correspondence
through a central-nervous-system mechanism in animal models. On the basis of this new information, weight loss in patients with congenital leptin deficiency who are receiving leptin treatment may result not only from an improvement in hyperphagia2 but also from increased energy expenditure owing to leptin-induced browning of white adipose tissue. We have now been able to analyze stromal– vascular cells isolated from subcutaneous white adipose tissue obtained from three patients with congenital leptin deficiency caused by a c.389delG mutation3 in the leptin gene. Subjecting all three samples to adipogenic differentiation ex vivo in the presence of leptin led to an increase in messenger RNA (mRNA) expression of the gene encoding uncoupling protein 1 (UCP1) (Fig. 1A). This protein is produced mainly in brown adipose tissue and is involved in the generation of heat by nonshivering thermogenesis, thereby regulating energy expenditure. Preliminary data also hinted at an increase in mRNA expression of UCP1 after leptin treatment in Simpson–Golabi–Behmel syndrome adipocytes (Fig. 1B).4,5 Our data suggest that leptin-induced browning
of white adipose tissue might be mediated not only by the central nervous system but also by a direct peripheral effect of leptin on adipocytes. Pamela Fischer-Posovszky, Ph.D. Jan-Bernd Funcke, M.Sc. Martin Wabitsch, M.D., Ph.D. University of Ulm Ulm, Germany [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Dodd GT, Decherf S, Loh K, et al. Leptin and insulin act on
POMC neurons to promote the browning of white fat. Cell 2015; 160:88-104. 2. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879-84. 3. Funcke J-B, von Schnurbein J, Lennerz B, et al. Monogenic forms of childhood obesity due to mutations in the leptin gene. Mol Cell Pediatr 2014;1:3. 4. Wabitsch M, Brenner RE, Melzner I, et al. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord 2001;25: 8-15. 5. Fischer-Posovszky P, Newell FS, Wabitsch M, Tornqvist HE. Human SGBS cells — a unique tool for studies of human fat cell biology. Obes Facts 2008;1:184-9. DOI: 10.1056/NEJMc1501146
Disorders of Plasma Sodium To the Editor: The review by Sterns (Jan. 1 issue)1 on disorders of plasma sodium concentration, which are among the most frequently encountered (and mismanaged) problems in medicine, was enhanced by the use of illustrative cases (which appear in the Supplementary Appendix, available with the full text of the article at NEJM.org). After the second patient had a subarachnoid hemorrhage, plasma hyponatremia associated with excessive urinary sodium loss developed. Did this patient really have the syndrome of inappropriate antidiuretic hormone secretion (SIADH), or did he have cerebral salt wasting, which is also seen in the clinical situation described? Information on the water balance (hypovolemic, euvolemic, or hypervolemic) would be helpful here, because cerebral salt wasting is associated with hypovolemia. The differential diagnosis of SIADH versus cerebral salt wasting is clinically relevant because the treatments are diametrically opposed.2
Axel Petzold M.D., Ph.D. UCL Institute of Neurology London, United Kingdom [email protected] No potential conflict of interest relevant to this letter was reported. 1. Sterns RH. Disorders of plasma sodium — causes, conse-
quences, and correction. N Engl J Med 2015;372:55-65. 2. Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol 2006;18:57-63. DOI: 10.1056/NEJMc1501342
To the Editor: The third case reviewed by Sterns is one in which a 30-year-old woman with symptomatic, desmopressin-associated hyponatremia has sodium overcorrection and neurologic injury after the discontinuation of desmopressin and is given a 3% saline infusion. There is no mention of how to treat this condition properly. My colleagues and I recently published a series of 15 cases of desmopressin-associated hypo-
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1267
The
n e w e ng l a n d j o u r na l
natremia.1 In 13 patients, neurologic injury and death resulted because of overcorrection of serum sodium concentrations consequent to the discontinuation of desmopressin and concurrent use of hypertonic saline. In 2 patients, desmopressin was continued and hypertonic saline was administered, and both survived, with no neurologic sequelae. Desmopressin-associated hyponatremia has the potential to become a common disorder as the use of desmopressin expands to include the treatment of enuresis in children and elderly patients.2 When treating this condition, it is important to recognize the development of severe, symptomatic hyponatremia in response to desmopressin and to continue to administer the drug along with hypertonic saline. Steven G. Achinger, M.D. Watson Clinic Lakeland, FL [email protected] No potential conflict of interest relevant to this letter was reported. 1. Achinger SG, Arieff AI, Kalantar-Zadeh K, Ayus JC. Desmo-
pressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series. Nephrol Dial Transplant 2014;29:2310-5. 2. Vande Walle J, Stockner M, Raes A, Nørgaard JP. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007; 2:232-8.
m e dic i n e
treatment of hyponatremic encephalopathy in the emergency department. This treatment was safe and effective and without systemic or neurologic complications.5 As much as 500 ml of 3% saline can be given safely in non-ICU settings. Michael L. Moritz, M.D. Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA [email protected]
Juan C. Ayus, M.D. Renal Consultants of Houston Houston, TX No potential conflict of interest relevant to this letter was reported. 1. Kerns E, Patel S, Cohen DM. Hourly oral sodium chloride
for the rapid and predictable treatment of hyponatremia. Clin Nephrol 2014;82:397-401. 2. Ayus JC, Arieff A, Moritz ML. Hyponatremia in marathon runners. N Engl J Med 2005;353:427-8. 3. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med 2008;18:111-21. 4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol Dial Transplant 2014;40:924.] 5. Ayus JC, Caputo D, Bazerque F, Heguilen R, Gonzalez CD, Moritz ML. Treatment of hyponatremic encephalopathy with a 3% sodium chloride protocol: a case series. Am J Kidney Dis 2014 November 25 (Epub ahead of print). DOI: 10.1056/NEJMc1501342
DOI: 10.1056/NEJMc1501342
To the Editor: Sterns endorses the use of 100-ml bolus infusions of 3% saline for the treatment of symptomatic hyponatremia. However, the appropriate route and setting for administration are not mentioned. A potential barrier to the use of 3% saline is the perception that it must be administered through a central catheter in an intensive care unit (ICU).1 We recommended peripheral intravenous administration of 100-ml infusions of 3% saline for the management of exercise-associated hyponatremia in medical tents.2 This approach is now the standard treatment for this condition3 and is recommended in the European Clinical Practice Guideline for the treatment of symptomatic hyponatremia of any cause.4 No information exists on how much 3% saline can be safely administered through a peripheral intravenous catheter. We recently reported the administration of 500 ml of 3% saline through a peripheral intravenous catheter over 6 hours for the
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of
To the Editor: We were surprised that Sterns did not refer to the recently published European hyponatremia guidelines1, which specifically do not recommend the use of vasopressin antagonists for any indication. Furthermore, Sterns’s statement that “to reduce symptoms and improve potential outcomes, chronic hyponatremia should be corrected gradually with the use of . . . vasopressin antagonists” is potentially dangerous and misleading. The focus should always be to treat the cause first. Vasopressin antagonists have never been shown to improve symptoms or outcomes, and the recommendation of their use is not consistent with labeling from the Food and Drug Administration or, to our knowledge, with the primary end point of any published paper. The author’s opinion on the use of vasopressin antagonists is not shared by the European Society of Intensive Care Medicine, the European Society of Endocrinology, or the European Renal Association– European Dialysis and Transplant Association.
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
Harry Peled, M.D. St. Jude Medical Center Fullerton, CA [email protected]
Paul E. Marik, M.D. Eastern Virginia Medical School Norfolk, VA No potential conflict of interest relevant to this letter was reported. 1. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice
guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;170:G1-G47 [Erratum, Eur J Endocrinol 2014; 171:X1.]. DOI: 10.1056/NEJMc1501342
The Author Replies: In response to Petzold: hyponatremia developed in the second patient despite the administration of large volumes of isotonic fluid; his weight increased and his hematocrit fell, suggesting plasma volume expansion. Some may choose to describe his condition as cerebral salt wasting, whereas others may prefer to call it SIADH with a physiologic natriuresis caused by iatrogenic hypervolemia. Treatment with 3% saline will increase the plasma sodium concentration, regardless of volume status or the terminology used.1 Achinger observes that a combined infusion of desmopressin and 3% saline avoids overcorrection of desmopressin-induced hyponatremia. This strategy is described in the fourth illustrative case in the Supplementary Appendix (available with the full text of the article) and in the text of the article and should be considered for patients with severe hyponatremia and a reversible cause of water retention, whether caused by desmopressin, hypovolemia, adrenal insufficiency, a thiazide diuretic, or drug-induced SIADH.2 Moritz and Ayus correctly observe that 3% saline can be administered through a peripheral vein. Unlike hypertonic glucose, 3% saline has not been reported to cause venous sclerosis or tissue damage from extravasation when admin-
istered peripherally.2 A standard pharmacy reference recently stopped mandating infusion in a central vein.3 In response to Peled and Marik: I would point out that I did refer to the European guidelines in my article and that the source I referenced4 (number 74 in the article) has the same content as the article they reference. I also stated that vasopressin antagonists are one of many therapeutic options (along with fluid restriction, salt, furosemide, and urea) that can be used to increase the plasma sodium concentration in patients with chronic hyponatremia who have mild or subtle symptoms. According to expert opinion that has been disputed by others,5 the European guidelines support the use of urea (unavailable in the United States) and discourage the use of vasopressin antagonists for any purpose.4,5 Experts on both sides of the Atlantic agree that vasopressin antagonists should not be used as initial therapy if hyponatremia is causing severe symptoms or if the plasma sodium concentration is less than 120 mmol per liter (see Table 1 of the article). Richard H. Sterns, M.D. University of Rochester School of Medicine and Dentistry Rochester, NY [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH:
what difference? J Am Soc Nephrol 2008;19:194-6.
2. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic
saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013;61:571-8. 3. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists, 2011. 4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol Dial Transplant 2014;40:924.] 5. Verbalis JG, Grossman A, Höybye C, Runkle I. Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia. Curr Med Res Opin 2014;30:1201-7. DOI: 10.1056/NEJMc1501342
Atypical Hyperplasia of the Breast To the Editor: In their article on the role of atypical hyperplasia in the assessment of breastcancer risk, Hartmann et al. (Jan. 1 issue)1 state that the International Breast Cancer Intervention
Study (IBIS) model does not provide accurate risk estimates for women with atypical hyperplasia. After the results of the study by Boughey et al.2 were reported in 2010, we noted that our model
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1269
through a central-nervous-system mechanism in animal models. On the basis of this new information, weight loss in patients with congenital leptin deficiency who are receiving leptin treatment may result not only from an improvement in hyperphagia2 but also from increased energy expenditure owing to leptin-induced browning of white adipose tissue. We have now been able to analyze stromal– vascular cells isolated from subcutaneous white adipose tissue obtained from three patients with congenital leptin deficiency caused by a c.389delG mutation3 in the leptin gene. Subjecting all three samples to adipogenic differentiation ex vivo in the presence of leptin led to an increase in messenger RNA (mRNA) expression of the gene encoding uncoupling protein 1 (UCP1) (Fig. 1A). This protein is produced mainly in brown adipose tissue and is involved in the generation of heat by nonshivering thermogenesis, thereby regulating energy expenditure. Preliminary data also hinted at an increase in mRNA expression of UCP1 after leptin treatment in Simpson–Golabi–Behmel syndrome adipocytes (Fig. 1B).4,5 Our data suggest that leptin-induced browning
of white adipose tissue might be mediated not only by the central nervous system but also by a direct peripheral effect of leptin on adipocytes. Pamela Fischer-Posovszky, Ph.D. Jan-Bernd Funcke, M.Sc. Martin Wabitsch, M.D., Ph.D. University of Ulm Ulm, Germany [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Dodd GT, Decherf S, Loh K, et al. Leptin and insulin act on
POMC neurons to promote the browning of white fat. Cell 2015; 160:88-104. 2. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879-84. 3. Funcke J-B, von Schnurbein J, Lennerz B, et al. Monogenic forms of childhood obesity due to mutations in the leptin gene. Mol Cell Pediatr 2014;1:3. 4. Wabitsch M, Brenner RE, Melzner I, et al. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord 2001;25: 8-15. 5. Fischer-Posovszky P, Newell FS, Wabitsch M, Tornqvist HE. Human SGBS cells — a unique tool for studies of human fat cell biology. Obes Facts 2008;1:184-9. DOI: 10.1056/NEJMc1501146
Disorders of Plasma Sodium To the Editor: The review by Sterns (Jan. 1 issue)1 on disorders of plasma sodium concentration, which are among the most frequently encountered (and mismanaged) problems in medicine, was enhanced by the use of illustrative cases (which appear in the Supplementary Appendix, available with the full text of the article at NEJM.org). After the second patient had a subarachnoid hemorrhage, plasma hyponatremia associated with excessive urinary sodium loss developed. Did this patient really have the syndrome of inappropriate antidiuretic hormone secretion (SIADH), or did he have cerebral salt wasting, which is also seen in the clinical situation described? Information on the water balance (hypovolemic, euvolemic, or hypervolemic) would be helpful here, because cerebral salt wasting is associated with hypovolemia. The differential diagnosis of SIADH versus cerebral salt wasting is clinically relevant because the treatments are diametrically opposed.2
Axel Petzold M.D., Ph.D. UCL Institute of Neurology London, United Kingdom [email protected] No potential conflict of interest relevant to this letter was reported. 1. Sterns RH. Disorders of plasma sodium — causes, conse-
quences, and correction. N Engl J Med 2015;372:55-65. 2. Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol 2006;18:57-63. DOI: 10.1056/NEJMc1501342
To the Editor: The third case reviewed by Sterns is one in which a 30-year-old woman with symptomatic, desmopressin-associated hyponatremia has sodium overcorrection and neurologic injury after the discontinuation of desmopressin and is given a 3% saline infusion. There is no mention of how to treat this condition properly. My colleagues and I recently published a series of 15 cases of desmopressin-associated hypo-
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1267
The
n e w e ng l a n d j o u r na l
natremia.1 In 13 patients, neurologic injury and death resulted because of overcorrection of serum sodium concentrations consequent to the discontinuation of desmopressin and concurrent use of hypertonic saline. In 2 patients, desmopressin was continued and hypertonic saline was administered, and both survived, with no neurologic sequelae. Desmopressin-associated hyponatremia has the potential to become a common disorder as the use of desmopressin expands to include the treatment of enuresis in children and elderly patients.2 When treating this condition, it is important to recognize the development of severe, symptomatic hyponatremia in response to desmopressin and to continue to administer the drug along with hypertonic saline. Steven G. Achinger, M.D. Watson Clinic Lakeland, FL [email protected] No potential conflict of interest relevant to this letter was reported. 1. Achinger SG, Arieff AI, Kalantar-Zadeh K, Ayus JC. Desmo-
pressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series. Nephrol Dial Transplant 2014;29:2310-5. 2. Vande Walle J, Stockner M, Raes A, Nørgaard JP. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007; 2:232-8.
m e dic i n e
treatment of hyponatremic encephalopathy in the emergency department. This treatment was safe and effective and without systemic or neurologic complications.5 As much as 500 ml of 3% saline can be given safely in non-ICU settings. Michael L. Moritz, M.D. Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA [email protected]
Juan C. Ayus, M.D. Renal Consultants of Houston Houston, TX No potential conflict of interest relevant to this letter was reported. 1. Kerns E, Patel S, Cohen DM. Hourly oral sodium chloride
for the rapid and predictable treatment of hyponatremia. Clin Nephrol 2014;82:397-401. 2. Ayus JC, Arieff A, Moritz ML. Hyponatremia in marathon runners. N Engl J Med 2005;353:427-8. 3. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med 2008;18:111-21. 4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol Dial Transplant 2014;40:924.] 5. Ayus JC, Caputo D, Bazerque F, Heguilen R, Gonzalez CD, Moritz ML. Treatment of hyponatremic encephalopathy with a 3% sodium chloride protocol: a case series. Am J Kidney Dis 2014 November 25 (Epub ahead of print). DOI: 10.1056/NEJMc1501342
DOI: 10.1056/NEJMc1501342
To the Editor: Sterns endorses the use of 100-ml bolus infusions of 3% saline for the treatment of symptomatic hyponatremia. However, the appropriate route and setting for administration are not mentioned. A potential barrier to the use of 3% saline is the perception that it must be administered through a central catheter in an intensive care unit (ICU).1 We recommended peripheral intravenous administration of 100-ml infusions of 3% saline for the management of exercise-associated hyponatremia in medical tents.2 This approach is now the standard treatment for this condition3 and is recommended in the European Clinical Practice Guideline for the treatment of symptomatic hyponatremia of any cause.4 No information exists on how much 3% saline can be safely administered through a peripheral intravenous catheter. We recently reported the administration of 500 ml of 3% saline through a peripheral intravenous catheter over 6 hours for the
1268
of
To the Editor: We were surprised that Sterns did not refer to the recently published European hyponatremia guidelines1, which specifically do not recommend the use of vasopressin antagonists for any indication. Furthermore, Sterns’s statement that “to reduce symptoms and improve potential outcomes, chronic hyponatremia should be corrected gradually with the use of . . . vasopressin antagonists” is potentially dangerous and misleading. The focus should always be to treat the cause first. Vasopressin antagonists have never been shown to improve symptoms or outcomes, and the recommendation of their use is not consistent with labeling from the Food and Drug Administration or, to our knowledge, with the primary end point of any published paper. The author’s opinion on the use of vasopressin antagonists is not shared by the European Society of Intensive Care Medicine, the European Society of Endocrinology, or the European Renal Association– European Dialysis and Transplant Association.
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
Harry Peled, M.D. St. Jude Medical Center Fullerton, CA [email protected]
Paul E. Marik, M.D. Eastern Virginia Medical School Norfolk, VA No potential conflict of interest relevant to this letter was reported. 1. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice
guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;170:G1-G47 [Erratum, Eur J Endocrinol 2014; 171:X1.]. DOI: 10.1056/NEJMc1501342
The Author Replies: In response to Petzold: hyponatremia developed in the second patient despite the administration of large volumes of isotonic fluid; his weight increased and his hematocrit fell, suggesting plasma volume expansion. Some may choose to describe his condition as cerebral salt wasting, whereas others may prefer to call it SIADH with a physiologic natriuresis caused by iatrogenic hypervolemia. Treatment with 3% saline will increase the plasma sodium concentration, regardless of volume status or the terminology used.1 Achinger observes that a combined infusion of desmopressin and 3% saline avoids overcorrection of desmopressin-induced hyponatremia. This strategy is described in the fourth illustrative case in the Supplementary Appendix (available with the full text of the article) and in the text of the article and should be considered for patients with severe hyponatremia and a reversible cause of water retention, whether caused by desmopressin, hypovolemia, adrenal insufficiency, a thiazide diuretic, or drug-induced SIADH.2 Moritz and Ayus correctly observe that 3% saline can be administered through a peripheral vein. Unlike hypertonic glucose, 3% saline has not been reported to cause venous sclerosis or tissue damage from extravasation when admin-
istered peripherally.2 A standard pharmacy reference recently stopped mandating infusion in a central vein.3 In response to Peled and Marik: I would point out that I did refer to the European guidelines in my article and that the source I referenced4 (number 74 in the article) has the same content as the article they reference. I also stated that vasopressin antagonists are one of many therapeutic options (along with fluid restriction, salt, furosemide, and urea) that can be used to increase the plasma sodium concentration in patients with chronic hyponatremia who have mild or subtle symptoms. According to expert opinion that has been disputed by others,5 the European guidelines support the use of urea (unavailable in the United States) and discourage the use of vasopressin antagonists for any purpose.4,5 Experts on both sides of the Atlantic agree that vasopressin antagonists should not be used as initial therapy if hyponatremia is causing severe symptoms or if the plasma sodium concentration is less than 120 mmol per liter (see Table 1 of the article). Richard H. Sterns, M.D. University of Rochester School of Medicine and Dentistry Rochester, NY [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH:
what difference? J Am Soc Nephrol 2008;19:194-6.
2. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic
saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013;61:571-8. 3. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists, 2011. 4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol Dial Transplant 2014;40:924.] 5. Verbalis JG, Grossman A, Höybye C, Runkle I. Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia. Curr Med Res Opin 2014;30:1201-7. DOI: 10.1056/NEJMc1501342
Atypical Hyperplasia of the Breast To the Editor: In their article on the role of atypical hyperplasia in the assessment of breastcancer risk, Hartmann et al. (Jan. 1 issue)1 state that the International Breast Cancer Intervention
Study (IBIS) model does not provide accurate risk estimates for women with atypical hyperplasia. After the results of the study by Boughey et al.2 were reported in 2010, we noted that our model
n engl j med 372;13 nejm.org march 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH DAKOTA STATE UNIV on March 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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