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Biomedical subjects

R Konda

Publications and source records attributed to R Konda.

At least 19 recordsLinked to original sources

Clinical significance of urinary interleukin-6 in children with reflux nephropathy.

PURPOSE: We determined urinary interleukin-6 (IL-6) in children with reflux nephropathy to evaluate the clinical significance of this cytokine in the progression of renal injury. MATERIALS AND METHODS: Enrolled in this study were 34 boys and 32 girls in whom 99mtechnetium dimercapto-succinic acid renal scan showed renal scarring. Vesicoureteral reflux had been corrected surgically at least 3 years before study entry. Urinary IL-6 was determined by enzyme-linked immunosorbent assay using spot urine samples. Simultaneously we measured serum creatinine, beta2-microglobulin, alpha1-microglobulin, urinary alpha1-microglobulin and albumin. In addition, IL-6 expression was assessed by immunohistochemical study in the scarred kidneys of 3 boys and 1 girl who underwent nephrectomy due to severe reflux nephropathy with little function on renal scan. RESULTS: Urinary IL-6 was significantly higher in children with severe bilateral renal scarring than in those with mild scarring and normal controls. Urinary IL-6 correlated significantly with serum alpha1-microglobulin (Spearman test p <0. 03), beta2-microglobulin (p <0.003), creatinine (p <0.02) and urinary albumin (p <0.0001). Histological evaluation revealed that IL-6 was predominantly expressed in the tubules in and adjacent to fibrotic areas. CONCLUSIONS: Our observations indicate that tubular IL-6 may be involved in the pathogenesis of tubulointerstitial injury in reflux nephropathy and urinary IL-6 may be a useful tool for monitoring the progression of reflux nephropathy.

Adolescent↗

Renin containing cells are present predominantly in scarred areas but not in dysplastic regions in multicystic dysplastic kidney.

PURPOSE: Hypertension is an important complication of multicystic dysplastic kidney and it has been suggested that it is induced by renin. Little information is available on renin production in this disease. To assess renin production we examined the distribution of renin containing cells in multicystic dysplastic kidneys using immunohistochemical methods. MATERIALS AND METHODS: Immunohistochemical examination of renin was performed in 29 multicystic dysplastic kidneys from 14 boys and 15 girls 1 month to 10 years old using rabbit anti-human renin antibodies. In all cases normal renal function was confirmed by the serum creatinine level and no proteinuria on urinalysis. Two patients had the complication of hypertension before removal of the multicystic dysplastic kidney but plasma renin activity was normal. RESULTS: Immunostaining of renin was observed in 26 of 29 multicystic dysplastic kidneys (90%). Histologically multicystic dysplastic kidney involved scarred and dysplastic areas. Renin positive cells were observed predominantly in the scarred areas, mainly in the juxtaglomerular apparatus of mature glomeruli, interlobular arteries and some mature tubules. Immunopositive renin was sparsely noted in the juxtaglomerular apparatus or Bowman's capsules of occasional immature glomeruli in dysplastic areas. CONCLUSIONS: Our observations suggest that multicystic dysplastic kidney may have the ability to produce renin. Renin producing cells in the juxtaglomerular apparatus of mature glomeruli and interlobular arteries in the scarred areas may be the predominant source of renin production in this organ.

Female↗

Role of leukocyte adhesion molecules in monocyte/ macrophage infiltration in weanling rats with unilateral ureteral obstruction.

BACKGROUND: Unilateral ureteral obstruction (UUO) of rats is a well-established model for studying obstructive nephropathy. Meanwhile, pathophysiology of pediatric obstructive nephropathy is not well understood. In this report, we studied monocyte/macrophage infiltration and expression of intercellular adhesion molecule 1 (ICAM-1) and macrophage antigen 1 (Mac-1) in weanling rats with UUO. METHODS: Three-week-old male Sprague-Dawley rats underwent left unilateral ureteral ligation. Both obstructed kidneys (OBK) and contralateral kidneys (CLK) were harvested at 3, 6, 12, 24, 72 and 120 h after surgery. Monocyte/macrophage infiltration and expression of ICAM-1 and Mac-1 were evaluated immunohistochemically, and results were compared with those of sham-operated control rats (SOK). RESULTS: Monocyte/macrophage infiltration was observed in the interstitium and perivascular region in the cortex of OBK within 6 h. The CLK and SOK showed slight monocyte/macrophage infiltration. Expression of ICAM-1 was markedly observed in the periarterial and peritubular interstitium and in renal cortical peritubular capillaries 12 h after obstruction. In CLK and SOK, ICAM-1 was slightly expressed in the endothelium of microvessels and parietal linings of Bowman's capsule. Expression of Mac-1 was detected mainly in cells infiltrating the perivascular interstitium in OBK. In CLK and SOK, few Mac-1-positive cells were observed. CONCLUSIONS: Adhesion molecules, ICAM-1 and Mac-1, are expected to recruit monocyte/macrophage infiltration into OBK of weanling rats with UUO.

Animals↗

Expression of platelet-derived endothelial cell growth factor and its potential role in up-regulation of angiogenesis in scarred kidneys secondary to urinary tract diseases.

The mechanism of neovascularization secondary to renal interstitial fibrosis is not well understood. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to promote angiogenesis. We examined the expression of PD-ECGF immunohistochemically in 9 normal kidneys and 26 scarred kidneys secondary to urinary tract diseases. To estimate up-regulation of angiogenesis, microvessels were counted by immunostaining endothelial cells for CD34. Immunostaining of PD-ECGF was observed in most Bowman's capsules, occasional tubules, and some interstitial mononuclear cells in normal kidneys. A remarkable increase of immunostained PD-ECGF was found in the tubules and interstitial mononuclear infiltrates in the scarred kidneys. The predominant cell type in the infiltrate was T cells (CD3(+)). The microvessel count and mean numbers of PD-ECGF(+) tubular and interstitial mononuclear cells increased with increasing interstitial fibrosis. A significant correlation was noted between microvessel count and the number of PD-ECGF(+) tubular cells (P = 0.0002) or PD-ECGF(+) interstitial mononuclear cells (P < 0.0001). Immunostaining of endogrin, a marker of endothelial proliferation, increased in the microvessels located in the fibrotic interstitial spaces. These results suggest that angiogenesis may play a critical role in the progression of tubulointerstitial injuries and that up-regulation of PD-ECGF may contribute to neovascularization.

Adolescent↗

Soluble interleukin-2 receptor in children with reflux nephropathy.

PURPOSE: Serum soluble interleukin-2 receptor level is a sensitive and quantitative marker of lymphocyte activation. We determined levels of serum soluble interleukin-2 receptor in children with reflux nephropathy to evaluate its clinical significance in the prediction for the progression of renal injuries. MATERIALS AND METHODS: Serum soluble interleukin-2 receptor values were determined in 63 children with reflux nephropathy. The group consisted of 37 boys and 26 girls 10 to 18 years old. T cells (naive and memory), B cells and macrophages were evaluated immunohistochemically in the scarred kidneys of 4 other patients (3 boys and 1 girl 5 to 16 years old) who underwent nephrectomy due to severe reflux nephropathy with little function seen on (99m)technetium-dimercapto-succinic acid (DMSA) renal scan. Levels of serum soluble interleukin-2 receptor were measured by an enzyme-linked immunosorbent assay. We simultaneously determined serum levels of creatinine and beta2-microglobulin, and urinary levels of alpha1-microglobulin and microalbumin. Individual functions of the right and left kidneys were estimated by renal dimercaptosuccinic acid uptake. RESULTS: Levels of serum soluble interleukin-2 receptor in the patients who had low total uptake of DMSA (right uptake plus left uptake) were significantly higher than those from patients with normal total uptake. Levels of serum soluble interleukin-2 receptor correlated significantly with levels of creatinine (r=0.616, p <0.0001) and beta2-microglobulin (r=0.803, p <0.0001), and levels of urinary alpha1-microglobulin (r=0.753, p <0.0001) and microalbumin (r=0.673, p <0.0001). A significant negative correlation was observed between levels of serum soluble interleukin-2 receptor and total DMSA uptake values (right uptake plus left uptake r=-0.678, p <0.0001). In the scarred kidneys leukocyte infiltrates were markedly increased in fibrosed spaces. The predominant cell type in these lesions was memory T cells. CONCLUSIONS: These results suggest that elevated levels of serum soluble interleukin-2 receptor are likely to reflect activated T cells in the kidneys of patients with reflux nephropathy and may be a useful predictor of progression of renal injury in these children.

Adolescent↗

Neonatal urinary ascites caused by urinary tract obstruction: two case reports.

Two cases of neonatal urinary ascites are reported, one (case 1) caused by posterior urethral valves associated with right vesicoureteral reflux, and the other (case 2) secondary to bilateral obstructed megaureter--a very rare cause. Abdominal distension, electrolyte imbalance, and an elevated BUN/serum creatinine ratio were noted at the time of hospitalization in both cases. These laboratory values promptly returned to normal after the establishment of appropriate urinary drainage, accomplished through bladder catheterization in case 1 and bilateral percutaneous nephrostomy in case 2. In case 1, transurethral resection of the posterior urethral valves was followed by resumption of normal urination. In case 2, bilateral ureteroneocystostomy with ureteral tapering was performed successfully. These are only the fifth and sixth cases of neonatal urinary ascites reported in the Japanese literature.

Ascites↗

[The intrarenal distribution of prostaglandin E2 and thromboxane A2 in the rat with unilateral ureteral obstruction or unilateral nephrectomy].

BACKGROUND: We evaluated the intrarenal distribution of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) on the rats that underwent unilateral ureteral obstruction (UUO), unilateral nephrectomy (UNX) or sham operation. METHODS: Male Sprague-Dawley rats were divided into three groups; left ureteral obstruction (UUO), left nephrectomy (UNX) and sham-operation (Control). They were sacrificed at 1, 3, 6, 12, 24 hours and Day 2, Day 3, Day 5, Day 7 and Day 9 after surgery. Intrarenal distribution of eicosanoids were immunohistochemically detected on both kidneys of UUO rats, and on right kidneys of UNX and Control rats. RESULTS: PGE2: In the obstructed kidneys, immunostained PGE2 increased in medullary interstitium at one hour to 6 hours, and in glomeruli and cortical interstitium at 6 hours. An increase of immunostained PGE2 was observed again in cortical interstitium at Day 3 to 5, and in medullary interstitium at Day 2 to 5. In the intact opposite kidneys, expression of immunostained PGE2 increased in glomeruli at Day 5 to 7, and in medullary interstitium at Day 3 to 5. In UNX, immunostained PGE2 increased in the medullary interstitium of the remnant kidneys at 3 hours and Day 3 to 7. On the other hand, an increase of immunostained PGE2 observed in glomeruli and cortical interstitium of these kidneys at Day 5 to 7. TxB2: In the obstructed kidneys, immunostained TxB2 increased in glomeruli and cortical interstitium at 6 hours, and in medullary interstitium at 3 to 12 hours. Predominant expression of TxB2 was observed in medullary interstitium at 3 hours compared to PGE2. We also observed an increase of immunostained TxB2 in cortical interstitium at Day 3 to 5, and in medullary interstitium at Day 2 to 5. In the intact opposite kidneys, immunostained TxB2 increased in medullary interstitium at 3 hours and Day 3. In the remnant kidneys of UNX, an increase of immunostained TxB2 was demonstrated in glomeruli at 6 hours and Day 7, and in medullary interstitium at 3 to 6 hours and Day 3 to 7. CONCLUSION: In the obstructed kidneys, imbalance between PGE2 and TxA2 may contribute to the progression of renal injuries. The fact that expression patterns of these eicosanoids in the opposite kidneys of UUO different from that of the remnant kidneys of UNK, even though both were similarly associated with functional loss of contralateral kidneys, suggested that the opposite kidneys of UUO were affected by any additional factors different from that responsible for the remnant kidneys of UNK.

Animals↗

Hydrometrocolpos with ectopic vaginal opening to the bladder. A case report.

A case of hydrometrocolpos with vaginal opening to the bladder is presented. A newborn female presented abdominal distention and postaxial polydactyly at birth. Clinical investigation revealed hydrometrocolpos, precocious puberty, urogenital sinus and other multiple malformations. The vagina was open to the bladder with a small orifice. Vaginal pull-through surgery and closure of the communication was performed. Over a hundred cases of hydrometrocolpos have been reported previously. However, we could not find a case of hydrometrocolpos with vaginal opening to the bladder among them.

Female↗

[Laparoscopic investigation of 74 cases of nonpalpable testis].

BACKGROUND: The objective of this study is to evaluate the results and advantages of laparoscopic investigation of nonpalpable testis. METHOD: Since March 1986 to May 1996, we performed laparoscopy to investigate 88 nonpalpable testes of 74 cases under general anesthesia. On condition that testis was found intraabdominally, orchiectomy or orchiopexy was performed subsequently. With a finding of vas deferens and/or spermatic vessels entering into internal ring, inguinal canal was explored surgically. If both vas deferens and spermatic vessels were absent or blind-ending intraabdominally, no further examination was performed with a diagnosis of vanishing testis. RESULTS: Location of testes found in this study were as follows. Twenty three (26.1%) testes were found intraabdominally, 36 (40.9%) were intracanalicularly, 13 (14.8%) were distal to external inguinal ring, and 16 (18.2%) were vanishing testes. To those 39 (44.3%) intraabdominal and vanishing cases did not need inguinal exploration. CONCLUSION: In conclusion, a laparoscopic examination for nonpalpable testis is the most effective and less invasive procedure to make sure or preclude the location of the gonad. And in 18% of those who were enrolled in this study, no further surgical interventions were needed. An accurate locating of nonpalpable testis permits site-specific planning of surgical management.

Adolescent↗

Followup study of renal function in children with reflux nephropathy after resolution of vesicoureteral reflux.

PURPOSE: We evaluated data collected for 10 years on children with reflux nephropathy to identify a means of predicting the prognosis. MATERIALS AND METHODS: A total of 15 boys and 13 girls were enrolled in this study at least 2 years after surgical and spontaneous resolution of vesicoureteral reflux in 25 and 3 patients, respectively. They were followed for more than 10 years and renal function was periodically evaluated. Urinary beta 2-microglobulin, alpha 1-microglobulin, N-acetyl-beta-D-glucosaminidase, microalbumin and 99mtechnetium dimercapto-succinic acid uptake were measured. RESULTS: Of the 28 patients 12 had high levels of urinary alpha 1-microglobulin during followup, including all 7 in whom renal function deteriorated. In 3 children with elevated alpha 1-microglobulin urinary microalbumin gradually increased after puberty. Although elevated levels of urinary beta 2-microglobulin, N-acetyl-beta-D-glucosaminidase and microalbumin were also observed, they were less predictive of renal function than alpha 1-microglobulin. CONCLUSIONS: These results suggest that elevated urinary levels of alpha 1-microglobulin may predict the risk of abnormal renal function in children with reflux nephropathy even before the appearance of significant proteinuria.

Acetylglucosaminidase↗

Urinary excretion of epidermal growth factor in children with reflux nephropathy.

PURPOSE: We determined urinary levels of epidermal growth factor in children with reflux nephropathy to evaluate the clinical significance of urinary epidermal growth factor. MATERIALS AND METHODS: We studied 59 boys and 41 girls 3 to 15 years old with reflux nephropathy, and 64 boys and 36 girls 3 to 15 years old who were healthy. Levels of urinary epidermal growth factor were determined by sandwich enzyme immunoassay using spot urine samples. We also determined the levels of serum creatinine, urinary alpha 1-microglobulin and urinary microalbumin. Absolute values of function of the left and right kidneys were assessed by 99mtechnetium dimercapto-succinic acid (DMSA) uptake. RESULTS: Levels of urinary epidermal growth factor gradually decreased with age in healthy children. There were low levels of urinary epidermal growth factor in 20 of the 44 patients (45%) with unilateral low DMSA uptake and 18 of the 19 (95%) with low total DMSA uptake (right and left uptakes). Urinary epidermal growth factor significantly correlated with serum creatinine (R = -0.702, p < 0.0001), urinary alpha 1-microglobulin (R = -0.606, p < 0.0001), urinary microalbumin (R = -0.708, p < 0.0001) and total DMSA uptake (R = 0.744, p < 0.0001). CONCLUSIONS: These results suggest that urinary epidermal growth factor may be a useful clinical tool to monitor functional nephron mass in children with reflux nephropathy.

Adolescent↗

[Renal function in children with reflux nephropathy followed up more than 10 years after disappearance of vesicoureteral reflux: usefulness of alpha 1-microglobulin as a marker to predict the prognosis of these children].

BACKGROUND: Although reflux nephropathy (RN) is one of the most important causes of renal failure in adolescence and young adulthood, we have no appropriate markers to know the future course of children with RN. In order to find out useful marker to predict the prognosis of these children, we analyzed the result of over ten years follow-up of children with RN. METHODS: We evaluated renal function in 25 patients (aged between 11 years and 23 years, 14 males and 11 females) with RN using urinary alpha 1-microglobulin (alpha 1 m), urinary albumin and 99mTc-dimercaptosuccinic acid (DMSA) renal scan. All patients were followed up more than 10 years after disappearance of vesicoureteral reflux. RESULTS: Of 25 patients, 13 showed high levels of urinary alpha 1 m (> 4.4 mg/gCr = upper normal limit) during follow-up period. Among them, renal dysfunction developed in 9 on DMSA renal scan and/or serum creatinin (Cr) level. Before puberty, all patients, even children with renal dysfunction (serum Cr > 1.0 mg/dl), remained in normal or slight high urinary albumin levels. Five cases, showed high levels of urinary alpha 1 m before puberty, demonstrated a remarkable increase of urinary albumin levels after puberty. CONCLUSION: From these results, it was suggested that urinary levels of alpha 1 m could be utilized as a marker to predict the prognosis of children with RN.

Alpha-Globulins↗

[Eighteen cases of multicystic kidney: natural history and renal function of the contralateral kidney].

PURPOSE: The objective of this study is to evaluate natural history of multicystic kidney (MCK) and renal function of the contralateral kidney. METHODS: We analyzed 18 children (7 boys and 11 girls) with unilateral MCK. The sizes of cysts were investigated by ultrasonography. Urinary beta 2-microgloblin (beta 2 m), alpha 1-microgloblin (alpha 1 m) and N-acetyl-beta-D-glucosaminidase (NAG) and albumin were determined as markers of tubular and glomerular damage. The renal function was evaluated by 99m Tc-dimercaptosuccinic acid (99 m Tc-DMSA) renal uptake rate. RESULTS: Nephrectomy was performed in 2 children. In 14 (87.5%) of 16 cases who were followed conservatively, the size of cysts was spontaneously reduced by 1-18 months (mean 6.4). Neither hypertension nor malignancy from the affected kidney has been observed in follow-up periods of 6-63 months. One patient had minor degree of contralateral ureteral dilatation which resolved spontaneously. Lower DMSA uptake rate of contralateral kidney was demonstrated in 63% (10/16). Markers of tubular damage were abnormally high in these patients. CONCLUSION: From these results, the most appropriate management of MCK is conservative with ultrasonic monitoring. Long-term follow-up testings with special care on contralateral renal function will be necessary because the overload to the contralateral healthy kidney may have already occurred during infancy and cause focal glomerulosclerosis and renal failure in future.

Aging↗

The distribution of renin containing cells in scarred kidneys.

PURPOSE: To evaluate changes in renal renin synthesis secondary to renal scarring from urinary tract disease, we investigated the immunohistochemical distribution of renin in normotensive children with scarred kidneys and determined whether renal renin content correlates with the degree of interstitial fibrosis. MATERIALS AND METHODS: We performed semiquantitative analysis of the immunohistochemical distribution of renin using rabbit anti-human renin antibody in the scarred kidneys of 3 boys and 17 girls with urinary tract disease. RESULTS: Immunoreactive renin was mainly present within the afferent arteriole. Immunostaining of the juxtaglomerular apparatuses, interlobular arteries and renin containing cells increased with the degree of interstitial fibrosis. Glomeruli disjointed from proximal tubules, that is atubular glomeruli, were observed in fibrosed areas and renin was distinctly noted in the juxtaglomerular apparatus of atubular glomeruli. CONCLUSIONS: Scarred areas may be responsible for the hyperproduction of renin and angiotensin II, which in turn promotes renal scarring and an increase in atubular glomeruli. This cycle may lead to progressive renal scarring.

Adolescent↗

Crossed ureteral ectopia with an ectopic blind-ending ureter.

A rare case of multiple urological anomalies is presented. The chief complaint of the patient, a 12-year-old girl, was urinary incontinence. Radiologic and endoscopic examinations revealed that the patient had a normal left kidney and ureter, a left ectopic blind-ending ureter that opened near the neck of the bladder, and right complete double ureters with an ectopic orifice that opened on the left of the external urethral meatus. This orifice was responsible for her urinary incontinence. Right ureteroneocystostomy was performed and the incontinence was cured. An attempt was made to explain the embryological origin of the anomalies observed in this case. We postulated that during development, on the left, there were three ureteral buds on the mesonephric duct. The first bud was at the normal position and drained the left kidney in a normal manner. The second bud was cranial from the normal position on the mesonephric duct and was associated with growth in an abnormal direction. This bud made contact with the upper portion of the right metanephric mass. The last bud grew between the two aforementioned buds. This bud was not draped by the metanephric mass and became the blind-ending ureter. On the right, one ureteral bud was located on the mesonephric duct and it made contact with a metanephric mass that became the right kidney. The upper part of the right kidney was drained by the ureter that had originally been located on the left mesonephric duct. This condition should be termed crossed ureteral ectopia rather than crossed renal ectopia, since the ureter was the structure that crossed.

Child↗

[Obstructive and reflux nephropathy].

Urinary tract obstruction and vesicoureteral reflux have marked effects on renal function. Renal interstitial fibrosis and glomerular hypertrophy with subsequent focal segmental glomerulosclerosis like changes are a common consequence of chronic obstruction and vesicoureteral reflux. Evidence suggests that vasoactive compounds and cytokines such as angiotensin II, nitric oxide, eicosanoids, TNF, TGF, EGF, PDGF, bFGF have a role in the hemodynamic and structural abnormalities that occur following obstruction of the urinary tract or vesicoureteral reflux. Use of modulators for these compounds appears to be beneficial for treatment of obstructive or reflux nephropathy in near future.

Chronic Disease↗

[Application of whole layer core biopsy of bladder wall to paravesical tumor].

We have reported the usefulness of percutaneous or transurethral whole layer core biopsy (WLCB) of bladder wall for staging of invasive bladder cancer. We have applied WLCB to 3 cases of paravesical tumor with good results. The first case was in a 3-year-old boy suspected of retrovesical sarcoma. Percutaneous WLCB revealed an inflammatory tumor of the Douglas cavity which was probably caused by perforation of appendix. The tumor disappeared by antibiotics alone. The second case was in a 37-year-old female with retrovesical tumor suspected to be ovarial cancer because of the high value of CA19-9 and CA125. Transurethral WLCB showed invasion of endometriosis to bladder muscle layer. The third case was in a 75-year-old female diagnosed by transurethral WLCB as sigmoid colon cancer invading until the deep bladder muscle layer. Cold cup punch biopsy was not informative in these 3 cases. Percutaneous or transurethral WLCB is safe and easy to perform, and is a technique recommended for diagnosis of pathology and bladder invasion of paravesical tumor.

Adult↗

[Effect of hydronephrosis on the contralateral blood flow and glomerular volume].

We designed a following experiment to appraise the effect of unilateral hydronephrosis on the contralateral kidney using weanling rats whose kidneys were in a growing stage. Rats were divided into 4 groups. Complete unilateral (left) ureteral obstruction (CUUO) was made on the experiment rats, and these went through the following procedures on the day 3 after CUUO; 1) Group R: CUUO released, 2) Group N: left nephrectomy performed, 3) Group S: CUUO continued. Sham-operations were performed on the days 0 and 3 to the controls. Renal cortical blood flow and glomerular volume of the contralateral (right) kidneys were determined on the days 5, 7, 9, 14 and 21. Blood flow to the renal cortex per unit volume (ml/min/100 cm3; measured with Laser blood perfusion monitor) in the contralateral kidneys increased gradually in the all groups, but statistical significance was not confirmed in the observed period between any groups. Increases in total renal blood flow (wet kidney weight times renal cortical blood flow per unit volume; g x ml/min/100 cm3) were proportional to the measured wet kidney weight in the all groups. Notably in the group N, a significant increase was noted compared to the group R and the controls. Glomerular volume (GV) of the contralateral kidneys did not show significant changes on the day 3 compared to the controls. GV significantly grew up during the day 5 to the day 14 (2 to 11 days after the relief of CUUO) in the group R and then it settled to the level of the controls on the day 21.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗