Quality of life before and one year following stem cell transplantation using an individualized and a standardized instrument.

OBJECTIVE: The aim was to prospectively measure quality of life in patients with malignant blood disorders following stem cell transplantation (SCT) using an individualized and a standardized measure. METHODS: Twenty-two consecutive patients were assessed before and one year following SCT, using a generic and disease-related version of the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) and the EORTC QLQ-C30. Results of the QLQ-C30 were compared with Swedish norm values. RESULTS: A majority of the patients reported concerns related to health before as well as one year after SCT, recorded by both instruments. Mean scores produced by the SEIQoL-DW, and four scales of the EORTC QLQ-C30, showed a change over time, indicating improved quality of life one year after SCT. In comparison with Swedish norm values for the EORTC QLQ-C30, SCT recipients reported a worse functioning. CONCLUSIONS: In addition to well-known disease and treatment-related problems, areas not typically included in standardized instruments were nominated in the disease-related SEIQoL-DW. Such areas included positive aspects, e.g. a changed view of life and oneself. The results support the use of the generic and disease-related SEIQoL-DW to achieve a comprehensive picture of patient's clinical situation under treatment or when recovering from illness.

Symptoms experienced by patients with peripheral vestibular disorders: evaluation of the Vertigo Symptom Scale for clinical application.

OBJECTIVES: To describe symptoms during an episode of dizziness in a sample of patients suffering from peripheral vestibular disorders and to compare them with the items in the Vertigo Symptom Scale. DESIGN: A descriptive study from a sample of patients with peripheral vestibular disorders. SETTING: Patients visiting a department of audiology at a university hospital. PARTICIPANTS: Twenty patients with peripheral vestibular disorders. The inclusion criteria were that the patient had had at least three spontaneous attacks of vertigo and/or was constantly unsteady during the last 3 months for at least 75% of the time when awake. MAIN OUTCOME MEASURES: Patients were instructed to complete a diary where they recorded symptoms that arose during an episode of dizziness. These symptoms were compared with the content of the Vertigo Symptom Scale. RESULTS: The most frequent symptoms as mentioned by the patients in their diaries were a feeling that things are spinning or moving around, nausea, feeling unsteady/about to lose one's balance, fatigue, headache, a feeling as if the ground you walk on is distant and ear-related such as tinnitus and a feeling of pressure in the ear. Pain in the heart or chest region, a heavy feeling in the arms or legs, pain in the lower part of the back and excessive sweating were not mentioned at all or by very few patients. Analysis showed that some of the symptoms included in the Vertigo Symptom Scale occurred less during an episode of dizziness than others in this sample of patients with peripheral vestibular disorders. CONCLUSION: It was found that the Vertigo Symptom Scale is an adequate base but may need to be developed for use in patients diagnosed with peripheral vestibular symptoms to be able to evaluate care and treatment.

Lung morphology after late fetal tracheal ligation in rats.

Pulmonary hypoplasia and persistent pulmonary hypertension are the main causes of mortality and morbidity in congenital diaphragmatic hernia (CDH). Prenatal tracheal occlusion accelerates lung growth, but the mechanism remains unknown. In order to be able to establish the accuracy of our experimental model for further molecular biological examinations, we evaluated the histologic structure of 1. fetal lungs subjected to tracheal occlusion compared to 2. normal fetal lungs, 3. hypoplastic lungs in CDH, and 4. normal neonatal lungs. One group of Sprague-Dawley rat fetuses were subjected to intrauterine tracheal ligation (TL) on gestational day 19 (n = 7). Control fetuses were obtained from the same litters as those subjected to TL (n = 8). Another group of pregnant Sprague-Dawley rats were given 100 mg nitrofen on gestational day 9.5 to create CDH (n = 8). All fetuses were delivered by cesarean section on day 21. Lungs from 1-day-old, healthy, non-operated, newborn Sprague-Dawley rats were also examined (n = 6). Lung weight to body weight ratio was significantly higher in the TL lungs (5.0 +/- 0.36 %), compared to control lungs (2.8 +/- 0.15 %), CDH lungs (1.9 +/- 0.12 %), and normal neonatal lungs (4.2 +/- 0.18 %). Volume density of alveolar air space and radial alveolar count (RAC) in TL lungs (52 +/- 1.4 %) (3.3 +/- 0.25) were significantly higher than in control lungs (34 +/- 3.4 %) (2.2 +/- 0.17) and in CDH lungs (16 +/- 1.7 %) (1.7 +/- 0.07). No significant differences were found between the TL and the normal neonatal group (59 +/- 1.4 %) (3.6 +/- 0.11). Fetal lungs after TL showed evidence of growth stimulation with increased volume density of alveolar air space and increased RAC, comparable to findings in normal neonatal lungs.

Increased renal metabolism in diabetes. Mechanism and functional implications.

The coupling between the Na+/glucose cotransporter and Na(+)-K(+)-ATPase (NKA) described for epithelial cells (1) prompted us to study in rats with streptozocin-induced diabetes the effect of increased tubular glucose load on tubular Na+ reabsorption, NKA-dependent O2 consumption (QO2), and NKA activity. Filtered glucose is mainly reabsorbed in the proximal tubuli via the phlorizin-sensitive Na+/glucose cotransporter. In this study, the diabetic rats had a significantly higher renal blood flow (RBF), glomerular filtration rate (GFR), and Na+ reabsorption than the control rats. Total renal QO2 as well as QO2 in cortical tissue, which consists mainly of proximal tubular cells, was significantly higher in diabetic than in control rats. The increase in tissue QO2 was entirely caused by increased NKA-dependent QO2. NKA activity, measured as rate of ATP hydrolysis, was increased in cortical tubular but not glomerular tissue from diabetic rats. Phlorizin treatment abolished the increase in NKA activity, Na+ reabsorption, and QO2, as well as the increase in RBF and GFR in diabetic rats. We conclude that diabetes is associated with increased renal O2 metabolism secondary to the increase in coupled Na+ reabsorption via the Na+/glucose cotransporter and NKA. The increased oxygen consumption might contribute to the hyperperfusion and hyperfiltration in the diabetic kidney.

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

Patients' experience of ambulatory self-administration of pamidronate in multiple myeloma.

The aim was to explore ambulatory self-administration of Pamidronate (Self-A-Pam) from a patient perspective in patients with multiple myeloma. Pamidronate is normally administered once a month as an intravenous infusion over 2 to 4 hours. Twenty-one patients were included, of whom 13 (6 women, 7 men) with a median age of 56 years (range 37-70) completed the educational program and subsequent ambulatory Self-A-Pam. An RN at the hospital initiated the Pamidronate therapy (90 mg). The patients then left hospital and later, on completion, they disconnected the infusion, either alone or with the assistance of a relative or significant other. Interviews were used to collect information about the experiences during the course of the Self-A-Pam. In total, 12 patients were interviewed after 3 doses of Self-A-Pam. One patient declined to participate in the interview. A qualitative analysis of the textual data was performed. Five main categories were identified: decision concerning Self-A-Pam, information and education, sources of practical help or support, effects of Self-A-Pam, and feelings and activities in relation to place (hospital, home, or public place). All 13 patients who started on Self-A-Pam went through 3 courses of Self-A-Pam during the study period. Many patients reported a gain in feelings of freedom/independence and time saving. However, some patients reported insufficient education and feelings of anxiety associated with the responsibility of handling the venous access device.

Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

Dopamine is a natriuretic hormone that acts by inhibiting tubular Na+, K(+)-ATPase activity by activation of the dopamine-1 receptor (the thick ascending limb [TAL] of Henle) or by a synergistic effect of dopamine-1 and dopamine-2 receptors (the proximal tubule). The dopamine-1 receptor is coupled to adenylate cyclase. In this article we show that prehypertensive Dahl salt-sensitive (DS) rats have a blunted natriuretic response to dopamine determined during euvolemic conditions compared with Dahl salt-resistant (DR) rats. Furthermore, we have examined the renal tubular effects of dopamine in DS and DR rats. Basal Na+,K(+)-ATPase activity was similar in DS and DR rats. In proximal tubule, dopamine (10(-5) M) inhibited Na+,K(+)-ATPase activity in DR but not in DS rats. The dopamine-2 agonist LY171555 (10(-5) M) together with dibutyryl cyclic AMP (10(-6) M) inhibited proximal tubule Na+,K(+)-ATPase activity in both DS and DR rats. LY171555 alone had no effect. In TAL, the dopamine-1 agonist fenoldopam (10(-5) M) inhibited Na+,K(+)-ATPase activity in DR but not in DS rats. Dibutyryl cyclic AMP (10(-5) M) inhibited TAL Na+,K(+)-ATPase activity in both DS and DR rats. In cell suspensions from the cortex and the medulla, activation of the dopamine-1 receptor significantly increased cyclic AMP content in DR but not in DS rats. The results indicate that DS rats lack the capacity to inhibit tubular Na+,K(+)-ATPase activity because of a defective dopamine-1 receptor adenylate cyclase coupling. This defect may contribute to the impaired natriuretic capacity in DS rats.

The final phase in acute myeloid leukaemia (AML): a study of cause of death, place of death and type of care during the last week of life.

The aim of this study was to increase the knowledge of the final phase in acute myeloid leukaemia (AML), a period which entails many complex medical and psychosocial decisions. Data on cause and place of death were gathered through a retrospective review of medical and nursing records of 106 patients with AML who had died during 1995-1997. We focused on the actual phase of the disease and to what extent the patients were prescribed palliative care. With increased knowledge of the dying process in AML there are options to discuss which approach would be the most preferred final phase for an AML patient.

Etoposide induction of tumor immunity in Lewis lung cancer.

PURPOSE: To determine if the antineoplastic effect of etoposide includes alteration in Lewis lung cancer cells which evoke an immunologic response in C57B1/6 host mice. METHODS AND RESULTS: Of C57B1/6 mice injected with 10(6) Lewis lung cancer (3LL) cells followed by treatment with a single 50 mg/kg dose of etoposide (VP-16), 60% survived over 60 days, in contrast to untreated control mice which died within 30 days. Approximately 40% of surviving mice rejected a subsequent challenge with 3LL. Their splenocytes protected naive mice injected with 3LL. To test if VP-16 treatment produced alterations in 3LL cells, which induce host immunity, leading to tumor rejection, C57B1/6 mice were injected with 3LL cells that had survived an 80-90% lethal concentration of VP-16 in vitro. These cells killed 75% of recipient mice but 60% of the surviving mice rejected challenge with 3LL. Splenocytes harvested from tumor-rejecting mice protected naive mice injected with 3LL. CONCLUSION: These results support the hypothesis that in addition to its antineoplastic cytotoxic effect, VP-16 induces changes in 3LL cells which are recognized by the host immune system resulting in immune rejection of 3LL. often immunosuppressive and therapeutic advantage is generally based on the tumor cytotoxicity of individual drugs or combinations of drugs [13]. Our earlier work showed a link between the use of cytotoxic chemotherapy with etoposide (VP-16) and the induction of an immune response against syngeneic murine leukemia in the intact host [16]. VP-16 is an immunosuppressive topoisomerase II-inhibiting drug which induces tumor cell apoptosis and is frequently used clinically to treat a variety of tumors [1, 3, 9, 10]. We have noted that the addition of cyclosporin A to VP-16 produces CD8 T lymphocyte-mediated tumor-specific immunity in mice bearing L1210 leukemia [17]. We have extended these experiments to a spontaneously arising non-carcinogen-induced neoplasm, Lewis lung cancer (3LL), and now report that surviving mice successfully treated with VP-16, in the absence of cyclosporin A, reject challenge with 3LL. In addition, results are presented to show that VP-16 modifies 3LL cells rendering them immunogenic. These findings are submitted to support the hypothesis that VP-16-induced cytotoxic changes include cellular membrane alterations in 3LL cells which are recognized by the immune system and cause rejection of this syngeneic lung tumor.

Composite energy deposition kernels for focused point monodirectional photon beams.

A 3D volume overlap algorithm has been developed for converting energy deposition kernels between arbitrary 2D and 3D irradiation geometries. The kernels can be used as convolution kernels in inverse radiation therapy planning and as accurate descriptions of the dose distributions for clinically important beam geometries. The new method of dose calculation combining Monte Carlo and analytical methods has introduced an improved accuracy in dose calculation on the fractional per cent level. The comparisons are also made for a wide range of photon spectra and irradiation geometries from narrow point monodirectional pencil beams to finite uniform beams, 4pi steradians isotropically converging beams and divergent beams from isotropic point sources. It is seen that the photon scatter penumbra is highest at low photon energies whereas the secondary electron penumbra is widest at high photon energies, making low energy beams more interesting for small targets and high energy beams most useful for large deep-seated targets.

Shaping of arbitrary dose distributions by dynamic multileaf collimation.

Traditionally, the shaping of non-uniform dose distributions has been performed by using wedges or compensating filters. The advent of high resolution multileaf collimators may largely eliminate the need for material attenuators for modification of the beam. This is achieved by a new technique for the shaping of arbitrary dose distributions by dynamic motion of the collimator leaves. By employing narrow elementary slit beams that correspond to the smallest possible opening of the multileaf collimator, the optimal density of such slit beams, i.e. opening density, can be determined automatically using a newly developed inversion algorithm. The present method has two major advantages (1) internal structures in the field can be created, controlled solely by steering the collimator leaves, (2) the opening density determined by the algorithm never gives rise to underdosage: this is important from a radiobiological point of view.

Gender differences in perceived health-related quality of life among patients with HIV infection.

This article explores how a group of human immunodeficiency virus (HIV)-infected patients perceived their health-related quality of life (HRQOL) in relation to their coping capacity expressed as sense of coherence. The emphasis was on gender differences. The sample consisted of 55 women (29%) and 134 men (71%), receiving outpatient medical care in a hospital. Self-report instruments, the health index, the HIV symptom scale, the well-being scale, the sense of coherence (SOC) scale and the Interview Schedule for Social Interaction were used. Disease status (HIV CDC classification, absolute CD4+ lymphocyte count and HIV/RNA) was also measured, and demographic data were collected. The total sample scored significantly worse self-rated health and weaker SOC than healthy controls. The HIV-infected women were significantly younger than the men (p < 0.0001). The majority of the women (60%) were infected by heterosexual transmission and of the men (58%) by homosexual/bisexual contacts. In the univariate analysis the women scored significantly less positive well-being (p < 0.05), weaker SOC (p < 0.05), and less social support (p < 0.01) than the men despite less advanced disease. Multiple regression analyses revealed that SOC was the strongest predictor of subjective HRQOL in both genders. The results suggest that health professionals who individualize their care of HIV-infected patients should try to be sensitive to the different ways in which men and women express their HRQOL.

The renal dopamine system.

Intrarenally formed dopamine induced natriuresis by inhibiting the activity of renal tubular Na/KATPase. This effect is mediated via a complex signal network, which includes inhibition of PP1 via the adenylyl cyclase-PKA-DARPP32 pathway and activation of PKC via the PLA2-arachidonic acid-20HETE pathway. The renal dopamine availability is a major determinant of the natriuretic effect of dopamine and is to a large extent modulated by the activity of COMT. The possibility that regulation of dopamine storage and release influences renal dopamine effects should be considered.

Housing breeding mice in three different IVC systems: maternal performance and pup development.

A proper cage environment is essential for the welfare of laboratory mice, especially for females during the energy demanding lactation period and for pups during early development and growth. The most common housing system for laboratory mice is individually ventilated cages (IVCs) of which there are different layouts and ventilation strategies available on the market. The present study investigates the impact of cage environment in three different IVC types, on the maternal performance of females, and pup development and growth in C57BL/6NCrl and Crl:NMRI Foxn1 nu mice. The results show differences in in-cage climate, female body weight, pup growth, feed and water consumption, and nest quality between cage types. There was a distinct effect of genotype in these differences, with the main effects found in NMRI NU mice. The results indicate that IVC systems might need to be managed differently for mice of different types and/or different physiological status. Many of the differences seen between cage systems could be drawn to the physical construction of the cage, such as location of feed hopper and location of air inlet and outlet. In conclusion, IVC in-cage climate affects the maternal performance of female mice and pup growth, but with differences between the two strains tested.

Validation of an extended version of the SEIQoL-DW in a cohort of Hodgkin lymphoma' survivors.

Individual measures of quality of life (QoL) have been initiated to overcome the possible limitations with standardized measures using predefined domains for evaluation. The Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) uses personal interviews to explore the five most important areas in life, both positive and negative, crucial for QoL. The nominated areas are rated regarding satisfaction and weighted to capture the importance of each selected area. The Swedish version has been extended with a disease-specific module, which evaluates the areas in life influenced by disease. The aim of this study was to validate the disease-specific SEIQoL-DW and furthermore, to evaluate the influence of the importance ratings on the overall index score in a cohort of Hodgkin lymphoma survivors. The results support the construct validity of the disease-specific SEIQoL-DW and indicate that the instrument appears to be a sensitive measure with ability to differentiate between groups with disparate subjective health status. The SEIQoL-DW succeeds to capture both positive and negative areas in life influenced by disease. The present study gave no evidence that the weighting procedure has any impact on the total index. The results support the use of the new extended version including a disease-specific module.

The natriuretic response to a dopamine DA1 agonist requires endogenous activation of dopamine DA2 receptors.

Dopamine produced in the kidney acts as a natriuretic hormone by inhibiting tubular Na+,K+-ATPase activity. Previous in vitro studies have shown that Na+,K+-ATPase activity in the proximal tubule is inhibited by a synergistic action of dopamine 1 (DA1) and dopamine 2 (DA2) receptors. This in vivo study, performed on rats, investigates whether the natriuretic response to DA requires a synergistic action of DA1 and DA2 receptors. The DA1 agonist, fenoldopam, significantly increased urinary sodium excretion, but there was no increase in sodium excretion when a DA1 agonist was given together with a DA2 antagonist. Neither DA1 nor DA2 antagonists had any influence on sodium excretion. The natriuretic response to fenoldopam was also significantly attenuated after the administration of benserazide, which inhibits aromatic acid decarboxylase and thereby suppresses the endogenous production of dopamine. In conclusion, the natriuretic effect of dopamine depends on the activation of both DA1 and DA2 receptors. The DA2 receptor appears to be constitutively activated by endogenous dopamine.

Renal hypertension following aortic constriction is abolished by angiotensin II converting enzyme inhibitor, but not by low-salt diet.

This study evaluates the role of different sodium intakes and the role of angiotensin II in the development and the maintenance of renovascular hypertension in rats with constriction of the aorta proximal to the renal arteries. The rats were studied 3 weeks after surgery when the hypertension was well established. Glomerular filtration rate was decreased and filtration fraction was increased in rats with proximal aortic constriction. Low and high salt intakes had no effect on glomerular filtration and filtration fraction. Treatment with angiotensin II converting enzyme inhibitor increased the glomerular filtration rate and reduced the filtration fraction in rats with proximal aortic constriction to the same levels as in control rats. Serum levels of angiotensin II were about the same in rats with proximal aortic constriction as in control rats. Conclusion. The renovascular hypertension in proximal aortic constriction is influenced by locally formed angiotension II but not by alterations in salt intake.

Photon beam energy deposition kernels for inverse radiotherapy planning.

A method for calculating energy deposition kernels for planar convergent isotropic irradiations of a point target has been developed. A geometric overlap algorithm is applied to pencil beam energy deposition kernels calculated by convolution of Monte Carlo generated point spread functions with the energy released by a point monodirectional photon beam. The geometric overlap interpolation technique is energy conservative and hence, for dosimetric purposes, more precise than interpolations based on smoothing techniques. Furthermore, due to the integration processes involved, most of the statistical noise in the original Monte Carlo data is eliminated. The resulting kernels have a precision and noise level corresponding to 10(9) - 10(10) Monte Carlo simulated photons. The kernels are useful for inverse conformation therapy planning, and for dose planning with small target volumes.

Renal function in different forms of renovascular hypertension in rats.

This study examines renal function in different rat models of renovascular hypertension. Hypertension was induced by constriction of the aorta proximal to the renal artery (PAC), by PAC and nephrectomy (PAC + Nx) or by renal artery stenosis (RAS). PAC + Nx is equivalent to the Goldblatt 1 kidney-I clip hypertension model. The PAC rats were studied 3 weeks after surgery. Hypertension was by then well established. GFR, measured as the clearance of inulin, was significantly lower in PAC rats than in control (C) rats. GFR was the same in PAC + Nx rats as in C rats, but significantly lower in PAC + Nx than in Nx rats. Kidney weight was significantly higher in PAC + Nx rats than in C rats. Filtration fraction (FF), measured as the ratio between GFR and the clearance of PAH, was significantly higher in PAC and PAC + Nx rats than in C and Nx rats. In RAS rats hypertension was not established until 6 weeks after surgery, and RAS is equivalent to Goldblatt 2 kidney-I clip hypertension. Renal artery constriction was moderate as judged from the weight ratio between the stenosed and contralateral kidneys. The GFR in the stenosed kidney was not significantly lower in the contralateral kidney. FF was significantly higher in RAS rats than in C rats in both the stenosed and the contralateral kidneys, but the increase was less pronounced than in PAC and PAC + Nx rats.

Mechanism of FK 506/520 action on rat renal proximal tubular Na+, K+-ATPase activity.

BACKGROUND: The neurotransmitter in renal sympathetic nerves, norepinephrine (NE), regulates the activity of proximal tubule (PT) Na+,K+-ATPase in a bidirectional manner via stimulation of alpha- and beta-adrenoceptors. The stimulatory alpha-adrenergic pathway is mediated by calcineurin, the target molecule for FK 506 and related compounds. We examined whether the FK 506 analogue FK 520, by interrupting the calcineurin-mediated alpha-adrenergic signaling pathway, enhance the inhibitory beta-adrenergic effect of NE on PT Na+,K+-ATPase activity. METHODS: The effects of three days of treatment with FK 520 were examined on rat renal PT Na+,K+-ATPase activity, measured as ouabain-sensitive ATP hydrolysis in single, microdissected PT segments. Renal function studies, including glomerular filtration rate (GFR) and urinary excretion of N-acetyl-3-D-glucoseaminidase (NAG), were examined using conventional clearance techniques after three days of treatment with FK 506. RESULTS: FK 520 treatment induced a pronounced and dose-dependent decrease in PT Na+,K+-ATPase activity. This effect was completely reversed by the competitive FK 520 antagonist, L 685 818, indicating that the effect was dependent on inhibition of calcineurin. To test whether the FK 520-induced decrease in Na+, K+-ATPase activity was mediated by enhanced beta-adrenoceptor signaling, the FK 520 effect was examined in rats pretreated with a beta-adrenoceptor antagonist (propranolol) or rats subjected to renal denervation. Both of these procedures prevented the FK 520-induced decrease in Na+,K+-ATPase activity. Thus, during FK 520 treatment, renal sympathetic nerves mediate an inhibitory effect on PT Na+,K+-ATPase activity via beta-adrenoceptors. Propranolol pretreatment also prevented FK 506-induced decreases in GFR and urinary excretion of NAG, an index of PT dysfunction. CONCLUSIONS: The results support the hypothesis that the net effect of the neurotransmitter NE on Na+,K+-ATPase activity is dependent on the balance between the alpha- and beta-adrenergic signaling pathways and suggest that agents that interfere with these pathways may, by altering the activity of tubular Na+,K+-ATPase, also alter the function of the renal tubular epithelial cell.