Cyst Index Research Articles

PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice.

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARα and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARα and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARα and FAO/OXPHOS genes is downregulated, and in vivo β-oxidation rate of 3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARα agonist. Fenofibrate treatment resulted in increased expression of PPARα and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/RC kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared with untreated littermate Pkd1RC/RC mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells, including M2-like macrophages. Finally, fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.

Repulsive guidance molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive guidance molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD.

Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease.

Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis (“Warburg effect”) plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min), BUN (0.69±0.26 vs 0.40±0.10 ml/min) and uric acid (0.38±0.20 vs 0.21±0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.

Predictive characteristic of simple bone cyst treated with curettage and bone grafting.

BackgroundThe efficiency of treating simple bone cyst (SBC) is low. Depending on the choice of treatment, a positive response occurs in 20 to 80 % of cases. These rates are unacceptable, particularly considering they concern the treatment of benign lesions affecting children. Although cyst curettage is one of the first known ways of treating SBC, no precise qualification criteria exists for this procedure. The aim of our study is to identify which type of cyst may be most effectively treated using curettage with grafting.MethodsA retrospective analysis was performed on 24 patients referred to our clinic for SBC treatment. To identify predictive factors, the group of patients who positively responded to treatment (Neer stages I and II, n = 14) were compared with the group in which recurrences occurred (Neer stages III and IV, n = 10).ResultsSignificantly fewer patients with lesions located in the humerus (chi2 = 9.351; p <0.05) and without pathological facture at the time of diagnosis (p = 0.017) were found in the group with no recurrence. The following radiological parameters were found to vary significantly between groups: cyst area (z = 3.121; p < 0.01), cyst index (z = 2.213; p <0.05) and cyst diameter ratio (z = 2.202; p <0.05). In the group with no recurrences, the mean values of these parameters were found to be lower than in group with poor response to treatment. No statistically significant differences regarding age, sex or type of bone graft (p > 0.05) were found. Recurrences were experienced by 10 patients (41.7 %) during the 3-year period after surgeryConclusionIn the group treated with curettage, associations were identified between worse treatment results and the location in the humerus, pathological fractures at the time of diagnosis, large cyst area, large cyst index and large cyst diameter.

Targeting of sodium–glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats

Renal tubular epithelial cell proliferation and transepithelial cyst fluid secretion are key features in the progression of polycystic kidney disease (PKD). As the role of the apical renal sodium-glucose cotransporters in these processes is not known, we tested whether phlorizin inhibits cyst growth and delays renal disease progression in a rat model of PKD. Glycosuria was induced by subcutaneous injection of phlorizin in male heterozygous (Cy/+) and wild-type Han:SPRD rats. Phlorizin induced immediate and sustained glycosuria and osmotic diuresis in these rats. Cy/+ rats treated with phlorizin for 5 weeks showed a significant increase in creatinine clearance, a lower 2-kidneys/body weight ratio, a lower renal cyst index, and reduced urinary albumin excretion as compared with vehicle-treated Cy/+ rats. Measurement of Ki67 staining found significantly lower cell proliferation in dilated tubules and cysts of Cy/+ rats treated with phlorizin, as well as a marked inhibition of the activated MAP kinase pathway. In contrast, the mTOR pathway remained unaltered. Phlorizin dose dependently inhibited MAP kinase in cultured tubular epithelial cells from Cy/+ rats. Thus, long-term treatment with phlorizin significantly inhibits cystic disease progression in a rat model of PKD. Hence, induction of glycosuria and osmotic diuresis (glycuresis) by renal sodium-glucose cotransporters inhibition could have a therapeutic effect in polycystic kidney disease.

Flexible intramedullary nailing in simple bone cysts of the proximal humerus

We designed and evaluated a modified cyst index using the Picture Archiving and Communication System software for treating simple bone cysts of the proximal humerus by preventive intramedullary flexible nail insertion in symptomatic children or adolescents. From January 2007 to December 2009, cases with a cyst index of at least 4 were enrolled in the study. Of 20 total cases, 19 were prospectively followed-up for at least 2 years. The mean patient age was 10.6 years (range, 7-15 years) and the mean modified cyst index was 6.56 (range, 4.95-8.25). The mean cyst healing period was 8.7 months (range, 4-30 months) and the mean follow-up period was 31.05 months (range, 24-42 months). Seventeen lesions (89%) were classified as completely healed and two (11%) were classified as healed with residual radiolucency. In all cases, no angular deformity was found on the final follow-up radiograph. Therefore, preventive flexible intramedullary nail insertion before the occurrence of a pathologic fracture because of simple bone cysts with a modified cyst index of at least 4 in the proximal humerus is an excellent treatment option. Therapeutic Level IV.

Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultures of ADPKD cyst-lining epithelial cells were obtained from five patients. Effects of CXB were measured by various assays to detect BrdU incorporation, apoptosis and proliferation in vitro. Additionally, effects of CXB on kidney weight, the cyst index, the fibrosis index, blood urea nitrogen (BUN), serum creatinine (SCr), serum 6-keto-PGF-1α, serum thromboxane-2 (TXB2) and renal PCNA expression were assessed in Han:SPRD rat, a well-characterized rodent model of PKD. CXB inhibited proliferation of ADPKD cyst-lining epithelial cells, blocked the release of VEGF from the cells and induced extensive apoptosis in a time- and dose-dependent manner. Moreover, CXB up-regulated the cell cycle negative regulator p21CIP/WAF1 and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2. Furthermore, CXB inhibited the expression of VEGFR-2 and Raf-1 in ADPKD cyst-lining epithelial cells. CXB markedly reduced the cyst index, the fibrosis index, leukocyte infiltration, BUN, SCr, serum 6-keto-PGF-1α, TXB2 and renal PCNA expression in Han:SPRD rat. We demonstrated for the first time that CXB could suppress renal cyst-lining growth both in vitro and in vivo in Han:SPRD rat. CXB can inhibit proliferation, suppress cell cycle progression, and induce apoptosis in ADPKD cyst-lining epithelial cells through the inhibition of the VEGF/VEGFR-2/Raf-1/MAPK/ERK signaling pathway.

Predictive Factors for Recurrence of Simple Bone Cyst of the Proximal Humerus

To evaluate factors predictive of recurrence following curettage of simple bone cysts (SBCs) in the proximal humerus. Records of 29 male and 3 female patients aged 3 to 22 (mean, 11) years who underwent curettage with or without bone grafting for a solitary SBC in the proximal humerus were reviewed. The appearance, size, location, activity level, and fracture pattern of each cyst were recorded. The cyst index indicated the risk of refracture. Recurrence was defined as a refracture or enlargement of the cyst. 31 patients presented with a pathological fracture. The main symptoms were pain (n=30), loss of function (n=22), and mass/swelling (n=15). 25 patients gave a history of trauma. The duration of symptoms was less than one month. 10 patients had recurrence after a mean of 10 (range, 4-27) months; 5 were refractures and another 5 were enlargement of the cysts. Six were treated conservatively and eventually healed, whereas 4 underwent further curettage. Factors predictive of recurrence were patient age 5 years or younger (p=0.014), right-sided cyst (p=0.01), larger cyst (p=0.039), multilocular cyst (p=0.004) and unimpacted fracture (p=0.04). Recurrence was not related to gender, cyst location, or cyst activity level. Most SBCs heal even if the fracture is treated expectantly. SBCs should be left alone unless symptomatic. If curettage is performed, grafts or bone substitutes should be used. More aggressive treatment might be necessary for unimpacted fractures to minimise the risk of recurrence.

Active Unicameral Bone Cysts in the Upper Limb are at Greater Risk of Fracture

To elucidate the natural history of unicameral bone cyst (UBC) and risk factors for pathological fracture. 14 males and 8 females (mean age, 9 years) diagnosed with UBC were reviewed. Cyst location, symptoms, and whether there was any fracture or surgery were recorded. Cyst parameters were measured on radiographs, and included (1) the cyst index, (2) the ratio of the widest cyst diameter to the growth plate diameter, and (3) the adjusted distance of the cyst border from the growth plate. There were 11 upper- and 11 lower-limb cysts. 13 patients had pathological fractures and 9 did not. 20 patients were treated conservatively with limb immobilisation; 2 underwent curettage and bone grafting (one resolved and one did not). Seven cysts resolved (5 had fractures and 2 did not). The risk of fracture was higher in the upper than lower limbs (100% vs 18%, p<0.001). Fractured cysts were larger than unfractured cysts (mean cyst index, 4.5 vs. 2.2, p=0.07). Active cysts were more likely to fracture. Conservative management had a 30% resolution rate. Surgery should be considered for large active cysts in the upper limbs in order to minimise the fracture risk.

Efficacy of aspiration and autogenous bone marrow injection in the treatment of simple bone cysts

Twenty eight patients with simple bone cyst that were treated by aspiration and percutaneous autogenous bone marrow injection were reviewed to evaluate the treatment outcome. There were 18 boys and ten girls. Their mean age was 10.9 +/- 2.75 years. Single injection was performed for 16 patients; the rest had double or triple injections. There were no operative complications. The mean follow-up was 34.7 +/- 6.87 months. The procedure succeeded in obtaining healing in 23 cysts (82%). Cysts with index of more than five and cortical thickness of less than 1 mm were significantly prone to pathological fractures and had significant poor results after treatment. Our results suggested that autogenous bone marrow injection is a safe and effective treatment method for simple bone cysts, but sometimes repeated injections are necessary. Cyst index and cortical thickness are good indicators for cyst aggressiveness and good predictors for treatment outcome.

Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat

In polycystic kidney disease, abnormal epithelial cell proliferation is the main factor leading to cyst formation and kidney enlargement. Cyclic AMP (cAMP) is mitogenic in cystic but antimitogenic in normal human kidney cells, which is due to reduced steady-state intracellular calcium levels in cystic compared to the normal cells. Inhibition of intracellular calcium entry with channel blockers, such as verapamil, induced cAMP-dependent cell proliferation in normal renal cells. To determine if calcium channel blockers have a similar effect on cell proliferation in vivo, Cy/+ rats, a model of dominant polycystic kidney disease, were treated with verapamil. Kidney weight and cyst index were elevated in verapamil-treated Cy/+ rats. This was associated with increased cell proliferation and apoptosis, elevated expression, and phosphorylation of B-Raf with stimulation of the mitogen-activated protein kinase MEK/ERK (mitogen-activated protein kinase kinase/extracellular-regulated kinase) pathway. Verapamil had no effect on kidney morphology or B-Raf stimulation in wild-type rats. We conclude that treatment of Cy/+ rats with calcium channel blockers increases activity of the B-Raf/MEK/ERK pathway accelerating cyst growth in the presence of endogenous cAMP, thus exacerbating renal cystic disease.

Unicameral bone cysts: etiology and treatment

Purpose of review: Unicameral bone cysts are common, benign, skeletal lesions of childhood. They weaken cortical bone and may lead to fracture. The cause of unicameral bone cysts is unclear. Obstruction of venous outflow is the currently favored hypothesis. Strategies ranging from radical resection to percutaneous drainage have been employed to treat unicameral bone cysts. Recent findings: Unicameral bone cyst cell isolates have recently been characterized. These cells express proteins involved in preosteoblast recruitment and differentiation of osteoblasts and osteoclasts. They also show an increased responsiveness to bisphosphonates. Current treatment favors minimally invasive or percutaneous techniques. Studies have evaluated injection of various substances; all showed good response. Others advocate stabilization with flexible nails. Use of the cyst index to assess fracture risk has fallen out of favor. Gaining popularity are computed tomography scans, both for risk assessment and treatment planning. Summary: Treatment of unicameral bone cysts remains challenging. Computed tomography is valuable in fracture prediction and treatment planning. Treatment goals include cyst involution and prevention of catastrophic complications. Multiple techniques exist to facilitate these goals. Despite much research, no single technique has proven superior. Common to all currently used modalities is cyst decompression. As more is understood regarding the cause of unicameral bone cysts, medical treatment may figure more prominently.

Cyst Index

Treatment is indicated for simple bone cysts (SBC) with high risk of fracture. The cyst index was described as a method to determine if a cyst is at high risk or low risk of fracture. The cyst index of 32 femoral and humeral SBCs was determined by 8 reviewers. The risk group cyst index was compared with whether a fracture took place. Sensitivities, specificities, and positive and negative predictive values were calculated across varying cutoff levels. Intraobserver and interobserver reliability testing for 10 cysts was made. Receiver operator curves demonstrate that no cutoff value gave an acceptable level of both sensitivity and specificity. The mean value for the cyst index was significantly different for different observers (P < 0.05). This study does not validate the cyst index to be an accurate predictor of fracture. The test has low intraobserver and interobserver reliability. The cyst index cannot reliably discriminate between the patients that will fracture and those that will not.

Treatment of Simple Bone Cysts with Percutaneous Injection of Autogenous Bone Marrow with Crushed Cancellous Allograft

Purpose : This study evaluated the feasibility and efficacy of a percutaneous injection of a mixture of autogenous bone marrow and crushed cancellous bone allografts for the treatment of simple bone cysts. Materials and Methods : Fifteen patients with a simple bone cyst were enrolled in this study. The mean age was 13.5 years (range, 4-32 years), and the mean follow-up period was 13.2 months (range, 8-19 months). The radiographic signs of the resolution of the cyst were categorized as healed, healed with a defect, persistent and recurrent. The groups of healed and healed with a defect were designated the positive response groups. Results : Fourteen patients responded to the treatment. Nine patients showed complete healing that was first seen radiographically at 3 months (range, 1-6 months). Five patients showed healing with a defect, but no patient required a second injection because the cysts were small and did not cause functional pain. There was no correlation between clinical responses and age, gender, location, cyst index and previous treatment modalities. One patient had a pathological fracture, which was treated successfully by open bone grafting with flexible intramedullary nailing. Conclusion : A percutaneous injection of a mixture of autogenous bone marrow and a crushed cancellous bone allograft may be an effective treatment for simple bone cysts.

Treatment of simple bone cysts with aspiration and a single bone marrow injection.

The authors report the results of percutaneous aspiration and injection of marrow into active, simple bone cyst in 17 cases. Slow regression of the cyst and progressive healing were obtained in 13 cases (76%), no response was observed in 2 cases (12%), and recurrence was observed in 2 others (12%) after a follow-up of 33.9 months. Cyst evolution was monitored by a cyst index, cyst diameter, and computer-assisted densitometric image analysis of serial radiographs.

Treatment of Simple Bone Cysts With Aspiration and a Single Bone Marrow Injection

The authors report the results of percutaneous aspiration and injection of marrow into active, simple bone cyst in 17 cases. Slow regression of the cyst and progressive healing were obtained in 13 cases (76%), no response was observed in 2 cases (12%), and recurrence was observed in 2 others (12%) after a follow-up of 33.9 months. Cyst evolution was monitored by a cyst index, cyst diameter, and computer-assisted densitometric image analysis of serial radiographs.

Poultry Litter Enhances Soybean Productivity in Field Infested with Soybean Cyst Nematode

ABSTRACT Soil infested with the soybean cyst nematode (SCN), Heterodera glycines, was amended with poultry litter in a three-year study designed to evaluate the effectiveness of the organic amendment for improving soybean productivity and reducing damage by the nematode. Poultry litter was split-applied at V2 and V5 stages of soybean development, at rates of 0, 5 or 10 t ha−1. The experimental plots were in Wicomico County, MD, and planted to Manokin (resistant) and Essex (susceptible) soybean cultivars. Cyst index was inversely correlated with poultry litter, although the difference between the 5 t ha−1 and 10 t ha−1 treatment was not significant. Poultry litter had a greater impact on reducing cyst infestation in Essex. Over the three-year period, cyst index increased incrementally on Manokin but this was significantly lower than on Essex. Nodule number and foliar N content were depressed by application of poultry litter. Shoot and root dry weight were improved by amending soil with 5 t ha−1 poultry litter, but were reduced by the 10 t ha−1 rate. Seed yield of both cultivars also tended to be reduced by 10 t ha−1 poultry litter treatment, but stimulated by the 5 t ha−1 treatment. The results indicate that 5 t ha−1 poultry litter is an effective means of improving productivity when soybean is grown in SCN-infested soil.

Field Population Dynamics of Soybean Cyst Nematode on Resistant and Susceptible Soybeans and Their Blends

Soybean cyst nematode (Heterodera glycines Ichinohe) (SCN) become an increasing problem in the upper midwest. In order to develop appropriate practices to manage SCN populations it is important to understand the population dynamics of SCN under field conditions. Soybean cyst nematode population dynamics were determined in naturally infested commercial soybean [Glycine max (L.) Merr.] fields in southern Minnesota on a monthly basis during 1991 and 1992 for an adapted susceptible (S) and a SCN Race 3 resistant (R) cultivar and three blends (25% R:75% S; 50% R:50% S; 75% R: 25% S). Population dynamics differed between sites and years. In 1991, fields with similar initial cyst densities were compared. Densities of second‐stage juveniles (J2) peaked in August at one site and gradually declined throughout the growing season at the other. Total cyst production was lower at the site where J2 densities declined. In 1992, fields with high and low initial egg densities were compared. SCN population densities increased when initial densities of J2 and eggs were low and decreased when initial J2 and egg densities were high. Physiological race of the nematode influenced population dynamics on resistant plants. The cyst index under field conditions for the resistant cultivar was 10 (moderately resistant) against Race and 32 (moderately susceptible) against Race 1. The blends generally lowered SCN population densities, but not significantly. Final egg density and cyst production for the resistant cultivar were significantly lower than the susceptible cultivar at each site. The use of SCN resistant cultivars alone or in a 75:25% mixture with a susceptible cultivar (25%) is recommended as a SCN population management strategy to delay shifts from one race to another thus prolonging the effectiveness of resistant cultivars.

Unicameral bone cysts. Natural history and the risk of fracture.

Unicameral bone cysts in 57 patients, seen at the Alfred I. duPont Institute between 1949 and 1982, were studied retrospectively. We present the natural history in several patients and report a "cyst index" which allows the progress of the cyst to be followed and makes it possible to determine whether there is a significant risk of fracture which would warrant treatment. We have found that measuring the cyst index in patients treated by injections of methylprednisolone acetate helps to assess the response to treatment.

Mucosal cysts in Barrett's mucosa with dysplasia.

The frequency of glandular cysts occurring in the Barrett's mucosa was investigated in areas adjacent to invasive adenocarcinoma in 32 resected esophagi. Cysts in the metaplastic glands of the Barrett mucosa were present in areas with and without dysplasia in 31 of the 32 specimens. The mean cyst index (i.e. the number of glandular cysts divided by the length-in mm-of mucosa analyzed) was 2.3 in the non-dysplastic Barrett mucosa, and 2.5 in the Barrett mucosa with dysplasia. Significantly lower indices (p less than 0.001) were found in areas with metaplastic glands covered by "healing" squamous epithelium (0.47) and in the gastric mucosa of the same patients (0.15) as well as in 10 control esophagi underneath normal squamous epithelium (0.11). The outlet of the dilated glands was often obstructed by clusters of dysplastic cells or papillary formations with atypical cells, substantiating on obstructive-causal mechanism in these cysts. Other cysts were partially or totally replaced by dysplastic epithelium. The present findings may be of importance for the histological differential diagnosis between dysplasia and highly differentiated adenocarcinomas in biopsy specimens from the Barrett Mucosa.