A safe transoral surgical approach to parapharyngeal tumor arising from deep lobe of parotid gland

The management of parapharyngeal tumor is surgical, but the approach remains a challenge. Attention should be paid to avoidance intra-operative bleeding or cranial nerves damage. We report a case of a 67-year-old male complaining of left-ear fullness. A submucosal mass arising from the lateral wall of oropharynx on the left side was observed. Magnetic resonance imaging detected a mass arising from the parotid gland, in particular from the deep lobe, and a fine needle biopsy was compatible with "Warthin tumor." We performed a mini-invasive transoral approach under magnification, previous isolation of homolateral vessels. The decision on which surgical approach to be used is determined by site, size vascularity, and histology of the tumor. A literature review of the main surgical approaches was performed. We performed a combined transoral dissection under magnification with cervicotomic exposure of the neck vascular bundle allowing to dissect the tumor and manage any intra-operative complications

NaPi-IIa interacting proteins and regulation of renal reabsorption of phosphate

Control of phosphate (Pi) homeostasis is essential for many biologic functions and inappropriate low levels of Pi in plasma have been suggested to associate with several pathological states, including renal stone formation and stone recurrence. Pi homeostasis is achieved mainly by adjusting the renal reabsorption of Pi to the body's requirements. This task is performed to a major extent by the Na/Pi cotransporter NaPi-IIa that is specifically expressed in the brush border membrane of renal proximal tubules. While the presence of tight junctions in epithelial cells prevents the diffusion and mixing of the apical and basolateral components, the location of a protein within a particular membrane subdomain (i.e., the presence of NaPi-IIa at the tip of the apical microvilli) often requires its association with scaffolding elements which directly or indirectly connect the protein with the underlying cellular cytoskeleton. NaPi-IIa interacts with the four members of the Na+/H+ exchanger regulatory factor family as well as with the GABAA-receptor associated protein . Here we will discuss the most relevant findings regarding the role of these proteins on the expression and regulation of the cotransporter, as well as the impact that their absence has in Pi homeostasi

Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption

During metabolic acidosis (MA), urinary phosphate excretion increases and contributes to acid removal. Two Na+-dependent phosphate transporters, NaPi-IIa (Slc34a1) and NaPi-IIc (Slc34a3), are located in the brush border membrane (BBM) of the proximal tubule and mediate renal phosphate reabsorption. Transcriptome analysis of kidneys from acid-loaded mice revealed a large decrease in NaPi-IIc messenger RNA (mRNA) and a smaller reduction in NaPi-IIa mRNA abundance. To investigate the contribution of transporter regulation to phosphaturia during MA, we examined renal phosphate transporters in normal and Slc34a1-gene ablated (NaPi-IIa KO) mice acid-loaded for 2 and 7days. In normal mice, urinary phosphate excretion was transiently increased after 2days of acid loading, whereas no change was found in Slc34a1−/− mice. BBM Na/Pi cotransport activity was progressively and significantly decreased in acid-loaded KO mice, whereas in WT animals, a small increase after 2days of treatment was seen. Acidosis increased BBM NaPi-IIa abundance in WT mice and NaPi-IIc abundance in WT and KO animals. mRNA abundance of NaPi-IIa and NaPi-IIc decreased during MA. Immunohistochemistry did not indicate any change in the localization of NaPi-IIa and NaPi-IIc along the nephron. Interestingly, mRNA abundance of both Slc20 phosphate transporters, Pit1 and Pit2, was elevated after 7days of MA in normal and KO mice. These data demonstrate that phosphaturia during acidosis is not caused by reduced protein expression of the major Na/Pi cotransporters NaPi-IIa and NaPi-IIc and suggest a direct inhibitory effect of low pH mainly on NaPi-IIa. Our data also suggest that Pit1 and Pit2 transporters may play a compensatory rol

Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters

Renal phosphate reabsorption across the brush border membrane (BBM) in the proximal tubule is mediated by at least three transporters, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Parathyroid hormone (PTH) is a potent phosphaturic factor exerting an acute and chronic reduction in proximal tubule phosphate reabsorption. PTH acutely induces NaPi-IIa internalization from the BBM and lysosomal degradation, but its effects on NaPi-IIc and Pit-2 are unknown. In rats adapted to low phosphate diet, acute (30 and 60min) application of PTH decreased BBM phosphate transport rates both in the absence and the presence of phosphonoformic acid, an inhibitor of SLC34 but not SLC20 transporters. Immunohistochemistry showed NaPi-IIa expression in the S1 to the S3 segment of superficial and juxtamedullary nephrons; NaPi-IIc was only detectable in S1 segments and Pit-2 in S1 and weakly in S2 segments of superficial and juxtamedullary nephrons. PTH reduced NaPi-IIa staining in the BBM with increased intracellular and lysosomal appearance. NaPi-IIa internalization was most prominent in S1 segments of superficial nephrons. We did not detect changes in NaPi-IIc and Pit-2 staining over this time period. Blockade of lysosomal protein degradation with leupeptin revealed NaPi-IIa accumulation in lysosomes, but no lysosomal staining for NaPi-IIc or Pit-2 could be detected. Immunoblotting of BBM confirmed the reduction in NaPi-IIa abundance and the absence of any effect on NaPi-IIc expression. Pit-2 protein abundance was also significantly reduced by PTH. Thus, function and expression of BBM phosphate cotransporters are differentially regulated allowing for fine-tuning of renal phosphate reabsorptio

pCLE detects mucosal neoplastic vascular pattern in gastric linitis plastica

Linitis plastica (LP) is a very aggressive and rare carcinoma with a scirrhous stroma that affects the submucosal and muscular layers of the stomach even without mucosal alterations. Lack of timely diagnosis is a crucial problem related to its prognosis and treatment. In this study, we investigated the LP-associated vascular pattern as a possible means to improve the diagnosis of these patients. During standard endoscopy, mucosal architecture, tortuosity and enlargement of vessels, as well as the presence of vascular leakage and efficiency of the blood flow were assessed in six LP patients using probe-based Confocal Laser Endomicroscopy (pCLE). In all LP patients, we detected abnormal changes in vasculature. The aberrant features of the vascular network were common to all LP patients examined and consisted of vessel enlargement, tortuosity, and leakage associated with the affected submucosal layer. This is the first study to highlight the presence of marked vascularization associated with LP, characterized by the presence of abnormal and non-functional vessels, similar to what is observed in neoplastic tissues. Therefore, the analysis of LP by pCLE may provide a new endoscopic approach and strategy to better define these patients

Expression and regulation of the renal Na/phosphate cotransporter NaPi-IIa in a mouse model deficient for the PDZ protein PDZK1

Inorganic phosphate (Pi) is reabsorbed in the renal proximal tubule mainly via the type-IIa sodium-phosphate cotransporter (NaPi-IIa). This protein is regulated tightly by different factors, among them dietary Pi intake and parathyroid hormone (PTH). A number of PDZ-domain-containing proteins have been shown to interact with NaPi-IIa in vitro, such as Na+/H+ exchanger-3 regulatory factor-1 (NHERF1) and PDZK1. PDZK1 is highly abundant in kidney and co-localizes with NaPi-IIa in the brush border membrane of proximal tubules. Recently, a knock-out mouse model for PDZK1 (Pdzk1−/−) has been generated, allowing the role of PDZK1 in the expression and regulation of the NaPi-IIa cotransporter to be examined in in vivo and in ex vivo preparations. The localization of NaPi-IIa and other proteins interacting with PDZK1 in vitro [Na+/H+ exchanger (NHE3), chloride-formate exchanger (CFEX)/putative anion transporter-1 (PAT1), NHERF1] was not altered in Pdzk1−/− mice. The abundance of NaPi-IIa adapted to acute and chronic changes in dietary Pi intake, but steady-state levels of NaPi-IIa were reduced in Pdzk1−/− under a Pi rich diet. This was paralleled by a higher urinary fractional Pi excretion. The abundance of the anion exchanger CFEX/PAT1 (SLC26A6) was also reduced. In contrast, NHERF1 abundance increased in the brush border membrane of Pdzk1−/− mice fed a high-Pi diet. Acute regulation of NaPi-IIa by PTH in vivo and by PTH and activators of protein kinases A, C and G (PKA, PKC and PKG) in vitro (kidney slice preparation) was not altered in Pdzk1−/− mice. In conclusion, loss of PDZK1 did not result in major changes in proximal tubule function or NaPi-IIa regulation. However, under a Pi-rich diet, loss of PDZK1 reduced NaPi-IIa abundance indicating that PDZK1 may play a role in the trafficking or stability of NaPi-IIa under these condition

Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression

Inorganic phosphate (Pi) reabsorption in the renal proximal tubule occurs mostly via the Na+/Pi cotransporter type IIa (NaPi-IIa) located in the brush-border membrane (BBM) and is regulated, among other factors, by dietary Pi intake and parathyroid hormone (PTH). The PTH-induced inhibition of Pi reabsorption is mediated by endocytosis of Na/Pi-IIa from the BBM and subsequent lysosomal degradation. Megalin is involved in receptor-mediated endocytosis of proteins from the urine in the renal proximal tubule. The recently identified receptor-associated protein (RAP) is a novel type of chaperone responsible for the intracellular transport of endocytotic receptors such as megalin. Gene disruption of RAP leads to a decrease of megalin in the BBM and to a disturbed proximal tubular endocytotic machinery. Here we investigated whether the distribution of NaPi-IIa and/or its regulation by dietary Pi intake and PTH is affected in the proximal tubules of RAP-deficient mice as a model for megalin loss. In RAP-deficient mice megalin expression was strongly reduced and restricted to a subapical localization. NaPi-IIa protein distribution and abundance in the kidney was not altered. The localization and abundance of the NaPi-IIa interacting proteins MAP17, PDZK-1, D-AKAP2, and NHE-RF1 were also normal. Other transport proteins expressed in the BBM such as the Na+/H+ exchanger NHE-3 and the Na+/sulphate cotransporter NaSi were normally expressed. In whole animals and in isolated fresh kidney slices the PTH-induced internalization of NaPi-IIa was strongly delayed in RAP-deficient mice. PTH receptor expression in the proximal tubule was not affected by the RAP knock-out. cAMP, cGMP or PKC activators induced internalization which was delayed in RAP-deficient mice. In contrast, both wildtype and RAP-deficient mice were able to adapt to high-, normal, and low-Pi diets appropriately as indicated by urinary Pi excretion and NaPi-IIa protein abundanc

Integrin binding site within the gC1q domain orchestrates EMILIN-1-induced lymphangiogenesis.

Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1-/- mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of α4 and α9β1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A-mutated EMILIN-1 (E1-E933A), unable to interact with α4 or α9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel "regulatory structural" role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain

Management of pheochromocytoma during pregnancy from diagnosis to laparoscopic adrenalectomy. A case report and review of literature

INTRODUCTION: Pheochromocytoma is an endocrine tumour of chromaffin cells. It can be diagnosed either sporadically or in the context of hereditary syndromes (e.g. Von Hippel Lindau, Neurofibromatosis type 1 and multiple neuroendocrine neoplasia type 2). During pregnancy, its frequency is very low (about 0,007%). This tumour causes paroxysmal hypertension in 0,1-0,6% pregnant women, because of an overproduction of catecholamines. If undiagnosed and nontreated, it's associated with high maternal and fetal mortality (40-50%). We report the case of a 30-year-old female diagnosed with pheochromocytoma during pregnancy at week 31 of gestation. In a multidisciplinary team made of surgeons, gynaecologists, anaesthetists, geneticists and endocrinologists we evaluated the case and according to literature, we choose a surgical approach after childbirth: performing a laparoscopic right adrenalectomy. DISCUSSION: In pregnancy, pheochromocytoma is a rare clinical condition. Gold standard treatment is laparoscopic adrenalectomy. However, the optimum timing of surgery is a challenge. CONCLUSION: Timely diagnosis of pheochromocytoma in pregnant women with hypertension and appropriate therapeutic management can lead to improve maternal, fetal and neonatal outcomes. The multidisciplinary team is necessary to recognize the symptoms and to adopt the right pre - and post - operative treatment. Laparoscopic adrenalectomy after delivery is safe and feasible even though the surgical procedure should be performed by an experienced surgeon. KEY WORDS: Pheochromocytoma, Pregnancy, Laparoscopic adrenalectomy and pregnancy, Management of pheochromocytoma, Laparoscopic adrenalectomy, Adrenalectomy, Pregnancy and pheochromocytoma

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

Renal reabsorption of inorganic phosphate (Pi) is mediated by the phosphate transporters NaPi-IIa, NaPi-IIc, and Pit-2 in the proximal tubule brush border membrane (BBM). Dietary Pi intake regulates these transporters; however, the contribution of the specific isoforms to the rapid and slow phase is not fully clarified. Moreover, the regulation of PTH and FGF23, two major phosphaturic hormones, during the adaptive phase has not been correlated. C57/BL6 and NaPi-IIa−/− mice received 5days either 1.2% (HPD) or 0.1% (LPD) Pi-containing diets. Thereafter, some mice were acutely switched to LPD or HPD. Plasma Pi concentrations were similar under chronic diets, but lower when mice were acutely switched to LPD. Urinary Pi excretion was similar in C57/BL6 and NaPi-IIa−/− mice under HPD. During chronic LPD, NaPi-IIa−/− mice lost phosphate in urine compensated by higher intestinal Pi absorption. During the acute HPD-to-LPD switch, NaPi-IIa−/− mice exhibited a delayed decrease in urinary Pi excretion. PTH was acutely regulated by low dietary Pi intake. FGF23 did not respond to low Pi intake within 8h whereas the phospho-adaptator protein FRS2α necessary for FGF-receptor cell signaling was downregulated. BBM Pi transport activity and NaPi-IIa but not NaPi-IIc and Pit-2 abundance acutely adapted to diets in C57/BL6 mice. In NaPi-IIa−/−, Pi transport activity was low and did not adapt. Thus, NaPi-IIa mediates the fast adaptation to Pi intake and is upregulated during the adaptation to low Pi despite persistently high FGF23 levels. The sensitivity to FGF23 may be regulated by adapting FRS2α abundance and phosphorylatio