Automated 3D ultrasound enables novice users to measure arteriovenous fistula maturation parameters with comparable accuracy to conventional duplex by trained sonographers: Results of a benchtop study.

BACKGROUND: Arteriovenous fistulae (AVF) are considered the preferred hemodialysis access but up to 50% of all AVF created in the United States never mature. Doppler ultrasound (DUS) is useful for predicting fistula maturity and impending fistula failure. DUS is resource-intensive and is associated with poor compliance rates in dialysis patients, ranging from 12% to 33%. METHODS: EchoSure is an FDA-cleared 3D Doppler ultrasound device that automatically delivers quantitative blood flow and anatomic vascular information. The technology can be used at the bedside by personnel without formal sonographic training, nullifying limitations of traditional Duplex ultrasound imaging. This study compared the EchoSure system in the hands of inexpert personnel to a traditional expert-operated DUS for rapid assessment of a benchtop model vascular system with flow, diameter, and depth expected in a human AVF. RESULTS: Both Duplex and EchoSure performed within the expected tolerance of ultrasound readings (35%) for volume flow, with the average error (AE) between the observed measurement and the ground truth being 8% for Duplex and 8% for EchoSure. However, the average coefficient of variation (CV) for Duplex pooled over all flow rate measurements was 17% versus 4% for EchoSure. Regarding diameter, Duplex measurements had AE of 15% with an average CV of 6% across all measurements versus EchoSure AE of 4% and average CV of 2%. Duplex and EchoSure measurements over all depths had the same AE of 2%. The two modalities were not statistically different for depth measurement (p = 0.05) but EchoSure measured closer to the ground truth for flow rate and vessel diameter (flow: p = 0.028, ρ = -0.07; diameter: p < 0.001, ρ = 0.69). The inexpert personnel using EchoSure acquired data 62% faster than the expert sonographers using the Duplex ultrasound (141 min for Duplex vs 87 min for EchoSure). CONCLUSIONS: EchoSure may offer an accurate and convenient alternative for imaging fistulas in the clinic.

Safe and effective HeRO graft placement: Technique and results.

OBJECTIVES: Hemodialysis Reliable Outflow (HeRO) grafts are used when venous outflow is inadequate to support conventional access. These have been perceived as complex to implant and being associated with high risk. We have evolved a defined protocol for insertion that minimizes morbidity and maximizes efficiency. METHODS: Our protocol includes staged intravenous access versus HeRO graft placement, reverse Trendelenburg positioning, subcutaneous access of the deep portion of the existing catheter, use of a stiff wire placed within the inferior vena cava, dilation of the tract to 8 mm, device lubrication, all insertion procedures directly visualized, and use of immediate access conduits with SuperHeRO connector. RESULTS: From 7/1/18 to 8/13/19, 55 HeRO grafts were placed at our institution following this protocol, average age 58 ± 15 (26-86) years (mean ± SD, range). 53 (96%) had had prior ipsilateral central access (13 by means of "inside out" 2 weeks prior) the other two had on-table access. Mean procedure time was 70 ± 26 (38-148) min. Excluding seven "complex" cases, procedure time for our first 20 cases using this protocol was 72 ± 29 min, while that of the last 28 was 62 ± 18 min (p < 0.05). One patient suffered acute CHF after unclamping; despite reclamping and ligation he died on POD 3 (mortality rate 2%). 71% were done as outpatients, and 47 of 53 evaluable patients (89%) had their grafts used within 36 h for dialysis. Only one patient (2%) has had an infection within 30 days (cellulitis). At a mean followup of 95 ± 105 (maximum 383) days, three additional patients have had graft infections requiring excision, for a total infection rate of 5/53 (9%). CONCLUSIONS: Our results suggest that HeRO graft placement can be performed with minimal morbidity and mortality on an outpatient basis. Short-term infection rates are low and 89% of patients have their grafts immediately accessed and are discharged without a catheter.

Results of first stage brachiobasilic and brachiobrachial fistula creation: Implications for staged versus single procedure decision making.

INTRODUCTION: Transposed brachiobasilic AV fistulas (BVT) have increasingly been performed in two stages. Published reports give conflicting results, perhaps in part as many reports of staged procedures eliminate those patients who "fail" the first stage (i.e. are lost to follow-up in addition to anatomic failure). METHODS: A prospectively maintained database was reviewed to identify all patients at two institutions who underwent the first stage of planned two-stage BVT by the senior author. Success in this context was defined as patients who eventually underwent second stage fistula creation, leaving the operating room after the second stage with a patent, transposed fistula. RESULTS: From October 2012 to June 2020, 218 patients underwent first-stage procedures. At the first visit, 185 (85%) of fistulas were patent, 23 (11%) were occluded, 8 (4%) of patients were lost to follow-up, and 2 (1%) died. In the interval before the second operation, another eight (4%) patients were lost to follow-up, two were cancelled for medical reasons, and two declined surgery, leaving a total of 173 patients who made it to the second stage (80%). At operation, four patients were found to have unusable veins, leaving a total of 169 patients who completed both stages. If all patients who underwent first stage are included, 77% of patients entering this pathway left the OR after their second stage with patent access. If those lost to follow-up are excluded, this number increases to 84%, while if all those lost to follow-up are assumed to mature, success increases to 85%. CONCLUSIONS: Depending on results in patients lost to follow-up, between 77% and 85% of patients undergoing first stage brachiobasilic fistulae undergo successful second stage transposition. These numbers are equivalent or slightly lower than published maturation rates for single-stage BVT, so there is little margin for failure at the second stage.

Use of a novel immediate access dialysis graft designed to prevent needle-related complications: A first-in-man case report.

Currently, there is no vascular access that possesses all ideal qualities for hemodialysis access, but attributes particularly lacking include: ease of identification (cannulation zone), ease of access, resistance to stenosis, durable to repetitive cannulation, resistance to infection, resistance to acute needle-related injuries, and instant hemostasis. The overall value of these attributes could be appreciated in the reduction of complications (patient burden and suffering, which can also result in increased healthcare costs), and improved safety and durability. In this case report, we present a novel hemodialysis access graft that has the potential to provide the following benefits: it is designed to be self-sealing and immediately usable post implant, easy to identify, easy to access, has more durable cannulation zones, and protects from needle-related injuries. This case report describes the first-in-man use of this novel graft technology to replace a giant, thrombotic, and difficult-to-access arteriovenous fistula to provide the patient with a potentially safer and more durable access that does not require placement of a bridging dialysis catheter. This single-patient experience suggests that implantation and function of this novel graft as a hemodialysis access is feasible in a human subject with end-stage renal disease, and it suggests that the novel properties (i.e. immediate use, easy identification, easy use, cannulation zone durability, and protection from needle-related injuries) of this graft seem to function as intended.

The role of surgery for assisted maturation after endovascular and percutaneous arteriovenous fistula creation.

Even in the best of circumstances, a significant number of patients will require adjunctive endovascular and/or surgical revision prior to achieving functional patency after endovascular or percutaneous AVF creation, at least within the United States. This rate appears to be higher after percutaneous AVF than after endovascular AVF, although because published reports of the former are mostly derived from American experience and those of the latter derived from experience outside the United States, it is unclear whether these differences are due to the technique itself or cultural and/or anatomic differences in dialysis access practices and patient populations. If arterial inflow is poor, this should be corrected first. When flow is adequate (perhaps 900 cc/min) but no single vein is cannulatable, a dominant suitable vein can be superficialized or transposed. If no suitable vein is dominant (most accurately assessed by using an intraoperative flowmeter), the best vein can be used, with or without occlusion of the other veins or reimplantation into the brachial artery. Finally, if the original anastomosis remains the sole supply to the cannulated vein, the original fistula has achieved assisted primary maturation (and assisted primary patency continues), while if a new arteriovenous anastomosis has been constructed, the original fistula has failed. We point out that for this reason as well as to best utilize the upper arm for later access, endovascular and percutaneous AVFs should be constructed and maintained within an atmosphere where both surgeons and non-surgeons work together on the overall access plan.

Efficacy and safety associated with the use of the Surfacer® Inside-Out® Access Catheter System: Results from a prospective, multicenter Food and Drug Administration-approved Investigational Device Exemption study.

PURPOSE: Thoracic central venous obstruction is commonly associated with the use of central venous catheters. The Surfacer System to Facilitate Access in Venous Occlusions Study was an Food and Drug Administration-approved US Investigational Device Exemption study designed to evaluate the performance and safety of the Surfacer System when used to facilitate central venous access in patients with thoracic central venous obstruction. METHODS: Thirty patients were enrolled in this prospective, multicenter, single-arm study between December 2017 and May 2019. Device performance and adverse events were collected peri-procedurally and at discharge. Enrollment included 15 female and 15 male subjects with a mean age of 55.5 ± 12.9 (range: 30-79) years. Twenty-eight patients (93.3%) required central venous access for hemodialysis access. Locations of thoracic central venous obstruction were graded from 1 to 4 based on severity and extension of venous occlusions. Seven patients (23.3%) had type 1, 6 (20.0%) type 2, 16 (53.3%) type 3, and 1 (3.3%) type 4 obstruction. RESULTS: Successful central venous catheter placement was achieved in 27 of 30 patients (90.0%). The procedure was discontinued in three (10.0%) due to tortuous anatomy discovered intraprocedurally. All 27 patients with successful CVC placement achieved adequate catheter patency and tip positioning with a mean overall procedural time and time to achieve central venous access with the Surfacer System being 44.1 ± 30.6 and 19.1 ± 25.1 min, respectively. There were no device-related adverse events or catheter malposition. CONCLUSION: The results of the SAVEUS Study confirm the safety and efficacy of the Surfacer System and the Inside-Out procedure when used for the placement of right-sided central venous access in patients with thoracic central venous obstruction.

Clinical outcomes associated with the use of the NexSite hemodialysis catheter with new exit barrier technology: Results from a prospective, observational multi-center registry study.

PURPOSE: Decreasing the risk of catheter related bloodstream infections (CRBSIs) remains a key focus for improving outcomes and reducing cost of care for hemodialysis (HD) patients. Recent studies demonstrate CRBSI rates can be improved by managing bacterial colonization at the catheter exit site. Herein we present the results of a study documenting the clinical performance of the NexSite HD catheter, a new tunneled central venous catheter which incorporates Exit Site Management (ESM) technology. METHODS: We conducted an observational study using a prospective, multi-center registry of HD patients implanted with the NexSite HD catheter. The primary endpoint for the study was CRBSI rate for a period up to 180-days following catheter placement. Secondary endpoints included device placement success rate, exit site healing, development of an exit site or tunnel infection, and early or late non-infectious catheter-related complications. All reasons for early non-elective catheter removal were recorded. RESULTS: A total of 115 HD patients at 6 sites were included in the final analysis. Cumulative catheter use was 10,924 days with a mean duration of 95 days. Seven patients experienced CRBSIs during the study period resulting in a CRBSI rate of 0.64 per 1,000 catheter-days. Seventy-four patients (64.3%) had either elective catheter removal (n = 56) or utilized the catheter for the entire 180-day observation period (n = 18). Thirty-five patients (30%) underwent non-elective device removal either due to CRBSI (n = 5), low flow (n = 16), exit site issues (n = 7), or for other causes (n = 7). Six patients died during the observation period with 1 death due to CRBSI-associated complications and the remaining 5 deaths attributed to non-device related causes. CONCLUSION: Our findings demonstrate that the NexSite HD catheter equipped with ESM technology can achieve a CRBSI rate in compliance with the NKF KDOQI (National Kidney Foundation Kidney Disease Outcome Quality Initiatives) Clinical Performance Guidelines stated goal of less than 1.0/1,000 catheter-days when used in hemodialysis patients using current standard of care nursing protocols.

Longitudinal dialysis adequacy and clinical performance of the VectorFlow hemodialysis catheter: a prospective study.

PURPOSE: To report clinical performance and longitudinal assessment of hemodialysis adequacy with the Arrow-Clark VectorFlow catheter, a symmetrical-tip device with a distal lumen configuration designed to reduce platelet shear stress and catheter thrombosis. METHODS AND MATERIALS: We prospectively enrolled patients who required de novo placement of a chronic tunneled catheter for hemodialysis or exchange of a dysfunctional catheter as part of an Institutional Review Board (IRB)-approved protocol. Catheter patency, Kt/V, mean blood-flow (Qb), and pump pressures were obtained at baseline and at monthly intervals to 90 days. RESULTS: Forty-six subjects were enrolled into the study. During the 90-day observation period, maximum blood-flow rate averaged 355-398 mL/minute; mean Qb averaged 333-392 mL/minute. Mean Kt/V values were consistently ≥1.5. Dwell-time was 15-114 days, for a total of 2997 catheter days (mean 71.4 days). Excluding patients who died during the study and those receiving surgical access, overall intervention-free catheter patency rate was 94.9%, 92.2% and 88.8% at days 30, 60, 90, respectively. There were no acute complications. During the follow-up period, three patients developed complications (6.5%). Two catheter infections occurred (0.7/1000 catheter days) and one catheter malfunctioned; a rate of 1.0/ 1000 catheter days for all complications. CONCLUSIONS: The VectorFlow catheter produced safe, effective hemodialysis with Kt/V ≥1.5. A single catheter occlusion occurred and a low rate of infection was seen. Results support the hypothesis that the VectorFlow design reduces thrombogenic risk during clinical performance.

Long-term variation in concentrations and mass loads in a semi-arid watershed influenced by historic mercury mining and urban pollutant sources.

Urban watersheds are significantly anthropogenically-altered landscapes. Most previous studies cover relatively short periods, without addressing concentrations, loads, and yields in relation to annual climate fluctuations, and datasets on Ag, Se, PBDEs, and PCDD/Fs are rare. Intensive storm-focused sampling and continuous turbidity monitoring were employed to quantify pollution at two locations in the Guadalupe River (California, USA). At a downstream location, we determined loads of suspended sediment (SS) for 14yrs., mercury (HgT), PCBs, and total organic carbon (TOC) (8yrs), total methylmercury (MeHgT) (6yrs), nutrients, and trace elements including Ag and Se (3yrs), DDTs, chlordanes, dieldrin, and PBDEs (2yrs), and PCDD/Fs (1yr). At an upstream location, we determined loads of SS for 4yrs. and HgT, MeHgT, PCBs and PCDD/Fs for 1yr. These data were compared to previous studies, climatically adjusted, and used to critically assess the use of small datasets for estimating annual average conditions. Concentrations and yields in the Guadalupe River appear to be atypical for total phosphorus, DDTs, dieldrin, HgT, MeHgT, Cr, Ni, and possibly Se due to local conditions. Other pollutants appear to be similar to other urban systems. On average, wet season flow varied by 6.5-fold and flow-weighted mean (FWM) concentrations varied 4.4-fold, with an average 7.1-fold difference between minimum and maximum annual loads. Loads for an average runoff year for each pollutant were usually less than the best estimate of long-term average. The arithmetic average of multiple years of load data or a FWM concentration combined with mean annual flow was also usually below the best estimate of long-term average load. Mean annual loads using sampled years were also less than the best estimate of long-term average by a mean of 2.2-fold. Climatic adjustment techniques are needed for computing estimates of long-term average annual loads.

Role of intravascular ultrasound imaging during endovascular interventions of failing hemodialysis access grafts.

BACKGROUND: Arteriovenous (AV) access graft complications represent a serious complication in patients undergoing hemodialysis. Angiography is one method of visualizing them. However, angiography is not always an effective means of detecting lesions that occur in this context. Intravascular ultrasound (IVUS) is an adjunct modality used to identify stenoses responsible for failing access by identifying multiple stenoses, including those that are most severe. The purpose of this study was to define the value of IVUS in patients with failing AV access grafts by comparing digital subtraction angiography (DSA) alone with DSA followed by IVUS. METHODS: This was a single-center randomized study comparing IVUS with DSA in patients with failing hemodialysis access grafts. It consisted of 100 randomized hemodialysis patients presenting with failing AV access who were being considered for endovascular intervention. Interventions in the control group were guided by DSA alone, whereas interventions in the test group were guided by DSA followed by IVUS. Patients were observed for 6 months after intervention. The primary end point was the time in days to AV access graft failure after the index intervention, expressed as median and interquartile range. Secondary analyses included influence of DSA and IVUS on index procedure decision-making and percentage of patients with AV access graft reinterventions or discontinuation through 3 and 6 months. RESULTS: Median time to first AV graft reintervention or discontinuation was 61 days in the test group and 30 days in the control group (P = .16), with analysis limited to patients who experienced reintervention or discontinuation (n = 59). IVUS resulted in a change in treatment plan in 76% (44/58) of patients, with no treatment change after IVUS in 24% (14/58) of patients. At 6 months, approximately 35% of patients in both the control and test groups remained free from reinterventions (P = .88). At 6 months, approximately 75% of patients in the control group and 80% of patients in the test group remained free from AV graft discontinuation or abandonment (P = .45). CONCLUSIONS: This pilot study suggests that addition of IVUS to standard angiography during endovascular interventions of failing hemodialysis access grafts holds potential to extend the time to the first reintervention. The data support the design and execution of an adequately powered randomized trial with longer follow-up to reliably discern the clinical benefit of IVUS as an addition to standard angiography in the setting of failing AV access grafts.

Granular Cell Tumor Within an Ovarian Mature Cystic Teratoma: Report of a Unique Case and Review of the Literature.

Granular cell tumors involving the female reproductive tract are rare, with only a small number of cases described. Of the reported cases, none are documented within an ovarian mature cystic teratoma (MCT). This report documents a case of a granular cell tumor, incidentally discovered within an ovarian MCT in a 50-yr-old woman undergoing a supracervical hysterectomy and left salpingo-oophorectomy. Although malignant transformation and other secondary ovarian neoplasms in MCT have been well documented, synchronous nonovarian benign neoplasms are reported much less frequently. The histogenesis of secondary tumors arising in MCT is incompletely understood, and the current case provides additional insight, especially pertaining to schwannian and neuroectodermal tumors arising in this setting. The current case, to the best of our knowledge, represents the first report of a granular cell tumor involving a mature teratoma of any site, with the diagnosis being supported by morphologic and immunohistochemical staining characteristics.

Prospective, Randomized, Concurrently-Controlled Study of a Stent Graft versus Balloon Angioplasty for Treatment of Arteriovenous Access Graft Stenosis: 2-Year Results of the RENOVA Study.

PURPOSE: To present final, 2-year data from randomized comparison of an expanded polytetrafluoroethylene stent graft (SG) and percutaneous transluminal angioplasty (PTA) for treatment of arteriovenous graft (AVG) anastomotic stenoses. MATERIALS AND METHODS: A 28-site, prospective, controlled US study enrolled 270 patients with malfunctioning AVG anastomotic stenoses of ≥ 50%; 138 patients underwent SG placement, and 132 underwent PTA alone. Follow-up imaging and intervention were event-driven. RESULTS: The study was completed by 191 patients (97 SG, 94 PTA). Five patients were lost to follow-up or withdrew; 74 patients died during the study (38 SG, 36 PTA). At 12 months, treatment area primary patency (TAPP) was SG 47.6% versus PTA 24.8% (P < .001), access circuit primary patency (ACPP) was SG 24% versus PTA 11% (P = .007), and index of patency function (IPF) was SG 5.2 months/intervention ± 4.1 versus PTA 4.4 months/intervention ± 3.5 (P = .009). At 24 months, TAPP was SG 26.9% versus PTA 13.5% (P < .001), ACPP was SG 9.5% versus PTA 5.5% (P = .01), and IPF was SG 7.1 months/intervention ± 7.0 versus PTA 5.3 months/intervention ± 5.2; estimated number of reinterventions before graft abandonment was 3.4 for SG patients versus 4.3 for PTA patients. There were no significant differences in adverse events (P > .05) except for restenosis requiring reintervention rates of 82.6% in PTA patients versus 63.0% in SG patients (P < .001). CONCLUSIONS: At 2 years, SG use provided a sustained, greater than 2-fold advantage over PTA in treatment area and overall access patency. Time to subsequent intervention was longer in the SG group.

Transcatheter anastomosis connector system for vascular access graft placement: results from a first-in-human pilot study.

PURPOSE: A lengthy healing and maturation period follows standard surgical preparation of a permanent arteriovenous access, often requiring or extending use of a venous catheter (VC) for hemodialysis. The InterGraft™ Anastomotic Connector System was developed for minimally invasive anastomosis of an arteriovenous graft (AVG). The venous and arterial InterGraft™ connectors are designed to provide optimized flow dynamics and may result in reduction of AVG stenosis. This pilot study evaluated placement procedure success, patency and safety of the InterGraft™ connectors. METHODS: Nine AVGs were implanted in nine patients currently receiving dialysis with a VC. The study allowed use of both connectors (n = 5) or use of the venous connector with a sutured arterial anastomosis (n = 4). Monthly ultrasound examinations were performed throughout the six-month follow-up. AVG angiography was performed at five months. Endpoints included procedure success (acceptable graft flow at end of procedure, without significant bleeding or need for emergent surgery), patency, and device-related major adverse events. RESULTS: Procedure success was attained in all patients. AVGs were used for dialysis within 17 days, on average, and VCs were removed. Three patients exited the study early for reasons unrelated to the InterGraft™ connectors. The remaining six patients had patent grafts: two with assisted and four with unassisted patency. AVG flow rates were greater than 1 L/minute. No dilatations or aneurysms were observed by angiography. There were no device-related major adverse events. CONCLUSIONS: The InterGraft™ connectors can be safely and successfully used for AVG anastomoses, with acceptable near-term patency. Further clinical evaluation is warranted.

The clinical use of a P63/cytokeratin7/18/cytokeratin5/14 antibody cocktail in diagnostic breast pathology.

An antibody cocktail directed against p63, cytokeratin (CK)5/14, and CK7/18 is reported to be useful in distinguishing noninvasive from invasive breast lesions and for the characterization of intraductal epithelial proliferations. However, limited studies evaluate its use in clinical practice. A retrospective review of breast material at a university medical center identified cases that were immunostained with the above antibody cocktail. Additional p63 immunostaining alone was performed to further determine the utility of the antibody cocktail in the evaluation of invasion. Of 50 breast cases identified, the antibody cocktail was used to confirm or exclude invasion in 44 (88%). Twenty-two (50%) of these had easily identifiable p63/CK5/14-positive myoepithelial cells, whereas the remainder lacked such staining, confirming the diagnosis of invasive carcinoma. In 27 cases with available diagnostic material for additional p63 immunostaining, the cocktail better highlighted myoepithelial cells by staining nuclei and cytoplasm. Easier identification of invasion was also facilitated by CK7/18 expression in invasive foci, especially those composed of single cells. Ten cases were immunostained to help determine the nature of an intraductal proliferation. The cocktail demonstrated a mosaic staining pattern of both CK7/18- and CK5/14-positive epithelial cells in 3 (30%) cases consistent with usual hyperplasia; homogenous CK7/18 expression in the remaining cases supported the diagnosis of atypical ductal hyperplasia or carcinoma in situ. In summary, the p63/CK7/18/CK5/14 cocktail stain appears to be a useful tool in diagnostic breast pathology, in the evaluation of possible invasion, particularly in the setting of minute foci of invasion as well as in epithelial proliferations.

Use of hybrid vascular grafts in failing access for hemodialysis: report of two cases.

Purpose: Vascular access morbidity represents one of the most common indications for readmission in patients with end-stage renal disease (ESRD). We report the use of hybrid grafts in two patients for revision of failed vascular access for hemodialysis (HD). Case Presentations: The first patient was a 45-year-old woman with ESRD who presented with an arteriovenous graft (AVG) that had required multiple interventions for maintenance in whom much of the graft was lined with covered stents. The patient presented with erosion of a stent in the AVG through the skin to the emergency department. The second patient was a 41-year-old man with ESRD who also had an AVG that had required multiple interventions for maintenance. He presented to clinic with chronic bleeding from the AVG after HD sessions. Both patients were taken to the operating room for salvage of part of the AVG through the use of hybrid vascular access grafts. The patients have passed six and three months from the procedure, respectively, without needing additional interventions. Conclusions: This technique demonstrates successful use of hybrid vascular access grafts, specifically inside existing grafts in locations that contain stents utilizing the existing venous resources in that arm to carry out the surgical repair, thereby preserving venous capital.

By the pricking of my thumbs, something wicked this way comes: sporadic cancers versus eponymous hereditary cancer predisposition syndromes.

Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation-an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum-was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown.

Group I mGluR-regulated translation of the neuronal glutamate transporter, excitatory amino acid carrier 1.

Recently, we demonstrated that mRNA for the neuronal glutamate transporter, excitatory amino acid carrier 1 (EAAC1), is found in dendrites of hippocampal neurons in culture and in dendrites of hippocampal pyramidal cells after pilocarpine-induced status epilepticus (SE). We also showed that SE increased the levels of EAAC1 mRNA ~15-fold in synaptoneurosomes. In this study, the effects of SE on the distribution EAAC1 protein in hippocampus were examined. In addition, the effects of Group 1 mGluR receptor activation on the levels of EAAC1 protein were examined in synaptoneurosomes prepared from sham control animals and from animals that experience pilocarpine-induced SE. We find that EAAC1 immunoreactivity increases in pyramidal cells of the hippocampus after 3 h of SE. In addition, the group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), caused an increase in EAAC1 protein levels in hippocampal synaptoneurosomes; this effect of DHPG was much larger (~3- to 5-fold) after 3 h of SE. The DHPG-induced increases in EAAC1 protein were blocked by two different inhibitors of translation but not by inhibitors of transcription. mGluR1 or mGluR5 antagonists completely blocked the DHPG-induced increases in EAAC1 protein. DHPG also increased the levels of glutamate receptor 2/3 protein, but this effect was not altered by SE. The DHPG-induced increase in EAAC1 protein was blocked by an inhibitor of the mammalian target of rapamycin or an inhibitor of extracellular signal-regulated kinase. These studies provide the first evidence EAAC1 translation can be regulated, and they show that regulated translation of EAAC1 is up-regulated after SE.

mRNA for the EAAC1 subtype of glutamate transporter is present in neuronal dendrites in vitro and dramatically increases in vivo after a seizure.

The neuronal Na(+)-dependent glutamate transporter, excitatory amino acid carrier 1 (EAAC1, also called EAAT3), has been implicated in the control of synaptic spillover of glutamate, synaptic plasticity, and the import of cysteine for neuronal synthesis of glutathione. EAAC1 protein is observed in both perisynaptic regions of the synapse and in neuronal cell bodies. Although amino acid residues in the carboxyl terminal tail have been implicated in the dendritic targeting of EAAC1 protein, it is not known if mRNA for EAAC1 may also be targeted to dendrites. Sorting of mRNA to specific cellular domains provides a mechanism by which signals can rapidly increase translation in a local environment; this form of regulated translation has been linked to diverse biological phenomena ranging from establishment of polarity during embryogenesis to synapse development and synaptic plasticity. In the present study, EAAC1 mRNA sequences were amplified from dendritic samples that were mechanically harvested from low-density hippocampal neuronal cultures. In parallel analyses, mRNA for histone deacetylase 2 (HDAC-2) and glial fibrillary acidic protein (GFAP) was not detected, suggesting that these samples are not contaminated with cell body or glial mRNAs. EAAC1 mRNA also co-localized with Map2a (a marker of dendrites) but not Tau1 (a marker of axons) in hippocampal neuronal cultures by in situ hybridization. In control rats, EAAC1 mRNA was observed in soma and proximal dendrites of hippocampal pyramidal neurons. Following pilocarpine- or kainate-induced seizures, EAAC1 mRNA was present in CA1 pyramidal cell dendrites up to 200µm from the soma. These studies provide the first evidence that EAAC1 mRNA localizes to dendrites and suggest that dendritic targeting of EAAC1 mRNA is increased by seizure activity and may be regulated by neuronal activity/depolarization.

Initial experience and outcome of a new hemodialysis access device for catheter-dependent patients.

OBJECTIVE: The effects of a new long-term subcutaneous vascular access device were studied in access-challenged patients who were poor candidates for fistulas or grafts due to venous obstruction. Bacteremia rates, patency, and function of the Hemodialysis Reliable Outflow (HeRO) Vascular Access Device (Hemosphere Inc, Minneapolis, Minn) were evaluated. METHODS: The HeRO device consists of a 6-mm expanded polytetrafluoroethylene graft attached to a 5-mm nitinol-reinforced silicone outflow component designed to bypass venous stenoses and enter the internal jugular vein directly, providing continuous arterial blood flow into the right atrium. The HeRO device was studied in a multicenter clinical trial to test the hypothesis that access-challenged patients would experience a statistically significant reduction in bacteremia rates compared with a tunneled dialysis catheter (TDC) literature control of 2.3/1000 days. HeRO-related bacteremia rates, adequacy of dialysis, patency, and adverse events were analyzed. RESULTS: The HeRO device was implanted in 36 access-challenged patients who were followed for a mean 8.6 months (9931 HeRO days). The HeRO-related bacteremia rate was 0.70/1000 days. All HeRO-related bacteremias occurred during the bridging period when a TDC was still implanted before HeRO graft incorporation. HeRO adequacy of dialysis (mean Kt/V) was 1.7. HeRO primary patency was 38.9%, and secondary patency was 72.2%. CONCLUSIONS: In access-challenged patients, a statistically significant reduction in HeRO-related bacteremia was noted compared with TDC literature. The device had similar function and patency compared with conventional arteriovenous graft literature.