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Biomedical subjects

R Risser

Publications and source records attributed to R Risser.

At least 19 recordsLinked to original sources

Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.

BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

Acute Disease↗

Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.

Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean +/- SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5 +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%) fell (P <.05). Administered UDCA was also conjugated predominantly with glycine (87%).

Bile↗

Relationship of uric acid concentrations and severe intraventricular hemorrhage/leukomalacia in the premature infant.

The purine metabolite hypoxanthine accumulates with hypoxia ischemia and with reperfusion is converted to uric acid (UA). We hypothesized that elevated UA concentration is a marker of previous hypoxia ischemia and would identify infants at greatest risk for having subsequent intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL). We determined the relationship between UA concentrations in the first postnatal day and the development of severe IVH, PVL, or both in 58 infants of birth weight 865 +/- 177 gm and gestational age 27 +/- 2 weeks. Severe IVH developed in 10 (17%) infants and PVL in 3 (5.1%) infants. UA concentrations on day 1 (obtained at 16 +/- 4 hours) were 7.9 +/- 2.8 mg/dl and increased to 9.5 +/- 2.58 mg/dl on day 2. UA concentrations on day 1 were higher in infants with severe IVH/PVL versus those in infants with neither condition: 10.2 vs 7.3 mg/dl (p = 0.005). Infants with hyperkalemia on the second postnatal day had higher UA concentrations on the first day versus infants with normal potassium levels: 11.7 +/- 2 mg/dl versus 6.8 +/- 1.8 mg/dl (p < 0.0005). Infants with severe IVH/PVL had higher potassium levels on day 2 versus infants with neither condition: 11.9 vs 6.9 mg/dl (p < 0.048). By univariate analysis UA concentrations were significantly related to gestational age (p = 0.005) and birth weight (p = 0.03). Only UA concentration (p = 0.004) and gestational age (p = 0.02) were related to IVH/PVL. By multivariate analysis UA remained significantly related to IVH/PVL even when adjusted for other clinical variables, with an odds ratio estimate of 1.63 (95% confidence interval 1.16 to 2.31). In conclusion, higher UA concentrations on the first postnatal day were associated with the subsequent development of severe IVH/PVL and with subsequent hyperkalemia. Elevated UA concentrations in the first postnatal day may help to identify a subset of premature infants at greatest risk for having subsequent hemorrhagic ischemic injury.

Birth Weight↗

Is there a role for continuation phase cognitive therapy for depressed outpatients?

Two pilot studies evaluated the rate of relapse or recurrence (i.e., major depressive disorder) after cognitive therapy (CT). Two sequential cohorts included outpatients who responded to acute phase CT (A-CT) and who agreed to monthly, treatment-free follow-up. In Study 1, the Kaplan-Meier technique estimated relapse and recurrence rates of 40% at 6 months, 45% at 8 months, 50% at 12 months, 67% at 18 months, and 74% at 24 months. In Study 2, responders to A-CT received 8 months (10 sessions) of continuation phase CT (C-CT). In Study 2, relapse or recurrence was 20% at 6 and 8 months, 27% at 12 months, and 36% at 18 and 24 months after A-CT. An exploratory log-rank test showed that relapse or recurrence-free survival was greater in Study 2 than in Study 1. If replicated, this result suggests that C-CT can reduce depressive relapse or recurrence. Alternative explanations are presented.

Adult↗

Altered amyloid protein processing in platelets of patients with Alzheimer disease.

BACKGROUND: beta-Amyloid peptide, the core component of neuritic plaques in brain areas in patients with Alzheimer disease (AD), is 1 cleavage product of the beta-amyloid precursor protein (APP) in neurons and platelets. Alternate cleavage products of intact 140- to 150-kd APPs in platelets include nonamyloidogenic 120- to 130-kd and 110-kd isoforms. The possible differential significance of these 2 isoforms, structurally similar to protease nexin II, is unknown. OBJECTIVE: To determine whether the ratio of the 120- to 130-kd APP isoform to the 110-kd APP isoform as processed in platelets correlates with the presence of AD and/or the apolipoprotein E4 (ApoE4) allele, which is a major risk factor for AD. SETTING: The Alzheimer Disease Center at The University of Texas Southwestern Medical Center at Dallas. METHODS: The APP isoforms were quantitated with the use of 2 different Western blot detection methods in platelets from 15 patients with AD and 19 control subjects in whom genotyping of apolipoprotein E was performed. RESULTS: The mean ratio of the 120- to 130-kd APP isoform to the 110-kd APP isoform in the patients with AD was significantly lower than that of the control subjects (5.98 vs 7.64; P = .03 [method 1] and 5.98 vs 7.92; P = .01 [method 2]) after adjusting for age and the increased incidence of ApoE4 in patients with AD. The lower APP ratios were also associated with increased age and with the presence of an ApoE4 allele. CONCLUSIONS: The APP processing in platelets of patients with AD is different from that of control subjects. This difference, largely caused by factors other than the ApoE4 genotype, may reflect chronic platelet activation in patients with AD. The use of these data to estimate "AD risk," by using the APP isoform ratio, indicates an odds ratio of 1.75, suggesting possible utility as an adjunct in the diagnosis of AD. Moreover, these findings may relate to analogous alterations in APP processing that may occur in brain areas affected by AD.

Aged↗

Early use of the Gore-Tex Stretch Graft.

This study reports firstly the overall outcome with the 4-7 mm tapered Gore-Tex Stretch Vascular Graft and secondly the feasibility of early (< 14 days) cannulation hemodialysis in 270 consecutive patients for first-time forearm loop placement. Ninety-six (36%) cases were cannulated within 14 days and 78 cases within 7 days. The overall results with the stretch graft are excellent. The statistically significantly worse outcome with early cannulation was mainly due to a select patient population (as determined by proportional hazards regression analysis) being more acutely ill, urgently needing hemodialysis and having no other options for needle puncture. A prospective randomized study, however, is warranted to fully resolve the safety issue of early cannulation.

Adolescent↗

Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers?

OBJECTIVE: Markers currently used to identify infants at highest risk for perinatal hypoxic-ischemic cerebral injury are insensitive in predicting the subsequent occurrence of neonatal seizures and/or neurodevelopmental sequelae, ie, cerebral palsy. To facilitate therapeutic strategies, early identification of the infant at highest risk for developing seizures secondary to hypoxia ischemia or asphyxia is critical, particularly if novel but potentially toxic therapies currently under experimental investigation become available for clinical use. METHODS: Ninety-six inborn term infants considered at high risk for having neonatal seizures secondary to hypoxia ischemia or asphyxia and admitted to the neonatal intensive care unit directly after labor and delivery were prospectively evaluated. Markers of high risk included the presence of moderate to thick meconium-stained amniotic fluid (MSAF), fetal heart rate (FHRT) abnormalities abruptio placentae, intubation and positive pressure ventilation in the delivery room (DR), chest compressions and epinephrine administration as part of resuscitation, a 5-minute Apgar score of 5 or less, umbilical cord arterial pH of 7.00 or less, and/or a base deficit of -14 mEq/L or more negative. RESULTS: Seizures developed in 5 (5.2%) of the 96 infants. High-risk markers included FHRT abnormalities only (n=36), FHRT abnormalities and MSAF (n=20), MSAF only (n=23), abruptio placentae (n=6), intubation in the DR (n=44), intubation in the neonatal intensive care unit (n=22), chest compressions (n=2), 5-minute Apgar scores of 5 or less (n=21), umbilical cord arterial pH of 7.00 or less (n=21), and base deficits of -14 mEq/L or more negative (n=19). By univariate analysis, significant relationships with seizures were found with Apgar scores, the need for intubation in the DR, umbilical cord arterial pH, and base deficit. Combinations of the identified risk markers showed a strong relationship with seizures with the following odds rations (ORs), 95% confidence limits, sensitivity, specificity, and positive predictive values (PPVs): (1) low cord pH and intubation, OR, 163 (confidence limits, 7.9 and 3343.7); sensitivity, 100%; specificity 94%; and PPV, 50%; (2) low cord pH and low 5-minute Apgar score, OR, 39 (confidence limits, 3.9 and 392.5); sensitivity, 80%; specificity, 91%; and PPV, 33.3%; and (3) low pH, intubation, and low 5-minute Apgar score, OR, 340 (confidence limits, 17.8 and 6480.6); sensitivity, 80%; specificity, 98.8%; and PPV, 80%. CONCLUSIONS: A combination of high-risk postnatal markers, specifically, a low 5-minute Apgar score and intubation in the DR in association with severe fetal acidemia, facilitates the identification within the first hour of life of term infants at highest risk for developing seizures secondary to perinatal asphyxia.

Abruptio Placentae↗

Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors.

BACKGROUND: Bilateral cystic periventricular leukomalacia (PVL) is a major cause of neurodevelopmental delay in the premature infant. Thus, early identification of the preterm infant at highest risk for the subsequent development of this lesion is critical. OBJECTIVES: The three objectives of this case-control study were: (1) to determine the basic characteristics of cystic PVL, (2) to assess the relationship of perinatal clinical events and PVL, and (3) to ascertain the feasibility of identifying early those preterm infants at highest risk for the development of PVL. METHODS: The medical records and cranial ultrasound scans (HUSs) were reviewed for 632 infants weighing less than 1750 g who were admitted to the neonatal intensive care unit between January 1992 and December 1993. PVL developed in 14 infants of 1285 +/- 301 g birth weight (BW) and 29.4 +/- 1.5 weeks' gestational age (GA); severe intraventricular hemorrhage (n = 21) and intraparenchymal echodensity (n = 12) developed in 33 infants of 904 +/- 248 g BW and 26.6 +/- 1.8 weeks' GA; and 585 infants of 1315 +/- 324 g BW and 29.7 +/- 2.4 weeks' GA with normal HUS findings (n = 473) or grade I or II intraventricular hemorrhage (n = 112) served as a comparison group. RESULTS: Cystic PVL was observed in 14 (2.3%) of 632 infants weighing less than 1750 g, more specifically, in 3.2% of infants weighing less than 1500 g. Cysts were noted from the 7th to 14th days of life in 10 infants and from the 20th to 46th days of life in 4 infants. Ten (70%) of the infants had relatively benign clinical courses, and most cases were detected by routine HUS surveillance. Over hypotension in the immediate perinatal period was noted in 3 (21%) infants; late hypotension developed in 1 additional infant. Univariate analysis indicate that two clinical indicators, prolonged rupture of membranes (PROM) and chorioamnionitis, were significant predictors of PVL. For PROM, the odds ratio estimate and the 95% confidence limit are 6.59 and 1.96 to 22.10, with a sensitivity of 28.6% and positive predictive value of 11.5%. Similar values for chorioamnionitis are 6.77 (1.77 to 25.93), with a sensitivity of 21.4% and positive predictive value of 11.5%. CONCLUSIONS: (1) Most cases of symmetric cystic PVL occurred in infants with relatively benign clinical courses and were only detected by routine ultrasound screening. (2) Postnatal systemic hypotension seems to be an uncommon associated event. (3) Preterm infants born to mothers with PROM and/or chorioamnionitis seem to be at an increased risk for the development of PVL and should be carefully evaluated.

Analysis of Variance↗

Cardiopulmonary resuscitation in the delivery room. Associated clinical events.

OBJECTIVES: To determine (1) what percentage of infants require chest compressions and medications as part of resuscitation in the delivery room, (2) the associated clinical events contributing to neonatal depression, and (3) the neonatal outcome of such children. DESIGN: Observational study. SETTING: Urban county hospital. RESULTS: For 2 years, 39 (0.12%) of 30,839 infants were administered chest compressions and/or epinephrine as part of cardiopulmonary resuscitation in the delivery room. Fifteen were term infants and 24 were premature. Five term infants had evidence of severe fetal acidemia (FA) (umbilical cord arterial pH < 7.00 and/or base deficit > or = -14 mEq/L); two died secondary to severe brain injury, and the neurologic examinations showed abnormalities in the three survivors. The 10 infants without severe FA exhibited an uncomplicated neonatal course. Five infants had evidence of severe FA; the neurologic examination showed abnormalities in four. Of the remaining 19 infants without severe FA, four died and five additional infants have moderate to severe brain injury. Abnormal outcome was more likely to occur with severe FA (P < .002). The presumed clinical events contributing to the neonatal depression were severe FA (n = 10), malpositioning of the endotracheal tube (n = 5), and ineffective or improper initial ventilatory support (n = 24). CONCLUSIONS: Cardiopulmonary resuscitation in the delivery room, resulting in administration of chest compressions and medications, is a rare event. Approximately one third of the infants had evidence of severe FA; in the remaining two thirds, ineffective or improper initial ventilatory support was the presumed mechanism for the continued neonatal depression. The appropriate therapeutic response to continuing neonatal depression should be to optimize ventilatory support before administering chest compressions or medications.

Cardiopulmonary Resuscitation↗

Cognitive deficits in asymptomatic first-degree relatives of Alzheimer's disease patients.

The present study was designed to determine whether neuropsychological deficits exist in asymptomatic first-degree relatives of Alzheimer's disease (AD) patients. The neuropsychological performances of 20 first-degree asymptomatic relatives of NINCDS-ADRDA diagnosed AD patients were compared to 20 normal controls without family history of AD. Cognitive functions assessed included intelligence, memory, overall brain function, verbal learning, and language and constructional abilities. Significant statistical differences were found between the groups across several cognitive areas indicating lower functioning in the first-degree relatives of AD patients. Fifty percent of the first-degree subjects but only 20% of controls showed a pattern of significant neuropsychological deficit. The results demonstrate neuropsychological deficits in asymptomatic first-degree relatives of AD patients, suggesting that preclinical markers for AD may be present long before the clinical manifestation of the disease.

Aged↗

Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates.

OBJECTIVE: Healthy very-low-birth-weight neonates (VLBW, < or = 1500 g) exhibit a high incidence of neutropenia according to Manroe's reference ranges for neutrophil indices. Since these reference ranges may be inappropriate for VLBW neonates, we determined the reference ranges for circulating peripheral neutrophils in VLBW neonates between birth and 28 days of age. METHODS: Serial, timed peripheral white blood cell counts (n = 1788) were prospectively obtained between birth and 28 days from 193 inborn, VLBW neonates delivered between January 1 and December 31, 1990. Data were divided into neutrophil counts obtained prior to (n = 630) and after (n = 1158) 60 hours of age. After excluding counts from neonates with perinatal and/or neonatal complications, values from "normal" neonates were compared to Manroe's reference ranges. Where indicated new ranges were developed. RESULTS: Although immature neutrophil (ATI) and immature:total neutrophil (I:T) values were within Manroe's reference ranges (P > .1) throughout the neonatal period, 67% of total neutrophil values (ATN) obtained prior to 60 hours of age were outside (P < .001) and 95% were considered neutropenic. Newly developed ATN reference ranges for VLBW neonates have a wider range of distribution compared to Manroe's results, primarily reflecting a decrease in the lower boundary. ATN values between 61 hours and 28 days also differed (P < .001), and new ranges had upper and lower boundaries of 6000 and 1100/mm3, respectively. Maternal hypertension was associated with neonatal neutropenia (P < .001) without abnormalities of ATI or I:T prior to day 3 of life; however, neutrophilia predominated after day 7. Between birth and 28 days > 70% of ATN values were abnormal in neonates with apnea, neutrophilia occurring in > 90% of counts; I:T values, however, were normal between 61 hours and 28 days. CONCLUSIONS: Normal preterm VLBW neonates have ATN reference ranges that differ significantly from that for larger, older neonates, demonstrating the effects of development on neutrophil dynamics. The predictability of neonatal infection using these new reference ranges requires additional study.

Humans↗

TAR-independent transactivation of the murine cytomegalovirus major immediate-early promoter by the Tat protein.

Tat is a transactivator of human immunodeficiency virus type 1 (HIV-1) that stimulates gene expression via an RNA target sequence (TAR) by augmenting transcriptional initiation and/or elongation from the HIV-1 long terminal repeat promoter. Here we show that Tat is able to transactivate the murine cytomegalovirus (MCMV) major immediate-early promoter (MIEP), which lacks sequence similarity with the HIV-1 long terminal repeat TAR element. Surprisingly, deletion of the upstream enhancer region (-610 to -146) of the MCMV MIEP abrogated Tat responsiveness. This result suggests that Tat requires a DNA target for function. Quantitation of RNA and protein indicates that Tat stimulates expression from the MCMV MIEP at both the transcriptional and translational levels. Deletion analysis of the MIEP indicates that there is likely to be interplay between the enhancer region, a sequence upstream of the known enhancer which negatively affects expression, and the Tat protein.

Animals↗

Cell fusion induced by the murine leukemia virus envelope glycoprotein.

To determine whether ecotropic murine leukemia virus (MuLV) envelope glycoproteins are sufficient to cause cell-to-cell fusion when expressed in the absence of virus production, we used an ecotropic MuLV, AKV, to construct env expression vectors that lack the gag and pol genes. The rat cell line XC, which undergoes cell-to-cell fusion upon infection with ecotropic MuLV, was transfected with wild-type env expression vectors, and high levels of syncytium formation resulted. Transfection of the murine cell line NIH 3T3 with expression vectors containing the wild-type or mutated env region did not result in syncytium formation. Immunoprecipitation analysis of the envelope glycoproteins expressed in NIH 3T3 and XC cells showed that the mature surface glycoprotein expressed in XC cells was of a much lower apparent molecular weight than that expressed in NIH 3T3 cells. Further characterization showed that most if not all of this difference was the result of differences in glycosylation. Finally, site-directed mutagenesis was used to introduce several conservative and nonconservative changes into the amino-terminal region of the transmembrane protein. Analysis of the effect of these mutations confirmed that this region is a fusion domain.

3T3 Cells↗

Xenon-133 SPECT-determined regional cerebral blood flow in Alzheimer's disease: what is typical?

A study of 76 consecutive xenon-133 SPECT studies of regional cerebral blood flow was undertaken to determine the frequency of various patterns of blood flow in cases of clinically diagnosed probable and possible Alzheimer's disease. The reference tomographic section was a slice 6 cm above and parallel to the canthomeatal line. With the use of this technique, the "classic" finding of bilateral temporoparietal (TP) flow reductions as the sole abnormality occurred in only 28% of cases. Bilateral TP reductions accompanied by bilateral or unilateral frontal flow reductions were nearly as common (24%), and other patterns accounted for the other 48% of cases.

Aged↗

Relationship between periventricular intraparenchymal echodensities and germinal matrix-intraventricular hemorrhage in the very low birth weight neonate.

The pathogenesis of the periventricular intraparenchymal echodense lesion (IPE) observed in association with germinal matrix-intraventricular hemorrhage (GM-IVH) in premature neonates is unclear. The objectives of this study were to determine (1) the temporal characteristics of GM-IVH and IPE, (2) the basic characteristics of the IPE, and (3) the relationship of clinical events, including surfactant administration, to IPE. One hundred twenty-four neonates of less than 1250 g birth weight were prospectively evaluated. IPE was defined as an echodensity greater than 1 cm in diameter by cranial sonography. Fifteen (12%) neonates developed IPE in association with GM-IVH (group 1); 33 neonates developed GM-IVH only (group 2) and 76 neonates without GM-IVH served as comparison group (group 3). IPE was essentially an asymmetrical lesion; both sides of cerebrum were equally affected. The lesion was diffuse in 9 neonates and focal in 5. IPE occurred both early, at 36 hours or before (n = 8), and later, ie, between 48 and 96 hours (n = 6). In one neonate IPE was diagnosed at autopsy. GM-IVH and IPE were noted simultaneously in neonate with the earlier onset IPE (diagnosed within 36 hours); GM-IVH preceded the IPE by 6 to 48 hours when the lesion was of a later onset. Surfactant was administered to 13 (87%) group 1, 24 (73%) group 2, and 35 (46%) group 3 neonates. Pulmonary hemorrhage developed in 9 (60%) of group 1, 3 (9%) group 2, and no group 3 neonates. Symptomatic patent ductus arteriosus occurred in 12 (75%) group 1, 15 (45%) group 2, and 15 (20%) group 3 neonates. The onset of symptoms associated with patent ductus arteriosus was earlier in group 1 vs group 2 or group 3 neonates, ie, 70 vs 172 hours. Nine (60%) group 1 neonates, 6 (18%) group 2, and 5 (7%) group 3 neonates died. The cranial sonogram was markedly abnormal in all 6 group 1 survivors. Stepwise polytomous logistic regression indicated that birth weight, gestational age, and emergent cesarean section were the best predictors of GM-IVH + IPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Apgar Score↗

Verapamil (VP) improves the outcome after renal transplantation (CRT).

Calcium antagonists (CATs) have a role in the management of certain types of renal insufficiency. These include prophylaxis against post-transplant-associated acute renal failure and cyclosporine A (CsA)-induced renal dysfunction. For the transplanted kidney, CATs may be beneficial in several settings. First, a CAT during organ procurement protects the kidney during ischemic periods. Second, CATs given perioperatively protect the kidney during reperfusion and early after transplantation. Third, CATs also offer protection against CsA nephrotoxicity.

Calcium Channel Blockers↗