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Several new therapeutic options both medicinal and surgical, have emerged for the treatment of Cushing's syndrome. In Cushing's disease caused by an adrenocorticotropin (ACTH) secreting pituitary adenoma, the introduction ofendoscopic pituitary surgery offers better visualization of the sella than does the traditional explorative surgery. However, at present it is unclear whether this will result in a better outcome. New drugs under investigation include universal somatostatin analogues such as SOM230, and a combination of a somatostatin analogue and dopamine agonist known as dopastatin. These agents may also be effective for the medicinal treatment of ectopic ACTH-secretion. Treatment with radioactive-labelled somatostatin-analogues such as 177lutetium octreotate is another option for these patients. The primary treatment for ACTH-independent Cushing's syndrome is laparoscopic adrenalectomy. In rare cases of bilateral adrenal hyperplasia, medicinal treatment aimed at new regulatory pathways of cortisol secretion can be applied.

Over the past few years, new diagnostic tests for Cushing's syndrome have become available. Some of the other, older diagnostic tests have fallen into discredit as they could not distinguish conditions from one another sufficiently well. New biochemical tests include midnight salivary cortisol measurement and the combined dexamethasone-corticotropin releasing hormone (CRH) test. The high dose dexamethasone test and the CRH-stimulation test have been abandoned as they were unable to differentiate between hypophysial and ectopic secretion of adrenocorticotropic hormone (ACTH). For the detection of ectopic ACTH-secreting tumours new imaging techniques, such as somatostatin receptor scintigraphy and positron emission tomography with 5-hydroxytryptophan, have become available.

Malignant mesothelioma is an aggressive tumor of the serosal surfaces of the lungs, heart, and abdomen. Survival rates are poor and effective treatments are not available. However, recent therapeutic regimens targeting thymidylate synthase (TS) in malignant mesothelioma patients have shown promise. We have reported the use of an antisense oligodeoxynucleotide targeting TS mRNA (antisense TS ODN 83) to inhibit growth of human tumor cells. To test the potential for antisense targeting of TS mRNA in treatment of malignant mesothelioma, we assessed and compared the effects of antisense TS ODN 83 on three human malignant mesothelioma cell lines (211H, H2052, and H28) and human nonmalignant mesothelioma cells (HT29 colorectal adenocarcinoma, HeLa cervical carcinoma, and MCF7 breast tumor cell lines). We report that ODN 83 applied as a single agent effectively reduced TS mRNA and protein in malignant mesothelioma cell lines. Furthermore, it inhibited malignant mesothelioma growth significantly more effectively than it inhibited growth of nonmalignant mesothelioma human tumor cell lines: a difference in susceptibility was not observed in response to treatment with TS protein-targeting drugs. In malignant mesothelioma cells, antisense TS both induced apoptotic cell death and reduced proliferation. In nonmalignant mesothelioma cells, only reduced proliferation was observed. Thus, antisense TS-mediated induction of apoptosis may be the basis for the high malignant mesothelioma sensitivity to antisense targeting of TS. Further preclinical and clinical study of TS antisense oligodeoxynucleotides, alone and in combination with TS-targeting chemotherapy drugs, in mesothelioma is warranted.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Tumors and metastases bearing the somatostatin receptor subtypes 2 (SSTR2) or SSTR5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs like 111In-pentetreotide. The sensitivity of 111In-pentetreotide scintigraphy for the detection of carcinoid tumors is 86-95%. The sensitivity of 111In-pentetreotide scintigraphy for the detection of gastrinomas, vasoactive intestinal polypeptide-secreting tumors, and glucagonomas as well as clinically non-functioning lesions is 75-100%. However, for insulinoma this is 50-60%. 111In-pentetreotide scintigraphy generally has a lower detection rate for benign pheochromocytomas than 123I-MIBG scintigraphy, but it can have a complementary role for the staging of malignant pheochromocytomas. It can also be used for the detection of extra-adrenal pheochromocytomas and paragangliomas. Most GH- and TSH-secreting pituitary adenomas can be visualized using 111In-pentetreotide. 111In-pentetreotide scintigraphy is negative in microprolactinomas and ACTH-secreting pituitary microadenomas. 111In-pentetreotide scintigraphy has been successful for the localization of extra-pituitary ACTH-secreting tumors and their metastases, and especially for occult tumors. A large variety of lesions in and around the pituitary region express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.

Diagnosis and treatment of patients with hypopituitarism needs careful clinical evaluation and individual optimization. Symptoms of hypopituitarism are variable, often insidious in onset and dependent on the degree of hormone deficiency. Diagnosis of hypopituitarism can be straightforward by measuring reduced basal hormone levels. Frequently, dynamic stimulation tests are indicated in equivocal basal hormone levels or to diagnose partial hormone deficiencies. Knowledge of the use and limitations of these dynamic tests is mandatory for proper interpretation. Hormone replacement therapy should be individualized, taking into account possible interactions. Persisting symptoms and reduced quality of life are frequently reported, explained by, at least in part, intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. In the present overview, the principles of diagnosis and treatment of hypopituitarism are discussed.

Postoperative meningitis is a well known complication of transsphenoidal surgery (TSS). The objective of this study was to evaluate whether postoperative external cerobrospinal fluid (CSF) drainage in case of intraoperative CSF-leakage, reduces the risk of postoperative meningitis. We retrospectively reviewed a series of 278 consecutive transsphenoidal operations. In all operations with intraoperative CSF leakage, an external lumbar drain (ELD) was inserted directly postoperatively, and removed after at least 5 days. The incidence of postoperative meningitis was compared with that in a previously studied series of 228 consecutive transsphenoidal operations, without insertion of an ELD in cases with intraoperative CSF leakage. In the present series, postoperative meningitis occurred in 2/278 (0.7%) operations, compared to 7/228 (3.1%) operations in the previous study period (P < 0.05). Intraoperative CSF leakage was noted in 70/278 (25.2%) operations. All these patients received an ELD immediately after surgery for at least 5 days. There were no reported complications of ELD insertion. In the present series, 1 of 70 (1.4%) patients with intraoperative CSF leakage developed meningitis, compared to 3 of 22 (13.6%) patients in the previous study (P < 0.05). The present report on 278 consecutive transsphenoidal operations shows that the routine insertion of an ELD in patients in whom intraoperative CSF leakage is observed significantly reduces the incidence of postoperative meningitis. Possibly, diversion of CSF prevents the formation of a CSF fistula and thereby the risk of infection. The role of prophylactic antibiotic treatment in patients with CSF rhinorrhea after TSS remains to be established.

In 1994, the Health Council of the Netherlands published a report entitled 'Genetic screening' which contained 12 criteria for genetic screening programmes. However, the list does not prioritize the various criteria. From the list we have selected two criteria that we consider to be the most important. Firstly, the genetic screening test should be able to discriminate between subjects who are likely to develop the disease and those who are not. Secondly, there should be an effective treatment for subjects with the genetic defect. From this point of view, for example, screening for the C282Y mutation is not a suitable approach for detecting primary haemochromatosis. Although 85-90% of the patients with this disease are homozygous for this mutation, the majority of the carriers will not develop the disease. The 12 criteria of the Health Council of the Netherlands are still applicable. However, when taking a decision as to whether or not genetic screening is useful, we recommend that priority be given to the two primary criteria.

Background: The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85-plus., Study Design: A cross-sectional comparison and prospective follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all-cause and specific causes of death., Results: Prevalence of C282Y homozygosity in both cohorts was 0.2% (1/661 and 1/552, respectively) and of C282Y heterozygosity was 12.4% (82/661) and 11.4% (63/552), respectively. These estimates coincide exactly with reported estimates in younger age groups. Median ferritin level was 97 microg L-1 (IQR 39-162) for heterozygous carriers and 89 microg L-1 (IQR 41-157) for noncarriers (P = 0.66). The serum ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at the time of enrollment in 1986, was 392 microg L-1. Cardiovascular morbidity was comparable between the C282Y heterozygous subjects and the noncarriers in both study cohorts. All-cause and cardiovascular mortality of carriers of the C282Y mutation was similar to that in noncarriers., Conclusions: We found two C282Y homozygous subjects, illustrating that homozygosity can be compatible with survival in very old ages. C282Y heterozygosity was not associated with history of cardiovascular disease morbidity, all cause mortality, cardiovascular mortality, or biochemical phenotype of haemochromatosis at old age.

Brain edema is one of the most common morbidity factors in patients with intracranial neoplasms and cerebrovascular pathology. Monitoring of intracranial pressure gives only an indirect and global measure of brain swelling. We have made an assessment of the applicability of Raman spectroscopy as an alternative method for assessing brain edema, which measures the water concentration in the tissue directly. Partial least-squares models were developed on the basis of Raman spectra measured in the 2600-3800-cm(-1) region, which predict the water fraction of brain tissue in the 0.75-0.95 range, with an accuracy better than 0.01.

Background: A pathophysiologic feature possibly involved in ischemic injury in transplant kidneys is mitochondrial dysfunction caused by disintegration of oxidative metabolic pathways. Because the ability to synthesize ATP by respiratory activity determines the organ's capacity to recover from ischemic injury, an assessment of respiratory activity may provide information related to graft viability., Methods: NADH fluorimetry can be used to monitor kidney cortex metabolism noninvasively. During perfusion with (an)-aerobic perfusate, NADH fluorescence images were recorded. We evaluated the NADH oxidation kinetics of 20 rat kidneys, which were divided over four experimental groups. For six minimally damaged kidneys and six kidneys that had been stored for one hour at 37 degrees C, perfusion was followed by transplantation. We related the kinetic parameters of these kidneys with their post-transplantation function and histology. The transplant function was monitored by serum creatinine and urea levels., Results: Storage of transplant kidneys for one hour at 37 degrees C significantly reduced the post-transplantation function. Isolated perfusion of grafts, however, was not detrimental for renal function. The rate of NADH oxidation decreased with decreasing graft quality, and a good correlation between NADH oxidation kinetics and post-transplantation function was found., Conclusions: A reduction of NADH oxidation rates as a consequence of warm ischemia supports the view that mitochondrial respiratory activity is impaired by ischemic injury. The correlation between NADH oxidation kinetics in perfused grafts and their post-transplantation function indicates that NADH fluorimetry may be useful in predicting the viability of preserved grafts prior to transplantation.

In this paper, an heuristic model of the personality characteristics of adolescents and the supportive dimensions of interactions, relationships and groups is presented. The model takes the concept of developmental tasks as its starting point and it is assumed that developmental tasks can be characterized in terms of four modalities: intentions, behaviour, cognitions and affect. The same four modalities can also be used to characterize dimensions of personality and aspects of interactional and relational support. The results of several empirical studies are presented to illustrate the model. Together, these studies present a transactional picture of the personality of adolescents and their relationships in which personality and relationships influence each other and jointly determine psychosocial functioning., (Copyright 1999 The Association for Professionals in Services for Adolescents.)

In a longitudinal study, Q-sort patterns of German preschool children were analyzed for personality prototypes and related to developmental outcomes up to age 12. Q-factor analyses confirmed 3 prototypic patterns that showed a high continuity and cross-judge consistency; were similar to those found for North American, Dutch, and Icelandic children; and can be interpreted as resilient, overcontrolled, and undercontrolled. Relations reported by R. W. Robins, O. P. John, A. Caspi, T. E. Moffitt, & M. Stouthamer-Loeber (1996) between these 3 patterns and the Big Five were fully replicated. Growth curve analyses showed that the 3 patterns predicted important developmental outcomes in both the social and the cognitive domains. Evidence was found for both traits and types: A continuous dimension of resiliency bifurcates in its lower part into two relatively discrete personality types, overcontrollers and undercontrollers.

In this study, the robustness of the Big Five personality factors in adolescents' self-ratings and peer nominations was investigated. Data were obtained on 2,001 adolescents attending secondary school (885 girls; 1,116 boys; M age = 14.5 years). Exploratory and confirmatory factor analyses on the self-ratings confirmed the Big Five personality factors. In contrast, exploratory analysis on the peer nominations revealed five different factors: Aggression-Inattentiveness, Achievement-Withdrawal, Self-Confidence, Sociability, and Emotionality-Nervousness. It is suggested that peers evaluate group members not in terms of their personality but in terms of their group reputation. Peer evaluations contributed substantially to the prediction of peer acceptance and rejection; the Big Five personality factors based on self-ratings did not.

To evaluate possible risk factors for meningitis, we retrospectively reviewed 228 transsphenoidal operations (in which a standard regimen of amoxicillin prophylaxis was used) for sellar pathology. The incidence of meningitis was 3.1% (seven of 228 cases). Cultures of preoperative specimens from the anterior nasal vestibule in three of seven patients yielded Staphylococcus aureus, but none of these patients developed S. aureus meningitis. Two of three patients with significant preoperative paranasal sinus abnormalities developed meningitis compared with only five of 225 patients without significant paranasal sinus abnormalities (P < .005). Three of 22 patients with intraoperative cerebrospinal fluid (CSF) leakage developed meningitis compared with four of 206 patients without intraoperative CSF leakage (P < .05). Six of seven patients with postoperative CSF rhinorrhea and only one of 221 patients without postoperative CSF rhinorrhea developed meningitis (P < .00001). In conclusion, postoperative CSF leakage is an important risk factor for meningitis after transsphenoidal surgery. Cultures of preoperative specimens from the anterior nasal vestibule did not have any predictive value in our study.

Objective: The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation., Patients: From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8-118 months)., Main Outcome Measures: Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 x 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol < 140 nmol/l and/or 24-hour urinary cortisol excretion < 250 nmol. During follow-up: serum cortisol, as well as serum cortisol in the 1 mg overnight dexamethasone-suppression test was measured in order to detect relapse of Cushing's disease., Results: Twelve of 29 patients were not in remission after surgery. These patients all had serum 11-deoxycortisol levels > 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient's experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol < 150 nmol/l after metyrapone, no relapse occurred., Conclusions: The metyrapone test is a useful test in the assessment of outcome of pituitary surgery for Cushing's disease, with a sensitivity of 100% and a specificity of 75% for the early detection of patients at risk of a relapse. Patients in whom a serum 11-deoxycortisol > 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

Objective: To study the effect of improved preoperative tumour localisation on the outcome of transsphenoidal surgery for Cushing's disease., Design: Retrospective., Setting: University Hospital Rotterdam, the Netherlands., Methods: The case records were studied of 61 patients, operated on for Cushing's disease due to a corticotrophin-secreting microadenoma (diameter < 10 mm), in the period January 1985-September 1995. From 1985, preoperative tumour localisation was performed with computed tomography (CT), from 1989 with Magnetic Resonance Imaging (MRI) and Bilateral Simultaneous Inferior Petrosal Sinus Sampling (BSIPSS). The definition of a successful operation was: morning serum cortisol < 500 nmol/l, and of cure: morning serum cortisol < 140 nmol/l or 24-hr cortisoluria < 250 nmol., Results: In 1985-1988, a microadenoma was localised preoperatively in 8/22 patients (36%), the operation was successful in 12 (55%), of which 4 (18%) were cured. In 1989-1991, a microadenoma was localised in 12/15 patients (80%), the operation was successful in 11 (73%), of which 4 (27%) were cured. In 1992-1995 a microadenoma was localised preoperatively in 23/24 patients (96%), the operation was successful in 19 (79%), of which 17 (71%) were cured. In the cured group, there was a low incidence (< 10%) of postoperative hypopituitarism in all three periods. There were 1, 0 and 1 recurrences of Cushing's disease respectively after initial cure., Conclusion: In our institution, improved preoperative localisation of corticotrophin-secreting hypophyseal microadenomas was associated with an important increase of success and cure rate of transsphenoidal surgery, while there was no increase in postoperative hypopituitarism or recurrences of Cushing's disease.

A 9-year longitudinal study of 99 children observed from ages 4 through 12 showed that inhibition toward strangers was strongly related to inhibition with peers, and test intelligence to social competence with peers, only in the first months of preschool socialization. These correlations decreased later on. Stranger inhibition and test intelligence were not predictive of social self-esteem in middle childhood. However, high inhibition and low competence in the peer group after 1 and 2 years of group socialization did predict low social self-esteem up to age 10. Discussion focuses on the processes that might mediate these correlative relations and on the role of relationship-unspecific traits and relationship-specific individual attributes for later social-emotional developmental outcomes.

Animal models may be helpful to gain insight into the long-term functional outcome of the hydronephrotic kidney. Inbred Brown-Norway rats frequently have kidneys with a delayed urine outflow. In 26 male rats 99mtechnetium-diethylenetriaminepentaacetic acid (Tc-DTPA) furosemide renography was performed to assess the presence and degree of obstruction, and the contribution of each kidney to the total glomerular filtration rate. The total glomerular filtration rate was measured as the plasma clearance of 51chromium-ethylenediaminetetraacetic acid. The measurements were first done at the age of 3 months, and repeated at ages 6, 10 and 15 months. From the renography curve we derived an obstruction score ranging from 0 (minimum) to 10 (maximum) based on the time to peak, the 99mTc-DTPA accumulation at 15 minutes and the furosemide response. Kidneys were classified as normal, obstructed or equivocal. At the first renography 21 kidneys were normal, 8 were equivocal and 23 were obstructed. The total obstruction score of the next 3 renographies indicated that 29 units were normal, 14 were equivocal and 9 were obstructed. Two groups of rats with unilateral hydronephrosis (hydronephrotic kidney-1 and hydronephrotic kidney-2) were selected based on the total obstruction score of all 4 renographies. These groups were compared with rats with 2 normal kidneys. The hydronephrotic kidney-1 rats had an obstruction score indicating equivocal obstruction, while the obstruction score of the hydronephrotic kidney-2 rats indicated obstruction. During the 15 months of followup the presence of a unilateral hydronephrotic kidney with an obstruction score indicating obstruction did not affect the contribution of the hydronephrotic kidney to the total glomerular filtration rate, or the total glomerular filtration rate. We conclude that the obstruction score of a hydronephrotic kidney in rats may change considerably with time. In cases in which renography suggested the permanent presence of ureteral obstruction the glomerular filtration rate remained stable. Thus, renal functional criteria did not indicate obstruction. In Brown-Norway rats a hydronephrotic kidney is able to maintain a normal glomerular filtration rate during at least 50% of the normal lfie span.

The purpose of the study was the assessment of cognitive functioning in 20 children (age 4-14 years) with end stage renal disease (ESRD) before and after kidney transplantations by means of an intelligence-test (WISC-R or WPPSI). Research questions were: I. do the test scores of children with ESRD deviate significantly from those of the norm-group before transplantation; 2. do the test scores of children with ESRD increase significantly from pre- to post-transplantation; 3. do the test scores of children with ESRD after transplantation deviate significantly from those of the norm-group. The results show that children with ESRD before transplantation perform significantly more poorly on the verbal part of the WISC-R. After transplantation they show a significant increase on cognitive functioning, mainly in the verbal part of the test. However, kidney transplantation does not cause a complete recovery of cognitive functioning; after transplantation children with ESRD still showed lower scores on several tasks (e.g. tasks concerning concentration).

In order to obtain more information on the long-term changes in renal function of hydronephrotic kidneys, we have measured the glomerular filtration rate (GFR) in rats with a congenital or an experimental unilateral hydronephrotic kidney (HK). In Brown Norway rats, with congenital hydronephrosis, the presence of an HK affected neither the total GFR nor the contribution of that kidney to the total GFR, during a follow-up of 70 weeks. In Wistar rats with experimental unilateral hydronephrosis two groups could be distinguished on the basis of the contribution of the HK to the total GFR. In the first, the contribution of the HK to the total GFR was not different from that of controls. This contribution as well as the total GFR remained similar to that of controls during the follow-up. In the second group, the contribution of the HK to the total GFR was reduced to 25%. In these rats the total GFR was slightly less than that of controls. The contribution of the HK to the total GFR remained unchanged for the next 56 weeks. It is concluded that the long lasting presence of unilateral hydronephrosis in rats does not necessarily result in a progressive loss of renal function with time.

Little attention has been paid to the changes in renal function that occur after kidney transplantation when donor and recipient differ markedly in size. We studied this phenomenon after isogeneic kidney transplantation in rats of varying body weight (BW). Renal functional parameters, such as the glomerular filtration rate (GFR), the effective renal plasma flow (ERPF), and the plasma levels of creatinine (Pcr) and urea (Pur) were determined at regular intervals following transplantation. In the initial experimental series, juvenile (BW approximately 150 g) and adult (BW approximately 300 g) rats were used. Four groups of transplant recipients were studied. These consisted of 2 groups of adult recipients of juvenile or adult donor kidneys, and 2 groups of juvenile recipients of juvenile or adult donor kidneys. These 4 groups were compared with adult and juvenile control rats, as well as with unilaterally nephrectomized (NX) rats. A comparison between the 2 groups of juvenile recipients revealed no significant difference in the GFR, ERPF, Pcr, or Pur levels after the transplantation of adult or juvenile donor kidneys. Nor were any significant differences found when comparing the functional parameters of the 2 groups of adult recipients after transplantation of adult or juvenile donor kidneys. The transplanted kidneys generally functioned at a level amounting to 80-90% of the GFR and 90-100% of the ERPF of NX rats of comparable BW. These observations are a clear indication of functional adaptation after kidney transplantation. The compensatory functional response is augmented--in case of a young donor kidney transplanted into an adult recipient, or attenuated--in case of an adult donor kidney transplanted into a juvenile recipient. In an additional experiment, kidneys were transplanted from very young rats (BW approximately 50 g) to adult recipients. It appeared that as early as two weeks after transplantation, renal function had reached adult kidney levels, as observed in the first experimental series. In conclusion, after isogeneic kidney transplantation in rats, the transplanted kidney generally adapts rapidly to the size of the recipient and functions like an inherent part of the recipient's body.

The renal handling of technetium-99m dimercaptosuccinic acid ([99mTc]DMSA) was studied in rats before and after treatment with Na-maleate (2 mmol/kg i.v.). In the control period, when measured 2 hr after the intravenous injection of [99mTc]DMSA, 39.9% of the injected dose was in the kidneys and 14.6% was in the bladder. After Na-maleate treatment, only 6.4% of the injected dose of [99mTc]DMSA was retained in the kidneys while 37.9% was found in the bladder. Subsequent studies revealed that Na-maleate produced a fall in the glomerular filtration rate, the effective renal plasma flow, and a generalized proximal tubular dysfunction. The latter was characterized by polyuria and an increased excretion of glucose, protein, albumin, calcium, and inorganic phosphate. It was concluded that proximal tubular dysfunction markedly alters the renal handling of [99mTc]DMSA. Whether this augmented urinary excretion is due to an inhibition of reabsorption or an enhanced cellular efflux of [99mTc]DMSA remains to be answered.

The renal handling of technetium-99m dimercaptosuccinic acid (99mTc DMSA) was studied in rats treated with high doses of nonradioactive DMSA to inhibit the renal uptake mechanism(s). A static scan was obtained 1 hour after the intravenous (iv) injection of 99mTc DMSA and the radioactivity in kidneys and bladder was calculated as a percentage of the injected amount. Total glomerular filtration rate (GFR) and effective renal plasma flow were also determined. Preloading with DMSA caused a fall in the renal accumulation of 99mTc DMSA together with a small increase in the amount excreted into the urinary bladder. Despite a stable GFR, the total amount of 99mTc DMSA handled by the kidneys (i.e., renal plus bladder activity) was reduced. These findings are compatible with the hypothesis that peritubular uptake and subsequent intracellular fixation are of importance in the renal accumulation of 99mTc DMSA. On the other hand, the radioactivity excreted into the urine probably stems from non-reabsorbed 99mTc DMSA initially filtered by the glomeruli.

Hypertension secondary to renal transplantation was studied in our experimental model in the rat. In this model an intravenous injection of donor strain blood into recipients of allogeneic donor kidneys prior to transplantation was used to prolong the allograft survival. A reduced renal function associated with the hypertension was suggestive of incomplete prevention of the rejection process. We studied the effect of cyclosporin A, either alone or as adjuvant immunosuppressive therapy, on renal function and systolic blood pressure. Either way, cyclosporin A resulted in normotensive allograft recipients and in a better function of the graft when compared with recipients pretreated with donor strain blood only.

Studied developmental and gender differences in distress behavior during separate phases of a medical treatment in 2 cultures. Distress reactions of 175 children with cancer (age 8 months-18 years 7 months) were observed during bone marrow aspirations (BMA) in 2 different treatment centers (one in the United States, one in The Netherlands) using a behavioral checklist (Procedure Behavioral Rating Scale). The BMAs contained a preparatory phase, the actual needle introduction, and a recovery period. In both cultures almost all separate distress behaviors occurred less in older children, except for increasing muscle tension during the actual puncture. Distress was highest during the needle introduction and significantly lower during the preparatory and recovery phases; in addition, somewhat different patterns of distress behavior were found in separate phases. Culture and sex differences were found. The latter were less robust than developmental and phase differences.

The development and reduction of distress in children with leukemia was studied during a frequently recurring medical procedure, i.e., a bone marrow aspiration (BMA). The role of a number of factors in the development of distress display in children during this procedure was studied. The intensity of distress display was assessed with a behavioral rating scale. The intensity of distress display was found to be independent of the physician who performed the punction, the part of the body to which the punction was administered, the number of previously administered BMA'S, whether the child had to undergo a lumbar puncture after the BMA, and whether the child was sedated. The intensity of distress display varied with age and sex of the child. The intensity of distress display was weaker in older children, but this age effect was stronger for boys than for girls. An experimental program was developed and administered in order to reduce distress display during medical treatment. This program consisted of three parts (relaxation, imagination of a pleasant situation and arousal of the concomitant feelings, as well as watching a model). The experimental program was found to be effective in reducing distress display in children. The amount of reduction was dependent of the number of prior BMA'S (the fewer the prior BMA'S, the greater the decrease) and of the level of pretreatment display of distress (the higher the level, the smaller the decrease.

Rat recipients of renal allografts and unilaterally nephrectomized control rats were studied to evaluate the response in blood pressure to prednisolone in diverse doses, and to determine the dosage required to achieve adequate immunosuppression without undue complication of hypertension. While a continuous infusion of 2 mg/kg/day or more of prednisolone proved effective in prolonging allograft survival time, this dosage increased the blood pressure of recipients as well as unilaterally nephrectomized control rats. In contrast to control rats, the recipients remained hypertensive after the cessation of prednisolone administration. This suggests that the high blood pressure observed during prednisolone administration was due to its hypertensive action. On the other hand, the high blood pressure remaining after cessation of the prednisolone administration is likely to be caused by an incomplete prevention of rejection. If recipients had received a transfusion of donor-strain blood prior to transplantation in combination with the infusion of 2 mg/kg/day or more of prednisolone, they became normotensive when the prednisolone infusion was ceased. By reducing the prednisolone dosage to 1 mg/kg/day in combination with donor-strain blood pretreatment, hypertension could also be eliminated during the first two weeks. In conclusion, effective immuno suppression can be achieved with prednisolone in rats, without inducing hypertension, provided prednisolone is administered at a low dosage in combination with adjuvant immunosuppression--i.e., donor-strain blood pretreatment.

Renal functional adaptation to additional nephrons was studied in rats in which a third kidney was transplanted isogeneically. Total renal function did not increase when an extra kidney was added. Quantitation of the contribution of each kidney, by means of a 99mTc-DTPA scan, showed that the glomerular filtration rate of the native kidneys had decreased to counterbalance the added function. The glomerular filtration rate of the transplanted kidneys as well as its number of glomeruli were 20% less than that of the intact native kidneys. The present findings once again illustrate the kidney's remarkable capacity for functional adaptation to a change in the total number of nephrons.

We have studied the effect of cyclosporine A (CyA) in male Wistar rats with only one kidney, that had been subjected to 45 min of warm ischemia (IS + NX). The effects were compared with those obtained in rats with either one (NX) or two intact kidneys (2K). Vehicle treated rats that underwent the same surgical procedure served as controls. The GFR and the ERPF were determined during and after the treatment period. The CyA was administered i.m. daily for a period of 5 days a week for a period of 4 weeks. The dosages were 15, 30, or 60 mg/kg/day in the short-term study, and 15 mg/kg/day in the long-term study. With only 5 days of treatment, changes in the GFR induced by CyA were more pronounced in IS + NX rats when compared with NX rats. Furthermore, in contrast with NX rats, the GFR did not completely recover in IS + NX rats. During the 4 week treatment we found that in all 3 models the GFR was less in the CyA treated rats than in the vehicle treated rats. The degree of impairment of the GFR differed in the various models. At the end of the treatment period, the GFR of the CyA treated rats (expressed as a percentage of the vehicle treated rats) amounted to 84% in 2K rats, 64% in NX rats, and 46% in IS + NX rats. After cessation of the CyA administration, there was a complete recovery of the GFR to control levels in 2K and NX rats. In IS + NX rats, however, the GFR remained significantly below that of vehicle treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)