Residual factor VII activity and different hemorrhagic phenotypes in CRM(+) factor VII deficiencies (Gly331Ser and Gly283Ser)

Two cross-reacting material-positive (CRM(+)) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected glycines belong to structurally conserved regions in the c184 through c193 and c140s activation domain loops, respectively. The natural mutants 331Ser-FVII and 283Ser-FVII were expressed, and in addition 331Ala-FVII and 283Ala-FVII were expressed because 3 functional serine-proteases bear alanine at these positions. The 331Ser-FVII, present in several asymptomatic subjects, showed detectable factor Xa generation activity in patient plasma (0.7% +/- 0.2%) and in reconstituted system with the recombinant molecules (2.7% +/- 1.1%). The reduced activity of recombinant 283Ala-FVII (7.2% +/- 2.2%) indicates that the full function of FVII requires glycine at this position, and the undetectable activity of 283Ser-FVII suggests that the oxydrile group of Ser283 participates in causing severe CRM(+) deficiency. Furthermore, in a plasma system with limiting thromboplastin concentration, 283Ser-FVII inhibited wild-type FVIIa activity in a dose-dependent manner.     

Bioactive glass enhances bone ingrowth into the porous titanium coating on orthopaedic implants

Purpose

The aim of the study was to verify the ability of nanoparticulate bioactive glass (BAG) to infiltrate into the porous titanium (Ti) layer on Ti-based implants to promote osseointegration.

Methods

The porous titanium layer on Ti-based implants was impregnated with nanoparticulate BAG. The implants without or with BAG were implanted bilaterally in tibial holes of ten New Zealand white rabbits. The rabbits were sacrificed after ten weeks for examinations. Beside histological examination, EDXS analysis of polished cross-sections of explanted implants was also performed with the aim to quantitatively evaluate the bone-to-pore contact and bone-in-pore ratio.

Results

After ten weeks, EDXS analyses of cross-sections of the explanted implants confirmed that bioactive glass was fully resorbed and that the pores throughout the thickness of the porous titanium layer were to a large extent filled with a new bone. In the absence of bioactive glass, only the outer part of the porous layer was filled with bone. The implants without BAG in the porous Ti-layer exhibited similar bone-to-pore contact, while significant improvement of bone ingrowth into the pores was observed for the implants with BAG (38%), as opposed to those without it (22%).

Conclusion

This study confirmed that the nanoparticulate bioactive glass within the porous titanium surface layer on implants promotes osseointegration and stimulates the formation of bone within the pores.     

Stage-Specific Impact of Tumor Location on Oncologic Outcomes in Patients With Upper and Lower Tract Urothelial Carcinoma Following Radical Surgery

BACKGROUND: Dissimilarities in management and outcomes exist between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB). OBJECTIVE: The aim of this study was to analyze the stage-specific impact of upper or lower urinary tract tumor location on oncologic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from 4335 patients with UCB treated with radical cystectomy (RC) and bilateral pelvic lymphadenectomy (PLND), 877 patients with ureteral UTUC, and 1615 with pelvicalyceal UTUC treated with radical nephroureterectomy (RNU). No patient received preoperative chemotherapy or radiation therapy. INTERVENTIONS: Patients were treated with RC and bilateral PLND or RNU. MEASUREMENTS: Outcomes were assessed according to primary tumor location. RESULTS AND LIMITATIONS: Compared to UTUC patients, UCB patients had more advanced tumor stage and higher grade, and they were more likely to harbor lymphovascular invasion (LVI) and lymph node metastasis (p<0.001). In non-muscle-invasive tumor stages, UCB patients were more likely to experience disease recurrence and mortality compared to renal pelvicalyceal tumor patients (p<0.002) but not ureteral tumors (p>0.05). In pT2 and pT3 tumors, there was no difference in outcomes between the three tumor locations. In pT4 tumors, patients with ureteral and pelvicalyceal tumors were more likely to experience disease recurrence and mortality compared to UCB patients (p<0.004). These stage-specific findings were unchanged after adjustment for the effects of age, gender, tumor grade, LVI, lymph node status, and adjuvant chemotherapy. This study is limited by its retrospective and multicenter nature. CONCLUSIONS: Stage-specific differences in outcomes exist between UCB and UTUC. The differentially worse outcomes by stage between UCB and UTUC patients underline the differences between both cancer entities and the need for individualized stage-specific management for each patient.     

Lymphangioma of the Gallbladder in Adults: Review of the Literature and a Case Report

Introduction  

Lymphangiomas of the gallbladder in adults are extremely rare with only 10 cases published worldwide to date.     

The clinical anatomy of the sinus node artery

BACKGROUND: Our basic aim was to describe the topographic relation between the sinus node artery and the superior posterior border of the interatrial septum with regard to the sinus node dysfunction that follows the superior transseptal approach to the mitral valve. METHODS: During our study 50 human hearts without previous pathologic alterations were analyzed. The position of the sinus node and the course of the sinus node artery were investigated. For identification of the origin of the artery, selective coronary angiograms were performed. The course of sinus node artery and its topographic relation to the interatrial septum was identified by the dry dissections of the hearts. Based on histologic and dry dissected specimens the exact position of the sinus node was determined. RESULTS: We found that the sinus node artery originates from the right coronary artery in 66% of examined cases and from the left coronary artery in 34% of cases. The sinus node artery crosses the superior posterior border of the interatrial septum in 54% of cases. CONCLUSIONS: Our results were compared with clinical studies focusing the incidence of the sinus rhythm disturbance after the superior transseptal approach. The incidence of rhythm disturbance varies from 52% to 60% of cases. Comparing our morphologic and clinical results we can state that the risk for intraoperative damage to the sinus node artery during the superior transseptal approach to the mitral valve is high.     

The efficacy of photon-initiated photoacoustic streaming in the removal of calcium silicate-based filling remnants from the root canal after rotary retreatment

The aim of the study was to evaluate the efficacy of photon-initiated photoacoustic streaming (PIPS) in the removal of filling remnants from root canals after rotary phase of retreatment and to examine the difference in the amount of residual material considering the type of sealer. Thirty-six extracted single-rooted human teeth were instrumented and randomly divided into three groups according to the filling material used: group 1: EndoSequence BC Sealer (Brassler, USA), group 2: MTA Fillapex (Angelus Solucoes Odontologicas, Londrina, Brasil), and group 3: AH Plus sealer (Dentsply DeTrey, Konstanz, Germany). Cold lateral condensation technique was used. After 2 weeks, the root canals were retreated with a rotary phase retreatment system (ProTaper Universal Retreatment, Maillefer, Ballaigues, Switzerland), followed by Er:YAG laser-activated irrigation (photon-initiated photoacoustic streaming, PIPS). The specimens were scanned in a micro-computed tomographic (micro-CT) device after root canal filling, after the rotary retreatment, and after the PIPS. There was significant reduction in the amount of filling material after the rotary phase of retreatment in all groups (p < 0.05), the highest in the MTA Fillapex group (p < 0.001) and no difference between the EndoSequence BC and the AH Plus (p = 0.608). There was significant reduction of the filling remnants after the PIPS in all groups (p < 0.05). The MTA Fillapex was the most easily removed during rotary phase of the retreatment, and there were no differences in the amount of the remaining filling material between EndoSequence BC and the AH Plus groups after rotary phase of the retreatment. The PIPS improved the removal of filling remnants in all groups.     

Torsion of a mesenchymal hamartoma of the liver in a 1-year-old boy

We report a case of a one-year-old boy who was referred to our clinic suspected of having acute abdomen. On physical examination, the abdomen was soft, diffusely tender with weak peristalsis. Ultrasonography and MRI of the right hemiabdomen demonstrated a well-defined, solid, expansive formation with slightly lobulated contours and an interspersed inhomogeneous structure with overall dimensions of 59?×?45?×?50?mm. After midline laparotomy was performed, a cystic tumor was found, twisted around a pedicle which was arising from the falciform ligament and it measured 5–6?cm in diameter. The tumor appeared to be necrotic. The mass was ligated and extirpated on the pedicle and sent for histopathological analysis. After the surgery, the boy was hemodynamically stable, without respiratory complications and all laboratory findings were within normal limits. Histopathological analysis showed that the tumor was composed of mesenchymal stroma with sparse glimpses of hepatocytes and bile ducts with partly cystic changes lined by orderly epithelium. Given the clinical data, histology and immunohistochemistry analysis (alpha-fetoprotein, CK8/18, hepatocyte, desmin and CD31) a diagnosis of a twisted mesenchymal hamartoma of the liver was made.     

Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC γ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.Nephrotic syndrome is characterized by proteinuria, sodium retention, and edema. Increased renal sodium reabsorption occurs in the cortical collecting duct (CCD),^1,2 where a rate-limiting step in transepithelial sodium transport is the epithelial sodium channel (ENaC), which is composed of the three homologous subunits: α, β, γ.³ENaC activity is regulated by hormones, such as aldosterone and vasopressin (AVP)^4,5; however, adrenalectomized rats and AVP-deficient Brattleboro rats are capable of developing nephrotic syndrome,^1,6 and nephrotic patients do not consistently display elevated levels of sodium-retaining hormones,^7,8 suggesting that renal sodium hyper-reabsorption is independent of systemic factors. Consistent with this, sodium retention is confined to the proteinuric kidney in the unilateral puromycin aminonucleoside (PAN) nephrotic model.^2,9,10There is evidence that proteases contribute to ENaC activation by cleaving the extracellular loops of the α- and γ-subunits.^11–13 Proteolytic activation of ENaC by extracellular proteases critically involves the cleavage of the γ subunit,^14–16 which probably leads to the release of a 43-residue inhibitory peptide from the ectodomain.¹⁷ Both cleaved and noncleaved channels are present in the plasma membrane,^18,19 allowing proteases such as channel activating protease 1 (CAP1/prostasin),²⁰ trypsin,²⁰ chymotrypsin,²¹ and neutrophil elastase²² to activate noncleaved channels from the extracellular side.^23,24 We hypothesized that the defective glomerular filtration barrier in nephrotic syndrome allows the filtration of ENaC-activating proteins into the tubular fluid, leading to stimulation of ENaC. The hypothesis was tested in the PAN nephrotic model in rats and with urine from patients with nephrotic syndrome.     

Spontaneous rupture of a hepatic cystadenoma and cystadenocarcinoma: report of two cases

Hepatobiliary cystadenomas and cystadenocarcinomas are rare tumors. Differentiating between these tumors and benign hepatic cysts may be difficult. Because of their rarity, diagnosis is often delayed and may result in inaccurate treatment, resulting in unnecessary morbidity and mortality. The purpose of this report is to draw attention to these entities and their complications. We report on two cases with spontaneous rupture of hepatobiliary cystadenoma and cystadenocarcinoma cysts, initially treated as simple hepatic cysts by aspiration, or by aspiration combined with sclerotherapy. The spontaneous rupture of the cysts appeared years after the initial treatment of the cysts, leading in one case to a prolonged stay in an intensive care unit. In both cases, a formal liver resection was carried out and microscopic investigations revealed a mucinous cystadenocarcinoma and cystadenoma. In conclusion, although hepatobiliary cystadenomas and cystadenocarcinomas are rare findings, they should not be forgotten in the diagnostic workshop when examining patients with hepatic cysts. If hepatobiliary cystadenomas and cystadenocarcinomas cannot be excluded following radiological imaging, surgery is recommended.