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We have previously shown that an excess of deoxycorticosterone acetate and high sodium chloride intake (DOCA/salt) in one-renin gene mice induces a high urinary Na/K ratio, hypokalemia, and cardiac and renal hypertrophy in the absence of hypertension. Dietary potassium supplementation prevents DOCA/salt-induced pathological processes. In the present study, we further study whether DOCA/salt-treated mice progressively develop chronic inflammation and fibrosis in the kidney and whether dietary potassium supplementation can reduce the DOCA/salt-induced renal pathological process. Results showed that (1) long-term DOCA/salt-treated one-renin gene mice developed severe kidney injuries including tubular/vascular hypertrophy, mesangial/interstitial/perivascular fibrosis, inflammation (lymphocyte's immigration), proteinuria, and high serum creatinine in the absence of hypertension; (2) there were over-expressed mRNAs of plasminogen activator inhibitor-1 (PAI-1), fibronectin, collagen type I and III, interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP1), transforming growth factor- β (TGF- β ), tumor necrosis factor-alpha (TNF- α ), osteopontin, Nuclear factor kappa B (NF-κB)/P65, and intercellular adhesion molecule (ICAM)-1; and (3) dietary potassium supplementation normalized urinary Na/K ratio, hypokalemia, proteinuria, and serum creatinine, reduced renal hypertrophy, inflammations, and fibrosis, and down-regulated mRNA expression of fibronectin, Col-I and III, TGF- β , TNF- α , osteopontin, and ICAM without changes in the blood pressure. The results provide new evidence that potassium and sodium may modulate proinflammatory and fibrotic genes, leading to chronic renal lesions independent of blood pressure.

Appendicular mucocele (AM) is a rare and potentially malignant entity linked to obstructive dilatation of the appendix with an intraluminal accumulation of mucoid material. Most AM is asymptomatic or simulates acute appendicitis. We report an exceptional case of AM discovered in the face of hypokalemia and aggravation of chronic kidney disease (CKD) without diarrhea in an old man. Investigations led to the diagnosis of AM in its malignant form complicated by gelatinous ascites. We retained mucinous hypersecretion as the cause of hypokalemia and acute renal failure. Aggressive surgery and intraperitoneal chemotherapy corrected hydroelectrolyte imbalance.

This study aimed to investigate the relationship between renal dysfunction and electrolyte abnormalities, which are adverse events of foscarnet used for cytomegalovirus infection. Of the Ninety hematopoietic stem cell transplantation patients, 32 who met the selection criteria were enrolled in this retrospective study. The study patients were divided into two groups according to whether they developed renal dysfunction. The incidences of hypocalcemia, hypokalemia, and hypomagnesemia with an increase of grade 2 or higher in the renal dysfunction group were 45.5%, 18.2%, and 27.3%, respectively. Additionally, in the renal dysfunction group, a significant correlation was observed between creatinine and calcium (r = -0.458, p  = 0.0244) and between creatinine and potassium (r = -0.520, p  = 0.0092). This study shows that renal dysfunction and electrolyte abnormalities may be closely related in HSCT patients receiving foscarnet; thus, it is a report that may contribute to the safety of continuous foscarnet treatment.

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

KCNJ16 encodes K ir 5.1 and acts in combination with K ir 4.1, encoded by KCNJ10, to form an inwardly rectifying K + channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This K ir 4.1/K ir 5.1 channel is critical for controlling basolateral membrane potential and K + recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na + handling. Previous work has shown that Kcnj16 -/- mice and SS Kcnj16-/- rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants in KCNJ16 by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Context: Cushing syndrome (CS) results in significant morbidity and mortality., Objective: To study acute and life-threatening complications in patients with active CS., Methods: We performed a retrospective cohort study using inpatient and outpatient records of patients with CS in a tertiary center. A total of 242 patients with CS were included, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. We collected acute complications necessitating hospitalization, from appearance of first symptoms of hypercortisolism until 1 year after biochemical remission. Mortality data were obtained from the national registry. Baseline factors relating to and predicting acute complications were tested using uni- and multivariate analysis., Results: The prevalence of acute complications was 62% in patients with benign pituitary CS, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Complications observed in patients with benign CS included infections (25%), thromboembolic events (17%), hypokalemia (13%), hypertensive crises (9%), cardiac arrhythmias (5%), and acute coronary events (3%). Among these patients, 23% had already been hospitalized for acute complications before CS was suspected, and half of complications occurred after the first surgery. Glycated hemoglobin (HbA1c) and 24-hour urinary free cortisol positively correlated with the number of acute complications per patient. Patients with malignant disease had significantly higher rates of acute complications. Mortality during the observation period was 2.8% and 59% in benign and malignant CS, respectively., Conclusions: This analysis highlights the whole spectrum of acute and life-threatening complications in CS, and their high prevalence even before disease diagnosis and after successful surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The most commonly reported pattern of anti-PD-1 induced colitis is an active colitis characterized by neutrophilic inflammation and prominent apoptosis. On the other hand, reports of collagenous colitis (which is a microscopic colitis) are exceptional. In this report, we describe an unusual case of anti-PD1-associated collagenous colitis in a 76-year-old man, treated with pembrolizumab for a stage IV cutaneous melanoma. Fourteen months after the start of pembrolizumab, the patient developed a grade 3 diarrhea (up to 9 stools per day) associated with profound hypokalemia. No bacterial, viral or parasitological infectious agents were found from stool analysis. The rectosigmoidoscopy showed colonic diffuse congestion with no ulceration. Systematic biopsies were performed during endoscopy. Histologically, the fragments analyzed revealed a moderately thickened subepithelial collagen layer (20-30μm thick) associated with a mild mixed inflammatory infiltrate within the lamina propria. There were no granuloma lesions, ulcerations or viral inclusion bodies. The patient was initially successfully treated with corticosteroids (prednisone) and temporary interruption of pembrolizumab. However, during corticosteroids tapering, a relapse was observed. The treatment was switched to budesonide, leading to a complete and definitive resolution of diarrhea. To date, budesonide has been stopped and pembrolizumab has not been restarted. Currently, there is a bone progression treated by radiotherapy alone. In case of a more important progression, a systemic treatment will be secondarily discussed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Hypokalemia is closely linked with the pathophysiology of primary aldosteronism (PA). Although hypokalemic PA is less common than the normokalemic course of the disease, hypokalemia is of particular importance for the manifestation and development of comorbidities. Specifically, a growing body of evidence demonstrates that hypokalemia in PA patients is associated with a more severe disease course regarding cardiovascular and metabolic morbidity and mortality. It is also well appreciated that low potassium levels per se can promote or exacerbate hypertension. The spectrum of hypokalemia-related symptoms ranges from asymptomatic courses to life-threatening conditions. Hypokalemia is found in 9-37% of all cases of PA with a predominance in patients with aldosterone producing adenoma. Conversely, hypokalemia resolves in almost 100% of cases after both, specific medical or surgical treatment of the disease. However, to date, high-level evidence about the prevalence of primary aldosteronism in a hypokalemic population is missing. Epidemiological data are expected from the recently launched IPAHK+study ("Incidence of Primary Aldosteronism in Patients with Hypokalemia")., Competing Interests: Research fund by NCCR Kidney.ch, (© Georg Thieme Verlag KG Stuttgart · New York.)

Potassium depletion affects AQP2 expression and the cellular composition of the kidney collecting duct. This, in turn, contributes to the development of a secondary form of nephrogenic diabetes insipidus and hypokalemic nephropathy. Here we show that after 14 days of potassium depletion, the cellular fraction of A-type intercalated cells increases while the fraction of principal cells decreases along the outer medullary collecting duct in rats. The intercalated cells acquired a novel distribution pattern forming rows of cells attached to each other. These morphological changes occur progressively and reverse after 7 days of recovery on normal rat chow diet. The cellular remodeling mainly occurred in the inner stripe of outer medulla similar to the previously seen effect of lithium on the collecting duct cellular profile. The cellular remodeling is associated with the appearance of cells double labelled with both specific markers of principal and type-A intercalated cells. The appearance of this cell type was associated with the downregulation of the Notch signaling via the Hes1 pathways. These results show that the epithelium of the collecting duct has a high degree of plasticity and that Notch signaling likely plays a key role during hypokalemia.

Antistaphylococcal penicillins such as nafcillin and oxacillin are among the first choices of treatment for severe invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections, although there has been limited safety evaluations between individual agents. Using the FDA Adverse Event Reports System (FAERS), oxacillin was observed to have a lower proportion of reports of acute renal failure (reporting odds ratio [ROR], 5.3 [95% confidence interval {CI}, 3.1 to 9.3] versus 21.3 [95% CI, 15.8 to 28.6], respectively) and hypokalemia (ROR, 0.7 [95% CI, 0.1 to 4.8] versus 11.4 [95% CI, 7.1 to 18.3], respectively) than nafcillin., (Copyright © 2020 American Society for Microbiology.)

Background: Multi-drug resistant Tuberculosis (MDR-TB) is a strain of Mycobacterium tuberculosis that is resistant to at least Rifampicin and Isoniazid drugs. The treatment success rate for MDR-TB cases is lower than for drug susceptible TB. Globally only 55% of MDR-TB patients were successfully treated. Monitoring the early treatment outcome and better understanding of the specific reasons for early unfavorable and unknown treatment outcome is crucial for preventing the emergence of further drug-resistant tuberculosis. However, this information is scarce in Ethiopia. Therefore, this study aimed to determine the intensive phase treatment outcome and contributing factors among patients treated for MDR-TB in Ethiopia., Methods: A 6 year retrospective cohort record review was conducted in fourteen TICs all over the country. The records of 751 MDR-TB patients were randomly selected using simple random sampling technique. Data were collected using a pre-tested and structured checklist. Multivariable multinomial logistic regression was undertaken to identify the contributing factors., Results: At the end of the intensive phase, 17.3% of MDR-TB patients had an unfavorable treatment outcome, while 16.8% had an unknown outcome with the remaining having a favorable outcome. The median duration of the intensive phase was 9.0 months (IQR 8.04-10.54). Having an unfavorable intensive phase treatment outcome was found significantly more common among older age [ARRR = 1.047, 95% CI (1.024, 1.072)] and those with a history of hypokalemia [ARRR = 0.512, 95% CI (0.280, 0.939)]. Having an unknown intensive phase treatment outcome was found to be more common among those treated under the ambulatory care [ARRR = 3.2, 95% CI (1.6, 6.2)], rural dwellers [ARRR = 0.370, 95% CI (0.199, 0.66)], those without a treatment supporter [ARRR = 0.022, 95% CI (0.002, 0.231)], and those with resistance to a limited number of drugs., Conclusion: We observed a higher rate of unfavorable and unknown treatment outcome in this study. To improve favorable treatment outcome more emphasis should be given to conducting all scheduled laboratory monitoring tests, assignment of treatment supporters for each patient and ensuring complete recording and reporting which could be enhanced by quarterly cohort review. Older aged and rural patients need special attention. Furthermore, the sample referral network should be strengthened.

Context: Gitelman syndrome (GS) is clinically heterogeneous. The genotype and phenotype correlation has not been well established. Though the long-term prognosis is considered to be favorable, hypokalemia is difficult to cure., Objective: To analyze the clinical and genetic characteristics and treatment of all members of 13 GS pedigrees., Methods: Thirteen pedigrees (86 members, 17 GS patients) were enrolled. Symptoms and management, laboratory findings, and genotype-phenotype associations among all the members were analyzed., Results: The average ages at onset and diagnosis were 27.6 ± 10.2 years and 37.9 ± 11.6 years, respectively. Males were an average of 10 years younger and exhibited more profound hypokalemia than females. Eighteen mutations were detected. Two novel mutations (p.W939X, p.G212S) were predicted to be pathogenic by bioinformatic analysis. GS patients exhibited the lowest blood pressure, serum K + , Mg 2+ , and 24-h urinary Ca 2+ levels. Although blood pressure, serum K + and Mg 2+ levels were normal in heterozygous carriers, 24-h urinary Na + excretion was significantly increased. During follow-up, only 41.2% of patients reached a normal serum K + level. Over 80% of patients achieved a normal Mg 2+ level. Patients were taking 2-3 medications at higher doses than usual prescription to stabilize their K + levels. Six patients were taking spironolactone simultaneously, but no significant elevation in the serum K + level was observed., Conclusion: The phenotypic variability of GS and therapeutic strategies deserve further research to improve GS diagnosis and prognosis. Even heterozygous carriers exhibited increased 24-h Na + urine excretion, which may make them more susceptible to diuretic-induced hypokalemia.

Hypokalemia contributes to the progression of chronic kidney disease, although a definitive pathophysiological theory to explain this remains to be established. K + deficiency results in profound alterations in renal epithelial transport. These include an increase in salt reabsorption via the Na + -Cl - cotransporter (NCC) of the distal convoluted tubule (DCT), which minimizes electroneutral K + loss in downstream nephron segments. In experimental conditions of dietary K + depletion, punctate structures in the DCT containing crucial NCC-regulating kinases have been discovered in the murine DCT and termed "WNK bodies," referring to their component, with no K (lysine) kinases (WNKs). We hypothesized that in humans, WNK bodies occur in hypokalemia as well. Renal needle biopsies of patients with chronic hypokalemic nephropathy and appropriate controls were examined by histological stains and immunofluorescence. Segment- and organelle-specific marker proteins were used to characterize the intrarenal and subcellular distribution of established WNK body constituents, namely, WNKs and Ste20-related proline-alanine-rich kinase (SPAK). In both patients with hypokalemia, WNKs and SPAK concentrated in non-membrane-bound cytoplasmic regions in the DCT, consistent with prior descriptions of WNK bodies. The putative WNK bodies were located in the perinuclear region close to, but not within, the endoplasmic reticulum. They were closely adjacent to microtubules but not clustered in aggresomes. Notably, we provide the first report of WNK bodies, which are functionally challenging structures associated with K + deficiency, in human patients.

Background: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously., Case Presentation: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L., Conclusions: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir.

Background: The prognostic value of long-term potassium monitoring and dynamics in heart failure has not been characterized completely. We sought to determine the association between serum potassium values collected at follow-up with all-cause mortality in a prospective and consecutive cohort of patients discharged from a previous acute heart failure admission., Methods: Serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings. The multivariable-adjusted association of serum potassium with mortality was assessed by using comprehensive state-of-the-art regression methods that can accommodate time-dependent exposure modeling., Results: The study sample included 2164 patients with a total of 16 116 potassium observations. Mean potassium at discharge was 4.3±0.48 mEq/L. Hypokalemia (<3.5 mEq/L), normokalemia (3.5-5.0 mEq/L), and hyperkalemia (>5 mEq/L) were observed at the index admission in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively. At a median follow-up of 2.8 years (range, 0.03-12.8 years), 1090 patients died (50.4%). On a continuous scale, the multivariable-adjusted association of potassium values and mortality revealed a nonlinear association (U-shaped) with higher risk at both ends of its distribution (omnibus P =0.001). Likewise, the adjusted hazard ratios for hypokalemia and hyperkalemia, normokalemia as reference, were 2.35 (95% confidence interval, 1.40-3.93; P =0.001) and 1.55 (95% confidence interval, 1.11-2.16; P =0.011), respectively (omnibus P =0.0003). Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Potassium normalization was independently associated with lower mortality risk ( P =0.001)., Conclusions: Either modeled continuously or categorically, serum potassium levels during long-term monitoring were independently associated with mortality in patients with heart failure. Likewise, persistence of abnormal potassium levels was linked to a higher risk of death in comparison with patients who maintained or returned to normal values., (© 2017 American Heart Association, Inc.)

Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5 , CACNA1D , ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development., (© 2017 Society for Endocrinology.)

Unilateral multiple adrenocortical micronodules (UMNs) constitute a rare subset of primary aldosteronism (PA) characterized by the hypersecretion of aldosterone derived from multiple small nodules in the zona glomerulosa of the unilateral adrenal grand. This case study describes a 49-year-old man with PA and UMNs who presented with muscle cramps at rest due to hypokalemia. The patient had a 6-year history of hypertension treated with antihypertensive drugs. Imaging studies revealed bilateral adrenal nodules as large as 5 mm. Adrenal venous sampling confirmed unilateral PA; therefore, the patient underwent the removal of the affected adrenal gland. Macroscopically, the removed adrenal gland exhibited irregular adrenocortical thickening accompanied by ill-defined, adrenocortical macronodules as large as 6 mm. The zona glomerulosa was histologically hyperplastic. However, an immunohistochemistry test of the steroidogenic enzymes revealed that these macronodules and the hyperplastic glomerular layer tested negative for CYB11B2. Moreover, we observed adrenocortical micronodules as large as 0.5 mm that tested immunohistochemically positive for CYP11B2 and HSD3B2 but negative for CYP17A1 and CYP11B1. Thus, UMNs were diagnosed. This case instructively indicates that a grossly or histologically detectable nodular lesion is not necessarily a culprit lesion for PA. Therefore, functional histopathology is indispensable for the correct subclassification of PA., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K + secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K + intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K + -mediated activation of Na-Cl cotransporter (NCC) in the kidney. In the distal convoluted tubules of mice eating a low-K + diet, we found increased KLHL3 phosphorylation at S433 (KLHL3 S433-P ), a modification that impairs WNK binding, and also reduced total KLHL3 levels. These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane. Increased phosphorylation of S433 was explained by increased levels of active, phosphorylated protein kinase C (but not protein kinase A), which directly phosphorylates S433. Moreover, in HEK cells expressing KLHL3 and WNK4, we showed that the activation of protein kinase C by phorbol 12-myristate 13-acetate induces KLHL3 S433-P and increases WNK4 levels by abrogating its ubiquitination. These data demonstrate the role of KLHL3 in low-K + -mediated induction of NCC; this physiologic adaptation reduces distal electrogenic Na + reabsorption, preventing further renal K + loss but promoting increased blood pressure.

Hyperpolarization-activated cationic and cyclic nucleotide-gated channels (HCN) comprise four homologous subunits (HCN1-HCN4). HCN channels are found in excitable and non-excitable tissues in mammals. We have previously shown that HCN2 may transport ammonium (NH4 (+)), besides sodium (Na(+)), in the rat distal nephron. In the present work, we identified HCN1 and HCN3 in the proximal tubule (PT) and HCN3 in the thick ascending limb of Henle (TALH) of the rat kidney. Immunoblot assays detected HCN1 (130 kDa) and HCN3 (90 KDa) and their truncated proteins C-terminal HCN1 (93 KDa) and N-terminal HCN3 (65 KDa) in enriched plasma membranes from cortex (CX) and outer medulla (OM), as well as in brush-border membrane vesicles. Immunofluorescence assays confirmed apical localization of HCN1 and HCN3 in the PT. HCN3 was also found at the basolateral membrane of TALH. We evaluated chronic changes in mineral dietary on HCN3 protein abundance. Animals were fed with three different diets: sodium-deficient (SD) diet, potassium-deficient (KD) diet, and high-potassium (HK) diet. Up-regulation of HCN3 was observed in OM by KD and in CX and OM by HK; the opposite effect occurred with the N-terminal truncated HCN3 in CX (KD) and OM (HK). SD diet did not produce any change. Since HCN channels activate with membrane hyperpolarization, our results suggest that HCN channels may play a role in the Na(+)-K(+)-ATPase activity, contributing to Na(+), K(+), and acid-base homeostasis in the rat kidney.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility., (Copyright © 2015 Bicanic et al.)

A 31-year-old woman with no significant past medical or family history was admitted with complaints of general weakness. Laboratory tests revealed: serum potassium 3.0 mEq/L, arterial blood pH 7.28, serum bicarbonate 17.8 mEq/L and urinary pH 7.0. Double-labeling confocal fluorescence microscopy using H(+)-ATPase and pendrin antibodies demonstrated a decreased expression of these proteins in the patient's renal collecting duct compared to normal controls. Anti-Sjögren's-syndrome-related antigen A (Anti-Ro/SS-A) and anti-Sjögren's syndrome type B (anti-La/SS-B) antibodies were strongly positive with very high titers, consistent with Sjögren's syndrome. We present a case of distal renal tubular acidosis-associated Sjögren's syndrome with a defect in H(+)-ATPase and pendrin in the renal collecting duct.

Background: In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated., Design Participants & Measurements: 2500 participants with CKD stage 1-4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used., Results: The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m(2). Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03-3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19-2.35) in sK = 3.5-4 mEq/L, respectively, compared with sK = 4.5-5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09-2.34) increased risk of ESRD compared with sK = 4.5-5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range., Conclusion: In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.

Clinical and genetic studies have suggested that a loss of function and gain of function mutation in the same gene can cause different diseases. The aim of this study was to test the hypothesis that inactivating mutations in WNK1 (with no K (lysine) protein kinase-1) or WNK4 could be a new candidate for causing hypokalemic salt-losing tubulopathy (SLT) in those patients with unknown genetic defects because SLT is the opposite phenotype to pseudohypoaldosteronism type II (PHAII). We screened 44 SLTs patients and found that 33 (75%) cases had homozygous or compound heterozygous mutations in CLCNKB or SLC12A3. Two novel missense mutations were identified in WNK1, but not in WNK4, in 2 of the remaining 11 patients. The WNK1 mutations occurred in the protein C-terminus domain, de novo and inherited, respectively. One of these WNK1 mutations was shown to reduce NCC protein membrane expression in vitro because of impairing the suppressive effect of WNK4-mediated inhibition. Taken together, our findings suggest that inactivating mutations in WNK1 may cause SLT, a phenotype opposite to that of PHAII caused by WNK1 intronic deletion., (© 2012 John Wiley & Sons A/S.)

Potassium depletion (K⁺-D) induces hypertrophy and hyperplasia of collecting duct cells, and potassium repletion (K⁺-R) induces regression of these changes. The purpose of this study was to examine the time courses of the changes in cellular composition, the origin of intercalated cells (ICs) and the mechanism responsible for these changes. SD rats received K⁺-depleted diets for 1, 7, or 14 days. After K⁺-D for 14 days some of the rats received normal diets for 1, 3, 5, or 7 days. In the inner stripe of the outer medulla, K⁺-D increased significantly the number and proportion of H⁺-ATPase-positive ICs, but decreased the proportion of H⁺-ATPase-negative principal cells (PCs). However, proliferation was limited to H⁺-ATPase-negative PCs. During K⁺-R, the cellular composition was recovered to control level. Apoptosis increased during K⁺-R and exclusively limited in H⁺-ATPase-negative PCs. Double immunolabeling with antibodies to PC and IC markers identified both cells negative or positive for all markers during both K⁺-D and K⁺-R. Electron microscopic observation showed that ultrastructure of AE1-positive some cells were similar to AE1-negative some cells during K⁺-R. LC3 protein expression increased significantly and autophagic vacuoles appeared particularly in PCs on days 14 of K⁺-D and in ICs on days 3 of K⁺-R. These results suggest that PCs and ICs may interconvert in response to changes in dietary K+ availability and that autophagic pathways may be involved in the interconversion.

Background: Low serum potassium (K) is associated with increased blood pressure, impaired cardiac function and renal dysfunction. Although lower serum K is associated with cardiac hypertrophy in animal models, the relationship of low serum K to the presence and severity of electrocardiographic left ventricular hypertrophy (LVH) is unclear., Methods: Baseline and yearly Cornell product LVH levels were examined in relation to low serum K (serum K ≤ 3.90 mEq/l, the lowest quartile of baseline K levels) in 8586 patients with baseline K levels. Patients were randomized to losartan-vs atenolol-based treatment and additional hydrochlorothiazide (HCTZ) therapy as needed., Results: After adjusting for age, sex, race, prior antihypertensive treatment, losartan vs atenolol therapy, HCTZ use, baseline diastolic and systolic pressure, body mass index, serum creatinine and urine albumin/creatinine ratio, baseline serum K ≤ 3.90 was associated with significantly higher mean baseline Cornell product LVH (2898 vs 2801 mm•ms, p = 0.001) and a 24% higher risk of Cornell product LVH > 2440 mm•ms at baseline (OR 1.24, 95% CI 1.11-1.38, p < 0.001). After also adjusting for baseline Cornell product and changes in diastolic and systolic pressure between baseline and each year of measurement, in-treatment serum K ≤ 3.90 determined yearly was associated with significantly higher mean Cornell product LVH at years 1-3 and with statistically significant 16-32% increased risks of LVH by Cornell product at years 1-4., Conclusions: A low serum K is independently associated with a greater likelihood and severity of Cornell product LVH during antihypertensive therapy.

Introduction: Osmotic demyelination syndrome (ODS) is increasingly recognized to involve extrapontine locations in addition to the better-known central pontine myelinolysis., Aims: This study describes clinical and radiological features of consecutive patients with ODS detected over 1 year., Methods: Patients fulfilling clinical and radiological criteria for ODS were prospectively enrolled and were followed with serial assessments during hospital stay and up to 253 days after discharge., Results: Eight patients (five females) aged 24-89 years were enrolled, comprising 0·06% of all admissions to the general medical and neurology services. All had preceding hyponatraemia and hypokalaemia of various aetiologies. One patient developed ODS after postpartum pituitary haemorrhage, which has been reported only rarely. Sodium levels were corrected at maximal rates exceeding 8 mmol/l/day. Neurological symptoms attributed to ODS began 3-15 days after clinical improvement following sodium correction in four patients; the remainder did not show any intervening lucent interval. Fifty per cent were stuporous at admission, 50% had seizures, 62·5% had symmetric parkinsonism, and 75% had prominent primitive reflexes. Stretch reflexes were absent in 25% and normal or brisk in the remainder. Magnetic resonance imaging (MRI) showed symmetric striatal lesions in all patients, with concomitant pontine involvement in only 25%. Four patients had poor outcomes (modified Rankin score >3), with prognosis dependent on the presence of severe systemic illness, liver dysfunction, encephalopathy, seizures, and degree of disability upon discharge from hospital. Patients with parkinsonism responded to dopaminergic therapy, with chorea, dystonia, and depression as later developments. This series is remarkable for the high incidence of extrapontine lesions, much more common than pontine involvement.

Burmese is an old and popular cat breed, however, several health concerns, such as hypokalemia and a craniofacial defect, are prevalent, endangering the general health of the breed. Hypokalemia, a subnormal serum potassium ion concentration ([K(+)]), most often occurs as a secondary problem but can occur as a primary problem, such as hypokalaemic periodic paralysis in humans, and as feline hypokalaemic periodic polymyopathy primarily in Burmese. The most characteristic clinical sign of hypokalemia in Burmese is a skeletal muscle weakness that is frequently episodic in nature, either generalized, or sometimes localized to the cervical and thoracic limb girdle muscles. Burmese hypokalemia is suspected to be a single locus autosomal recessive trait. A genome wide case-control study using the illumina Infinium Feline 63K iSelect DNA array was performed using 35 cases and 25 controls from the Burmese breed that identified a locus on chromosome E1 associated with hypokalemia. Within approximately 1.2 Mb of the highest associated SNP, two candidate genes were identified, KCNH4 and WNK4. Direct sequencing of the genes revealed a nonsense mutation, producing a premature stop codon within WNK4 (c.2899C>T), leading to a truncated protein that lacks the C-terminal coiled-coil domain and the highly conserved Akt1/SGK phosphorylation site. All cases were homozygous for the mutation. Although the exact mechanism causing hypokalemia has not been determined, extrapolation from the homologous human and mouse genes suggests the mechanism may involve a potassium-losing nephropathy. A genetic test to screen for the genetic defect within the active breeding population has been developed, which should lead to eradication of the mutation and improved general health within the breed. Moreover, the identified mutation may help clarify the role of the protein in K⁺ regulation and the cat represents the first animal model for WNK4-associated hypokalemia.

Background: The rate-corrected QT interval (QTc) prolongation is a risk factor for sudden cardiac death and may be induced by antipsychotic drugs., Objective: To determine the clinical characteristics associated with QTc prolongation (440 msec or greater) in children and adolescents hospitalized for treatment of psychiatric disorders., Method: We determined the frequency of baseline prolongation of QTc in 811 psychiatric pediatric inpatients (15.5 ± 2.4 years of age). QTc duration was 440 msec or greater (range 441-481 msec) in 16 patients (1.97%). In a 1:5 nested case-control design, the 16 patients with prolonged QTc were age- and gender-matched with 80 patients with QTc of <421 msec., Results: Patients with normal and prolonged QTc had similar utilization of antipsychotics (43.8% vs. 40.8%) and daily chlorpromazine equivalents (165 ± 110 vs. 168 ± 218 mg). Hypokalemia (p = 0.009) and obesity (p = 0.032) were more common among patients with prolonged QTc. The correlation between obesity and QTc prolongation was confirmed in logistic regression analysis., Conclusions: In a large cohort of youth hospitalized for treatment of psychiatric disorders, a prolonged QTc on admission was rare and correlated with the presence of obesity, but not with current use of antipsychotic drugs.

Pure motor hemiparesis is a vascular syndrome that is occasionally mimicked by central or spinal pathologies. However, metabolic neuromuscular disorders have not been reported to mimic this condition. We present a 52-year-old male patient with hypokalemic paralysis who presented with the early symptoms of acute-onset pure motor hemiparesis. Neurological examinations revealed right-sided weakness without bulbar, extraocular, or respiratory involvement. Ischemic stroke was initially diagnosed on the basis of the acute-onset unilateral motor deficit and the patient's history of hypertension, stroke, and previous cerebral infarctions. The right hemiparesis and weakness of the left limbs worsened on the day after admission. The patient's weakness rapidly reversed after correction of hypokalemia, and a diagnosis of hypokalemic paralysis was finally established. This unusual hemineurological presentation should alert medical personnel to the possibility of reversible metabolic neuromuscular disorders, thereby avoiding delayed diagnosis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

History and Clinical Findings: A 28-year-old woman presented with dizziness and arterial hypertension. She reported a daily intake of 300 mg liquorice., Investigations: Laboratory analysis revealed hypokalaemia of 2.5 mmol/l and an elevated serum renin activity of 18.6 µg/l/h. Abdominal ultrasound and magnetic resonance imaging showed a circumscribed non-homogenuous round lesion (18 × 22 mm) in the upper third of the right kidney. Selective catheterization of the renal veins revealed increased renin activity in blood from the right renal vein, suggestive of a renin-producing tumor., Treatment and Course: Initially antihypertensive therapy with the direct renin receptor antagonist aliskiren was started and followed by a partial nephrectomy, which brought about adequate blood pressure and potassium levels., Conclusion: The constellation of hypokalaemia and hypertension often leads to important causes of secondary hypertension such as primary hyperaldosteronism or renal artery stenosis. But less frequent causes should also be considered in the differential diagnoses, such as liquorice overindulgence or reninoma., (© Georg Thieme Verlag KG Stuttgart · New York.)

We report hypokalaemic quadriparesis presenting in a 43-year-old woman. Evaluation revealed hypokalaemic quadriparesis secondary to underlying distal renal tubular acidosis, also known as type 1 RTA. Four years after the diagnosis of RTA, the patient developed joint pain, and investigation revealed systemic lupus erythematosus with lupus nephritis. RTA is one of the very rare presentations of systemic lupus erythematosus. Thus, tubular dysfunction should be carefully assessed in patients with systemic lupus erythematosus. Similarly, patients with RTA should be evaluated for underlying lupus. Our patient was successfully treated with mycophenolate mofetil and steroids.

Rhabdomyolysis is a rare presentation of hypokalemia, although muscle weakness is a well known manifestation of marked hypokalemia. Here, we report a case of primary hyperaldosteronism due to unilateral aldosterone-producing adenoma in a 14 year-old girl who developed rhabdomyolysis following hypokalemia. To our knowledge, this is the first case of adrenocortical adenoma presenting with rhabdomyolysis in a child.

We report the case of a 54-year-old man, without particular pathological antecedents admitted to the emergency of the university hospital of Monastir, for right renal colic. Radiography of the urinary tract without preparation and renal echography showed bilateral renal lithiasis and a right ureteral lithiasis. The interrogation revealed concept of vomiting after which the patient felt relieved. The biological assessment objectified an hypochloremic metabolic alcalosis, an increase in the anion gap, a severe impaired renal function of obstructive origin and an hypokaliemia. The presence of the lithiasis did not explain on its own the metabolic disorders of this patient. The other investigations showed that initial pathology was an evolutionary bulb ulcer into pre-stenosis justifying treatment by omeprazole and explaining the biological disorders.

Hypokalemic periodic paralysis (HOPP) is a rare disease associated with attacks of muscle weakness and hypokalemia. In the present study, immunoprecipitation/Western blotting has shown that a HOPP patient was deficient in sarcolemmal K(ATP) channels. Real-time RT-PCR has revealed that HOPP has decreased mRNA levels of Kir6.2, a pore-forming K(ATP) channel subunit, without affecting the expression of other K(ATP) channel-forming proteins. Based on these findings, we conclude that HOPP could be associated with impaired expression of Kir6.2 which leads to deficiency in skeletal muscle K(ATP) channels, which may explain the symptoms and clinical signs of this disease.

Animal and human studies suggest that hypertonic saline is a potential therapeutic agent to assist with the medical treatment of patients with traumatic brain injury. It may have a place as osmotherapy to decrease brain size, predominantly of uninjured brain and has several potential advantages over mannitol. Hypertonic saline has clinically desirable physiological effects on cerebral blood flow, intracranial pressure and inflammatory responses in models of neurotrauma. Animal studies support its use, but definitive human trials using mortality end-points in brain trauma are lacking. Hypertonic saline may be considered a therapeutic adjunct to the medical management of traumatic brain injury, awaiting definitive evidence to support routine use.

Hypokalemic nephropathy is associated with alterations in intrarenal vasoactive substances, leading to vasoconstriction, salt-sensitivity, and progression of interstitial fibrosis. In this study, we investigated whether hypokalemic nephropathy might also involve impaired renal angiogenesis. Sprague-Dawley rats that were fed low-potassium diets developed peritubular capillary loss that began in the inner stripe of the outer medulla (week 2) and progressed to the outer stripe of the outer medulla (week 4) and cortex (week 12). These changes were associated with increased macrophage infiltration, increased expression of both monocyte chemoattractant protein-1 and TNF-alpha, and a loss of vascular endothelial growth factor and endothelial nitric oxide synthase. Renal thiobarbituric acid-reactive substances, markers of oxidative stress, were increased late in disease. In conclusion, hypokalemic nephropathy is associated with impaired renal angiogenesis, evidenced by progressive capillary loss, reduced endothelial cell proliferation, and loss of VEGF expression.

Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP) -producing tumor only rarely occurs in patients with nonpancreatic disease. A 49-year-old woman was referred for evaluation of a right adrenal tumor incidentally diagnosed by abdominal ultrasound during the investigation of chronic watery diarrhea. Laboratory findings showed hypokalemia and excessive production of VIP and catecholamines. After surgical resection of the tumor, diarrhea subsided and both electrolytes and affected hormone levels normalized. Immunohistochemical examination confirmed a diagnosis of pheochromocytoma, which contained VIP-positive ganglion-like cells. We herein present the clinical and histogenetic implications of this rare clinical entity, with literature review.

We have previously noted that in neonatal myocytes grown in culture, reductions in extracellular K+ concentration produced a hypertrophic response as assessed by induction of early response genes, atrial natriuretic peptide and skeletal actin and repression of the alpha 3 isoform of the sodium pump in a dose dependent manner. Similarly, decreases in media K+ concentration caused increases in cytosolic calcium concentration in a dose dependent manner, which correlated with repression of alpha 3 expression. In the current study we demonstrate that decreases in media K+ concentration caused increases in cytosolic calcium concentration in isolated adult rat cardiac myocytes. These increases are potentiated by the addition of the cardiotonic steroid, ouabain and blocked by the addition of the Src kinase inhibitor Herbimycin A. In parallel studies performed in vivo, when rats subjected to dietary K+ restriction were subsequently subjected to partial (5/6th) nephrectomy for 4 weeks, cardiac growth was greater than in rats fed a control diet. These data suggest that hypokalemia may produce phenotypic alterations consistent with cardiac hypertrophy as well as potentiate the cardiovascular effects of cardiotonic steroids.

An 8-year-old, spayed female, domestic shorthair cat with a history of hyperthyroidism, anorexia, dehydration, cervical ventroflexion, and behavioral changes was referred to the Iowa State University College of Veterinary Medicine. The cat was obtunded, with severe dehydration (15%) and hypothermia (86 degrees F), and severe muscle atrophy and fasciculations. Serum biochemical abnormalities included severe hypernatremia (195 mmol/L, reference interval 155-165 mmol/L), hyperchloridemia (161 mmol/L, reference interval 123-131 mmol/L), and hypokalemia (3.6 mmol/L, reference interval 4.0-5.7 mmol/L). Calculated osmolality was 418 mOsm/kg (reference interval 280-305 mOsm/kg), attributable to the hypernatremia. The cat was kept warm and given fluid and glucocorticoid therapy and supportive measures but remained unresponsive. Hypernatremia and hyperosmolality improved through day 3, when the cat died suddenly. At necropsy, a 1.25-cm mass was found in the area of the thalamus and interthalamic adhesion that extended to the ventral aspect of the cerebrum. The histologic and immunohistochemical diagnosis was B-cell lymphoma. Hypernatremia and hyperosmolality in this cat were attributed to primary adipsia and hypothalamic dysfunction secondary to effacement of central nervous system tissue by neoplastic lymphocytes. To the authors' knowledge, this is the first reported case of central nervous system lymphoma, confirmed by use of immunohistochemical analysis as a B-cell phenotype, associated with hypernatremia. It also is the first reported case of lymphoma in animals limited to the thalamus, hypothalamus, and cerebrum, with no involvement of the spinal cord.

Hypokalemic nephropathy caused by prolonged K(+) deficiency is associated with metabolic alkalosis, polydipsia, polyuria, growth retardation, hypertension, and progressive tubulointerstitial injury. Its pathophysiology, however, remains unclear. We performed gel-based, differential proteomics analysis of kidneys from BALB/c mice fed with high-normal-K(+) (HNK), low-normal-K(+) (LNK), or K(+)-depleted diet for 8 wk (n = 6 in each group). Plasma K(+) levels were 4.62 +/- 0.35, 4.46 +/- 0.23, and 1.51 +/- 0.21 mmol/L for HNK, LNK, and KD mice, respectively (p < 0.0001; KD vs. others). With comparable amounts of food intake, the KD mice drank significantly more water than the other two groups and had polyuria. Additionally, the KD mice had growth retardation, metabolic alkalosis, markedly enlarged kidneys, renal tubular dilation, intratubular deposition of amorphous and laminated hyaline materials, and tubular atrophy. A total of 33 renal proteins were differentially expressed between the KD mice and others, whereas only eight proteins were differentially expressed between the HNK and LNK groups, as determined by quantitative intensity analysis and ANOVA with Tukey's post hoc multiple comparisons. Using MALDI-MS and/or quadrupole-TOF MS/MS, 30 altered proteins induced by K(+)-depletion were identified as metabolic enzymes (e.g., carbonic anhydrase II, aldose reductase, glutathione S-transferase GT41A, etc.), signaling proteins (14-3-3 epsilon, 14-3-3 zeta, and cofilin 1), and cytoskeletal proteins (gamma-actin and tropomyosin). Some of these altered proteins, particularly metabolic enzymes and signaling proteins, have been demonstrated to be involved in metabolic alkalosis, polyuria, and renal tubular injury. Our findings may lead to a new road map for research on hypokalemic nephropathy and to better understanding of the pathophysiology of this medical disease when the functional and physiological significances of these altered proteins are defined.

Objective: The extent of renal damage over long-term binge/purges has not been well documented in bulimia nervosa (BN)., Method: We describe a 52-year-old woman with longstanding BN subsequent to an 8-year history of anorexia nervosa (AN)., Results: The patient showed chaotic binge/purges and chronic severe hypokalemia after recovery from AN at age 26 years, and renal biopsy showed juxtaglomerular hyperplasia, which was diagnosed as pseudo-Bartter's syndrome., Discussion: Over the following 26 years, the patient's eating behaviors remained chaotic, and her renal function gradually deteriorated. After the patient died of pneumonia and sepsis at age 52 years, autopsy of her kidney showed chronic interstitial nephritis, proximal tubular swelling, and diffuse glomerular sclerosis, suggesting chronic glomerular injury associated with long-term binge/purges. To our knowledge, this is the first case report of a patient with BN with long-term binge/purges who developed an eventual "end-stage kidney" characterized by hypokalemic nephropathy and diffuse glomerulosclerosis., (Copyright 2005 by Wiley Periodicals, Inc.)