text:
There has been a flurry of publications in the field of hyperkalemia with 3 separate trials of oral potassium binding agents within a week of each other (Sodium Zirconium in JAMA, and NEJM and Patiromer in NEJM) and a potentially related observational trial on the risks of co-trimoxazole in patients on RAAS blockade in the BMJ. With all that reading to get through, the next NephJC on Tuesday Dec 2nd will be a double whammy. We will look at the HARMONISE trial of ZS-9, and a large study of co-trimoxazole and potential associations.
Trim-Sulfa and Sudden Death in patients receiving inhibitors of renin-angiotensin system.
The first paper for discussion is a large, Canadian, case control series, by the Canadian Drug Safety and Research Effectiveness Network, published in the BMJ.
The hypothesis is the risk of sudden death in patients on RAAS blockade is higher following administration of specific antibiotics rather than amoxicillin. To answer their question, they searched 17 years of records representing over 1.6 million patients. They identified 39,879 with a label of sudden death and a subsequent group of 1,027 that had a prescription for the target antibiotics in the 7 days prior to dying.
The authors write: "In the primary analysis, co-trimoxazole was associated with a significantly increased risk of sudden death within seven days relative to amoxicillin (OR 1.8 C.I 1.5-2.24)"
Ciprofloxacin was associated with a somewhat lower risk of sudden death. I found it strange that norfloxacin, which has similar QT prolonging properties to ciprofloxacin, had had no such risk. The authors speculate this observed association may be due to trimethoprim's activity as an ENaC antagonist. There are a number of important limitations to consider. There was no indication for antibiotics recorded. Also, the cases and controls had some important differences in terms of diuretic use and co-morbidities. Only 8.2% of the cases had renal disease, the stage of which was unclassified.
The authors can only speculate about a possible mechanism involving hyperkalaemia as no K levels were obtained for any of these patients, nor any ECG to help explain the effect of ciprofloxacin.
Harmonise: Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia.
ZS-9 is a zirconium silicate, a non-absorbable potassium binding agent. It is an inorganic cation exchanger crystalline with the capacity to bind both potassium and ammonium in the GI tract. Its creators tout its non-absorbable nature as the key to minimising systemic side effects. HARMONISE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial spanning 44 centres. Inclusion criteria was simply a serum K of ≥ 5.1 on 2 occasions.
Initially, 258 patients who met eligibility criteria were given ZS-9 10g three times daily. If they achieve normokalaemia within 48 hours, they were then randomized to a placebo, or increasing doses of ZS-9 once daily. The mean eGFR was 46 ml/min/1.73m2 and no ESKD patients are represented.
Did it work? The short answer is yes. ZS-9 had a reasonable rapid rate of onset and within 2 hours, serum Potassium has dropped by −0.4 mEq/L (95% CI, −0.5 to−0.4) and was - 1.1 mEq/L by 48hours. Encouragingly, it seems generally well tolerated with some edema and hypokalemia as the doses increased. In conclusion, this is a well executed phase 3 trial and ZS-9 has potential to be a well tolerated and predictable treatment option for hyperkalemia.
The authors quite rightly point out we still have no data beyond 4 weeks, nor have we any meaningful endpoint such as mortality or hospital admissions. It is an encouraging study none the less, and should lead to FDA approval and another tool in our kit.
Full post can be seen at www.nephjc.com
Authored by Eoin O'Sullivan.
Wednesday, November 26, 2014
There was a fascinating case published a couple of months ago in the American Journal of Medicine. I have a particular interest in this case as it was my clinic mentor, Julian Seifter, who made the diagnosis and published the case. I have waiting for a long time to write a post about it but couldn't until the paper came out.
The case is a 50yr old man with a history of CKD, quadraplegia and an ileal conduit who was being investigated for CKD. His serum creatinine was 3mg/dl and a creatinine clearance was done to estimate his GFR. His urine creatinine concentration was 175mg and his calculated creatinine clearance was only 3 mls/min. At this point, RRT was recommended and the suggestion was that his serum creatinine overestimated his GFR because of reduced muscle mass.
However, because the urine creatinine still seemed inordinately low and he had no symptoms, an inulin clearance was done which revealed a true GFR of 21 ml/min. What could explain this discrepancy?
A urine culture grew diphtheroids, staphlococcus and streptococcus. Although creatinine, once it is produced in the muscle cannot be metabolized in humans, some bacteria produce creatininase and as a result are able to break it down. Corynebacterium is a diphtheroid that has been associated with the production of creatininase. Dr. Seifter suspected that there was a creatininase-producing bacterium in the ileal conduit that was metabolizing the creatinine leading to a falsely low creatinine clearance. To confirm this, he took a sample of the patient's urine, added a known quantity of creatinine and incubated it for 24 hours at 20 degrees. The results are shown in the figure below.
Our GI tract has some creatininase-containing bacteria but under normal circumstances, the amount of creatinine clearance that they contribute is negligible - less than 2 ml/min GFR equivalent. However, in individuals with advanced CKD, both the relative and total clearance contributed by these GI bacteria increases such that in people with a GFR <10 the contribution of gut clearance can be as high as 4ml/min or approximately 50%. The opposite can also occur. The highest serum creatinine I ever saw was in a 50yr old woman with inflammatory bowel disease. She weighed 40kg but her admission creatinine was 38mg/dl. Despite this, she felt relatively well. She had previously undergone multiple bowel resections and had almost no functional bowel remaining. As a result, she had no gut clearance of creatinine and no upper limit to her serum creatinine concentration.
One final note, the urea clearance was not useful in the above patient either - his urine also contained urease - the clue to this was a very high urine pH (>9) in the presence of a mild metabolic acidosis and no history of RTA.
One final note, the urea clearance was not useful in the above patient either - his urine also contained urease - the clue to this was a very high urine pH (>9) in the presence of a mild metabolic acidosis and no history of RTA.
Posted by Gearoid McMahon at 2:09 PM 1 comments
Labels: CKD, creatinine, Gearoid McMahon
Thursday, November 20, 2014
Almost all the formulas we use in the management of the disorders of water homeostasis are derived from the Edelman equation. I am presenting where these formulas come from for the math aficionados.
Edelman equation
· Original Edelman equation (J Clin Invest. 1958;37:1236-56):
[Na+] = {1.1 x (Nae + Ke)/TBW} – 25.6
Where [Na+] = plasma sodium concentration, Nae=total body exchangeable sodium, Ke=total body exchangeable potassium, TBW = total body water.
· Simplified Edelman equation: [Na+] = (Na + K)/TBW
· [Na+] x TBW = Na + K
· Na + K = [Na+] x TBW
Calculating Free Water Deficit (FWD)
Method #1 (Using baseline weight, certainty about what % of body weight is water)
1. Assuming only pure water has been lost, the total body sodium and potassium remain constant so the total body sodium and potassium at baseline (Na + K)baseline and the total body sodium and potassium after water loss (Na + K)current are equal:
· (Na + K)baseline = (Na + K)current
2. Total body sodium and potassium can be expressed as sodium concentration ([Na+]) multiplied by total body water (TBW):
· [Na+]baseline x TBWbaseline = [Na+]baseline x TBWcurrent
· TBWcurrent = [Na+]baseline x TBWbaseline/[Na+]current … (1)
3. Free water deficit can be expressed as:
· FWD = TBWbaseline – TBWcurrent … (2)
4. Then replacing (1) in (2):
· FWD = TBWbaseline – ([Na+]baseline x TBWbaseline)/[Na+]current
· FWD = TBWbaseline x (1 – [Na+]baseline/[Na+]current)
5. If [Na+]baseline is considered normal at 140 mEq/L then:
· FWD = TBWbaseline x (1 – 140/[Na+]current)
Method #2 (Using current weight, uncertainty about what % of body weight is water)
1. Assuming only pure water has been lost, the total body sodium and potassium remain constant so the total body sodium and potassium at baseline (Na + K)baseline and the total body sodium and potassium after water loss (Na + K)current are equal:
· (Na + K)baseline = (Na + K)current
2. Sodium and potassium masses can be expressed as sodium concentration ([Na+]) multiplied by total body water (TBW):
· [Na+]baseline x TBWbaseline = [Na+]current x TBWcurrent
· TBWbaseline = [Na+]current x TBWcurrent/[Na+]baseline … (1)
3. Free water deficit can be expressed as:
· FWD = TBWbaseline – TBWcurrent … (2)
4. Then replacing (1) in (2):
· FWD = [Na+]current x TBWcurrent/[Na+]baseline – TBWcurrent
· FWD = TBWcurrent x ([Na+]current/[Na+]baseline - 1)
5. If [Na+]baseline is considered normal at 140 mEq/L then:
· FWD = TBWcurrent x ([Na+]current/140 - 1)
Calculating Rate of Infusion of Hypertonic Saline
Method # 1: Na deficit formula
Deriving Na deficit formula
1. Na deficit = Nagoal – Nacurrent … (1)
2. Since Na + K = [Na+] x TBW, then Na = [Na+] x TBW – K … (2)
3. Replacing (2) in (1)
· Na deficit = TBWgoal x [Na+]goal – Kgoal – {TBWcurrent x [Na+]current – Kcurrent}
4. Assuming TBW and K remain constant, so TBWgoal = TBWcurrent, and Kgoal = Kcurrent, then TBW = TBWgoal = TBWcurrent and K is cancelled out from equation:
· Na deficit = TBW x [Na+]goal – TBW x [Na+]current
· Na deficit = TBW x ([Na+]goal – [Na+]current)
5. Since now we aim for an increase in [Na+] of 6 mEq/L, so [Na+]goal – [Na+]current = 6 mEq/L then:
· Na deficit = TBW x 6 mEq/L
Calculating volume of infusate
· Volume of infusate = Na deficit x (1000 mL/513 mEq)
Calculating rate of infusion
· Rate of infusion = volume of infusate/24h
Method #2: Adrogue-Madias formula
Deriving Adrogue-Madias formula
1. [Na+] = (Na + K)/TBW … (Edelman equation)
· [Na+]current = (Nacurrent + Kcurrent)/TBWcurrent
· [Na+]current x TBWcurrent = (Nacurrent + Kcurrent) … (1)
2. [Na+]goal will be the new [Na+] that results when we administer 1L of an infusate containing Nainfusate and Kinfusate, then:
· [Na+]goal = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) …(2)
3. Substracting [Na+]current from both terms of equation (2), then:
· [Na+]goal – [Na+]current = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) – [Na+]current
4. But [Na+]goal – [Na+]current is the same as change in [Na+], then:
· Change in [Na+] = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) – [Na+]current
· Change in [Na+] = {(Nacurrent + Kcurrent + Nainfusate + Kinfusate) – (TBWcurrent + 1) x Nacurrent}/(TBWcurrent + 1)
· Change in [Na+] = {Nacurrent + Kcurrent + Nainfusate + Kinfusate – ([Na+]current x TBWcurrent –[Na+]current)}/(TBWcurrent + 1) … (3)
5. Replacing equation (1) in (3), then:
· Change in [Na+] = {Nacurrent + Kcurrent + Nainfusate + Kinfusate – (Nacurrent + Kcurrent) - [Na+]current}/(TBW + 1)
6. Cancelling out Nacurrent + Kcurrent then:
· Change in [Na+] = {Nainfusate + Kinfusate - [Na+]current}/(TBWcurrent + 1)
Calculating volume of infusate
· Volume of infusate = {1000 mL x (Change in [Na+])goal}/(Change in [Na+])
· Volume of infusate = {1000 mL x 6 mEq/L}/(Change in [Na+])
Calculating rate of infusion
· Rate of infusion = volume of infusate/24h
Posted by Dr. Helbert Rondon at 5:13 PM 0 comments
Labels: Edelman equation, Helbert Rondon, hypernatremia, hyponatremia
Tuesday, November 18, 2014
SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination.
[This is the final post in the five-part series covering some important and often overlooked (and under-published) issues and concepts in the management of severe hyponatremia. While this is not, by any means, an exhaustive discussion of the topic, I hope that these posts will not only help the readers enhance their understanding of the pathophysiology of severe hyponatremia but also help them manage it more effectively with a lot less stress and mental anguish.]
In this video post, I discuss --- what I find to be --- an extremely useful method of calculating the dose of sodium chloride based infusions and predicting response to therapy while treating chronic severe hyponatremia.
Posted by Hashim Mohmand
Posted by Gearoid McMahon at 4:46 PM 5 comments
Monday, November 17, 2014
Michelle P Winn Endowed Lectureship, ASN 2014
Michelle did her undergraduate studies at the University of North Carolina before going to medical school at East Carolina University. She then entered Duke University for residency and fellowship before joining the Duke faculty. Despite spending most of her career at Duke she remained a true Tar Heel (UNC) fan!
She received her training in classical human genetics from Drs Jeffery and Peggy Vance at the Duke Center for Human Genetics. In collaboration with another longtime friend and collaborator and early mentor at Duke, Dr Peter Conlon, Michelle began investigating the genetic heterogeneity of FSGS.
- Together Drs Winn and Conlon collected what is now one of the largest Familial FSGS datasets in the world.
- Michelle's early work linked familial FSGS in one large family from New Zealand to a locus on chromosome 11.
- Following this she identified TRPC6 as the cause for FSGS in this family. This was a seminal paper published in Science and introduced an ion channel and calcium into the burgeoning field of podocyte biology.
- Michelle's further work on TRPC6 made a huge contribution to the understanding of the biology of TRPC6 in kidney disease.
- She described linkage of a gene causing MPGN type III,
- identified TNXB mutations causing vesicoureteral reflux,
- was involved in studies of genetic factors influencing the development and progression of IgA nephropathy
- a hybrid CFHR3-1 gene causing familial C3 glomerulopathy.
- Her work also helped to define the disease burden and impact of other FSGS causing genes such as INF2, NPHS2 and PLCe1.
- She discovered Anillin a new gene causing FSGS,
- a new mutation in the WT1 gene
- added further insights into the function and regulation of TRPC6 in podocytes.
Posted by Andrew Malone at 12:59 PM 2 comments
Labels: Andrew Malone, C3 Glomerulopathy, FSGS, genetics of kidney disease, IgA Nephropathy, Michelle Winn, MPGN, podocyte biology, TRPC6, VUR
Tuesday, November 11, 2014
Blogger night at #KidneyWk14 on Thursday
Field House Philly sports bar. Look for Joel in his AJKD hat.
Posted by Matt Sparks at 1:47 PM 0 comments
Labels: ASN Renal Week
Sunday, November 9, 2014
Nephrology fellows events at ASN #KidneyWk14
Marriott Downtown, Grand Ballroom, Salon H
Fellows In Training Bowl (Mystery Case Debate): Nov 14th 2-3PM
Convention Center, Room 119A
Fellows In Training Bowl (Jeopardy game Nephrology Challenge): Nov 14th 3-4PM
Convention Center, Room 119A
Meet the Experts Session Nov 15th 9:30AM - 10:30AM (Meeting the ASN Award Winners)
Convention Center, Hall D
Fellows Forum Nov 15th 10:30-11:30AM
Convention Center, Room 203
Fellows Poster Discussion Section Nov 15th 2-3PM
Convention Center, Room 112
h/t Kenar Jhaveri
Posted by Matt Sparks at 5:03 PM 0 comments
Labels: ASN Renal Week
Thursday, November 6, 2014
NephJC Live at ASN Kidney Week 2014
The Nephrology twitter journal club will come to life on Saturday 15th November at Kidney Week in
NephJC co-founders Dr Joel Topf and Dr Swapnil Hiremath will co-host the event
at the Double Tree hotel. Philadelphia
There will be 2 live presentations on the day, both of which are sure to stimulate active discussion. There will be a study, presented by Dr. Deirdre Sawinski of
, looking at transplanting
HIV positive kidneys into seropositive donors. Dr Francis Wilson will also
present his RCT on acute kidney injury. University of Pennsylvania
The event is filling up so please visit www.nephjc.com before this Sunday November 9th to register. For those of us who cannot make it to
the event will, as ever, be live tweeted using #NephJC. Philadelphia
Posted by Paul Phelan at 2:17 PM 0 comments
Wednesday, November 5, 2014
Preventing PD Peritonitis: What's the Evidence?
Peritoneal dialysis associated peritonitis is the second commonest cause of death among PD patients (35/1000 years) and the most common cause of treatment failure. It confers a CV risk of 7 times normal for 6 months following the bacteremia, so we need to remain ever vigilant when dealing with PD patient, and its worth refreshing our knowledge on how to prevent this feared complication. There is a paucity of high quality evidence for many of the most fundamental questions in PD. Such is the lack of evidence, the International Society for Peritoneal Dialysis (ISPD) have issued a consensus document where they state they are unable to issue formal guidelines.
The best resources I have found on the topic are a Kidney International supplement from 2006, and the ISPD document already mentioned. In the first instance, which patients are at risk of developing peritonitis? The best described risk factors are hypoalbuminemia (similar to the association in haemodialysis patients), Staph aureus carriage at inception of dialysis (HR 1.53), initiation of PD early after catheter insertion (HR 0.98/day), PD after transplant failure (HR 2.18), lower hemoglobin (HR 0.88/gram/l), faster PD transport rates (HR 2.92) and previous peritonitis. A special risk group to consider are those PD patients undergoing invasive procedures such as endoscopy or IUD insertion. There is evidence that antibiotic prophylaxis using cephalosporins may help reduce peritonitis rates.
The cornerstone of peritonitis prevention is minimizing contamination risk with effective hand washing and immaculate exchange technique. Specialized nurse-led training is key. If peritonitis occurs, retraining and re-education are the most important interventions. Home visits by PD nurses can cut recurrence rates in half, and should be performed where possible. A Cochrane review could find no RCT data to support any particular insertion technique, catheter type, number of cuffs or positioning. It demonstrated that of all catheter-related interventions designed to prevent peritonitis in PD, only disconnect (twin-bag and Y-set) systems have been proved to be effective. Topical antibiotic prophylaxis is a standard of care and there are multiple RCTs demonstrating the efficacy of mupirocin cream application at the exit site. Ointment is to be avoided as it can erode the catheter polymer. In contrast, nasal mupirocin is more difficult to justify. Cochrane point out that while there is trial data that nasal mupirocin reduces exit-site/tunnel infection, it has no effect on peritonitis rates. Preoperative intravenous prophylaxis reduces early peritonitis but not exit-site/tunnel infection.
Recent published trials in the area of antimicrobial prophylaxis have been disappointing. They include the Honeypot study, discussed previously on RFN, which demonstrated the application of honey to exit sites approximately doubled the risk of developing peritonitis in diabetic patients. The MP3 study published in JASN in 2012 found polysporin to increase rates of fungal exit site infections without any improvement in primary outcomes of exit site infection or peritonitis. Finally, a special mention goes to cats, who are responsible for at least 25 case reports of pastuerella peritonitis, as well as an assortment of other bugs. Not to be outdone, rodents feature in the case reports also, coining the term "hamster bite peritonitis" caused by pastuerella aerogenes.
In summary, technique and continuing re-education are of fundamental importance, as are topical antibiotics to prevent exit site infection. Beyond this, trial data are severely lacking and local opinion and consensus must guide practice.
Authored by Eoin O'Sullivan
Posted by Paul Phelan at 1:48 PM 0 comments
Friday, October 31, 2014
SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination.
1. Losing Control: In the preceding posts, I explained how sudden emergence of water diuresis as the predominant mechanism by which rapid overcorrection of serum sodium happens in cases of severe chronic hyponatremia. Few situations or more stressful in nephrology than when we suddenly find that serum sodium has increased by 12 mmol or more within a few hours. The usual scurried response is the immediate administration of 5% dextrose water, DDAVP are both. There has recently been some evidence that using DDAVP with D5W rapidly re-lower the sodium is well tolerated. But, as it was illustrated in this paper, the response to these therapies is very unpredictable with the usual clinical course being a rather erratic series of rises and falls in serum sodium.
Two mechanisms are responsible for the vast majority of cases of overcorrection due to emergence of water diuresis. (1) a sudden drop in plasma ADH/AVP levels due either to resolution of a transient source of ADH secretion or repletion of subclinical hypovolemia and (2) in cases of solute depletion hyponatremia, the sudden availability of solute (in the form of saline solutions or protein load) in the setting of an appropriately suppressed ADH. The common feature of both these phenomena is the very low level of plasma ADH which allows water diuresis.
2. Gaining Back the Control: So how can we prevent the sudden water diuresis which is the hallmark of serum sodium overcorrection? We've argued above that the lack of sufficient ADH or sudden turning off of the ADH secretion is responsible for the sudden loss of free water in the urine. To address this issue specifically, in this paper by Sood et al, the Rochester group tested a very simple yet brilliant idea: why not keep the SIADH state from turning off by creating a robust iatrogenic state of SIADH? This was achieved by giving IV DDAVP 2mg every 8 hours (1 mg was tried as well but there was some breakthrough diuresis; also q6hr schedule was also tried). What this does is, by greatly reducing urine output, stabilize the denominator in Edelman's equation (i.e. almost eliminated changes in TBW, see figure in previous post) and turn the patient into the proverbial beaker, into which now sodium, potassium and water can be added as needed to control the rate of sodium correction. In their series of 25 patients with starting serum sodium of less than 120 mEq/L, quoting directly from the abstract, "Mean changes in serum sodium levels during the first and second 24 hours of therapy were 5.8 +/- 2.8 (SD) and 4.5 +/- 2.2 mEq/L, respectively, without correction by >12 mEq/L in 24 hours or >18 mEq/L in 48 hours and without a decrease during therapy." There was no difference in the predicted and actual correction of sodium and there were no adverse effects associated with the treatment.
Essentially, by converting the patients into human "beakers" by inducing iatrogenic SIADH and then infusing 3% saline at the desired rate allow for safe and predictable rise in serum sodium without any complications.
Our experience with this protocol has been extremely gratifying. When this protocol was used very carefully, the serum sodium correction graph was almost invariably an almost straight line: Something that we almost never see with the traditional method of treatment of severe hyponatremia.
Once a serum sodium is between 125 and 130 mmol/L DDAVP can be discontinued while closely watching the patient.
There are a few important points that need to be mentioned here.
#1 --- It has to be clarified to the nursing staff that the DDAVP needs to be given exactly every 8 hours and the dose cannot be missed. If the dose is missed, there can be breakthrough large volume diuresis in about 10-12 hours from the last dose which can cause overcorrection.
#2 --- The water content of all fluids given/ingested will be retained. Therefore a very strict fluid restriction needs to be enforced. In the IV fluids being given to the patient's in the form of infusions with antibiotics etc. need to be accounted for by calculation.
#3 --- in patients with congestive heart failure lasix can be used if it seems like fluid overload is becoming a problem.
#4 --- if a double-lumen PICC line is being used for 3% saline infusion and for drawing labs, the hypertonic infusion should be held for a few minutes before a drawing serum sodium level. Recirculation can give a falsely elevated sodium level. An important clue in this situation would be that there would be no large change in urine output that would be expected with a true sudden rise in serum sodium.
This protocol is somewhat opposite of what we have traditionally been taught regarding treatment of severe hyponatremia. Given how stress-free and easy the management of severe hyponatremia has become with this for me and other colleagues, I expect this protocol to gain more widespread acceptance over the next few years. I would also like to know if anybody has had experience with this protocol, good or bad.
Hyponatremia remains a clinical challenge but is also fun and stimulating at the same time. A little time spent on determining the physiology at work and using more quantitative methods of choosing the doses of 3% saline coupled with good results for the patient make it very rewarding as well.
Posted by Hashim Mohmand
Posted by Hashim Mohmand
Posted by Gearoid McMahon at 8:55 AM 3 comments
Tuesday, October 28, 2014
FSGS biomarker updates—suPAR, B7-1, CD40 and more…
FSGS is the most common glomerular disorder causing end-stage kidney disease in the USA with a high post-transplant recurrence rate of 20-50%. Furthermore, the treatment of post-transplant recurrent FSGS is extremely challenging. While reading a recent article on biomarkers predicting post-transplant recurrent FSGS by Delville et al. (discussed below), it seemed a good idea to cover recent advancement in FSGS research.
suPAR (soluble plasminogen activator receptor)
Since the first report by Wei et al. of suPAR as a circulating permeability factor causing FSGS, there has been extensive research to elucidate its role in FSGS. Although administration of suPAR molecule to mice was initially thought to be sufficient to cause proteinuria mimicking FSGS, via activation of integrin beta 3 and derangement of actin cytoskeleton, the situation does not seem that straightforward. As Reiser et al. discussed, there are challenges to overcome: existence of different suPAR isoforms with different disease modifying effects; heterogeneity of FSGS itself, which make it complicated to interpret correlation between levels of suPAR and disease activity; involvement of suPAR in other disease process, including cardiovascular disease (KI 2014). However, suPAR remains an intriguing molecule and potential biomarker in FSGS disease process.
A case series in the NEJM from Peter Mundel's group in the end of 2013 brought us to an excitement for personalized treatment of a subgroup of B7-1 positive FSGS patients. They found strong B7-1 stain in primary FSGS as well as post-transplant recurrent FSGS. These patients were successfully treated with abatacept (CTLA4-Ig), resulting in complete remission of proteinuria. The hypothetical pathophysiological mechanism was via direct interaction of B7-1 and integrin beta 1 causing podocyte actin cytoskeleton changes. However, it was followed by comments and larger case series (AJKD 2014) questioning specificity of the immunostaining and treatment effect of abatacept. Exploration of this costimulatory molecule in FSGS was just started and further research is needed.
Micro RNA(s) as biomarkers for FSGS disease activity
A group from China suggested that certain micro RNAs are associated with disease activity (level of proteinuria) and progression (Zhang et al. CJASN and AJKD 2014). Potential candidates are miR-186 (involved in cell cycle control, AKT and insulin signaling etc.) and miR-125b (involved in NFkB signaling etc.). However, their contribution to pathogenesis is not clear so far.
Pre-transplant antibody panel (including anti-CD40) to predict post transplant recurrent FSGS
Expanding potential FSGS biomarkers is the publication by Delville et al. The authors did a beautiful translational work using human serum in protein arrays, validation of specific auto-antibodies and further experimentation using cell cultures and animals models. The authors elegantly showed that pre-transplant antibody panel, especially anti-CD40 antibody, can predict risk of post-transplant recurrent FSGS.
In more detail, they started by comparing pre-transplant sera of non-recurrent FSGS (nrFSGS) vs recurrent FSGS (rFSGS), identifying 789 autoantibodies upregulated only in rFSGS but not in nrFSGS. Then those antibodies were enriched for those Ab with antigen targets expressed in kidney (151 autoAbs) and more specifically in glomeruli (10 autoAbs). They validated the 7-antibody panel (CD40, CGB5 (chorionic gonadotropin b), PTPRO (protein tyrosine phosphatase receptor O), FAS (TNF receptor superfamily member 6), P2RY11 (P2Y purinoceptor 11), SNRPB2 (small nuclear retinoid X receptor a), and APOL2 (Apolipoprotein 2)) in rFSGS vs nrFSGS cohort, and obtained ROC AUC of 0.92. Surprisingly, anti-CD40 itself had a high ROC AUC (0.77). Then, the involvement of rFSGS-anti-CD40 IgG to enhance FSGS recurrence was confirmed in vitro—rFSGS-anti-CD40 IgG caused actin cytoskeleton derangement in podocyte cell culture—, as well as in vivo—co-injection of rFSGS-anti-CD40 IgG and suPAR molecule markedly enhanced proteinuria (in a suPAR-dependent manner), which was inhibited by CD40-blocking antibody or in CD40 knockout mice. This suggests that by checking pre-transplant anti-CD40 antibody, we may be able to identify a high risk FSGS recurrence group. To manage these patients, current options are: peritransplant plasmaphresis or rituximab. Interesting to see if CD40 antagonist or blocking antibody can play a role in preventing/treating rFSGS in the clinic...
Naoka Murakami
Posted by Leonardo V Riella, MD, PhD at 6:51 PM 0 comments
Labels: B7-1, FSGS, Leonardo Riella, suPAR, transplant nephrology
Friday, October 24, 2014
SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 3)
In my previous post concerning chronic severe hyponatremia, I explained how over corrections of serum sodium of large magnitude required a dilute large volume diuresis, often precipitated by resolution of a transient source of ADH secretion. In this post I will discuss two phenomena which are particularly dangerous as they carry significant risk of producing large volume water diuresis.
1. Subclinical Volume Depletion: As mentioned in my previous post, we noticed during our review of a large number of cases of severe hyponatremia treated with 3% saline that most of the patients whose serum sodium eventually overcorrected responded to small volumes of 3% saline as if they were volume depleted, with sudden emergence of water diuresis. Interestingly, most of these patients were initially considered to be euvolemic by experienced nephrologists.
This very interesting paper reviewed the literature concerning the value of physical examination in diagnosing volume depletion. The conclusion, rather humbling, was that other than in cases of severe volume depletion our physical exam was quite inaccurate in diagnosing volume depletion. This is especially concerning considering that establishing a patient's volume status forms the major decision point in the ubiquitous diagnostic algorithm for hyponatremia.
According to the paper, reliable signs of volume depletion usually are visible with the loss of about 20% of the intravascular volume. The ADH secretion and response to volume depletion starts with volume losses as low as 5-8% of the effective intravascular volume. This implies that the patient may have significant ADH secretion, contributing to the relative excess water retention causing hyponatremia, while clinically appearing euvolemic. It also means small volume bolus may switch off this ADH secretion, causing water diuresis and sudden rise in serum sodium.
Subclinical volume depletion as a contributor to hyponatremia should always be considered a possibility especially when starting therapy with 3% saline.
2. Solute Depletion Hyponatremia: The so called "Tea and Toast Diet " hyponatremia and "Beer Potomania" are examples of solute depletion hyponatremia. As nicely described by Dr. Berl, our solute intake limits our ability to excrete free water. Even with a maximally dilute urine of around 50 mOsm/L, a person consuming a 300 mOsm/d diet can only excrete 6 L of urine (300/50=6). Such a person will become hyponatremic with drinking more than 6 L of fluids a day because any water in excess of 6 L per day excretory capacity will be retained in the body. It is important to note that this water retention is not due to ADH secretion. ADH is often suppressed in such patients. The renal danger of this pathophysiological mechanism is that whenever such patient is "presented" with solute (IV normal saline, high-protein meal which would generate BUN or even 3% saline!), without a high ADH level to prevent it, the added solute is used to rapidly excrete free water that has been "trapped" in the body.
As an example, consider the case of the 26-year-old female that I briefly alluded to in the previous post. She presented with a serum sodium of 108 mEq/L after being on an exclusively alcohol diet for the last 2 weeks. She received 2 L of normal saline in the ER (154 mEq x2 = 308 mEq of Na). Using the Edelman equation (see figure) and an initial total body water of 32 L, if we do not account for urine output, that amount of added NaCl would have raised the serum sodium to about 111 mEq/L. But the actual rise of serum sodium was to 131 mEq/L in about 5 hours accompanied by almost 7 liters of dilute urine output. Her kidneys used the roughly 300 mEq of sodium in the NS bolus to excrete more than 6 liters of maximally dilute urine (300/50=6 L, remember the earlier calculation?) and almost perfectly accounts for the 23 mEq/L rise in serum sodium (by reducing the denominator, TBW).
This would have also happened if she had received the same amount of NaCl in the form of 3% saline as in such cases the volume of infusate matters less than the amount of solute delivered.
I hope this case illustrates how dangerous solute depletion hyponatremia can be and how easy it can be to precipitate an overcorrection of serum sodium in such patients. This raises a very important question: if even treatment with 3% saline is so unreliable in patients with chronic severe solute depletion hyponatremia, how can we safely treat such patients? That will be the subject of my next post.
In conclusion, subclinical volume depletion and solute depletion pose a particularly tricky challenge in the management of chronic hyponatremia as sudden rises in serum sodium level can happen rather easily in these patients with, what would otherwise seem to be, rather innocuous treatment with saline solutions.
Posted by Hashim Mohmand
Posted by Hashim Mohmand
Posted by Gearoid McMahon at 12:57 PM 1 comments
Monday, October 20, 2014
SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 2)
I mentioned in the previous post that severe hyponatremia is multifactorial and that the contributing etiological factors in any given case may be transient and reversible. In this post I would like to stress the importance of closely monitoring the urine output of the patient in addition to frequent monitoring of the plasma sodium. Urine output is an extremely important clinical parameter that needs to be monitored closely but is not really mentioned in textbooks and handbooks.
Overcorrection by more than 12 mEq/L in 24 hours is not easy to achieve if the patient has a stable state of antidiuresis. In an anuric patient with total body water of 32 L and a starting serum sodium of 108 mEq/L would require an infusion of more than 750 mL of 3% saline: a prescription not many of us would order. In fact, during our review of cases of severe hyponatremia we found that the very popular Adrogue-Madias equation grossly underestimated the sodium correction in the majority of patients. Most of the patients' sodium corrected far in excess of what the equation predicted.
The reason for that is that these equations treat the patients as if they were beakers that we can add sodium to and watch the plasma sodium rise as predicted. However, unless the patient is on dialysis or in oliguric renal failure, they also lose free water in the urine, a fact that the equation does not take into consideration. In fact, in our case series every patient that had an overcorrection of sodium beyond the desire goals, and had adequate documentation of ins and outs, had a documented large volume dilute diuresis. Invariably, such large-volume water diuresis emerged suddenly as if an ADH switch was turned off, suggesting resolution of a transient source of ADH secretion.
While small, sudden increases in serum sodium are certainly possible with the addition of too much sodium to the system, very large and dangerous increases require simultaneous loss of free water. A very illustrative case is one of a 26-year-old female I managed a couple of years ago. She presented with a serum sodium of 108 mEq/L and received the inescapable 2 L of normal saline bolus in the ER and about 5 hours later her serum sodium was 131 mEq/L. With an estimated total body water of 32 L (and using the Edelman equation, see figure), if we considered her oliguric and try to account for the rise in serum sodium slowly on the basis of addition of sodium chloride to the system, we would require about 1.9 L of 3% saline to be infused in a 5 hour period! However it is perfectly explained by the almost 7 L of water diuresis that emerged with the 2 L saline bolus. More on this case in a later post.
In conclusion, very close monitoring of urine output should be an important and integral part of the early management of severe hyponatremia. The sudden emergence of water diuresis is often the earliest sign of a rising serum sodium and should prompt a stat plasma sodium check. I have often relied upon a well documented q2hr urine output in ICU setting more so than the q2-4hr sodium levels which are fraught with the issue of delayed venipuncture and delays in reporting.
Posted by Hashim Mohmand
In conclusion, very close monitoring of urine output should be an important and integral part of the early management of severe hyponatremia. The sudden emergence of water diuresis is often the earliest sign of a rising serum sodium and should prompt a stat plasma sodium check. I have often relied upon a well documented q2hr urine output in ICU setting more so than the q2-4hr sodium levels which are fraught with the issue of delayed venipuncture and delays in reporting.
Posted by Hashim Mohmand
Posted by Gearoid McMahon at 9:03 PM 2 comments
Monday, October 13, 2014
SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 1)
Severe chronic hyponatremia (<120 mEq/L) remains the #1 reason nephrologists lose sleep on call nights and rightly so. The fear of overcorrection and the risk of central pontine myelinolysis (CPM) or osmotic demyelination syndrome (ODS), however uncommon they actually might be, has been drilled into our brains since the beginning of medical school.
In this post and the few that follow, I will attempt to address some aspects of chronic severe hyponatremia which have traditionally not been included when hyponatremia is taught or written about or have only recently been backed by some evidence and have not yet made their way into the textbooks. The recently released guidelines also did not address some of these issues. While this is not, by any means, an exhaustive discussion of the topic, I hope that these posts will not only help the readers enhance their understanding of the pathophysiology of severe hyponatremia but also help them manage it more effectively with a lot less stress and mental anguish.
The Schrier-Berl algorithm for diagnosis of hyponatremia has been used successfully for decades for teaching, and for reasoning through the differential diagnosis at the bedside. It is an integral part of every medicine textbook and pocket handbook. It takes us to our diagnosis through 3 decision points: Plasma osmolarity, volume status and urine sodium sequentially. While the algorithm holds true for the garden variety mild to moderate hyponatremia, it almost invariably breaks down in case with very severe hyponatremia.
During our extensive review of cases of severe hyponatremia treated with 3% saline, we seldom came across a case in which there was only one isolated cause for hyponatremia. Rather, they were almost always two or more possible etiologies. In addition, many patients that were initially considered to be euvolemic by experienced nephrologists, responded to 3% saline as if they were volume depleted. Lastly, the clinical course of these patients during the hospitalization seemed to suggest many of these causes of inappropriate release of ADH were transient and reversible (SSRIs, acute nausea, postop state etc.). The patients' physiology seemed to change from time to time, with overcorrection of sodium invariably accompanied by large-volume water diuresis as these transient sources of ADH were "switched off."
It was, however, the paper by Sood et al that finally looked at the possible different etiologies for cases of severe hyponatremia as shown in the table (see image), which I consider the single most important table in all of recent hyponatremia literature. They showed for the first time for multiple etiologies and processes are at play, some fixed and some transient in generating severe hyponatremia.
It is of paramount importance, that in the workup of hyponatremia, especially severe cases, we do not limit our reasoning through the differential diagnosis to comply with the algorithm that we have so familiar with but constantly look for multiple etiologies and transient causes of SIADH, especially subclinical volume depletion (low urinary sodium can be helpful here), as often it is the resolution of these causes that leads to the large-volume water diuresis and overcorrection.
Posted by Hashim Mohmand
Posted by Gearoid McMahon at 9:43 PM 5 comments
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NW Miami-Dade
Car Crashes Into NW Miami-Dade Home
A home in Northwest Miami-Dade was damaged Monday when an SUV slammed into the side.
MDPD: Man Shot And Killed On Bicycle
A man was shot several times while riding his bicycle Sunday.
Police Standoff Ends Peacefully In NW Miami-Dade, Subject Not Found
A standoff with police took place Thursday afternoon, but ended peacefully.
Teen Dies From Stray Bullet In Drive-By At Park
A teenage girl who was shot while simply sitting on a park bench has died, police said late Friday.
Five People Shot In NW Miami-Dade
Police are investigating the shooting of five people in Northwest Miami-Dade late Thursday evening.
13-Year-Old Recovering After Getting Grazed By Bullet
Jawan Douglas, 13, continues to recover Friday after being grazed in the head by a bullet while walking home.
MDPD: 13-Year-Old Boy Grazed By Bullet
Police responded to a shooting in NW Miami-Dade Thursday night where a 13-year-old boy was reportedly grazed by a bullet.
Man Dead After Police-Involved Shooting
Miami-Dade police are investigating a deadly shooting involving two of their officers.
Child In Hospital After Shooting In Northwest Miami-Dade
Miami-Dade police are investigating a report of a child that was shot while inside a car Saturday evening.
Bullet Casings Litter Road Where Teen Shot In NW Miami-Dade
A South Florida teenager remains hospitalized after being shot outside his Northwest Miami-Dade home Monday morning.

subset: commoncrawl


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The All-Star Five Pack gives fans a ticket to their choice of four different BlueClaws regular season games, plus the South Atlantic League All-Star Game, presented by Kimball and Community Medical Centers, OceanFirst Bank, and ShorePoint Distributing Company.
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November 28, 2014
A task force has been formed to determine if the annual Veishea celebration at Iowa State University should continue following last week's crowd disturbance near the Ames campus.
University President Steven Leath announced the 20-member group Thursday. Tom Hill, senior vice president for student affairs, will lead it. The group includes student leaders and staff as well as the mayor of Ames and the police chief.
People gathered during the multi-day Veishea celebration are accused of overturning cars and toppling light poles early on the morning of April 9th. One student was injured. The disturbance led to Veishea's suspension for this school year.
The group will study the celebration's history and offer recommendations to Leath before the end of June.
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I do believe some shots are available free of charge from the County Health Dept.
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What's coming up soon …
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Most of the courses are delivered at Cambridge Regional College's Science Park Campus. However, we also run a series of Management Workshops at Corpus Christi College in their superb conference rooms. These are very reasonably priced and are booked directly with Corpus Christi on 01223 337144 or via their website at www.corpus.cam.ac.uk/conferences
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Oh Google, your sense of humour sleighs us
Suggests SUSE Storage could quickly become its number two product line
A run down of bargains being planned for 28 November
Firms say no gamer credentials were pilfered
Android 5.0 flagship is trickier to pull apart than last year's Nexus 5
UK retailer confirms smartphone is struggling to match last year's Galaxy S4
Changes afoot in the telecoms industry
Backdoor.Regin said to have been used in international spying campaigns since 2008
Still no word when it will be back up and running
But Apple keeps quiet on persistent problems
Drastic measures could be taken to 'restore competition online'
Rumoured service will be separate to firm's Prime Instant Video offering
Updated Everything you need to know about Apple's debut wearable device
And treat us to an anticlimactic video of the sting
Chinese firm claims it will become the world's number one smartphone manufacturer
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Brings out dedicated and hybrid cloud services
Never sign anything slipped under your door if you can still taste toothpaste
Everything you need to know about Samsung's 2015 Android smartphone
Raises maximum file size to 5TB as AWS plays catch up
Column As Ubergate rumbles on, time to bring you up to speed
We pit the two Android 5.0 Lollipop tablets head to head based on their specs
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Eminem's mom writes a book; Lynn Spears' postponed
Filed under: Life & Style, Celeb Parents, Rumors, Playground Bureau, Behaving Badly
Marshall Mather's mom is fed up and she's not taking it anymore. The rapper known as "Eminem" cannot be happy about his mother's tell-all book, due out in 2008.
In the publication, good ol' Mominem finally spills the beans on Mather's background, and like rapper Vanilla Ice, it is a lot less ghetto than the public was lead to believe.
"After his first album, Infinite, flopped, he reinvented himself as white trailer trash with a crazy welfare mom. I was shocked when I first heard the lyrics... but he constantly reassured me it was all a big joke... I went along with it for Marshall's sake." say Debbie Nelson.
However, after years of being treated poorly her son's fans, Debbie Nelson has had enough. "This book is my way of setting the record straight," she explains.
In other celebrity mom literature news, the day after sixteen year old Jamie Lynn Spear's surprise pregnancy was announced, her mother's book Pop Culture Mom: A Real Story of Fame and Family in a Tabloid World , which was due out on Mother's Day has been put on hold by its Christian publishing house.
Perhaps they just needed time to change the title to: Pop-Tart Mom: A Story of Fame and a Tabloid Family in the Real World?
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pinkieme's Mom Answers Activity
My husband has lost interest in sex since our baby's birth. What should I do?
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The 8th Annual Jump Session Show: A Swing Dance Extravaganza
* Additional fees apply.
The last date listed for The 8th Annual Jump Session Show was Friday May 24, 2013 / 7:00pm.
Most Popular Music Event Nearby
Slapstick Musical Comedy Beaumount & Caswell in Hacienda Holiday
- Full Price:
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Tempers, libidos and cast members all fly high in Teatro ZinZanni's production of <em>Beaumount &...Learn More
Venue Details
We often enjoy a light dinner at Fonte Cafe and Wine Bar before shows at Benaroya. Much nicer than the choices in the hall.Seattle Men's Chorus Holiday Concert: Play It Again Santa dining • Jun 17 2014 star this tip starred
If you arrive in time to park in the lot, parking is no problem. But don't kid yourself thinking you'll find free street parking.Seattle Men's Chorus Holiday Concert: Play It Again Santa travel • Jun 17 2014 star this tip starred
Reviews & Ratings
Featured review from Goldstar Member
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We thought the show was interesting and worth the (discounted) price of admission. The performers, including the bridge skits were fun; although the vaudeville routines may have been a bit too extensive after a while. However, it's possible they were necessary to allow any staging for the next performers to be completed. Our primary motivation, though, was to see Meschiya Lake and her Little Big Horns. We had seen Ms. Lake earlier in a local performance with the Seattle Rep Jazz Orchestra, and she was terrific. We had also "heard" she and her band on several YouTube recordings. Unfortunately, after the main dance program, everyone not possessing a wrist band for additional participation in the show was ushered out through a side entrance. Although we bought discount tickets through Goldstar, we bought the higher priced tickets which were supposedly good for additional attendance. We were not given any instructions or told about any need to "register" at a desk in the lobby in order to see and/or take part in the additional parts of the show, particularly hearing the band perform for dancing on the Benaroya stage or in the auditorium lobby. We were also "forced" to go down and up several flights of stairs in order to be ushered out of the auditorium. Stairs are particulary difficult of one of us, so we found that treatment very uncomfortable, as we did the need to leave in the first place. In sum, then, we enjoyed the main show, but were displeased with the "forced" exit and the manner in which it was carried out.
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Absolutely fantastic! I've been to this show twice and it always delivers. Full of awe for the producer, Tonya Morris, and the director/writer, Gabriella Cook, who somehow bring together dozens and dozens of dancers and musicians from across the...continued
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I'm an experienced swing dancer myself, and I've been to a lot of conventions - enough to know that what we saw on stage were amateurs, ranging from very talented to quite amateurish. Unfortunately, when you end up paying $21/ticket, you don't...continued
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I really didn't expect this show to be so entertaining! The cast was so talented, and the music was fun and upbeat. Definitely a toe-tapping event!
All proceeds from the Jump Session Show are donated to Camp Fire USA Snohomish. 100% of this donation is used to spread jazz dance programming to the local youth.
Photo credit: Danny Ngan


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Locked In For Life
By Peter Kryvor | October 16th, 2014 | General | No Comments
Right from the beginning, God has addressed and endorsed the idea of long life as part of His covenant with man. In Genesis 6:3, He said "yet his days shall be one hundred and twenty years". This wasn't a one-time proclamation. In Psalm 91:16 he states "With long life I will satisfy him and show him My salvation". On top of that, in Proverbs 3:1-2, He admonishes us "My son, do not forget my law, but let your heart keep my commands, for length of days and long life and peace they will add unto you". Praise the Lord for long life!


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Bowl Bus Tailgating Travel to Sun Life Stadium in Miami Gardens, FL!
We've sent 44 buses to Sun Life Stadium!
Bowl Bus provides bus transportation to Sun Life Stadium. Our social reservation system shuttles you from your town to the Stadium and back. Click a Game below or check out all the other Stadiums...
Upcoming Games
Panthers @ Hurricanes Hurricanes host the University of Pittsburgh Panthers November 29, 2014
Ravens @ Dolphins Dolphins host the Ravens December 7, 2014
Vikings @ Dolphins Dolphins host the Vikings December 21, 2014
Jets @ Dolphins Dolphins host the Jets December 28, 2014
Orange Bowl December 31, 2014
Looking for how to get to Sun Life Stadium in Miami Gardens? Bowl Bus is the fun, safe, and green way to get there and back for less than the cost of driving!
Other Upcoming Events at Sun Life Stadium
Bowl Bus is Rally Bus: The Social Mobility Network
Miami Reggae Festival
on November 22, 2014 via Rock & Bus
Completed Games
Seminoles @ Hurricanes Hurricanes hosted the Seminoles on November 15, 2014
Bills @ Dolphins Dolphins hosted the Bills on November 13, 2014
Chargers @ Dolphins Dolphins hosted the Chargers on November 2, 2014
Tar Heels @ Hurricanes Hurricanes hosted the Tar Heels on November 1, 2014
Packers @ Dolphins Dolphins hosted the Packers on October 12, 2014
Bearcats @ Hurricanes Hurricanes hosted the Bearcats on October 11, 2014
Blue Devils @ Hurricanes Hurricanes hosted the Blue Devils on September 27, 2014
Chiefs @ Dolphins Dolphins hosted the Chiefs on September 21, 2014
Red Wolves @ Hurricanes Hurricanes hosted the Red Wolves on September 13, 2014
Patriots @ Dolphins Dolphins hosted the Patriots on September 7, 2014
Rattlers @ Hurricanes Hurricanes hosted the Rattlers on September 6, 2014
Rams @ Dolphins Dolphins hosted the Rams on August 28, 2014
Cowboys @ Dolphins Dolphins hosted the Cowboys on August 23, 2014
Stadium Information
Whether you are heading north from Miami or south from Fort Lauderdale, there is surely one thing that will catch your eye. Like a giant beacon beaming in from a distance, Sun Life Stadium is a structure one in its own. It is the fortress the Miami Dolphins call home.
Although a successful franchise, the Florida sun that shines year round has many fans elsewhere on game-day. For those fans that bleed aqua and orange, there is no place like Sun Life Stadium on a Sunday afternoon.
There is no problem getting to the stadium, parking, tailgating, or going into the stadium. A very well set up area, Sun Life Stadium provides a simple and convenient parking and tailgating area that is an easy walk to the stadium. There are portable bathrooms set up around the tailgating areas and there are many bathrooms in the stadium.
The parking allows for tents to be set up as well as grills, tables and tailgate games. There is also ideal room to throw around a football, even at full capacity.
Directions to Sun Life Stadium? Take Bowl Bus instead!
Location: 2267 NW 199th Street, Miami Gardens, FL
Capacity: 75,192
Completed: 1987
Official Site: http://www.sunlifestadium.com/


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Definition: This entry gives the total length of navigable rivers, canals, and other inland bodies of water.
Source: CIA World Factbook - Unless otherwise noted, information in this page is accurate as of January 1, 2012See also: Waterways map
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The great diversity of presentations in software applications deals with fulfillment of various type of graphic interface constructions related to different programming languages. Moreover, in the Internet era html pages play a main role because of the increasing complexity of Web applications. In Software Engineering, the use of design patterns is proven remarkable for the design and reuse of software components. Visual design patterns (ViDP) are useful to define interaction schemas between user and computer. By the some token, visual design patterns are useful to incorporate common interfaces of interaction schemas between user and computer. This paper describes the extensible presentation language (XPL), a presentation language based on visual pattern. XPL framework implementation will be discussed in details and a case study showing the benefits of employing XPL will be presented.
A not-for-profit organization, IEEE is the world's largest professional association for the advancement of technology.© Copyright 2014 IEEE - All rights reserved. Use of this web site signifies your agreement to the terms and conditions.


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On September 22, 2014, the SEC announced its largest whistleblower award to date under its Dodd-Frank whistleblower bounty program. It awarded $30-$35 million to an anonymous whistleblower who the Commission said provided original information about an ongoing fraud that would otherwise have been difficult to detect. That information led to the successful enforcement of an SEC action as well as unspecified related actions. The SEC stated that the whistleblower's award would have been even higher if he/she had not unreasonably delayed in coming forward, though the agency did not apply the unreasonable delay consideration as severely as it otherwise would have because some of the delay occurred before the whistleblower program's inception.
Tag Archives: dodd-frank
Second Circuit Holds Dodd-Frank Whistleblower Provision Does Not Apply Extraterritorially
Last week, in Liu v. Siemens, AG, the Second Circuit held that the Dodd-Frank Act's whistleblower retaliation provision (15 U.S.C. 78u-6(h)(1)) does not apply extraterritorially, in the first Second Circuit decision to address the international scope of Dodd-Frank's whistleblower protections against retaliation. Liu, a citizen and resident of Taiwan, was a compliance officer for Siemens China Ltd., a wholly owned subsidiary of Siemens AG. Siemens AG is a German corporation with shares listed on the New York Stock Exchange. Liu claimed Siemens wrongfully terminated his employment in retaliation for reporting that Siemens China Ltd. employees were making improper payments to Chinese officials in North Korea and China in connection with the sale of medical equipment in those countries, in violation of the Foreign Corrupt Practices Act ("FCPA").
SEC Charges Hedge Fund Adviser with Whistleblower Retaliation under Dodd-Frank
On June 16, 2014, the SEC issued its first-ever charge of whistleblower retaliation under section 922 of the Dodd-Frank Act, charging a hedge fund advisor and its owner with "engaging in prohibited principal transactions and then retaliating against the employee who reported the trading activity to the SEC." Read More
U.S. Commodity Futures Trading Commission Issues First Whistleblower Award
On Monday, May 19, 2014, the U.S. Commodity Futures Trading Commission ("CFTC") issued its first award to a whistleblower under its Dodd-Frank bounty program.
The Commission will pay $240,000 to an unidentified whistleblower who "voluntarily provided original information that caused the Commission to launch an investigation that led to an enforcement action" in which the judgment and sanctions exceeded $1 million. The heavily redacted award determination on the CFTC's website does not reveal the name of the implicated company, the nature of the wrongdoing involved, the percentage of bounty the whistleblower received (which is required to be between 10 and 30 percent pursuant to the statute), or the factors considered in determining the percentage of the bounty.
Prior to this first grant of an award to a whistleblower under the CFTC's Dodd-Frank bounty program, there were 25 denials of award claims. The reasons for the denials primarily fell into one or more of several categories:
- the individuals provided information before the passage of Dodd-Frank;
- they did not file a form TCR as required by the regulations;
- they did not provide information "voluntarily" but rather in response to a Commission request; and/or
- the information did not cause the Commission to open or expand an investigation or significantly contribute to a success of a Commission matter.
Time will tell whether this first award will have any effect on the number of whistleblowers who report to the CFTC or the quality of information the Commission receives.
Bon Voyage! Dodd Frank Whistleblower Claim Shipped to Arbitration
In Murray v. UBS Securities, LLC, Judge Failla in the Southern District of New York compelled arbitration of a Dodd-Frank whistleblower retaliation claim, holding that nothing in the anti-retaliation provision, 15 U.S.C. 78u-6(h), precludes the arbitration of these claims. Read More
Moving Right Along: The Office of Whistleblower Issues Its 2013 Annual Report
The SEC released its Fiscal Year 2013 Annual Report (the "Report") to Congress on the Dodd-Frank Whistleblower Program on November 15, 2013. The Report analyzes the tips received over the last twelve months by the SEC's Office of the Whistleblower ("OWB") and provides additional information about the whistleblower award evaluation process. Read More
Dodd-Frank Retaliation Cases Continue To Be a Mixed Bag For Companies
Two new Dodd-Frank decisions over the last week contain mixed results for employers. Read More
SEC Issues Huge Bounty Award of $14 Million to Whistleblower under Dodd-Frank
Today the SEC announced that it is issuing a whistleblower award of over $14 million to a whistleblower who provided information that resulted in the recovery of investor funds. The significant whistleblower award comes after many critics have questioned the success of the SEC's whistleblower award program which, to date, has only issued two much smaller awards since the program's inception in 2011. The first award payment was issued in August 2012 for approximately $50,000. The second award, paid to three whistleblowers for information that stopped a sham hedge fund, has paid out approximately $25,000 with an expected total payout of $125,000. Read More
Fifth Circuit Defines "Whistleblower" Narrowly Under Dodd-Frank
On July 17, 2013, the Fifth Circuit issued the first circuit court decision interpreting Dodd-Frank's anti-retaliation provision. In Asadi v. G.E. Energy (USA), L.L.C., the Fifth Circuit held that, to be protected under Dodd-Frank's anti-retaliation provision, an individual must be a "whistleblower," which is defined by the statute as an individual who has made a report to the SEC. Notably, this holding directly conflicts with the SEC's regulations interpreting the Act, as well as five district court decisions that had all held that employees who make internal reports to company management are protected under Dodd-Frank even if they did not make reports to the SEC. Rejecting these analyses, the Fifth Circuit based its decision on the plain wording of the statute, which it found to be unambiguous in protecting only "whistleblowers" as defined by the Act. Read More
Will the Latest Opinion by A District Court Adopting a Broad Definition of Who is a Whistleblower Encourage More Internal Reporting?
In May, another New York federal district court ruled that an employee need not report a disclosure directly to the Securities and Exchange Commission ("SEC") to be afforded the protections under the anti-retaliation provisions of the Dodd-Frank Act, but that internal disclosures within a company are covered. Read More


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|Spank The Monkey
This is a fast-paced and humorous fun game. The aim of the game is simple, you'll need to use your mouse pointer or other pointing device to grab the glove and then spank the monkey as fast and hard as you can. You'll be rewarded if you can spank faster than 200mph....Good luck!
|< قبل
|بعد >


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The Top 10 In Action Sports
01This British Council Is Trying To Make Skateboarding A Crime...
02Want To Escape The UK And Surf Every Day? This Is The Place To Go…
03Snowfall In New York Has Been So Deep, People Can't Get Out Of Their Houses
04What Do You Get If You Cross A Zip-Wire With A Roller Coaster?
0523 #FirstWorldProblems People Encounter When Skiing
067 Awkward Moments Every Brit Experiences When Surfing Abroad
07'Has Skiing Made Me Bald?' - What Do You Contemplate When You're On The Chairlift?
08This Squaw Valley Ski Edit Is Not To Be Missed...
09This 22 Year Old Student Took Three Years To Make This Adventure Film. The Result Is Truly Beautiful…
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Stamp on Indian Wild Flowers: Dibang Chirita
Home - Chandigarh
Pincodes from 52 locations of Chandigarh are available. Please click on a link below to continue.Burail
The age of technology has both revived the use of writing and provided ever more reasons for its spiritual solace. Emails are letters, after all, more lasting than phone calls, even if many of them r 2 cursory 4 u. ~Anna Quindlen


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Bad news, friends. You've reached a page that doesn't exist. Try searching below instead.
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The "Game of Thrones" star wants more male nudity in the raunchy medieval-fantasy series.
in Sports, Viral Videos
WATCH: Odell Beckham's amazing catch
It could be the greatest catch of his career: Watch Giants' wide receiver Odell Beckham pull in a TD with just one hand.
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LearnPad - The Tablet Computer Designed for EducationQuote:
branches the Android OS into an enterprise specific configuration with device management software. There is certainly the market for it.
Seriously amazing at managing android devices. You can change entire desktop with folders and apps from SEN to KS1 in seconds from either the management software or the pupils can do it themselves by scanning a bar code. Lovely bit of software.


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Fox News and NPR go inside a concept aimed at a new, digitally connected generation. Egraphs may not involve ink but they'll make you think about the future of autograph collecting.
Egraphs Getting Media Buzz
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Steiner: Go for the Sure Thing When Buying Sports Memorabilia
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Yankees Loss Cost Steiner
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Thirteen years and a hundred school shootings later, why is Hollywood still obsessed with this one?
Columbine: A True Story author Jeff Kass takes issue with numerous conclusions reached by Dave Cullen, whose book Columbine has received a great deal of national attention. But that's nothing compared to Brian Rohrbough, whose son Daniel was murdered in the April 20, 1999 attack on the high school w ... More >>
Photo by John JohnstonBrian Rohrbough. A report about the tenth anniversary of the massacre at Columbine High School that was originally slated to run on Oprah's April 20 program, but host Oprah Winfrey ordered it yanked at the last minute. In a statement, Winfrey says she made the decision because ... More >>
As pointed out earlier today in a blog about the many media appearances of Columbine principal Frank DeAngelis, Colorado journalist Dave Cullen, author of the widely praised volume Columbine, was scheduled to appear on Oprah today, the tenth anniversary of the massacre at the high school. However, y ... More >>


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Jacqueline Fernandez Launches Latest Range Of Bodyshop Products
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Product DescriptionNo more guessing yardage or hold over, fumbling with a shaky, handheld rangefinder or losing sight of a trophy shot - all thanks to the Eliminator II Laser Scope from Burris. The Eliminator II knows the precise horizontal distance to your trophy and exactly what your cartridge will do. It lights a 1/3-MOA illuminated aiming dot showing exactly where your shot will go. This sophisticated technology is made incredibly simple: enter one of 123 drop numbers into the Eliminator, and in a split second, it factors your distance and the ballistics of your cartridge or load to present you with a lighted dot for a precise hold over.
For greater versatility, the new X38 reticle is designed to work at any magnification setting. Choose to sight in at 50, 100, or 200 yds. A proprietary mounting system allows for the lowest possible mounting. Ergonomic activation buttons with sleek design. Functions reliably in temperatures from -15°F to 140°F. Waterproof, shockproof, fogproof, and withstands the toughest hunting conditions. Elevation and windage adjustment with 1/4" clicks at 100 yards. Scope is powered by a single CR-2 battery (included) that lasts for approximately 1,100 cycles. Includes cartridge chart.
The Burris Unconditional Forever Warranty covers their entire product line, including glass, coatings, electronics, scope tubes, and everything in between. Quality optics and customer service the way it should be-no questions and no excuses.


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FP International
Section: Gas, Air and Atmospheric Packaging | Category: Material Handling Sy... | Edge Protectors | Dispatch Handling Sy... | Bubble Film | Bags/Pouches
FP International manufactures protective packaging products and packaging systems, including air cushions, loose fill made of 100% recycled polystyrene, potato starch loose fill, and Kraft paper cushioning.
Huhtamaki Protective Packaging
Section: Package Protection | Category: Trays | Transport Packaging | Protective Packaging | General Packaging Ma... | Edge Protectors
Huhtamaki Protective Packaging is the world leader in the design and manufacture of molded fiber products. This three-dimensional packaging is produced from 100% recycled paper and used by companies focussed on cost-effective and efficient packaging.
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Editing of Bulbapedia is currently restricted. Please see this message for more details.
Pokémon Omega Ruby and Alpha Sapphire have arrived!
Check BNN and Bulbanews for up-to-date Pokémon news and discuss it on the forums or in our IRC channel.
From Bulbapedia, the community-driven Pokémon encyclopedia.
AR has several referrals:
- For the augmented reality markers used by Pokédex 3D, see AR Marker
- For the cheating device commonly abbreviated as AR, see Action Replay
- For the TCG expansion commonly abbreviated as AR, see Platinum: Arceus


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Our third visit, another long weekend and a great chance to catch up and relax Phil and Catherine are wonderful hosts, home baking and fantastic breakfasts Beautiful Lodge with well appointed rooms Thanks for the great time We will be back!
- Reservation Options:
- TripAdvisor is proud to partner with Agoda, Booking.com, Expedia, Hotels.com, Priceline, Travelocity, Venere, Odigeo and Tingo so you can book your Antria Boutique Lodge reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Antria Boutique Hotel Blenheim
- Antria Boutique Lodge Blenheim, Marlborough, New Zealand


text: You can replace the Normal.dot template with your new template. Create a new template the way you wish your Normal.dot to look and save it as a template. Go to your Templates directory under the said user in the Documents and settings directory and you should now have a second Word template called Winword2 remove the Winword template and rename Winword2 to Winword, Word will now launch with the new Normal.dot settings.


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Green Day Releases Trailer For First Of Three Albums '¡Uno!'
Legendary pop-rockers Green Day announced plans to release 3 new albums in quick succession back in April and now the trailer for the first album has been revealed. The albums are to be called ¡Uno!, ¡Dos!, and ¡Tré! and will be released shortly after one another on September 25, November 13, and January 15.
After the announcement, fans were left in the dark until now with the release of this trailer for ¡Uno! which shows a behind-the-scenes look at the band in the studio. You can hear a snippet of a song on the album and at the end the album artwork is revealed.
What do you think of Green Day's return to music? Are you excited for the new albums? Tell us below!
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- Bruno Mars Returns with Mark Ronson in "Uptown Funk"
- Watch Meghan Trainor's Candy-Colored "Lips Are Movin" Video
- Get The Party Started With Chase Rice's 'We Goin' Out' Lyric Video (PREMIERE)


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Gymnastics Head Coach Bill Ryden announced that four gymnasts are to join the Arizona gymnastics team next fall.
Arizona women's swimming and diving defeated UCLA 155-145
Mesa Community College transfer Harry Busby has signed a National Letter of Intent to play tennis at the University of Arizona beginning with the 2015-16 academic year, head coach Tad Berkowitz announced on Friday.
The University of Arizona soccer team beat Oklahoma State 1-0 on Friday afternoon and advanced to the second round of the NCAA Tournament.
The men's and women's cross country teams competed in the 2014 NCAA West Regional on Friday in Stanford, Calif.
Arizona women's golf added two new players, Gigi Stoll and Danielle Lee, to its roster for the 2015-16 season during this week's National Letter of Intent signing period.
ESPNU's Road Trip, a weekly half-hour show showcasing schools' athletic departments and student life, made a stop at Hillenbrand Stadium on Friday as Arizona took the show's spotlight for this Saturday's football game against Washington.
If freshman receiver/kick return specialist ever gets the ball in his hands in the open field, special things are bound to happen
Get to Know Your Ticket: Washington
The Arizona men's basketball program will face Michigan State at Joint Base Pearl Harbor-Hickam on Nov. 11, 2016, as part of the 2016 Armed Forces Classic.
Arizona defeated Oregon in four sets at McKale Center (25-19, 25-14, 22-25, 25-13) on Thursday night
Five-star recruit Camila Wesbrooks signed a National Letter of Intent to play tennis at the University of Arizona beginning with the 2015-16 academic year, head coach Vicky Maes announced on Thursday.


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Property to let in Kirkhill Road, Gartcosh, Glasgow G69
£575 pcm (£133 pw)
Old Gartloch Road, Gartcosh, G69Flat to rent - 2 bedrooms
This modern apartment is located in the small village of Gartcosh just off the M73 and approximately 15 mins drive from Glasgow. The accommodation comprises of large reception hallway, bright lounge open plan to modern fitted kitchen with integrated... More details
Note: Distances are straight line measurements
- Gartcosh (0.2 miles)
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Marketed by Cairn Properties, G12. Call 0141 846 0132£580 pcm (£134 pw)
Newabbey Road, Gartcosh, Glasgow G69Flat to rent - 2 bedrooms
Immaculate 2 bedroom (master en-suite) top floor flat set within modern development with stunning views, gas central heating & double glazing. More details
Note: Distances are straight line measurements
- Gartcosh (0.1 miles)
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Marketed by Allied Homes, G42. Call 0141 376 0627


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SingStar Shame - The Gibson Collection
Some people have higher thresholds than others for public humiliation. Some people have none at all. Step forward Ellie.
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Cubby Houses
Kids Cubby Houses
Our Wooden Tudor Style Cubby Houses are not only unique in design, but they are also available in a prefabricated panel kit which can be erected in approx 2hrs by 2 people.
Whether you decide to purchase 'Alice' or 'Jack' or you have purchased a Kids Cubby elsewhere, we can help you with your Cubby House fitout as we also stock such products askids sofas, kids table and chairs, retro toy kitchens, toy pianos, kids recliners, kids activity tables plus more.
Product Reviews
I purchased this beautiful Cubbyhouse in October 2013, I have three children (11, 7 and a 20 months). They all love to hang out and play in the Cubby and we are very pleased with the overall standard of construction.
Jack's Cubby House
We bought this Cubby 3 months ago from Hip Kids and have just put it up. My kids love it. We bought it because it had the double doors so it was easy for the kids drive up their bikes. Assembly was straight forward and have painted it in neutral colours to match our house. It's a lot of cubby for the price we paid, great value compared to similar size cubbies currently on the market
perfect play house
My daughter has had this cubby house for over a year & it's been a wonderful addition to our backyard. I agree that it is quite time consuming to set up & paint but well worth it. It comfortably has space for a few children to play happily, we've had 5 in ours & the high pitched roof makes it easy for adults to join in the fun too. We love this cubby & I'm sure that it will provide years of fun to come.
Best Christmas Present Ever!!
My wife and I had been deliberating about a Christmas present for our three beautiful granddaughters for some time and, being a customer of Hip Kids in the past we investigated the Cubby Houses as something that would suit the girls who were aged 7, 4 and 2 at Christmas 2013. The problem of how to present the surprise was solved by a laminated enlargement of the promotional photos and a Christmas card from Nona & Poppa! The Alice Cubby proved to be immense fun from the moment we opened the packages, right through to completion of the construction process. I am ecstatic with the end product and can only give the construction the highest praise. Assembly was easy and all components fitted perfectly. I will say however that the task is not simple and setting up the floor does require some knowledge and a reasonable level of trade skills to do it properly. The girls just love it and often have their cousins around for "coffee in the cubby". The boys are so impressed that we have purchased the workshop cubby for their Christmas this year!
Very happy little girl
I got the mini alice for my daughters 3rd birthday and she absolutely loves it! it is a perfect size for our small yard yet big enough for her and her little friends to hang out in. Dad and Grandpa put it together without issues although my dad is quite handy with building things. The most difficult part was building up the floor as our property is not level and the painting took time which isn't a problem if you enjoy painting like me!! This beautiful little cubby house was worth every cent, great quality and looks fantastic. My order for this cubby house was just after xmas and I was worried I may not get delivery on time but everyone I spoke to regarding this purchase from the first phone call to the final delivery man were all an absolute pleasure, all extremely helpful and friendly. I could not recommend them high enough and a special thank you to Sue who bent over backwards on her family holiday to make sure everything ran smoothly for me.