuppression in paediatric patients who have undergone orthotopic heart transplantation (OHT), a retrospective study was undertaken in 12 children and five infants (median age 3.5 years). Preoperative diagnoses were cardiomyopathy in seven and congenital heart disease in 10 patients. Immunosuppression was induced by cyclosporin, azathioprine, methylprednisolone, and antihuman lymphocyte immune globulin. It was maintained with cyclosporin and azathioprine. After induction, five patients received no further steroids. The remainder, except one, required only pulses for rejection (13 episodes or 0.51 episodes/patient year). Long term complications included hypertension in six, and renal impairment in three children. There were no early or late deaths from infection. Actuarial survival was 94% at one year. Of the children followed up for more than one year, all demonstrated an increase in height SD scores (mean (SD) -2.15 (1.35) to -1.15 (1.16)). We conclude that a steroid-sparing maintenance immunosuppression regimen can be successfully employed in paediatric OHT, and that significant catch-up growth can be achieved postoperatively.

Azathioprine↗
PubMed1992

Radioimmunoassay of soluble insulin-like growth factor-II/mannose 6-phosphate receptor: developmental regulation of receptor release by rat tissues in culture.

The soluble form of the insulin-like growth factor-II/mannose 6-phosphate receptor, which has been detected in serum from a variety of species, is synthesized and released by rat tissue explants in culture. Investigations into its regulation and function, however, have been hampered by inadequate means of quantification. In this paper a RIA that enables sensitive and specific quantification of soluble receptor from serum and conditioned medium is described. In order to further clarify the source of soluble receptor in serum and to determine whether release of receptor from rat tissues is under developmental regulation, receptor release from rat explants was examined and compared to serum levels of receptor. Heart, skeletal muscle, kidney, and liver explants from fetal, neonatal, weanling, and adult rats were cultured in serum-free medium, and the conditioned medium was analyzed by RIA for the presence of receptor. Soluble receptor release was highest for fetal and neonatal tissues, with weanling and adult tissues showing dramatically decreased levels. Release of soluble receptor varied between tissues, with the tissue-specific pattern altering during development, such that while heart and muscle appeared as major tissues of release in fetal animals, the liver was the tissue of highest release in adult animals. It is concluded that release of soluble receptor by rat tissues is developmentally regulated, with levels of receptor in serum reflecting the pattern of release from tissues. The RIA will prove a useful tool for further examination of the regulation and function of the soluble insulin-like growth factor-II/mannose 6-phosphate receptor.

Animals↗
PubMed1991

Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration.

Transforming growth factor-beta 1 (TGF-beta 1) is a potent mito-inhibiting substance that is thought to play an important function in regulating hepatocyte proliferation during liver regeneration. In this investigation, we have shown by immunohistochemistry that hepatocytes containing significant intracellular concentrations of TGF-beta 1 12 h after a two-thirds partial hepatectomy. This increase in hepatocyte TGF-beta 1 concentration was initially confined to those cells that resided in the periportal region of the liver. The elevation of intracellular TGF-beta 1 was, however, transient, and within 36 h, the hepatocytes positive for TGF-beta 1 had changed in a wavelike fashion from the periportal to the pericentral region of the liver lobules. By 48 h, most hepatocytes no longer contained TGF-beta 1. Interestingly, this temporary increase in TGF-beta 1 always preceded the onset of hepatocyte replication by approximately 3-6 h. Since TGF-beta 1 mRNA has been shown to be absent from hepatocytes normally and throughout liver regeneration, these results imply that the increase in intracellular TGF-beta 1 resulted from an augmented uptake. We have further shown that the insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man-6-P) receptors were up-regulated during liver regeneration and that the increased expression of this receptor co-localized in those hepatocytes containing elevated concentrations of TGF-beta 1. The latent TGF-beta 1 phosphomannosyl glycoprotein complex has been shown to bind to the IGF-II/Man-6-P receptor. Therefore, our data are consistent with the hypothesis that this latent complex is internalized through the IGF-II/Man-6-P receptor to the intracellular acidic prelysosomal/endosomal compartments where the mature TGF-beta 1 molecule could be activated by dissociation from the latent complex.

Animals↗
PubMed1991

Synthesis of the acid-labile subunit of the growth-hormone-dependent insulin-like-growth-factor-binding protein complex by rat hepatocytes in culture.

Insulin-like growth factors (IGFs) circulate predominantly in a growth-hormone-dependent ternary complex of 125-150 kDa. This study investigates the production of the alpha-subunit of this complex, an acid-labile glycoprotein without intrinsic IGF-binding activity, which binds to the IGF-binding protein IGFBP-3 in the presence of IGFs. Medium conditioned by primary cultures of rat hepatocytes produced alpha-subunit with similar complex-forming activity to purified rat serum alpha-subunit. Bovine growth hormone stimulated hepatocyte production of both IGF-I and alpha-subunit. IGF-I tracer bound to pure rat IGFBP-3 was converted from approx. 60 kDa to 150 kDa by serum alpha-subunit, whole rat serum or rat hepatocyte culture medium; this converting activity was destroyed by transient acidification. In contrast, IGF-I bound to hepatocyte-medium IGF-binding proteins could not be converted into a high-molecular-mass from by purified rat serum alpha-subunit. Rat serum and hepatocyte-medium alpha-subunit appeared identical by electrophoretic analysis, since reaction of either with cross-linked IGF-I.IGFBP-3 tracer resulted in bands of molecular mass 130 kDa and 160 kDa, probably representing intact and partially deglycosylated complexes. However, IGF-binding proteins in rat serum and hepatocyte medium were different, in that affinity labelling of medium binding proteins, depleted of endogenous IGFs, showed no evidence of the 50-60 kDa cluster of bands characteristic of rat serum IGFBP-3. We conclude that rat hepatocytes in primary culture produce alpha-subunit similar to that in rat serum; however, alpha-subunit is unable to form ternary complexes with hepatocyte IGF-binding proteins, since cultured hepatocytes do not secrete IGFBP-3.

Animals↗
PubMed1991

Long-term pacing in heart transplant recipients is usually unnecessary.

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited to patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.

Adult↗
PubMed1991

Secretion of soluble insulin-like growth factor-II/mannose 6-phosphate receptor by rat tissues in culture.

The insulin-like growth factor-II/mannose 6 phosphate receptor, which binds both IGF-II and mannose 6-phosphate containing proteins, such as lysosomal enzymes, has been detected in the serum of several species. Neither the source nor the role of this soluble, truncated form of the membrane receptor has been determined. This study has examined the ability of a variety of rat tissues in culture to synthesize and release soluble receptor. Explants (1 mm3) of 21-day fetal, neonatal and adult rat tissues were cultured in serum-free medium and the conditioned medium analyzed for the presence of receptor. Using IGF-II binding and immunochemical techniques, receptor was detected in media from heart, kidney, liver, lung and muscle explants. [35S]cysteine labeling indicated that de novo synthesis of the soluble receptor occurs in the cultured explants and can be inhibited by cycloheximide. This rat tissue explant culture system demonstrates that soluble receptor is released by a number of tissues, and should provide a useful model for further investigations into its function and regulation.

Affinity Labels↗
PubMed1990

Developmental regulation of insulin-like growth factor-II/mannose 6-phosphate receptor mRNA in the rat.

This study examined levels of insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-II/M6PR) mRNA in tissues of rats at different stages of growth. Northern blot analysis of total RNA from tissues of rats aged 2, 9, 21 and 42 days and from 21 day fetal rats was carried out using a cDNA probe to the IGF-II/M6PR. Northern blots showed this probe hybridized to a single 9kb band in all tissues tested. Highest hybridization signals were detected in fetal and neonatal tissues with levels rapidly decreasing after birth. For all age groups tested the highest signal was obtained with heart followed by muscle, lung, and kidney, with liver and brain showing lower levels of message. These results indicate that IGF-II/M6PR mRNA is developmentally regulated, and suggest a role for the IGF-II/M6PR in fetal and neonatal growth.

Aging↗
PubMed1990

Insulin-like growth factor-II/mannose-6-phosphate receptors are increased in hepatocytes from regenerating rat liver.

Insulin-like growth factor-II (IGF-II) receptor levels were determined in hepatocytes from sham-operated and two thirds hepatectomized rats. [125I]IGF-II binding to confluent cultures increased 2-fold in cells isolated 24 and 48 h after hepatectomy compared to that in cells from sham-operated rats. Receptor levels increased from 1.74 +/- 0.14 x 10(4)/cell (sham-operated) to 3.60 +/- 0.31 x 10(4)/cell (hepatectomized; P = 0.002), with no change in affinity of IGF-II binding (Ka = 6.4 x 10(9) M-1). As previously reported, receptor levels increased in cells plated at low density, but this effect was decreased in cells from hepatectomized rats (80% increase) compared to that in cells from control rats (300% increase). Serum IGF-I levels decreased 50% 24 h after partial hepatectomy (P less than 0.001), but returned to normal levels by 48 h. However, IGF-I synthesis was not decreased in hepatocytes isolated 24 h after partial hepatectomy, suggesting that decreased serum levels are due to decreased liver mass. Circulating IGF-II levels were not altered by partial hepatectomy, and IGF-II production was not detected in hepatocytes from sham-operated or hepatectomized rats. Transforming growth factor-beta is thought to terminate hepatocyte proliferation upon complete liver regeneration. In hepatocytes from sham-operated or hepatectomized rats transforming growth factor-beta totally blocked DNA synthesis, but had no effect on elevated IGF-II receptor levels after partial hepatectomy. Concomitant with increased IGF-II receptor levels, hepatocytes from hepatectomized rats were more sensitive to IGF-II stimulation of DNA synthesis. [3H]Thymidine incorporation in the presence of epidermal growth factor (50 ng/ml) was stimulated 66% by IGF-II (300 ng/ml) in control cells compared with 220% in cells from hepatectomized animals. These results suggest that IGF-II and the IGF-II receptor may play a role in liver regeneration.

Animals↗
PubMed1990

Increased expression of insulin-like growth factor-II/mannose-6-phosphate receptor in regenerating rat liver.

This study examined the effect of two thirds hepatectomy on rat liver insulin-like growth factor-II (IGF-II) receptors and IGF-II receptor messenger RNA (mRNA) levels. IGF-II receptor levels were determined in liver plasma membrane and Golgi/endosome fractions from sham-operated and hepatectomized rats by ligand binding and immunoblotting after electrophoresis. After hepatectomy, IGF-II receptors increased initially in the plasma membrane (within 24 h of surgery) to 4-fold control levels, remained elevated for 72 h, and declined to control levels at 120 h when liver regeneration is near complete. However, Golgi/endosome levels of IGF-II receptors did not increase until 48 h, showing a maximum increase of 3.5-fold at 72 h after surgery and returning to control values at 120 h. The 9-kilobase mRNA for IGF-II receptor, determined by slot blotting with a complementary DNA probe, increased 2.5-fold within 24 h of surgery, attaining a maximum stimulation of 4-fold at 48 h, and then decreasing to normal levels by 120 h. These changes show that, after partial hepatectomy, IGF-II receptors increase rapidly at the cell surface, possibly due to receptor translocation from intracellular pools. This is followed by an increase of IGF-II receptor mRNA and increased receptor synthesis, resulting in an increase in total cellular receptors. These results suggest a role for IGF-II receptors in regenerating liver, perhaps in cell proliferation and/or in tissue remodeling.

Animals↗