Genomic integration of ERRγ-HNF1ß regulates renal bioenergetics and prevents chronic kidney disease.

Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1ß) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1ß. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1ß loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1ß-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model.

BACKGROUND: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. METHODS: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. RESULTS: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. CONCLUSIONS: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

Nasoseptal cyst after septorhinoplasty: late and unusual but preventable compliation.

Nasoseptal cyst after septorhinoplasty: late and unusual but preventable complication. INTRODUCTION: Formation if a slowly growing cyst following septorhinoplasty is a rare but serious complication. Mucous cyst is more common than foreign body inclusion cyst. Typically, these cysts present as a solitary lesion that develops in the subcutaneous pace over the nasal bone along the line of nasal osteotomy several months or years after initial surgery. Rarely, the cyst onnects with the nasal septum. Surgery is the treatment of choice and consists of either complete excision of the cyst apsule or marsupialization of the cyst. ase report: A nasoseptal mucous cyst developed in a 46-year-old woman 10 years after septorhinoplasty. We successfully narsupialized the cyst with an endonasal endoscopic approach. onclusion:. Cysts can be removed by either complete resection of the cyst capsule or marsupialization via endonasal endoscopy. To prevent cyst formation, initial surgery must be conducted nontraumatically and tissue remnants cleared to prevent dispersion into subcutaneous spaces.

Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases.

OBJECTIVE: Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. DESIGN: Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. RESULTS: Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17ß-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. CONCLUSIONS: PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.

Use of Mitomycin C to reduce the incidence of encapsulated cysts following ahmed glaucoma valve implantation in refractory glaucoma patients: a new technique.

BACKGROUND: To evaluate the surgical outcome of Ahmed glaucoma valve (AGV) implantation with a new technique of mitomycin C (MMC) application. METHODS: This is a retrospective study. All patients with refractory glaucoma underwent FP-7 AGV implantation. Two methods of MMC application were used. In the traditional technique, 6 × 4 mm cotton soaked with MMC (0.25-0.33 mg/ml) was placed in the implantation area for 2-5mins; in the new technique, the valve plate first was encompassed with a thin layer of cotton soaked with MMC, then inserted into the same area. A 200 ml balanced salt solution was applied for irrigation of MMC. The surgical success rate, intraocular pressure (IOP), number of anti-glaucoma medications used, and postoperative complications were analyzed between the groups. RESULTS: The surgical outcomes of two MMC applied techniques were compared. The new technique group had only one case (2.6%) of encapsulated cyst formation out of 38 eyes, while there were eight (19.5%) cases out of 41 eyes the in traditional group. The difference was statistically significant (P = 0.030). According to the definition of success rate, there was 89.5% in the new technique group and 70.7% in the traditional group at the follow-up end point. There was a significant difference between the two groups (P = 0.035). Mean IOP in the new technique group were significantly lower than those of the traditional group at 3 and 6 months (P < 0.05). CONCLUSIONS: By using a thin layer of cotton soaked with MMC to encompass the valve plate, the new MMC application technique could greatly decrease the incidence of encapsulated cyst and increase the success rate following AGV implantation.

Parotid duct relocation in buccal mucosa cancer resection.

Buccal mucosal cancer is commonly seen in India with patients presenting in advanced stages of the disease. Its excision commonly mandates division of parotid duct as a part of disease or its margin. We have adopted a simple method to salvage the parotid gland by cannulating the duct and rerouting the saliva into the oral cavity at a different site. This has now become a protocol at our center. A total of 562 patients from 2002 to 2012 have undergone this procedure. This has markedly reduced the incidence of sialocele and parotitis in early postoperative period, which may delay wound healing and subsequent radiotherapy.

[A 59-year-old patient with recurrent flushes and bland hepatic cyst]. / 59-jähriger Patient mit rezidivierendem Erröten bei blander Leberzyste.

A 59-year-old patient was admitted to hospital with recurrent flush symptoms and pathologically elevated 5-hydroxyindoleacetic acid (5-HIAA) levels in urine. A known cystic lesion of the liver which had been followed for years by ultrasound examinations and was regarded as a bland hepatic cyst was identified as a metastasis of a neuroendocrine neoplasm of the ileum. In two sequential surgical interventions the primary tumor with mesenteric lymph node metastases as well as the cystic liver metastasis could be resected. After surgical treatment an R1 situation at the mesenteric site and suspicious para-aortic lymph nodes remained. The long established treatment of factor-V Leiden mutation by anticoagulation with phenprocoumon was supplemented by deep subcutaneous injection of lanreotide autogel every 4 weeks. Currently, there is no evidence for progressive disease and the patient is without clinical signs of a carcinoid syndrome.

Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways.

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD.

Effect of vitamin C on the growth of experimentally induced endometriotic cysts.

AIM: The aim of this study was to investigate the effect of vitamin C on the growth of experimental endometriotic cysts. MATERIAL AND METHODS: The endometrium of the uterine horn wall (diameter, 4 mm) was implanted onto the inner surface of the anterior abdominal wall of 40 Wistar albino adult female rats, by laparotomy. The day after the implantation, the rats were randomly assigned into four groups (control group and experimental groups [V1, V2, and V3]) comprising 10 rats each. For 6 weeks, the control group (Group C) received 1 mL distilled water, whereas the experimental groups (Groups V1, V2, and V3) received 0.5 mg, 1.25 mg, and 2.5 mg of vitamin C in 1 mL of distilled water, respectively. The doses were given via oral gavage once per day. At the end of the administration, a second laparotomy was performed and endometriotic cyst volumes and weights of rats among the groups were compared. In addition, the stromal and glandular tissue and the natural killer cell contents of the cysts were compared among the groups. RESULTS: The cyst volume in Group V3 and the cyst weights in Groups V2 and V3 were significantly lower than those in Group C. The natural killer cell content in Groups V1, V2, and V3 was significantly lower than that in Group C. Stromal and glandular tissue contents of the groups were not significantly different. CONCLUSIONS: The dose-dependent vitamin C supplementation significantly reduced the volumes and weights of the endometriotic cysts.

Progesterone induced mesenchymal differentiation and rescued cystic dilation of renal tubules of Pkd1(-/-) mice.

Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary disease affecting the kidneys, is caused in 85% of cases by mutations in the PKD1 gene. The protein encoded by this gene, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment, which regulate the tissue architecture and differentiation. However, how such mutations result in the formation of cysts is still unclear. We performed a precise characterization of mesenchymal differentiation using PAX2, WNT4 and WT1 as a marker, which revealed that impairment of the differentiation process preceded the development of cysts in Pkd1(-/-) mice. We performed an in vitro organ culture and found that progesterone and a derivative thereof facilitated mesenchymal differentiation, and partially prevented the formation of cysts in Pkd1(-/-) kidneys. An injection of progesterone or this derivative into the intraperitoneal space of pregnant females also improved the survival of Pkd1(-/-) embryos. Our findings suggest that compounds which enhance mesenchymal differentiation in the nephrogenesis might be useful for the therapeutic approach to prevent the formation of cysts in ADPKD patients.

Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model.

BACKGROUND: Nephronophthisis (NPHP), the most frequent genetic cause of end-stage kidney disease in children and young adults, is characterized by a variable number of renal cysts associated with cortical tubular atrophy and interstitial fibrosis. The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling pathway involved in the production of profibrotic mediators. The relationship between p38 MAPK and renal fibrosis in NPHP2 is unknown. METHODS: We administered a selective p38 MAPK inhibitor, FR167653, in a NPHP2 mouse model (inv/inv, invΔC mice) from 3 to 6 weeks old, and the kidneys were examined at 6 weeks of age. Phosphorylation of p38 MAPK (p-p38 MAPK) protein levels, the degree of renal fibrosis, messenger RNA (mRNA) levels for extracellular matrix genes and mRNA levels for transforming growth factor in the kidneys were studied. Effect of an extracellular signal-regulated protein kinase (ERK) kinase (MEK) inhibitor on renal fibrosis was also evaluated. RESULTS: Expression of extracellular matrix genes and p-p38 MAPK were increased in the NPHP2 mouse model kidney. FR167653 successfully decreased p-p38 MAPK levels, the degree of fibrosis and extracellular matrix gene expressions. However, the FR167653 did not prevent cyst expansion, abnormal cell proliferation and acceleration of apoptosis and did not influence ERK activation. In contrast, MEK inhibition reduced both cyst expansion and fibrosis without affecting p38 MAPK activation. CONCLUSIONS: These results suggest that inhibition of p38 MAPK reduced renal fibrosis but not cyst expansion, cell proliferation and apoptosis in NPHP2 model mice. Our results suggest that p38 MAPK and ERK signaling pathways independently affect renal fibrosis in inv mutant mice.

Fenestration of Peritoneal Catheter to Avoid Abdominal Pseudocyst Formation after Ventriculoperitoneal Shunts: A Technical Note.

Ventriculoperitoneal shunt (VPS) is a well-known procedure in the neurosurgical field. However, it has high complication and reoperation rates. Abdominal pseudocyst (APC) formation is a rare complication of VPS with reports in the literature varying from 4 to 10%. In this article, we report a simple and effective technique, with no additional cost, to avoid APC formation by making small multiple slits along the length of the peritoneal catheter.

Mucous cysts of the nose: a postrhinoplasty complication?: a long-term follow-up.

Mucous cysts are very rare complications following rhinoplasty; less than 20 cases have been reported in literature. We present 2 new cases. The first case presented a cyst located beneath the glabella and above the articulation between the spina nasalis and the os nasale. The lesion first appeared 22 months following elective rhinoplasty. The treatment was complete surgical excision using a direct open approach. In the second case, a cyst was indentified between the right inner canthus and the sidewall of the nose. It appeared 6 months following elective rhinoplasty. The treatment was complete surgical excision through a transcartilaginous approach. Both patients had good postoperative results with no evidence of recurrence after a 7- and 8-year follow-up period, respectively. We believe that it is possible to prevent the appearance of mucous cysts after rhinoplasty, with careful dissection and avoidance of dispersion of mucosal material into a subcutaneous plane.

Does intervention in utero preserve the obstructed kidneys of fetal lambs? A radiological and pathological study.

OBJECTIVE: Ureteropelvic junction obstruction is a common cause of end-stage pediatric nephropathy. Our aim was to investigate whether in utero decompression can influence its development. METHODS: A silastic tube was tied around the superior segment of the left ureter to cause partial unilateral obstruction in 22 fetal lambs at 75-85 days of gestation. Three weeks later, tubes were removed in 10 of the fetuses. A single sham procedure was performed on 4 control fetuses. Intravenous pyelography (IVP) and pathological evaluations were conducted in obstructed, decompressed and control subjects. RESULTS: IVP revealed damaged renal function in obstructed subjects. Macroscopically, obstructed kidneys were larger but weighed less and had thinned parenchyma. Microscopy revealed cortical cysts of various sizes and interstitial fibrosis. The number of glomeruli was markedly decreased. In contrast, decompressed kidneys were visualized during IVP, and pathological changes were greatly ameliorated. CONCLUSIONS: Relief of obstruction in utero seems to prevent or attenuate development of nephropathy in lambs. Clinical application of this procedure should proceed with caution until further data are obtained.

Differential diagnosis and management of a recurrent hepatic cyst: a case report and review of literature.

Echinococcus granulosus, which causes cystic echinococcosis, is an uncommon condition in the United States. We report a case of a 78-year-old Caucasian female who presented to her primary care physician in 1999 with right upper quadrant pain. She had a history of frequent foreign travel. Abdominal imaging demonstrated a 12.5-cm hepatic cyst. The cyst was drained and the pathology report on the fluid indicated no bacterial, parasitic, or malignant etiology. Serology tests for Entamoeba and Echinococcus antibodies were negative. The patient underwent multiple hepatic cyst aspirations until 2008 for recurring symptoms. In 2008, abdominal imaging demonstrated solid internal components within the cyst. Repeat Echinococcus antibodies ordered were abnormally elevated. Cyst aspiration demonstrated Echinococcus protoscolex. We report this case to discuss the diagnosis and management of hydatid cyst and to emphasize that with increasing globalization, physicians must maintain a high index of clinical suspicion for parasitic etiologies in patients with hepatic cysts.

Antisense vimentin cDNA combined with chondroitinase ABC reduces glial scar and cystic cavity formation following spinal cord injury in rats.

The formation of glial scar and cystic cavities restricts axon regeneration after spinal cord injury. Chondroitin sulphate proteoglycans (CSPGs) are regarded as the prominent inhibitory molecules in the glial scar, and their inhibitory effects may be abolished in part by chondroitinase ABC (ChABC), which can digest CSPGs. CSPGs are secreted mostly by reactive astrocytes, which form dense scar tissues. The intermediate filament protein vimentin underpins the cytoskeleton of reactive astrocytes. Previously we have shown that retroviruses carrying full-length antisense vimentin cDNA reduce reactive gliosis. Here we administered both antisense vimentin cDNA and ChABC to hemisected rat spinal cords. Using RT-PCR, Western blotting and immunohistochemistry, we found that the combined treatment reduced the formation of glial scar and cystic cavities through degrading CSPGs molecules and inhibiting intermediate filament proteins. The modified intra- and extra-cellular architecture may alter the physical and biochemical characteristics of the scar, and the combined therapy might be used to inhibit glial scar formation.

Olive leaf extract counteracts cell proliferation and cyst growth in an in vitro model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts, leading to chronic kidney disease. Since the available treatment for ADPKD is limited, there is emerging interest for natural compounds as potential therapeutic candidates. The aim of our study was to investigate whether an olive leaf extract may be able to counteract the cyst growth in an in vitro model of ADPKD. We treated WT9-12 cells with an olive leaf extract (OLE). In monolayer culture we evaluated cell viability by the MTT assay, protein expression by western-blot analysis and apoptosis by DNA laddering and TUNEL assays. For functional studies we used transient transfection and ChIP assays. Intracellular calcium measurement was performed with a spectrofluorimeter using a fluorescent probe. 3D-cell-culture was used for cyst growth studies. OLE reduced the WT9-12 cell growth rate and affected intracellular signaling due to high c-AMP levels, as OLE reduced PKA levels, enhanced p-AKT, restored B-Raf-inactivation and down-regulated p-ERK. We elucidated the molecular mechanism by which OLE, via Sp1, transactivates the p21WAF1/Cip1 promoter, whose levels are down-regulated by mutated PKD1. We demonstrated that p-AKT up-regulation also played a crucial role in the OLE-induced anti-apoptotic effect and that OLE ameliorated intracellular calcium levels, the primary cause of ADPKD. Finally, using a 3D-cell-culture model we observed that OLE reduced the cyst size. Therefore, multifaceted OLE may be considered a new therapeutic approach for ADPKD treatment.

Lactoferrin and lactoferricin endocytosis halt Giardia cell growth and prevent infective cyst production.

Lactoferrin (LF) is an 80 KDa iron-binding glycoprotein that plays a significant role in the innate immune system and is considered to be an important microbicide molecule. It has been suggested to be effective in the treatment of giardiasis, an intestinal disease caused by the protozoan parasite G. lamblia. However, the molecular mechanisms by which LF exerts its effect on this parasite are unknown. Most of the microbicidal activity of human or bovine LF (hLF or bLF) has been associated with the N-terminal region of the mature LF - lactoferricin (LFcin). LFcin is produced by pepsin cleavage of the native protein in vitro and likely in vivo. In this work, we analyse the participation of the endocytic machinery of G. lamblia in the internalization of bLF and bLFcin and their effects on cell homeostasis. Our results show that, when bLF or bLFcin are internalized by receptor-mediated endocytosis, cell growth stops, and morphological changes are produced in the trophozoites, which ultimately will produce immature cysts. Our findings contribute to disclose the fine mechanism by which bLF and bLFcin may function as an antigiardial molecule and why they have therapeutic potential to eradicate giardiasis.

[Late complication after mesh repair of incisional hernias: pseudocyst formation]. / A hegsérvek hálóval történo rekonstrukcióját követo késoi szövodmény: a pseudocysta-képzodés.

INTRODUCTION: Using mesh for hernia repair is a very common procedure; they are particularly useful for postoperative incisional hernias. The most common complications of mesh repair are seroma, haematoma or abscess formation. Previous literature data suggested that fibrotic cyst formation appearing in the late postoperative period is relatively rare. However, more recent studies and our own experience indicate that its incidence is more common and we have to consider it in the differential diagnosis of the complications of hernia repair. PATIENTS: 148 incisional hernia mesh repairs were carried out between a period of 1st January, 2001 to 31st December, 2005. Fibrotic pseudocyst formation was observed in five cases. All developed as a late complication between 4 to 25 months postoperatively. An onlay polypropylene mesh was used in each case. All five patients underwent a wide excision of the pseudocyst wall and they recovered without complications. DISCUSSION: The etiology of pseudocyst formation is unclear. Nevertheless, a possible relationship between the development of seroma and haematoma can not be ruled out, despite no fibrotic pseudocyst formation was observed in the early postoperative period. There is no evidence whether the characteristics of the mesh or the way of implantation would have any effect on pseudocyst formation, as well. It is noted that the only treatment of this late complication is surgical excision. Pseudocyst formation might be prevented by the application of sublay and minimally invasive techniques.