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The resonance energy of an amide can be calculated through comparison with a model amine and a model ketone (or aldehyde) with subtraction of the “residual” fragments. This classical approach, employing gas-phase experimental enthalpies of formation, corresponds to ca. 70 kJ mol−1 (≈ 16 kcal mol−1) for N,N-dimethylacetamide (DMA), a value close to that of the C(O)-N rotational barrier. Using a similar approach to explore the resonance energy of the DMA radical cation leads to the question of whether the amine radical cation or the ketone/aldehyde radical cation is the most appropriate model. An additional complication is whether the amide radical cation loses a π electron or an nO electron. These issues are analyzed. For DMA radical cation, the π orbital loses the electron and spin is mostly localized at nitrogen. A negative resonance energy of ca. 22 kJ mol−1 (5 kcal mol−1) is obtained. This somewhat surprising result can be attributed to reduced stabilization due to delocalization of a single electron relative to an electron pair and its significant localization on nitrogen which is exceeded by coulombic destabilization of the carbonyl carbon by the adjacent nitrogen.

The etiology of hyponatremia is often multifactorial. The most common causes include hypovolemia from gastrointestinal (GI) or other fluid losses, thiazide diuretics, and SIAD [citeref rid="ref1"1/citeref]. In this chapter, we will discuss hypovolemic hyponatremia, as well as the clinical parameters that help distinguish between hypovolemic and euvolemic states. These include not only the urine [Na+] concentration but also the fractional uric acid excretion, a parameter that can be employed even when diuretics have been prescribed [citeref rid="ref2"2/citeref,citeref rid="ref3"3/citeref,citeref rid="ref4"4/citeref,citeref rid="ref5"5/citeref,citeref rid="ref6"6/citeref,citeref rid="ref7"7/citeref]. Among the common causes of hypovolemic hyponatremia are GI fluid loss, a range of endocrinopathies [citeref rid="ref7"7/citeref], and thiazide-induced hyponatremia, which is best considered as a distinct entity, in particular because recent data suggest that it has a genetic predisposition. Also, the discontinuation of thiazide is a key step in treatment [citeref rid="ref2"2/citeref,citeref rid="ref7"7/citeref]. The management of hypovolemic hyponatremia starts with confirming its presence and determining the underlying cause. Correction focuses on the appropriate use of isotonic fluid to effect volume repletion while avoiding an overly rapid rise in serum [Na+] concentration.

Diuretics are commonly prescribed to treat the sodium retention, volume expansion, and hypertension characteristic of CKD. With reduced renal function, delivery of the drugs to their renal tubular sites of action is impaired, potentially leading to diminished potency. In addition, reduced GFR and alterations in sodium transport at other tubular sites can reduce the natriuretic effect of delivered drug. To use diuretics effectively in CKD, clinicians must understand these changes in diuretic pharmacokinetics and pharmacodynamics. This chapter reviews the sites and mechanisms of action of diuretics, describes how diuretic pharmacology is affected by CKD and details how best to overcome diuretic resistance. Much of the focus is on the loop agents, which are the most potent class of diuretics and the mainstay of treatment in CKD. The use of other classes of diuretics is also covered, as is the use of diuretics to treat specific subsets of CKD patients.

Interest in the low carbonyl IR frequency of 2-hydroxy-N,N-bis(2-hydroxyethyl)acetamide (2) initially prompted our interest in the amide rotational barrier of this molecule and four related amides that present a variety of hydrogen-bonding possibilities. In the course of this study, a previously incorrect structural assignment was established as N,N-bis[2-(acetyloxy)ethyl]-acetamide (6). In acetonitrile-d3, the carbonyl IR frequencies of the five amides were all essentially normal amide frequencies. Despite very different hydrogen-bonding possibilities in the five amides, no clear trends emerged in the comparison of the rotational barriers (ΔG‡), and the rotational barriers were essentially normal for amides. The rotational barrier of 2 did not vary over one order of magnitude difference in concentration.

Background: Hyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Methods: We analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ≤130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH). Results: Thiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (Δdaily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest Δdaily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived. Conclusions: Despite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.

Overall body fluid concentration is regulated within a narrow range by the concerted action of the hypothalamic-pituitary axis to influence water intake through thirst and water excretion via the effect of vasopressin, or antidiuretic hormone, on renal collecting duct water permeability. Sodium is the principal extracellular cation; abnormalities in overall effective body fluid concentration, or tonicity, manifest as disturbances in serum sodium concentration. Depending on its severity and chronicity, hyponatremia can lead to significant symptoms, primarily related to central nervous system function. Failure to correct hyponatremia can lead to permanent neurologic damage, as can over rapid correction. It is thus essential to stay within specific limits for correction, particularly for chronic hyponatremia. Hypernatremia also leads to central nervous system dysfunction, although goals for its correction rate are less well established. This Core Curriculum article discusses the normal regulation of tonicity and serum sodium concentration and the diagnosis and management of hypo- and hypernatremia.

1-Methyl-4-silatranone could exhibit the structural aspects of a typical silatrane including a short N–Si bond distance reflecting a dative bond. But given the significant amide resonance in a [3.3.3] bridgehead bicyclic lactam, the lone pair could be shared with the carbonyl group leading to a very long N–Si bond, essentially a “non-silatrane.” Ab initio calculations (MP2/6-311 + G*) predict that ground state conformations of this molecule are best regarded as lactams rather than silatranes, the most stable having a calculated N–Si bond length of 2.902 A and an N–CO bond length of 1.387 A. The calculated transition state for inversion of the amide ring retains very little amide resonance (N–CO, 1.440 A). Some of this loss is compensated through tightening of the N–Si bond (2.422 A), leading to a net energy of activation of ca 8 kcal/mol. Attempts to synthesize 1-methyl-4-silatranone using conventional pathways successful for 1-methylsilatrane [condensations employing N,N-bis(2-hydroxyethyl)glycolamide in place of tris(2-hydroxyethyl)amine] were unsuccessful. This is due to the net loss in resonance energy of the amide reactant relative to that in the [3.3.3] system, the essential absence of the N–Si dative bond, and the rigidity introduced by the planar amide linkage in the starting material. A more likely pathway to successful synthesis should be formation of the amide linkage in the final step.

Density functional calculations and up to five different basis sets have been applied to the exploration of the structural, enthalpy and free energy changes upon conversion of the azepine to the corresponding N-oxide. Although it is well known that azepines are typically much more stable than their 7-azanorcaradiene valence isomers, the stabilities are reversed for the corresponding N-oxides. Structural, thermochemical as well as nucleus-independent chemical shift (NICS) criteria are employed to probe the potential aromaticity, antiaromaticity and nonaromaticity of N-methylazepine, its 7-azanorcaradiene valence isomer. For the sake of comparison, analogous studies are performed on N-methylpyrrole and its N-oxide.

Nearly four decades ago, we published a simple chemical regularity: the proton affinity of MHa is higher than that of MHb when “a” is greater than “b.” Some new thoughts about this pattern of chemical energetics are presented in the current study.

The N- and O-protonated tautomers of 1-azabicyclo[3.3.1]nonan-2-one are predicted computationally to be comparable in stability. This was experimentally verified. The same theoretical models are employed to explore a wider range of bridgehead bicyclic lactams. Some additional examples are identified: some slightly preferring N-protonation and some O-protonation. Winkler–Dunitz parameters are employed to see if a pattern in geometry would emerge to help in the prediction of protonation preference. A number of larger bicyclic lactams are identified as possibly being hyperstable in O-protonation.

Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field.

Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications.

An earlier study fit calculated dynamic 13C-NMR spectra in trifluoroacetic acid (TFA) (with added sulfuric acid) to slow exchange between N-protonated and O-protonated tautomers of 1-azabicyclo[3.3.1]nonan-2-one. The present study reports simultaneous observation of both carbonyl 13C peaks in 40% sulfuric acid/60% TFA at −40 °C. This furnishes the only example in which experimental carbonyl 13C chemical shifts may be compared with a neutral lactam (in TFA or CDCl3) with its N-protonated and O-protonated derivatives. The seemingly anomalous upfield chemical shifts (experimental and computational) of the 13C carbonyl peaks in this N-protonated lactam (and other twisted N-protonated lactams) relative to the free bases are compared with data for unstrained protonated lactams and amides. The results are rationalized through conventional resonance structures. Copyright © 2012 John Wiley & Sons, Ltd.

Hyponatremia in critically ill patients is a common and challenging problem. Increased levels of arginine vasopressin almost always contribute to the etiology. Inhibition of the vasopressin receptor with a vasopressin receptor antagonist (vaptan) is a novel approach to the treatment of hyponatremia. Vaptans are well suited to the treatment of chronic hyponatremia associated with syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and hypervolemic states like cirrhosis or congestive heart failure. No data are available on the use of vaptans in acute hyponatremia, and they are not indicated in hypovolemic hyponatremia. The focus of this review is the treatment of critically ill patients with hyponatremia with vaptans and other measures.

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P = 0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

Protonation of typical unstrained amides and lactams is heavily favored at oxygen. In contrast, protonation of the highly distorted lactam 1-azabicyclo[2.2.2]octan-2-one is heavily favored at nitrogen. What structures occupy "crossover boundaries" where N- and O-protonation are nearly equienergetic? Density function theory calculations at the B3LYP/6-31G* level, as well as QCISD(T)/6-31G* calculations, predict that 1-azabicyclo[3.3.1]nonan-2-one favors N-protonation at nitrogen only very slightly (

2,8-Dioxabicyclo[5.1.0]octa-3,5-diene ("2,3-epoxyoxepin") has been postulated as an intermediate in ring-opening metabolism of benzene. Density functional theory (B3LYP/6-31G*) is employed to study the activation and reaction energies for ring-opening isomerization of 2,3-epoxyoxepin, its 4,5-benzo derivative, and its 3,6-hexamethylene derivative. The results are compared with published experimental data. The markedly different fates of these three molecules suggest a means for testing the postulated metabolic pathway.

Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

The energies of the highest-occupied molecular orbitals (HOMOs) are known to be excellent predictors of the reactivities of biogenic hydrocarbons, such as terpenes, with reactive atmospheric oxidants including O3, OH, and NO3. Structure–Activity Relationships (SARs) have also been effectively employed in such studies and related to HOMO energies and lowest ionization energies (ionization potentials). This study employs density function theory (DFT), at the B3LYP/6-31G** level, to predict vertical ionization energies (IPv) for a structurally diverse group of sesquiterpenes, each of which has been reported in air samples collected in the lower troposphere. The availability of published UV photoelectron spectra for nine sesquiterpenes permits comparison of experimental and theoretical vertical ionization energy data. The experimental and theoretical data show a good correlation (average discrepancy ± 0.07 eV). This enables predictions of reactivities for sesquiterpenes whose tropospheric lifetimes may last only a few hours before their transformations into secondary organic aerosols (SOA) close to their emission sources.

Four broad approaches to decreasing the number of cargo tank rollovers were evaluated: driver training, electronic stability aids, improvements in design of the vehicle itself, and highway design. A study of rollover crash statistics confirmed many expectations, but a few of the factors were not as strong as might have been expected. The portion of rollovers that occur on freeways is 15% to 20%. A driver error of one kind or another (e.g., decision or performance error) figures in about three-fourths of cargo tank rollovers. Inattention and distraction account for about 15%. Evasive maneuvers were a factor in 5% to 10% of rollovers. Drivers must be trained to appreciate the diverse causes for rollovers and to anticipate the situations that lead to them. Adherence to viable work and rest schedules is crucial. Electronic stability aids automatically slow the truck when it rounds a curve too fast. They can be remarkably effective in preventing this scenario. However, crash statistics and anecdotal accounts consistently show many other factors that can lead to rollovers. Significant reductions in rollover rates can be achieved with modest changes in vehicle stability. Cargo tank trailers of improved stability are currently available for some cargoes. When mountainous terrain or other factors dictate highway designs that can contribute to rollovers, drivers need to be made aware through signage or dispatch instructions. A comprehensive benefit–cost analysis, conducted from a societal point of view during a 20-year window, projected that the improvements will be cost beneficial.

The syndrome of inappropriate antidiuretic hormone secretion is the most common cause of hyponatremia in clinical practice, but current management of hyponatremia and outcomes in patients with syndrome of inappropriate antidiuretic hormone secretion are not well understood. The objective of the Hyponatremia Registry was to assess the current state of management of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion in diverse hospital settings, specifically which diagnostic and treatment modalities are currently used and how rapidly and reliably they result in an increase in serum sodium concentration ([Na(+)]). A secondary objective was to determine whether treatment choices and outcomes differ across the United States and the European Union.The Hyponatremia Registry recorded selected diagnostic measures and use, efficacy, and outcomes of therapy for euvolemic hyponatremia diagnosed clinically as syndrome of inappropriate antidiuretic hormone secretion in 1524 adult patients with [Na(+)] ≤130 mEq/L (1034 from 146 US sites and 490 from 79 EU sites). A subgroup of patients with more rigorously defined syndrome of inappropriate antidiuretic hormone secretion via measurement of relevant laboratory parameters was also analyzed.The most common monotherapy treatments for hyponatremia in syndrome of inappropriate antidiuretic hormone secretion were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%); 11% received no active agent. The mean rate of [Na(+)] change (mEq/L/d) was greater for all active therapies than no active treatment. Hypertonic saline and tolvaptan produced the greatest mean rate of [Na(+)] change (interquartile range, both 3.0 [6.0] mEq/L/d) compared with lower interquartile range rates of [Na(+)] change for isotonic saline (1.5 [3.0] mEq/L/d) and fluid restriction (1.0 [2.3] mEq/L/d). The general pattern of responses was similar in both the US and EU cohorts. At discharge, [Na(+)] was135 mEq/L in 75% of patients and ≤130 mEq/L in 43% of patients. Overly rapid correction occurred in 10.2% of patients.Current treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion often uses therapies with limited efficacy; the most commonly chosen monotherapy treatments, fluid restriction and isotonic saline, failed to increase the serum [Na(+)] by ≥5 mEq/L in 55% and 64% of monotherapy treatment episodes, respectively. Appropriate laboratory tests to diagnose syndrome of inappropriate antidiuretic hormone secretion were obtained in50% of patients; success rates in correcting hyponatremia were significantly higher when such tests were obtained. Few outcome differences were found between the United States and the European Union. A notable exception was hospital length of stay; use of tolvaptan was associated with significantly shorter length of stay in the European Union but not in the United States. Despite the availability of effective therapies, most patients with syndrome of inappropriate antidiuretic hormone secretion were discharged from the hospital still hyponatremic.

The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG.Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted.A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P .001), and receiving dialysis at the time of surgery (62% vs 80%; P .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16).Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft.

Postinfectious glomerulonephritis (PIGN) is a rare etiology of de novo glomerulonephritis following kidney transplantation. To date, there have only been eight cases reported in the literature. We report an additional three patients transplanted at our institution between January 2000 and October 2004 who had clinical and pathologic findings consistent with posttransplant PIGN. All three patients were type 1 diabetics. One had received a cadaveric kidney transplant, one a simultaneous kidney-pancreas transplant, and the third a living related kidney transplant followed by a pancreas transplant. All patients were on triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and prednisone. In each case, an acute decline in allograft function developed in association with a known or suspected infectious process, and renal biopsies revealed an immune complex glomerulonephritis with features of PIGN. All regained renal function with treatment of their known or suspected infections and without specific therapies for their glomerulonephritis, including corticosteroids.

The first non-peptide vasopressin receptor antagonist (VRA) was recently approved by the United States Food and Drug Administration, and several others are now in late stages of clinical development. Phase 3 trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. Although tachyphylaxis to the hydro-osmotic effect of these agents does not appear to occur, their use is accompanied by an increase in thirst, and they do not always eliminate altogether the need for water restriction during treatment of hyponatremia. Experience with use of these agents for treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia is limited. Further studies are needed to determine how they are best used in these situations, but the risk of overly rapid correction of hyponatremia seems low. Results of long-term trials to determine the ability of VRAs to reduce morbidity or mortality in congestive heart failure or to slow the progression of polycystic kidney disease are awaited with great interest.

The first unambiguous observation of an oxepin-2,3-oxide is reported. Between 5 and 10 °C it rearranges rapidly to its isomer 1H-2-benzopyran-1-carboxaldehyde. In contrast, 2,3-oxides of monocyclic oxepins rearrange to stable, ring-opened dialdehydes or diketones.

Background Acute humoral rejection (AHR) has been associated with enhanced graft loss. Our study compared the renal allograft survival of patients with AHR treated with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) with allograft survival in patients with acute cellular rejection (ACR). Methods. We retrospectively analyzed all kidney transplants performed at our institution between January 1999 and August 2001 (n=286). Recipients were classified into three groups according to biopsy reports: AHR, ACR, or no rejection. The ACR group was further divided into early and late rejection ( 90 days posttransplant, respectively). Results. After a mean follow-up of 569±19 days, the incidence of AHR was 5.6% (n=16). Recipient presensitization, delayed graft function, early rejection, and higher creatinine at diagnosis were characteristic of AHR. Most AHR patients (14/16) were treated with PP and IVIG. One patient received only IVIG, whereas another received only PP. All AHR patients were given steroid pulses, but only four received antilymphocyte therapy because of concomitant severe ACR. The ACR group comprised 43 patients (15%). One patient with mild rejection received no therapy, 20 improved with steroids alone, and 22 required additional antilymphocyte therapy. One-year graft survival by Kaplan Meier analysis was 81% and 84% in the AHR and ACR groups, respectively (P=NS). Outcomes remained similar when AHR patients were compared with those with early ACR. Conclusions. We conclude that AHR, when diagnosed early and treated aggressively with PP and IVIG, carries a short-term prognosis that is similar to ACR.

Delayed graft function (DGF) in cadaver kidney transplants is a common problem and is often due to acute tubular necrosis (ATN). DGF in transplants may have a deleterious effect on long-term graft survival. Since thyroid hormone has been shown to hasten recovery from ATN in experimental models, we designed a trial to determine if a defined course of triiodothyronine (T3) would improve the short- or long-term outcome of patients with DGF in cadaveric transplants. A prospective, randomized, placebo controlled, double blind trial of T3 was carried out in patients with DGF in cadaveric renal transplants. End-points were percentage requiring dialysis, percentage recovering function, time to recovery and length of hospital stay. Long-term outcomes were percentage grafts functioning at 1 year and mean serum creatinine at 1 year. Forty-four patients were randomized to receive either T3 or placebo. Three patients were dropped from each group when early biopsies disclosed that DGF was due to rejection. The groups were well matched by age, cold ischemia time of the graft, and percentage reactivity to a random panel of antigens. Baseline thyroid function studies, including T3, reverse T3 (rT3), and thyroid stimulating hormone (TSH) levels, were similar between the two groups and typical of 'euthyroid-sick syndrome'. T3 had no effect on percentage requiring dialysis, time to recovery, percentage recovering function, or length of stay. At 1 year follow-up, graft function was similar in both groups and significantly lower than that seen in patients with good initial function. Thyroid hormone, given early in the course of DGF in cadaver kidney recipients, had no effect on the course of DGF. Long-term graft function is impaired in patients who experience post-transplant DGF compared to those who have good initial function.

Protonation of amides most often occurs on oxygen, unless the amide bond is twisted out of planarity allowing the more favored nitrogen protonation to occur. Protonation of oxygen is believed to take place over that of nitrogen due to increased resonance stabilization of the O-protonated species. Resonance energies for O- and N-protonated dimethylacetamide are quantitated using quantum chemically calculated proton affinities for the two sites.