Choledochal cyst associated with duodenal atresia: case report and review of the literature.

We report a rare case of choledochal cyst (CC) associated with congenital duodenal atresia (DA) and annular pancreas (AP). A girl was born at 37 weeks of gestation weighing 2,974 g with a prenatal diagnosis of DA. She underwent a duodenoduodenostomy for type III DA with an AP 1 day after birth. At 4 years of age, she was admitted for evaluation of cholangitis and pancreatitis. Radiological studies demonstrated a fusiform-type CC with pancreaticobiliary maljunction (PBMJ). Excision of the CC and hepaticojejunostomy were performed. The patient was discharged without complications. Despite the fact that CC, DA, and AP are embryologically closely related entities, to the best of our knowledge, only eight such cases have been documented. We must be aware of the possible combination of CC in the follow-up of the patients with DA associated with AP.

Congenital anomalies induced by triamcinolone acetonide in murine embryos.

INTRODUCTION: We have studied the morphogenesis of anorectal malformations in mice using retinoids. Several investigators have reported an interaction between glucocorticoids and retinoids. It was supposed that glucocorticoids had some effects on the morphogenesis of murine embryos similar to retinoids. Therefore, we investigated alterations in the morphogenesis of murine embryos after triamcinolone acetonide (TAC) administration. MATERIAL AND METHODS: TAC was administered in a single dose (15 mg/kg or 30 mg/kg body weight) to pregnant ICR-SLC mice on embryonic day 7 (E7), 8, 9, and 10. They were sacrificed on E18, and fetuses were examined for internal and external malformations. Randomly chosen fetuses were embedded in paraffin for immunohistochemical staining of the glucocorticoid receptor (GR). RESULTS: The groups given 15 mg/kg TAC had one peak in the incidence of cleft palate on E9 (100 %) and the groups given 30 mg/kg TAC showed a biphasic pattern in the incidence of cleft palate on E7 and E10. No other anomalies were found. GR expression was marked in the subepithelial layer of palatal processes in the treated specimens. CONCLUSION: The group given 15 mg/kg TAC on E9 provided a good model of cleft palate in ICR-SLC mice, and cleft palate was probably induced by various factors including disturbance of the bone morphogenetic protein (BMP) signaling pathway, shown by GR overexpression.

Significance of the anomalous arrangement of the pancreaticobiliary duct in the etiology of biliary atresia.

BACKGROUND/PURPOSE: The anomalous arrangement of the pancreaticobiliary duct (AAPBD) is one theory used to explain the etiology of biliary atresia. We investigated whether AAPBD could be involved and evaluated its significance for the etiology of biliary atresia. MATERIALS AND METHODS: Of 43 patients with biliary atresia, the area between the common bile duct and the duodenum could be visualized by operative cholangiogram in 5 patients with an uncorrectable type of biliary atresia. Three of the 5 showed an anomalous arrangement of the pancreaticobiliary duct. In these 3 patients, the type of anomalous arrangement of the pancreaticobiliary duct and the length of the common channel were studied by operative cholangiogram. Histological findings of the gallbladder and the common bile duct were examined in addition to the measurement of the serum amylase levels. RESULTS: All 3 patients showed AAPBD with the P-C type of pancreaticobiliary junction. The length of the common channel ranged from 7 mm to 12 mm. Two of the 3 cases did not show an elevated serum amylase level. Epithelial hyperplasia of the gallbladder was observed in one patient, while the other two showed no hyperplasia. Inflammatory changes in the mucosa of the gallbladder and the common bile duct were not remarkable in these 3 patients. CONCLUSIONS: From these results it seems that AAPBD in biliary atresia might not be an etiological factor for atresia of the extrahepatic bile duct, but might be an associated anomaly in biliary atresia. Other factors should be examined to clarify the etiological factor leading to lumenal obstruction of the extrahepatic bile duct.

The significance of steroid therapy after hepatoportoenterostomy in infants with biliary atresia.

PURPOSE: Despite improvements in the surgical management of biliary atresia (BA), it is still difficult to maintain good bile flow. In the present study, we examined steroid therapy and determined the appropriate dose to achieve freedom from jaundice after hepatoportoenterostomy (HPE) in the uncorrectable type of BA. METHODS: A retrospective clinical analysis was done in 23 of 29 (79 %) cases who had become jaundice-free after undergoing HPE with steroid therapy between 1988 and 2004. A correlation between the total or mean steroid dose and the postoperative jaundice period (serum total bilirubin > 1.0 mg/dl) was evaluated using linear regression analysis. The regimen was as follows: prednisolone was given intravenously, starting with 3 to 5 mg/kg/day, and then gradually tapered with repetition until freedom from jaundice was achieved. RESULTS: Age at HPE was 72 +/- 20 days (mean +/- SD), and the postoperative jaundice period was 108 +/- 68 days. Total and mean steroid doses were 118 +/- 73 mg/kg and 1.31 +/- 0.8 mg/kg/day, respectively. There was no correlation between the total steroid dose and the period of jaundice. However, there was a significant correlation between the mean steroid dose and the period of jaundice (p = 0.021). CONCLUSION: A high mean dose of steroids could shorten the jaundice period after HPE in the uncorrectable type of BA.

Effects of herbal medicine Dai-Kenchu-to on anorectal function in children with severe constipation.

AIM: We administered the herbal medicine Dai-Kenchu-To (DKT) to children with severe chronic constipation or with severe constipation after surgery for anorectal malformations. We then objectively assessed the effect of DKT on anorectal function by manometric study in addition to using a clinical scoring system. PATIENTS AND METHODS: Ten children with severe chronic constipation and 5 children with severe constipation after surgery for anorectal malformations were assessed. These 15 children received 0.3 g/kg/day of DKT for periods ranging from 3 months to 1 year. We objectively assessed their bowel function, sphincter function and rectal reservoir function by anorectal manometry and clinical scoring. RESULTS: In 10 children with severe chronic constipation, the clinical score after administration of DKT (7.2 +/- 0.8) improved significantly compared with that before administration of DKT (4.6 +/- 2.9) (p < 0.02). The threshold sensation volume and the maximum tolerable volume after administration of DKT significantly (p < 0.05; p < 0.01) decreased (128 +/- 63 ml vs. 69 +/- 18 ml; 229 +/- 99 ml vs. 144 +/- 47 ml), and rectal compliance after administration of DKT also significantly (p < 0.05) decreased (12.4 +/- 10.9 ml/cmH(2)O vs. 4.7 +/- 3.9 ml/cmH(2)O). CONCLUSION: The present study demonstrated that DKT had a favorable clinical effect on severe constipation in children, and anorectal manometry showed an improvement in their rectal reservoir functions. It appears that the results were secondary to DKT-stimulated peristalsis of the intestine, which promoted regular bowel habits.

Bleeding tendency as a first symptom in children with congenital biliary dilatation.

AIM OF THE STUDY: Although a bleeding tendency as a first symptom is a critical condition in congenital biliary dilatation (CBD), the clinical details of this symptom remain unclear. We assessed this condition in children with CBD in this paper. MATERIALS AND METHODS: Sixty-five children with CBD were treated at our institute between 1983 and 2004. The children, initially presenting with bleeding manifestations such as intracranial hemorrhage and bloody stools, were defined as the bleeding group, and the remaining children with digestive symptoms such as abdominal pain and vomiting were defined as the digestive group. The clinical features were compared between these two groups. RESULTS: In 6 of the 65 cases, bleeding manifestations were noted (9.2 %). All six had cystic-type choledochal dilatation. The mean age of the bleeding group was significantly younger than that of the digestive group, and bleeding was more frequent, especially in infants less than 12 months of age. In a laboratory study, the bleeding group showed a more prolonged blood coagulation time than the digestive group did. Serum amylase and lipase levels in the bleeding group were almost normal, while those in the digestive group were significantly higher. The direct bilirubin level in the bleeding group was significantly higher than that in the digestive group. CONCLUSIONS: Disturbed blood coagulation due to vitamin K deficiency related to cholestasis results in a bleeding tendency in children with CBD. Therefore, pediatric surgeons should be aware of this rare but critical condition which can be prevented by rapid and precise treatment with vitamin K supplementation.

Prevention of warm ischemic injury by neuropeptide bombesin in small bowel transplantation.

PURPOSE: This study investigated whether preoperative administration of neuropeptide bombesin (BBS) had a protective effect against IR/I and subsequent acute rejection. METHODS: Allogeneic SBTx was performed heterotopically in rats (n = 18). That were administered FK506 (0.32 kg/d) daily. The rats were divided into three groups of six rats each: group 1, BBS(-)5: warm ischemic time (WIT); 5 minutes without BBS; group 2, BBS(-)15: WIT; 15 minutes without BBS; group 3, BBS(+)15: WIT; 15 minutes with BBS. The specimens were obtained from the stoma site at 1 hour after reperfusion and on postoperative days (PODs) 1 and 7. The graft mucosal state and degree of acute rejection were evaluated by H and E staining. The apoptotic cells in the crypt lesion were evaluated using TUNEL immunohistochemistry. An apoptotic index (AI) was calculated for quantitative analysis. RESULTS: H and E staining revealed that on POD 1 the mucosal villi were shortened in the BBS(-)15 group compared with the other two groups. One hour after reperfusion, the AI in BBS(-)15 group was 125.0 per thousand +/- 37.2 per thousand, which was significantly higher (P < .05) than that in the BBS(-)5 group (32.6 per thousand +/- 5.0 per thousand) or the BBS(+)15 group (32.0 per thousand +/- 3.0 per thousand). On POD 7, the AI in the BBS(-)15 group was 63.7 per thousand +/- 5.03 per thousand, which was significantly higher (P < .05) than in the BBS(-)5 (17.3 per thousand +/- 4.6 per thousand) or the BBS(+)15 group (12.3 per thousand +/- 3.06 per thousand). CONCLUSIONS: Even a short WIT of 15 minutes induced considerable allograft mucosal damage, which also heightened the possibility of acute rejection. Exogenous BBS prevented mucosal damage by IR/I and was also beneficial to prevent acute rejection.

FK506 induces the atrophy of enteric ganglia in small bowel transplantation, which can be prevented by the neuropeptide bombesin.

PURPOSE: FK506, which is widely used for immunosuppression, is reported to have neurotoxicity. However, its neurotoxicity for transplanted graft enteric ganglia (TGEG) has never been reported. The aim of this study was to investigate whether FK506 has a neurotoxic effect on TGEG, and whether bombesin (BBS) prevents such atrophy. METHODS: Eighteen rats that underwent syngertic heterotopic small bowel transplantation (SBTx) using a cuff method were divided into three groups of six rats each; A: SBTx alone, B: SBTx with FK506, C: SBTx with FK506/BBS. Either BBS (10 mg/kg/d) or normal saline was infused continuously from day 14 to 28. Rats in groups B and C were administered FK506 (0.32 mg/kg/day, intramuscularly) daily. Analysis of TGEG was performed using immunohistochemistry with protein gene product (PGP) 9.5. The ganglionic number was obtained by counting PGP9.5-positive ganglia in each graft. RESULTS: The number of TGEG were reduced significantly in group B (51.5 +/- 7.7 ganglia per cross section (G/CS)) compared with group A (69.7 +/- 6.0 G/CS), but were well preserved in group C (84.8 +/- 10.2 G/CS). There were significant differences between groups B and C (P < .001) and also between groups A and C (P < .001). CONCLUSION: FK506 showed severe neurotoxicity on transplanted grafts, and bombesin could rescue TGEG against FK506 neurotoxicity.

Neuroendocrine-immune modulation may be useful for allograft-specific immunosuppression in small bowel transplantation.

PURPOSE: The authors have previously demonstrated that the neuropeptide bombesin (BBS) prevented allograft mucosal atrophy under tacrolimus (TRL) immunosuppression for rats small bowel transplantation (SBT). The present study investigated whether BBS had immunosuppressive effects on small bowel allografts. METHODS: Allogeneic SBT was performed heterotopically in rats (n = 12) that received daily administration of 0.1 mg/kg/d TRL from postoperative day 0 to day 14. Rats divided into two groups of six rats each were administered BBS or normal saline as a control. Biopsy of the allograft was performed from the stomal site on postoperative days 6, 10, and 14. The state of the graft mucosal villi was evaluated by H & E staining and TUNEL immunohistochemistry. RESULTS: By postoperative day 14, extensive mucosal destruction accompanied by heavy transmural cellular infiltration had developed in the control group. Lymphocytes and plasma cells infiltrated the lamina propria of the allograft without the distorting villous architecture in the BBS group. The TUNEL index of graft mucosa in the control group was 1.26% +/- 0.37% (mean +/- SD) and that in the BBS group, 0.59% +/- 0.20%, respectively (p < .001). CONCLUSION: This study demonstrated an immunosuppressive effect of bombesin on transplanted allografts, which might dramatically reduce the dose of TRL required for postoperative immunosuppression.

Morphology of the enteric nervous system in the hindgut of an infant with cloacal exstrophy.

The authors describe the morphology of the enteric nervous system in the hindgut of an infant with cloacal exstrophy. Cloacal exstrophy was diagnosed at 32 weeks' gestation using prenatal ultrasonography. The baby was delivered at 34 weeks' gestation and underwent a separation of the cecum from bladder halves, reapproximation of hemibladders, closure of the omphalocele and pubic symphysis, and a distal colostomy. Intestinal wall specimens were obtained at colostomy from the distal end of the rudimentary hindgut. Serial frozen sections were prepared for histochemical acetylcholinesterase staining. Histological investigations demonstrated a strikingly crowded, immature enteric ganglia and prominent bundles of wandering cholinergic nerves. These findings suggest the unique pathology of the enteric nervous system development in cloacal exstrophy, in which the rudimentary hindgut behaves as a blind alley of the migratory pathway for neural crest-derived cells during embryogenesis. Histological examinations of the hindgut enteric nervous system in cloacal exstrophy may be beneficial for evaluating the postnatal development of the distal colon which might be utilized for a pull-through procedure.

Alteration of cell adhesion and cell cycle properties of ES cells by an inducible dominant interfering Myb mutant.

The Myb transcription factors, c-Myb, A-Myb, and B-Myb, regulate cell differentiation and/or proliferation. To investigate the role of B-Myb in embryogenesis, we introduced an inducible dominant interfering Myb protein (MERT) into embryonic stem (ES) cells, which express B-Myb as an exclusive member of Myb family. Disruption of normal B-Myb function by the conditional activation of MERT caused a drastic morphological alteration of ES cells and G(1)-S cell cycle arrest. The inhibition of B-Myb function by MERT dissociated tightly packed ES cell colonies into dispersed single cells that subsequently detached from the culture dish. Cell adhesion analyses revealed that suppression of B-Myb function reduced the adhesion with extracellular matrix proteins, such as laminin, collagen, and fibronectin. This reduction was presumably due to decreased cell surface expression of beta1 integrin. Embryoid body formation was also severely retarded by the activation of MERT. This impairment was attributed to reduced expression of E-cadherin, which functions as a homophilic intercellular adhesion molecule. Simultaneously, blocking B-Myb function did not alter the expression of differentiation markers. Our data indicate that B-Myb plays important roles in regulating cell adhesion and cell cycle progression. These results are well consistent with the recent report on the phenotype of B-Myb null mice and show that the regulation of cell adhesion is an important B-Myb function that has not yet been assumed.

Chromosomal mapping of quantitative trait loci that influence renal hemodynamic functions.

BACKGROUND: Impaired renal hemodynamic function has been suspected to be responsible for hypertension in the spontaneously hypertensive rat (SHR). METHODS AND RESULTS: We measured renal hemodynamic functions, including the glomerular filtration rate, renal plasma flow, and renal vascular resistance, in an F2 rat population derived from spontaneously hypertensive and Wistar-Kyoto (WKY) rats and performed a genome-wide screening to map quantitative trait loci that influence these functions to gain insight into the relationship between renal hemodynamic functions and blood pressure control. The D1 Mit7 locus was identified as a major locus that influenced renal hemodynamic functions, and we transferred the SHR chromosomal segment around the D1 Mit7 locus into the WKY strain. The congenic rats exhibited impaired renal hemodynamic functions. The systolic blood pressure of the congenic rats was significantly higher than that of age-matched WKY rats, but only at nighttime. No significant differences in systolic blood pressure during daytime or diastolic blood pressure were observed between the 2 strains. CONCLUSIONS: We have identified a chromosome segment that influences renal hemodynamic function. The SHR chromosome segment around the D1 Mit7 locus had significant, but not dramatic, effects in increasing blood pressure in the WKY genetic background. However, further studies will be necessary to determine the significance of this locus in SHR hypertension.

Human prostacyclin synthase gene and hypertension : the Suita Study.

BACKGROUND: Prostacyclin (prostaglandin I(2)) is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. Therefore, it has been considered to play an important roles in cardiovascular disease. On the basis of the hypothesis that variations of the prostacyclin synthase gene may also play an important role in human cardiovascular disease, we performed a screening for variations in the human prostacyclin synthase gene. METHODS AND RESULTS: We have detected a repeat polymorphism in the promoter region of the human prostacyclin synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region, which encodes a tandem repeat of Sp1 transcriptional binding sites, varied between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter activity in cultured human umbilical vein endothelial cells. We then investigated the possible association of this repeat polymorphism with blood pressure in a large population-based sample (the Suita Study), which consisted of 4971 Japanese participants. Multivariate models indicated that participants with the R3R3, R3R4, or R4R4 genotype (SS genotype, n=80) had significantly higher systolic pressure (P=0.0133) and pulse pressure (P=0.0005). The odds ratio of hypertension (140/90 mm Hg) for the SS genotype was 1.942 (95% confidence interval 3.20 to 1.19, P=0.0084). CONCLUSIONS: Repeat polymorphism of the human prostacyclin synthase gene seems to be a risk factor for higher pulse pressure and is consequently a risk factor for systolic hypertension in the Japanese population.

The 3'-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in the type 2 diabetic Japanese population.

A newly identified 3'-untranslated region (UTR) polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PPP1R3) was associated with insulin resistance and type 2 diabetes in Pima Indians (Xia J, Scherers W, Cohen PTW, Majer M, Xi T, Norman RA, Knowler WC, Bogardus C, Prochazka M: A common variant in PP1R3 associated with insulin resistance and type 2 diabetes. Diabetes 47:1519-1524, 1998). Thus, we investigated the frequency of polymorphism of the adenine- and thymine-rich element (ARE-1 and its variant ARE-2) in 426 Japanese type 2 diabetic and 380 nondiabetic subjects using a polymerase chain reaction (PCR)-restriction enzyme fragment length polymorphism (RFLP) method. The allele frequency of the ARE-2 variant in diabetic subjects was higher than that in nondiabetic subjects (0.34 vs. 0.29; P < 0.05), even though its frequency in Japanese subjects was lower (P < 0.001) than the reported value in Pima Indians (0.56). An aspartate polymorphism at codon 905 was 100% coupled to the ARE-2 allele, and its allele frequency was higher also in diabetic subjects. Although a serine substitution at codon 883 was partially linked with the ARE-2 allele, there was no difference between diabetic and nondiabetic subjects. These results indicate that the frequency of polymorphism of the PPP1R3 gene (ARE-2 and Asp905) is different between two ethnic groups and is increased in Japanese people with type 2 diabetes, suggesting that these variants may be a possible marker for searching for diabetogenic genes.

A clinical analysis of prognostic parameters of survival in children with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) still has a high mortality because of accompanying lung hypoplasia and persistent pulmonary hypertension. Although prognostic parameters based on perinatal measurements have been proposed, our ability to accurately predict the surgical results remains insufficient. METHODS: We treated 55 infants with CDH from 1981 to 2004. Among them, 46 patients presented respiratory distress within the first 24 hours of life. Results of surgical treatment in the 46 infants were retrospectively correlated with gender, birth weight, gestational age at diagnosis, laterality, cardiac anomalies, diaphragmatic defect area, contents of herniated viscera, and the great vessel diameters measured by echocardiography. RESULTS: Out of 46 CDH neonates, 27 (58.7 %) survived and 19 (41.3 %) died aged 3 to 17 days. Non survivors had a significantly larger diaphragmatic defect and more frequent liver herniation. Out of possible predictive parameters studied, an index of the main pulmonary artery (cross-sectional area/diaphragmatic defect area ratio) most closely correlated with the surgical outcomes. CONCLUSIONS: The postoperative prognosis of CDH infants does not depend only on pulmonary hypoplasia, but also on other factors including the magnitude of abdominal visceral herniation. In this series of patients, the most reliable prognostic predictor was a clinical index reflecting the degree of both pulmonary hypoplasia and diaphragmatic maldevelopment.

Proliferation and cell death of embryonic primitive erythrocytes.

Erythropoietin (EPO) is the principal regulator for the production of adult-type definitive erythrocytes (EryD). EPO not only stimulates both the proliferation and differentiation of EryD progenitors, but also maintains the viability of EryD progenitors. Compared to the abundant knowledge about the function of EPO in EryD production, the roles of EPO in the production of embryonic-type primitive erythrocytes (EryP) are less clear. The effects of EPO on EryP proliferation and differentiation were investigated using EryP purified from developing mouse embryos and the cells obtained from mouse embryonic stem cells using an in vitro differentiation induction. Immature EryP of both in vivo and in vitro origin responded to EPO stimulation and underwent apoptosis with EPO deprivation. In contrast, there were no significant differences between the cultures with and without EPO, when fully mature EryP were examined, that is, EryP lost its dependency on EPO stimulation with maturation. These results show that EPO functions as a survival factor for immature embryonic EryP as well as immature EryD progenitors.

Isolation of preferentially expressed genes in the kidneys of hypertensive rats.

By differential hybridization, three complementary DNAs designated as S3, S2, and SA were isolated, and the corresponding messenger RNAs (mRNAs) were differentially expressed between the kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. S3 is identical to cytochrome P450 IV A2. SA encoded a protein of 546 amino acid residues, and its carboxyl terminal region had a slight homology to luciferase. No homologous sequence has been reported in S2 sequences. S3 mRNA was about four times more abundantly expressed in the kidneys of 28-day-old SHR than in those of age-matched WKY rats, but there was no difference at age 16 weeks. A low NaCl diet positively modulated the expression of the S3 gene. S2 mRNA was almost undetectable in the kidneys of 28-day-old WKY rats but was clearly detected in those of age-matched SHR. The expression level of S2 mRNA in the livers of 16-week-old SHR was about five times higher than that of age-matched WKY rats. The expression of S2 mRNA in the livers was modulated by dietary NaCl and captopril. SA mRNA was more than 10 times more abundantly expressed in the kidneys of SHR than in those of WKY rats from age 4 weeks. With the administration of captopril, the expressions of SA mRNA in the livers of SHR were positively modulated. Because these three genes are not only differentially expressed between SHR and WKY rats but also related to sodium metabolism or blood pressure control, the identification of these genes may provide important probes to examine the mechanisms of hypertension.

Genetic analysis of renin gene expression in rat adrenal gland.

We examined the mechanism of the increased renin mRNA concentration in the adrenal glands of spontaneously hypertensive rats (SHR). In 52 female F2 rats (25 to 27 weeks of age) derived from SHR and Wistar-Kyoto rats, we determined blood pressure, renin mRNA concentration in the adrenal gland, plasma renin activity, plasma aldosterone concentration, and genotype of the renin gene. Eighteen of the F2 rats were fed a high salt (8%) diet for 14 days. The renin mRNA concentration in the adrenal glands showed a significant correlation with the genotype of the renin gene in the normal salt diet group (P <.0001), whereas this relationship was not observed in the high salt group. Multivariate analysis revealed that the plasma aldosterone concentration in the normal diet group was significantly explained (P=.0004, R2=.454) by plasma renin activity (P=.0005), the renin mRNA concentration in the adrenal gland (P=.0496), and the genotype of the renin gene (P=.0236). The SHR allele of the renin gene was associated with a lower aldosterone concentration. On the other hand, in the high salt diet group, only the genotype of the renin gene showed a significant relationship with plasma aldosterone concentration (P=.0237). Again, the SHR allele of the renin gene was associated with a lower aldosterone concentration. We can conclude that the higher renin mRNA concentration in the SHR adrenal glands is governed by the SHR allele of the renin gene or renin gene locus. The renin mRNA concentration in the adrenal gland exerts a minor influence on aldosterone synthesis. Paradoxically, the SHR allele of the renin gene or renin gene locus confers a lower rate of aldosterone synthesis at 25 to 27 weeks of age, the mechanism of which remains to be determined.