Beyond genetics: epigenetic code in chronic kidney disease

Beyond genetics: epigenetic code in chronic kidney disease: "

Beyond genetics: epigenetic code in chronic kidney disease

Kidney International 79,
23 (January (1) 2011). doi:10.1038/ki.2010.335

Authors: Rama S Dwivedi, James G Herman, Timothy A McCaffrey
& Dominic S C Raj

The best succinct review of epigenetics

Theory of gastric CO(2) ventilation and its control during respiratory acidosis: implications for central chemosensitivity, pH regulation, and diseases causing chronic CO(2) retention Gastric CO(2) ventilation during respiratory acidosis.

Theory of gastric CO(2) ventilation and its control during respiratory acidosis: implications for central chemosensitivity, pH regulation, and diseases causing chronic CO(2) retention Gastric CO(2) ventilation during respiratory acidosis.: "

Theory of gastric CO(2) ventilation and its control during respiratory acidosis: implications for central chemosensitivity, pH regulation, and diseases causing chronic CO(2) retention Gastric CO(2) ventilation during respiratory acidosis.

Respir Physiol Neurobiol. 2010 Dec 6;

Authors: Dean JB

The theory of gastric CO(2) ventilation describes a previously unrecognized reflex mechanism controlled by neurons in the caudal solitary complex (cSC) for non-alveolar elimination of systemic CO(2) during respiratory acidosis. Neurons in the cSC, which is a site of CO(2) chemosensitivity for cardiorespiratory control, also control various gastroesophageal reflexes that remove CO(2) from blood. CO(2) is consumed in the production of gastric acid and bicarbonate in the gastric epithelium and then reconstituted as CO(2) in the stomach lumen from the reaction between H(+) and HCO(3)(-). Respiratory acidosis and gastric CO(2) distension induce cSC/vagovagal mediated transient relaxations of the lower esophageal sphincter to vent gastric CO(2) upwards by bulk flow along an abdominal-to-esophageal (= intrapleural) pressure gradient the magnitude of which increases during abdominal (gastric) compression caused by increased contractions of respiratory muscles. Esophageal distension induces cSC/nucleus ambiguus/vagovagal reflex relaxation of the upper esophageal sphincter and CO(2) is vented into the pharynx and mixed with pulmonary gas during expiration or, alternatively, during eructation. It is proposed that gastric CO(2) ventilation provides explanations for 1) the postprandial increase in expired CO(2) and 2) the negative P(blood-expired)(CO)difference that occurs during increased metabolic CO(2) production. Furthermore, it is postulated that gastric CO(2) ventilation and alveolar CO(2) ventilation are coordinated under dual control by CO(2) chemosensitive neurons in the cSC. This new theory, therefore, presupposes a level of neural control and coordination between two previously presumed dissimilar organ systems and supports the notion that different sites of CO(2) chemosensitivity address different aspects of whole body pH regulation. Consequently, not all sites of central chemosensitivity are equal regarding the mechanism(s) activated for CO(2) elimination. A distributed CO(2) chemosensitive network-at least nine different areas in the CNS, including the cSC, have been reported to date-may reflect the complexity and dynamic nature of the fundamental neural circuitry required to achieve CO(2)/pH regulation across multiple organ systems under various states of arousal, oxygenation, pH status, and redox state. Moreover, coordination of respiratory and digestive control networks through the cSC could also account for the frequent co-expression of pulmonary diseases that cause chronic respiratory acidosis (and overstimulation of cSC neurons) with peptic ulcer disease or gastroesophageal reflux disease.

PMID: 21144912 [PubMed - as supplied by publisher]

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Evolutionary biology: Genomic hourglass

Evolutionary biology: Genomic hourglass: "

Evolutionary biology: Genomic hourglass

Nature 468, 7325 (2010). doi:10.1038/468768a

Authors: Benjamin Prud'homme & Nicolas Gompel

Comparative genomics studies reveal molecular signatures of the controversial 'phylotypic' stage — a time when embryos of members of an animal phylum all look more alike than at other embryonic stages. See Letters p.811 & p.815

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Developmental biology: Placenta key to fetal growth rate

Developmental biology: Placenta key to fetal growth rate: "

Developmental biology: Placenta key to fetal growth rate

Nature 468, 7324 (2010). doi:10.1038/468603d

Gestation period varies widely in the mammalian world, with some species developing twice as fast as others in the womb. This is largely because of differences in the arrangement of fetal and maternal tissues in the placenta.Isabella Capellini at Durham University, UK, and her

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Developmental biology: Placenta key to fetal growth rate

Developmental biology: Placenta key to fetal growth rate: "

Developmental biology: Placenta key to fetal growth rate

Nature 468, 7324 (2010). doi:10.1038/468603d

Gestation period varies widely in the mammalian world, with some species developing twice as fast as others in the womb. This is largely because of differences in the arrangement of fetal and maternal tissues in the placenta.Isabella Capellini at Durham University, UK, and her

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Placental microRNA expression in pregnancies complicated by preeclampsia.

Placental microRNA expression in pregnancies complicated by preeclampsia.: "

Placental microRNA expression in pregnancies complicated by preeclampsia.

Am J Obstet Gynecol. 2010 Nov 18;

Authors: Enquobahrie DA, Abetew DF, Sorensen TK, Willoughby D, Chidambaram K, Williams MA

OBJECTIVE:: The role of posttranscription regulation in preeclampsia is largely unknown. We investigated preeclampsia-related placental microRNA (miRNA) expression using microarray and confirmatory quantitative real-time polymerase chain reaction experiments. STUDY DESIGN:: Placental expressions of characterized and novel miRNAs (1295 probes) were measured in samples collected from 20 preeclampsia cases and 20 controls. Differential expression was evaluated using Student t test and fold change analyses. In pathway analysis, we examined functions/functional relationships of targets of differentially expressed miRNAs. RESULTS:: Eight miRNAs were differentially expressed (1 up-regulated and 7 down-regulated) among preeclampsia cases compared with controls. These included previously identified candidates (miR-210, miR-1, and a miRNA in the 14q32.31 cluster region) and others that are novel (miR-584 and miR-34c-5p). These miRNAs target genes that participate in organ/system development (cardiovascular and reproductive system), immunologic dysfunction, cell adhesion, cell cycle, and signaling. CONCLUSION:: Expression of miRNAs that target genes in diverse pathophysiological processes is altered in the setting of preeclampsia.

PMID: 21093846 [PubMed - as supplied by publisher]

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The "Great Obstetrical Syndromes" are associated with disorders of deep placentation.

The "Great Obstetrical Syndromes" are associated with disorders of deep placentation.: "

The 'Great Obstetrical Syndromes' are associated with disorders of deep placentation.

Am J Obstet Gynecol. 2010 Nov 20;

Authors: Brosens I, Pijnenborg R, Vercruysse L, Romero R

Defective deep placentation has been associated with a spectrum of complications of pregnancy including preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. The disease of the placental vascular bed that underpins these complications is commonly investigated with targeted biopsies. In this review, we critically evaluate the biopsy technique to summarize the salient types of defective deep placentation, and propose criteria for the classification of defective deep placentation into 3 types based on the degree of restriction of remodeling and the presence of obstructive lesions in the myometrial segment of the spiral arteries.

PMID: 21094932 [PubMed - as supplied by publisher]

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D2-40/podoplanin expression in the human placenta.

D2-40/podoplanin expression in the human placenta.: "

D2-40/podoplanin expression in the human placenta.

Placenta. 2010 Nov 20;

Authors: Wang Y, Sun J, Gu Y, Zhao S, Groome LJ, Alexander JS

Placental tissue expresses many lymphatic markers. The current study was undertaken to examine if D2-40/podoplanin, a lymphatic endothelial marker, was expressed in the human placenta, and how it is altered developmentally and pathologically. We examined D2-40/podoplanin and VEGFR-3 expressions in placentas from normotensive pregnancies at different gestational ages and in placentas from women with clinically defined preeclampsia. D2-40 expression in systemic lymphatic vessel endothelium served as a positive control. Protein expression for D2-40, VEGFR-3, and β-actin was determined by Western blot in placentas from normotensive (n = 6) and preeclamptic (n = 5) pregnancies. Our results show that D2-40/podoplanin was strongly expressed in the placenta, mainly as a network plexus pattern in the villous stroma throughout gestation. CD31 was limited to villous core fetal vessel endothelium and VEGFR-3 was found in both villous core fetal vessel endothelium and trophoblasts. D2-40/podoplanin expression was significantly decreased, and VEGFR-3 significantly increased in preeclamptic placental tissues compared to normotensive placental controls. Placental villous stroma is a reticular-like structure, and the localization of D2-40 to the stroma suggests that a lymphatic-like conductive network may exist in the human placenta. D2-40/podoplanin is an O-linked sialoglycoprotein. Although little is known regarding biological functions of sialylated glycoproteins within the placenta, placental D2-40/podoplanin may support fetal vessel angiogenesis during placenta development and reduced D2-40/podoplanin expression in preeclamptic placenta may contribute to altered interstitial fluid homeostasis and impaired angiogenesis in this pregnancy disorder.

PMID: 21095001 [PubMed - as supplied by publisher]

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Maternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at Term.

Maternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at Term.: "

Maternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at Term.

Hypertension. 2010 Nov 22;

Authors: Melchiorre K, Sutherland GR, Baltabaeva A, Liberati M, Thilaganathan B

Preeclampsia is a disease associated with significant cardiovascular morbidity during pregnancy and in later life. This study was designed to evaluate cardiac function and remodeling in preeclampsia occurring at term. This was a prospective case-control study of 50 term preeclampsia and 50 normal pregnancies assessed by echocardiography and tissue Doppler analysis. Global diastolic dysfunction was observed more frequently in preeclampsia versus control pregnancies (40% versus 14%, P=0.007). Increased cardiac work and left ventricular mass indices suggest that left ventricular remodeling was an adaptive response to maintain myocardial contractility with preeclampsia at term. Approximately 20% of patients with preeclampsia at term have more evident myocardial damage. Diastolic dysfunction usually precedes systolic dysfunction in the evolution of ischemic or hypertensive cardiac diseases and is of prognostic value in the prediction of long-term cardiovascular morbidity. The study findings also have significant implications for the acute medical management of preeclampsia.

PMID: 21098311 [PubMed - as supplied by publisher]

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The Role of Embryonic Origin in Preeclampsia: A Comparison of Autologous In Vitro Fertilization and Ovum Donor Pregnancies.

The Role of Embryonic Origin in Preeclampsia: A Comparison of Autologous In Vitro Fertilization and Ovum Donor Pregnancies.: "

The Role of Embryonic Origin in Preeclampsia: A Comparison of Autologous In Vitro Fertilization and Ovum Donor Pregnancies.

Obstet Gynecol. 2010 Dec;116(6):1387-1392

Authors: Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL, Rosenwaks Z

OBJECTIVE:: To compare the risk of gestational hypertension and preeclampsia in pregnancies conceived through standard in vitro fertilization (IVF) using autologous oocytes with pregnancies conceived using donated oocytes. METHODS:: We conducted a retrospective, matched cohort study of women undergoing IVF using autologous compared with donor oocytes between 1998 and 2005. Women with live births resulting from oocyte donor pregnancies were matched for age and plurality (singleton or twin) with women undergoing autologous IVF. Primary outcomes were the incidence of preeclampsia or gestational hypertension (with and without proteinuria) in the third trimester. Data on preterm delivery, low birth weight, and embryo cryopreservation were also recorded. RESULTS:: Outcome data were available for 158 pregnancies, including 77 ovum-donor recipient pregnancies and 81 pregnancies using autologous oocytes. There were no differences in age, parity, and gestational type between the two cohorts. The incidence of gestational hypertension and preeclampsia was significantly higher in ovum-donor recipients compared with women undergoing autologous IVF (24.7% compared with 7.4%, P<.01, and 16.9% compared with 4.9%, P=.02, respectively). Ovum-donor recipients were more likely than women undergoing autologous IVF to deliver prematurely (34% compared with 19%). This association remained after controlling for multiple gestation (odds ratio 2.6, 95% confidence interval 1.04-6.3). Sixteen pregnancies from cryopreserved embryos were more likely to have hypertensive disorders of pregnancy (odds ratio 5.0, 95% confidence interval 1.2-20.5). CONCLUSION:: Pregnancies derived from donor oocytes and cryopreserved-thawed embryos may be at a higher risk for hypertensive disorders of pregnancy. These findings inform future research and help counsel women using assisted reproductive technology. LEVEL OF EVIDENCE:: II.

PMID: 21099607 [PubMed - as supplied by publisher]

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Combination of loop diuretics with thiazide-type diuretics in heart failure.

Combination of loop diuretics with thiazide-type diuretics in heart failure.: "

Related Articles

Combination of loop diuretics with thiazide-type diuretics in heart failure.

J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34

Authors: Jentzer JC, DeWald TA, Hernandez AF

Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via 'sequential nephron blockade,' first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.

PMID: 21029871 [PubMed - in process]

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Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia.

Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia.: "

Related Articles

Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia.

J Am Soc Nephrol. 2010 Nov 4;

Authors: Gankam-Kengne F, Soupart A, Pochet R, Brion JP, Decaux G

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the blood-brain barrier, inhibited microglial activation, decreased both the expression of IL1α and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans.

PMID: 21051736 [PubMed - as supplied by publisher]

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Managing Overly Rapid Correction of Chronic Hyponatremia: An Ounce of Prevention or a Pound of Cure?

Managing Overly Rapid Correction of Chronic Hyponatremia: An Ounce of Prevention or a Pound of Cure?: "

Related Articles

Managing Overly Rapid Correction of Chronic Hyponatremia: An Ounce of Prevention or a Pound of Cure?

J Am Soc Nephrol. 2010 Nov 11;

Authors: Kamel KS, Halperin ML

PMID: 21071525 [PubMed - as supplied by publisher]

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Hereditary renal tubular disorders.

Hereditary renal tubular disorders.: "

Related Articles

Hereditary renal tubular disorders.

Semin Nephrol. 2009 Jul;29(4):399-411

Authors: Chadha V, Alon US

The multiple and complex functions of the renal tubule in regulating water, electrolyte, and mineral homeostasis make it prone to numerous genetic abnormalities resulting in malfunction. The phenotypic expression depends on the mode of interference with the normal physiology of the segment affected, and whether the abnormality is caused by loss of function or, less commonly, gain of function. In this review we address the current knowledge about the association between the genetics and clinical manifestations and treatment of representative disorders affecting the length of the nephron.

PMID: 19615561 [PubMed - indexed for MEDLINE]

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New Alternatives to the Treatment of Acute Liver Failure

New Alternatives to the Treatment of Acute Liver Failure: "Publication year: 2010
Source: Transplantation Proceedings, Volume 42, Issue 8, October 2010, Pages 2959-2961
E., Pareja , M., Cortes , A., Bonora , P., Fuset , F., Orbis , ...
Introduction: Acute-on-chronic liver failure (ACLF) is defined as an acute deterioration of a chronic liver disease. The most effective treatment in these patients is orthotopic liver transplantation (OLT), which is highly limited by the donor shortage. The aim of this study was to increase the usefulness of hepatocyte transplantation (HT) as a bridge or alternative to OLT. Methods: During the last 2 years, we have performed HT in 3 patients with ACLF. The diagnosis was graft cirrhosis due to hepatitis C virus in 2 of them, who were already included on waiting lists for retransplantation, and the third, unknown alcoholic cirrhosis. Results: After the first..."

Epidemiology of Pneumonia in Kidney Transplantation

Epidemiology of Pneumonia in Kidney Transplantation: "Publication year: 2010
Source: Transplantation Proceedings, Volume 42, Issue 8, October 2010, Pages 2938-2940
I., Hoyo , L., Linares , C., Cervera , M., Almela , M.A., Marcos , ...
Background: Pneumonia remains an important cause of morbidity among solid organ transplant recipients. Methods: We prospectively evaluated all renal transplant patients at our center from July 2003 to December 2008 who had pneumonia that required hospitalization. We gathered data regarding underlying diseases as well as pretransplant, transplant, and posttransplant characteristics. Pneumonia defined according to the Centers for Disease Control and Prevention criteria was classified depending on its origin as community acquired or nosocomial. In all patients, microbiologic samples of respiratory secretions and blood were collected at the physician's discretion. The indication to perform a fiberoptic bronchoscopy was the presence of multiple, bilateral, or..."

Protective effect of immunosuppressive treatment before orthotopic kidney autotransplantation

Are we going to start immunosuppresion prior to transplant if this translates?


Protective effect of immunosuppressive treatment before orthotopic kidney autotransplantation: "Publication year: 2010
Source: Transplant Immunology, In Press, Accepted Manuscript, Available online 27 October 2010
Federico, Cicora , Natalia, Lausada , Daniela N., Vasquez , Paola, Cicora , Guerrieri, Diego , ...
Background: Ischemia reperfusion injury (IRI) is one of the risk factors for delayed graft function, acute rejection and long term allograft survival after kidney transplantation. It's an independent antigen inflammatory process that produces tissue damage. Our objective was to study the impact of immunosuppressive treatment (IS) on IRI applying only one dose of IS before orthotopic kidney autotransplantation. Methods: Twenty-four rats allocated in four groups were studied. One group served as control (G1: autotransplanted rats without IS) and the rest received IS 12 h before kidney autotransplantation (G2: Rapamycin, G3: Mycophenolate mofetil and G4: Tacrolimus). Results: Improved renal function and systemic inflammatory response were found..."

Effectiveness of a Barber-Based Intervention for Improving Hypertension Control in Black Men: The BARBER-1 Study: A Cluster Randomized Trial [Original Investigation]

Effectiveness of a Barber-Based Intervention for Improving Hypertension Control in Black Men: The BARBER-1 Study: A Cluster Randomized Trial [Original Investigation]: "

Background Barbershop-based hypertension (HTN) outreach programs for black men are becoming increasingly common, but whether they are an effective approach for improving HTN control remains uncertain.

Methods To evaluate whether a continuous high blood pressure (BP) monitoring and referral program conducted by barbers motivates male patrons with elevated BP to pursue physician follow-up, leading to improved HTN control, a cluster randomized trial (BARBER-1) of HTN control was conducted among black male patrons of 17 black-owned barbershops in Dallas County, Texas (March 2006–December 2008). Participants underwent 10-week baseline BP screening, and then study sites were randomized to a comparison group that received standard BP pamphlets (8 shops, 77 hypertensive patrons per shop) or an intervention group in which barbers continually offered BP checks with haircuts and promoted physician follow-up with sex-specific peer-based health messaging (9 shops, 75 hypertensive patrons per shop). After 10 months, follow-up data were obtained. The primary outcome measure was change in HTN control rate for each barbershop.

Results The HTN control rate increased more in intervention barbershops than in comparison barbershops (absolute group difference, 8.8% [95% confidence interval (CI), 0.8%-16.9%]) (P = .04); the intervention effect persisted after adjustment for covariates (P = .03). A marginal intervention effect was found for systolic BP change (absolute group difference, –2.5 mm Hg [95% CI, –5.3 to 0.3 mm Hg]) (P = .08).

Conclusions The effect of BP screening on HTN control among black male barbershop patrons was improved when barbers were enabled to become health educators, monitor BP, and promote physician follow-up. Further research is warranted.

Trial Registration clinicaltrials.gov Identifier: NCT00325533

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Reading Dialysis tech

Reading about the technical aspects of dialysis. Things that caught my attention

1) Circuit - arterial line - pressure montior- predialysis pressure monitor - kidney - post dialysis pressure monitor - venous side
2) recirculation - happens thru cardiopulmonary circ + at the fistula

3) Temperature fall across the circuit of 1 c can lead to the equivalent of 20% of BMR

4) conductivity/volumetric methods of mixing dialysate

5)batch processing vs. continous flow dialysate

6)effect of reynolds number- type of flow and shear stress

viscosities and flow calculations

Introduction to concept of dialysance.

conductivity for dialysate and how each ion can affect it. donan equilibrium

all these concepts are ringing in the ear all necessitating further reading, ideally fluid dynamics/calculus

PD peritonitis

Bear with my typos as I am learning touch typing.

Today talked about PD Peritonitis.

Staph Epi is the most common. Others of note include staph.aureus, strep, enterococci.
Gram negatives are not common and when they occur include E Coli, pseudomonas,acinetobacter etc.
You do not want to see pseudomonas or fungal or TB as they mean Catheter removal, as very difficult to eradicate

In PD fluid, a white cell count of > than 100 and PMN > 50 are needed for diagnosis. Occasionally it can be predominant eosinophilia.

Treatment is initially with Vanc+Gent/ceftaz till organism identified. You can give in every exchange or in 1 bag with a dwell for 6-8 hours.

Secondary peritonitis is from a primary intraabdominal problem like a perforated diverticulum or ischemic bowel etc. and it is polymicrobial in nature. So, on a gram stain if you find both gram+ and gram- think about secondary causes.

Relapse is PD peritonitis with the same organism in less than 4 weeks after finishing therapy

Long QT syndrome

What is the basis for a normal action potential in pacemaker cells and normal myocardial cells?
Myocardial cells phase 0 is from rapid entry of sodium channel.Transient phase 1 is due transient outwars potassium current. Phase 2 is due to calcium entry being balanced by potassium exit. Phase 3 is from unbalanced potassium exit.Phase 4 is repolarization phase with mostly Na+K+ ATPase being active and some potassium channel being open with little movement due to compensating electrochemical forces as per Nernst equation.

Pacemaker cells have very small element of Phase 0 sodium activity and is mostly calcium lead.


Why is the T wave not opposite of QRS? and why?

Subendocardial M cells have a longer Action potential when compared with epicardial myocytes. so though they depolarize first, they do not repolarize first.


What is the defect in LQTS?

There are many defects but 3 account for most. Ks accounts for LQTS1, Kr accounts for LQTS2, INa accounts for LQT3


How do the mutations affect the channel function?

Either they interfere with the functioning of normal subdivision or is a production defect by reduced number

What are the T wave patterns in LQTS?

Broad based T in LQTS1, Notched T in LQTS 2 , Tall and Notched in LQTS 3


When do you call the QT as prolonged?
When it is > 430 in makes and > 450 in females .



Patient is dead do you still need to make a diagnosis?

Ofcourse you have the family waiting to die!


What do you ask in family history?
Not just for SCD but for others like deafness/Seizures


What are the other causes of LQTS?
Many drugs  and electrolyte imbalances

What about genetic testing?

Can check for the ones you know but a negative doesnot exclude in the presence of other criteria

How is sex going to affect the presentation?
Estrogens block K channels, so prolong APD and hence QT. So prior to puberty males are likely to die more and vice versa afterwards

How about pregnancy?
Increases the risk and the increased risk remains till 6 months postpartum

Is the degree of QT prolongation important?

Yes the longer the QT the more likely for Torsades

What activities precipitate Torsades?

LQT1 - Physical exp swimming
LQT2- sudeen loud noise alarm clock
LQT3-no arousal needed

Does the type of mutation matter?
Yes it does - depending on which domain is affected the pore part/ the cytoplasmic domain or extracellular

dominant negative versus haploinsufficiency

What are the treatments that can be used?
Beta blocker,LCDS,AICD

Once AICD is it a done deal?
Still have to use beta blocker and also avoid major physical activities

Is AICD cost effective in LQTS?
It is at least 10-20 times cheaper per life saved when compared with CHF

What is electrical storm?
> 2 shocks in < 24 hours

Why does mexileten or lidocaine make sense?
How does a prolonged QT lead PVT?
Where do the antiarrhytmics act?What are the subtyeps in 1?
What are the other congenital syndromes that we need to remember for sudden death?
Are the capacitators already charged ready to go in AICD?
Does the AICD always need to shock to terminate VT? and how can it do it?
How does hypokalemia cause PVT IN long QT?
what is the problem with bazett's ? undercorrects at tachy and over corrects at brady.

Polycystic Kidney disease

Attended a grand round on polycystic kidney disease. Left with a lot more questions than I entered with.

OK Polycystin is a part of cilia and it detects motion. If it is screwed up as it does in PKD, you get cysts.

The organs affected like Kidney, liver(Bile), colon (Feces), lung - bronchiectasis(Air) , seminal vesicles(semen) have some thing flowing in a direction.

Only in the CVS it is kind of funky in that

1)Why is it only the circle of willis is affected?  Has it got to do with the fact that blood flow can reverse its direction in COW unlike other systemic blood vessels and needs polycystin to detect the direction of blood flow, so that it can make the needed adjustments in flow so that the brain gets it's blood supply.

What about MVP and AR? Is there a role for polycystin here as well as it is the place where you want the blood to flow in one direction.

2) What is the role of estrogen in altering the function of polycystin?

3) If PKD was so bad, how did it survive evolution ? Was it a case of positive selection or Was it a case of a recent mutation that has not entirely gone through the rigor of evolution?

If it was a case of positive selection, under what conditions was it selected and what are the benefits of PKD?

More reading to do!!!

Tumor lysis in renal cell carcinoma

Doing a morning report on RCC on being treated with Sunitinib lead to AKI.

What is Sunitinib?
A molecule(not antibody) which inhibits multiple tyrosine kinase motifs of second messenger systems of chemokines like VEGF.

It has some crazy side effects like

1) Hypothyroidism
2) Cardiac failure
3) HTN/Proteiuria a.k.a Bevacizumab like
4) Pancreatitis

Only one report of TLS

Coming to TLS

Criteria does not have creatinine!!!

Has uric acid>8
potassium>6
Calcium< 7
Phosphate> 4.5

If preexisting abnormalities in the above values due to some other pathologies take a 25% change.

If cr >1.5x of previous it becomes clinical TLS

TLS most commonly happens in rapidly proliferating tumors.
Why?
They need all the purines for the DNA/RNA for them to grow and when it breaks down as we all know what we get is uric acid

Rapidly proliferating leukemias and lymphomas are the ones at highest risk

TLS happens within 48 hrs of chemo and anything beyond is unlikely from TLS

Why do the electrolyte changes happen?

Potassium is intracellular and when the chemo lyses the cell it comes out
same applies to phosphate/urate

calcium goes down due to phosphate binding with it

How is the kidney affected?

Uric acid precipitates and blocks up the nephrons

What do we do about TLS
1) Prevent it by
   - IV fluids - keep the uric acid low in concentration in the kidney
   - Allopurinol - only useful preemptive and does not prevent xanthine and hypoxanthine from precipitating!
   - Uricase - melt the uric acid simple

Bicarbonate is unproven as it will make uric acid soluble but calcium phosphate insoluble:(

2)Treat
    - HD - Takes out uric acid
    - Uricase