Excessive Water Retention Research Articles

Markers of Vascular Dysfunction in Hypertension.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

Structural dependence of concentrated skim milk curd on micellar restructuring

This study was conducted to establish an understanding of how milk concentration modulates the rennet curd structure. Rennet-induced gelation and renneting under slow acidification achieved using glucono-δ-lactone (GDL) and structural properties of reconstituted skim milk gels at two concentration levels (9 and 25 % total solids) were studied by measuring variations in (a) viscoelastic behaviour, (b) micellar size, charge density, diffusivity, and (c) hydrophobicity using dynamic rheometry, dynamic light scattering and fluorimetry, respectively. Concentrated milk showed a greater estimated hydrodynamic radius of casein micelles, lower zeta (ζ)-potential, ratio of serum to total Calcium (Ca) and charge density and increased surface hydrophobicity, all supporting the view that micellar restructuring particularly sub-particle transfer takes place and contributes to rapid gelation. Moreover, hydrophobic interactions occurred very quickly (within 5 min in combined gels, 10 min for renneting only), demonstrating their pivotal role during the flocculation stage. All gels exhibited a solid viscoelastic character as the elastic modulus (G′) was greater than loss modulus (G″) while both G′ and tan δ (G''/G′) were frequency-dependent. Frequency sweeps classified the concentrated gels into three stiffness categories caused by the level of rennet or GDL as rigid, hard and soft, whereas an increased flow-like behaviour (high tan δ), restricted diffusion and excessive water retention revealed limited structural rearrangements (contraction & macrosyneresis) during curd ageing. Acidification increased the diffusion rate in control curd, thus, enhanced contractive rearrangements, macrosyneresis and curd strength. Findings suggest that micellar restructuring induced by milk concentration is the principal modulator of the curd structure.

The estetrol-drospirenone-containing contraceptive as a drug of choice for patients with mastalgia

The problem of mastalgia is widespread: up to 70% of women report regular or episodic pain in the mammary gland. The role of benign breast disease in the occurrence of these complaints was noted only in 10–30% of cases, while in most women mastalgia is a manifestation of premenstrual syndrome caused by excessive water retention in the body. As a therapy for such patients, the optimal solution would be to prescribe a new combined oral contraceptive containing 15 mg of estetrol and 3 mg of drospirenone. The uniqueness of this combination in this situation lies in the pronounced antimineralocorticoid effect of drospirenone, supported by a high safety profile of estetrol, including a reduced risk of developing breast cancer compared to other combined oral contraceptive.

Growth performance: A comparative analysis of African catfish, Clarias gariepinus fingerlings reared in a cage, concrete pond and earthen pond systems

A comparative study between fingerlings reared in a cage, concrete pond, and earthen pond systems was conducted between March and August 2019. The fish net cage was constructed with ½ netting materials (210 D/9), nylon twine (210 D/9 and 210 D/8), and ropes (10mm PE and 4mm PE, as a house in which the fish fingerlings were stocked. The stocked fish were held captive in the fishnet while water flows through it. This is Treatment 1 (T1). A concrete pond of 10 m x 10 m x 15 m was constructed, as Treatment II (T11). Simultaneously an earthen pond measuring 10m x 10mx 15m was constructed entirely from soil materials both manually and mechanically in a site with excess water retention potential near Otamiri River beside the Fisheries Department of the University of Agriculture. This is Treatment III (T111). Each of the treatments was stocked with 1,500 Clarias gariepinus fingerlings of 10gms average weight and managed simultaneously for the 6 months. Data were analysed by simple descriptive statistics. The result showed 83.3%, 93.3%, and 96.7% survival rates in a cage, concrete pond, and earthen pond systems. Average weight at harvest (gm) and total weight at harvest (gm) of 332.6 gm and 415.7 gm for cage fish farming, 250.6gm and 350.8gm for concrete pond systems, and 250.6 gm and 280.65 gm for earthen pond system. The survival rate in cage culture (83.3%) was low due to high water depth, as the cage was floated; hence fingerlings could not maximize feed intake at the initial stage. The 96.7% suggest that the earthen point system has the highest production rate. Adequate care should be taken to ensure maximal utilization of feed given to the fish in cage floater in water.

Hyponatremia in Cirrhosis: An Update.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.

Upregulation of Renal ENaC Activity in Spontaneously Hypertensive Rats Is Independent of Aldosterone

Spontaneously hypertensive rat (SHR) has been widely used as a model to interrogate the contribution of the kidney to the pathogenesis of essential hypertension in humans. Elevation of blood pressure in SHR has been associated with altered renal function, since predisposition to hypertension can be transferred with a transplanted kidney into a normotensive Wistar‐Kyoto (WKY) strain. Renal defects result in excessive water and sodium retention leading to increased circulating volume and blood pressure. Abnormally elevated Na+ reabsorption in SHR is associated with the overactive renin‐angiotensin‐aldosterone system (RAAS) and with the increased abundance of the renal epithelial Na+ channel (ENaC) responsible for final regulation of sodium reuptake in the kidney and pivotal for long‐term blood pressure control. The existing data on regulation of ENaC by RAAS components in SHR is inconsistent and molecular determinants of excessive ENaC activation remain largely obscure. In the present study, we tested the efficacy of aldosterone antagonism to inhibit ENaC activity, decrease renal Na+ reabsorption and reduce blood pressure in SHR of both sexes. Where necessary, age‐matched (12–15 week‐old) WKY rats were used as controls. Consistent with previously published data, enzyme immunoassay analysis revealed elevated circulating aldosterone levels and semi‐quantitative immunoblotting – higher expression of renal ENaC protein in SHR when compared to WKY controls. Patch‐clamp experiments in split‐opened collecting ducts showed that ENaC activity was moderately increased in SHR when compared to WKY. Systemic administration of aldosterone antagonist, spironolactone (30 mg/kgBW·day) did not affect renal ENaC activity or protein abundance in SHR. Aldosterone antagonism did not alter the expression of sodium‐chloride co‐transporter (NCC) in the kidneys of SHR. Tail‐cuff plethysmography showed that treatment with spironolactone at doses 30–200 mg/kgBW·day for 2 weeks failed to decrease blood pressure in SHR and did not result in any detectable changes in urinary sodium excretion. We did not observe any sex‐specific differences pertaining to ENaC activity or responsiveness to spironolactone in SHR males and females. Thus, we conclude that aldosterone is not a primary driver of excessive ENaC‐dependent renal Na+ reabsorption in SHR.

Graphene and reduced graphene oxide based microporous layers for high-performance proton-exchange membrane fuel cells under varied humidity operation

Cathode microporous layers (MPLs) play an important role in the performance of proton exchange membrane (PEM) fuel cells through two-phase flow and interfacial effects. In this study, alternative graphene-based MPLs are developed and characterized by ex-situ methods and fuel cell polarization experiments at 100% and 20% cathode relative humidity (RH). The studied MPLs include: graphene (GN), reduced graphene oxide (RGO), graphite (GR) and their composites with conventional carbon black (CB). GN and RGO promote interfacial contact and adhesion to the catalyst layer (CL). These MPLs show improved kinetic and ohmic polarization compared to CB, but limit oxygen gas transport at 100% RH due to excessive water retention. The addition of CB to create composite MPLs, however, mitigates water retention near the CL by capillary suction. Hence, maximum power densities improve by 68% and 22% compared to the original GN and RGO MPLs, and is also 28% higher for the GN + CB MPL than for the CB MPL alone. At 20% RH, the graphene-composite MPLs demonstrate remarkable performance preservation (1.4 mV h−1 voltage decrease for GN + CB vs. 464 mV h−1 for CB at 1000 mA cm−2). Through extensive physical and performance evaluations, this study provides a comprehensive understanding of how graphene materials behave in MPLs under varied humidity.

Application of 2D electrical resistivity imaging and cone penetration test (CPT) to assess the harzadous effect of near surface water on foundations in Lagos Nigeria

Adequate information on the condition of the subsurface is very important for site evaluation for engineering purposes. In this study two dimensional (2D) geoelectrical resistivity survey and cone penetration tests were conducted to study the hazardous effect of excess near surface water on the foundation of building in a reclaimed land located at Victoria Island area of Lagos State. The results of the inverted 2D geoelectrical resistivity data revealed three distinct geoelectrical layers characterized by low to moderate electrical resistivity of 2.23 and 129Ωm and 9.46 to 636Ωm respectively. The topsoil is characterized by wet sandy soil, which is underlain by sandy clay and banded at the below by a geologic formation of low resistivity which is suspected to be clay. The clay material may be responsible for the excess water retention observed in the area. The CPT method on the other hand revealed a geological formation of low resistance to penetration between 2-3 kg/cm2 from the topsoil to a depth of 7 m, which may be the effect of excess water in the near surface. This study revealed that the foundation of building may not be founded directly on the soil in any reclaimed land as this may result in collapse as a result of upward migration of water to the near surface.

The Effect of Early Excessive Weight Gain on the Development of Hypertension in Pregnancy.

Background Previous studies have shown an association between total excessive gestational weight gain and hypertension in pregnancy. However, this may be a reflection of excessive water retention associated with the pathophysiology of hypertensive disorders of pregnancy. Early excessive weight gain, prior to the third trimester, results in greater maternal fat deposition and inflammation, which has also been associated with the development of hypertension. By focusing on early excessive weight gain, the association between maternal weight gain and the future development of hypertension can be examined. Objective To evaluate the association between early excessive maternal weight gain and the development of hypertension during pregnancy. Study Design This was a secondary analysis of a longitudinal cohort study of 1,441 women without chronic hypertension who were enrolled in a prospective study evaluating maternal angiogenic factors and the prediction of preeclampsia. Initial body mass index (BMI) was calculated by weight and height at the first study visit. Early excessive maternal weight gain was defined as weight gain by 28 weeks that exceeded the Institute of Medicine (IOM) guidelines and was calculated utilizing the maximum amount of weight gain per week recommended by the IOM based on the patient's starting BMI (normal: 0.45 kg; overweight: 0.32 kg; obese: 0.27 kg). Hypertension was defined as a sustained systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg. Logistic regression was used to determine the association between early excessive weight gain, initial BMI, and the development of hypertension, including gestational hypertension and preeclampsia, during pregnancy. Results Of 1,441 women, 767 (53.2%) had weight gain that exceeded the IOM guidelines in the first 28 weeks and 154 (10.8%) developed hypertension during pregnancy. Women whose weight gain exceeded the IOM guidelines were more likely to develop hypertension even after adjusting for relevant confounders (12.5 vs. 8.6%; p = 0.02; adjusted odds ratio [OR] = 1.70; 95% confidence interval [CI]: 1.18-2.44; p < 0.01). Obese women had a 2.4-fold increased risk of developing hypertension, even after controlling for excessive weight gain (adjusted OR = 2.44; 95% CI: 1.66-3.59; p < 0.01) Conclusions Early excessive maternal weight gain and initial BMI are independently associated with the diagnosis of a hypertensive disorder of pregnancy. Women should be counseled regarding the benefits of achieving a normal BMI prior to pregnancy and appropriate weight gain during pregnancy, as well as the potential harms of excessive weight gain related to perinatal outcomes.

The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells-a Potential Target for Pharmacological Intervention in Cardiovascular Diseases.

Arginine-vasopressin (AVP) stimulates the redistribution of water channels, aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. By this AVP directs 10% of the water reabsorption from the 170 L of primary urine that the human kidneys produce each day. This review discusses molecular mechanisms underlying the AVP-induced redistribution of AQP2; in particular, it provides an overview over the proteins participating in the control of its localization. Defects preventing the insertion of AQP2 into the plasma membrane cause diabetes insipidus. The disease can be acquired or inherited, and is characterized by polyuria and polydipsia. Vice versa, up-regulation of the system causing a predominant localization of AQP2 in the plasma membrane leads to excessive water retention and hyponatremia as in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), late stage heart failure or liver cirrhosis. This article briefly summarizes the currently available pharmacotherapies for the treatment of such water balance disorders, and discusses the value of newly identified mechanisms controlling AQP2 for developing novel pharmacological strategies. Innovative concepts for the therapy of water balance disorders are required as there is a medical need due to the lack of causal treatments.

Hyponatremia in Neurotrauma: The Role of Vasopressin.

Hyponatremia is frequent in patients suffering from traumatic brain injury, subarachnoid hemorrhage, or following intracranial procedures, with approximately 20% having a decreased serum sodium concentration to <125 mmol/L. The pathophysiology of hyponatremia in neurotrauma is not completely understood, but in large part is explained by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The abnormal water and/or sodium handling creates an osmotic gradient promoting the shift of water into brain cells, thereby worsening cerebral edema and precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively, morbidity and mortality increases through seizures, elevations in intracranial pressure, and/or herniation. The excess mortality in patients with severe hyponatremia (<125 mmol/L) extends beyond the time frame of hospital admission, with a reported mortality of 20% in hospital and 45% within 6 months of follow-up. Current options for the management of hyponatremia include fluid restriction, hypertonic saline, mineralocorticoids, and osmotic diuretics. However, the recent development of vasopressin receptor antagonists provides a more physiological tool for the management of excess water retention and consequent hyponatremia, such as occurs in SIADH. This review summarizes the existing literature on the pathophysiology, clinical features, and management of hyponatremia in the setting of neurotrauma.

Hyponatremia in cirrhosis: pathophysiology and management.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. The development of ascites in patients with cirrhosis is multi-factorial. Portal hypertension and the associated systemic vasodilation lead to activation of the sodium-retaining neurohumoral mechanisms which include the renin-angiotensin-aldosterone system, sympathetic nervous system and antidiuretic hormone (ADH). The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume resulting in the development of ascites. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and ascites leads to impairment of the kidneys to eliminate solute- free water. This leads to additional compensatory mechanisms including non-osmotic secretion of ADH, also known as arginine vasopressin, further worsening excess water retention and thereby hyponatremia. Hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic marker both before and after liver transplant. The management of hyponatremia in this setting is a challenge as conventional therapy for hyponatremia including fluid restriction and loop diuretics are frequently inefficacious. In this review, we discuss the pathophysiology and various treatment modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with cirrhosis.

Micro-topographical surface alteration caused by tillage and irrigation canal maintenance and its consequences on excess water development

The most common forms of low relief plains created by agriculture are ridges and furrows that develop parallel to ploughing and irrigation or drainage canals. These micro-forms influence the surface run-off conditions of a field, as they act as overland flow paths or barriers depending on their orientation, resulting in the development of excess water. The consequences of excess water retention are soil degradation and crop loss, which for example, in 2011 threatened 11% of the agricultural lands of Hungary. The goals of the present research are to evaluate the spatial distribution and morphology of forms created by tillage and irrigation or drainage canal maintenance, and to study their effect from the point-of-view of blocked drainage and excess water build-up. The studied tillage ridges were formed during the last 20 years and their height reaches 0.19–0.26m. The ridges block the overland flow and facilitate the development of excess water on 14.1% of the study area. Along 85.4% of the canal banks canal berms appear. Their average height is 0.38m (max: 1.43m) and width is 17m (max: 54.8m). Considering the height of the tillage ridges, they have less influence on overland flow than that of the canal berms, but, due to the low relief of the area, both play an important role in disconnecting overland flow routes. Thus (dis)connectivity could develop within an agricultural plot as the higher parts of the plot could be disconnected from the lower parts by ridges, and the canal berms disconnect the plot and the artificial drainage system. Regarding overland flow, ridges and berms disconnect the plots from their drainage canals (buffer function), and in the natural drainage routes they act as barriers. The dis-connectivity function of the studied forms increases over time and as a result of intensive tillage. Therefore, they will play a more and more important role in altering overland flow and developing excess water hazard.

Nutritional Support to Critically Ill Patient

DOI: http://dx.doi.org/10.3329/jbsa.v23i1.18156 Journal of BSA, 2010; 23(1): 30-33

Unpredictable Nature of Tolvaptan in Treatment of Hypervolemic Hyponatremia: Case Review on Role of Vaptans

Hyponatremia is one of the most commonly encountered electrolyte abnormalities occurring in up to 22% of hospitalized patients. Hyponatremia usually reflects excess water retention relative to sodium rather than sodium deficiency. Volume status and serum osmolality are essential to determine etiology. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. Vasopressin antagonists like tolvaptan seem promising for the treatment of euvolemic and hypervolemic hyponatremia in heart failure. Low sodium concentrations cause cerebral edema, but the overly rapid sodium correction can also lead to iatrogenic cerebral osmotic demyelination syndrome. Demyelination may occur days after sodium correction or initial neurologic recovery from hyponatremia. The following case report analyzes the role of vasopressin antagonists in the treatment of hyponatremia and the need for daily dosing of tolvaptan and the monitoring of serum sodium levels to avoid rapid overcorrection which can result in osmotic demyelination syndrome (ODS).

Molecular insights from dysregulation of the thiazide‐sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide‐induced hyponatraemia

Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon syndrome (GS), the phenotypic inverse of the salt-wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low-dose thiazide diuretics or a low-salt diet. Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) and hence salt retention. Herein, we discuss the key role of STE20/sporulation-specific protein 1 (SPS1)-related proline/alanine-rich kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of Gordon syndrome and TIH may increase our understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side-effects.

GW24-e2982 Research on T. C. M Syndromes Discipline of Congestive Heart Failure Based on Literature Analysis and Retrospective Analysis of Clinical Cases

ObjectivesTo discuss the characteristics of TCM syndrome factors and distribution discipline of congestive heart failure, and provide basis for the establishment of diagnosis criteria on essential syndromes.Methods1) Based on databases...

Etiology and management of hypertension in chronic kidney disease

Abstract Hypertension is ubiquitous in the chronic kidney disease. Impaired salt excretion leads to increased extracellular fluid volume and consequent hypertension in renal disease. It is assumed that the excess salt and water retention increases the blood flow to the tissues, which sets in motion the phenomenon of autoregulation. The tissue arterioles vasoconstrict, under the influence of various mediators to decrease the excessive blood flow. The resulting vasoconstriction increases the peripheral vascular resistance, resulting in hypertension. The kidney and central nervous system in integrated manner play role in development of hypertension in chronic kidney disease. Recently, more light has been shed on the multitude of factors and pathophysiologic mechanisms that lead to hypertension in the renal disease. The level of blood pressure is most likely determined by the level of the peripheral vascular resistance and volume status in combination. If the peripheral vascular resistance is not appropriately lowered in the face of hypervolemia, hypertension results. In this review, evidence for the different pathophysiologic mechanisms that have been postulated to explain renal hypertension is presented.

The Curious Case of Yasmin ® : When Does a generic‘s Label Induce Doctors to Practice a Patented Method of use?

*Arnall Golden Gregory LLP, 171 17th Street NW, Atlanta, GA 30305, USA Tel.: +1 404 873 8512 E-mail: clark.sullivan@agg.com In a decision with interesting implications for the pharmaceutical industry, the Federal Circuit on April 16, 2012, rejected efforts by Bayer Schering Pharma AG to enforce a method of treatment patent against Lupin, Ltd and several other generic challengers, because the object of the treatment claimed in the patent was only described in the ‘Pharmacology’ section of the generic label, as opposed to the ‘Indications and Usage’ section [1]. The patent at issue – the so-called ‘652 patent’ – relates to Yasmin, an oral contraceptive approved by the US FDA for the prevention of pregnancy [101]. In the ‘652 patent’, Bayer claimed a method of using its oral contraceptive to achieve three simultaneous effects: a contraceptive (or gestagenic) effect, an anti-androgenic effect (which reduces the activity of male hormones and can be effective in treating conditions such as hirsutism or acne) and an anti-aldosterone effect (also known as an antimineralcorticoid effect, which can be effective in reducing excess water retention in the body). Claim 1 is representative and it recites: “a method of simultaneously achieving, during premenopause or menopause a gestagenic effect, antiandrogenic affect and an antialdosterone effect in a female patient in need thereof comprising administering an amount of dihydrospirorenone to said female patient, wherein said amount of dihydrospirorenone is effective to simultaneously achieve a gestagenic effect, antiandrogenic effect and antialdosterone effect in said patient.” The fact that this patent was a method of treatment patent was crucial to the eventual decision because, unlike new molecule patents or pharmaceutical composition patents, a generic drug company never actually performs a method of treatment and, thus, never directly infringes the method. Rather, they are approved solely on the basis of bioequivalence testing, which is typically performed in healthy subjects. Therefore, the question for purposes of patent infringement is whether the generic company has taken some action to induce doctors and patients to perform the patented method in violation of 35 U.S.C. §271(b) (which states that “Whoever actively induces infringement of a patent shall be liable as an infringer” ) [2]. To demonstrate inducement liability under section 271(b), the patentee must establish that the alleged infringer had “knowledge that the induced acts constitute patent infringement” [3]. In addition, “Inducement requires evidence of culpable conduct, directed to encouraging another’s infringement, not merely that the inducer had knowledge of the direct infringer’s activities” [4]. In other words, the generic manufacturer must know that it is inducing acts that constitute patent infringement and it must take some affirmative act towards encouraging infringement. Since generic

Two Unusual Pediatric Cases of Dilutional Hyponatremia

Dilutional hyponatremia, although not uncommon, is an underestimated problem in the pediatric population. In most cases, it results from excessive hydration or water retention, also described as the so-called water intoxication. One of the most known causes is the use of desmopressin in enuretic children. This drug enhances the free water reabsorption in the renal collecting ducts. The addition of the anticholinergic agent oxybutynin aggravated the condition by causing a dry mouth with excessive thirst and water intake in our first case. Dietary water overconsumption, either voluntary or involuntary, is a phenomenon seen in formula-fed babies. But in our second case, a game involving forced ingestion of large amounts of water had serious consequences including hyponatremia-related coma. An effort should therefore be made to inform caretakers about the risks of these games. These cases, provoked by rather unusual and peculiar causes, illustrate again that electrolytes and especially serum [Na(+)] are key points to be determined in a child with diminished consciousness. Moreover, an accurate history including the intake of medication and dietary information should be made.