Multifunctional Cell Regulation Activities of the Mussel Lectin SeviL: Induction of Macrophage Polarization toward the M1 Functional Phenotype.

SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel ß-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.

Clinical Significance of Physical Examination for Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) show various physical findings, but their clinical significance has not been systematically evaluated.Methods and Results: This study evaluated 105 consecutive patients with HCM who had undergone phonocardiography and external pulse recording. Physical examinations included a visible jugular a-wave (Jug-a), audible 4th sound (S4), and double or sustained apex beat. The primary outcome was a composite of all-cause death and hospitalization for cardiovascular disease. A total of 104 non-HCM subjects served as controls. The prevalence of visible Jug-a in the seated or supine position, audible S4, and a sustained or double apex beat in patients with HCM were 10%, 71%, 70%, 42%, and 27%, respectively, all of which were significantly higher than in the controls (0%, 20%, 11%, 17%, and 2%; P<0.001 for all comparisons). The combination of visible Jug-a in the supine position and audible S4 yielded a specificity of 94% and sensitivity of 57%. During a follow-up period of 6.6 years, 6 patients died and 10 were hospitalized. The absence of audible S4 was a predictor of cardiovascular events (hazard ratio, 3.91; 95% confidence interval, 1.41 to 10.8; P=0.005). CONCLUSIONS: Detection of these findings has clinical importance in the diagnosis and risk stratification of HCM prior to the use of advanced imaging techniques.

Jugular Venous Pressure and Kussmaul's Sign as Predictors of Outcome in Heart Failure.

Simplifying the estimation of internal jugular venous pressure (JVP) as visible or not visible above the right clavicle in the sitting position has attracted attention for risk assessment in patients with heart failure (HF). It remains unclear whether this simple assessment, combined with its inspiration response known as Kussmaul's sign, is useful in patients with HF who vary in features such as HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).This study consisted of 246 patients who were admitted for the management of HF. JVP was assessed before discharge and considered high if visible at rest. The inspiration response was also examined. The primary outcome was a composite of all-cause death and hospitalization for worsening HF.One year after discharge, primary outcome events occurred in 91 patients (37%). The incidence of primary outcome was higher in patients with a high JVP at rest (odds ratio, 5.06; 95% confidence interval, 2.31-11.1; P = 0.0001) or with inspiration (odds ratio, 5.93; 95% confidence interval, 2.14-16.4; P < 0.01) than in patients without high JVP conditions. These findings were similarly observed among patients with HFrEF and HFpEF (odds ratios, 3.53 and 6.76; 95% confidence intervals, 1.68-8.68 and 2.19-15.5; P = 0.01 and < 0.01, respectively) and in subgroup analysis stratified by baseline characteristics of the patients.A high JVP at rest and with inspiration as assessed by this simple, practical method may be useful for risk assessment in patients with HF, independent of baseline characteristics.

Amiloride is a suitable fluorescent substrate for the study of the drug transporter human multidrug and toxin extrusion 1 (MATE1).

Human multidrug and toxin extrusion 1 (MATE1; SLC47A1) is highly expressed in the kidneys and the liver. It plays a significant role in drug and endogenous compound disposition, and therefore, a rapid evaluation of its inhibition is important for drug development and for the understanding of renal and hepatic physiology. Amiloride is a potassium-sparing diuretic used for treating hypertension; it also demonstrates strong fluorescence in organic solvent or detergent solutions. In this study, we investigated the transport characteristics of amiloride by human MATE1. Cellular accumulation of amiloride was evaluated in control vector- or MATE1-transfected HEK293 cells. Cells were lysed with 1% sodium dodecyl sulfate, and fluorescence was measured using a microplate reader at wavelengths of 364ex and 409em. With ammonium prepulse-induced intracellular acidification, MATE1 transported amiloride at an extracellular pH of 7.4. The uptake demonstrated an overshoot phenomenon and saturated, with the Km and Vmax being 23.5 µM and 1.01 nmol/mg/min, respectively. MATE1-mediated amiloride transport also presented with a bell-shaped pH profile that reached a maximum pH value of 7.4. The inhibitor sensitivity of MATE1-facilitated amiloride transport was similar to those of known substrates, such as tetraethylammonium and metformin. Among the tested inhibitors, pyrimethamine demonstrated the most potent inhibition with an IC50 value of 0.266 µM. Furthermore, MATE1 was found to be inhibited by fampridine, which was previously considered to be a non-inhibitor of MATE1. This study demonstrates that amiloride is a suitable fluorescent substrate for the in vitro study of the transport activity of MATE1.

Absent fourth heart sound as a marker of adverse events in hypertrophic cardiomyopathy with sinus rhythm.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) in sinus rhythm commonly show the fourth heart sound (S4). The lack of S4 may be a marker of impaired atrial function in HCM patients with sinus rhythm. METHODS AND RESULTS: This retrospective study consisted of 47 patients with HCM who had undergone phonocardiography and a cardiopulmonary exercise test. The primary outcome was a composite of cardiac death, stroke, hospitalization for worsening heart failure, and newly developed atrial fibrillation (AF). S4 was detected in 38 of 43 patients with sinus rhythm (88%). Peak oxygen consumption was the highest in 38 sinus rhythm patients with S4 (23.6 ± 5.6 mL/kg/min), middle in five sinus rhythm patients without S4 (19.3 ± 6.7 mL/kg/min), and lowest in four patients with AF (15.7 ± 3.3 mL/kg/min, p = 0.01). After a median of 40.5 months, the incidence of the primary outcome was higher in patients without S4 than in those with S4 (33% vs. 8%; hazard ratio, 6.17; 95% confidence interval, 1.02 - 37.4; p = .04) and higher in sinus rhythm patients without S4 than in those with S4 (60% vs. 8%; hazard ratio, 12.05; 95% confidence interval, 2.31 - 71.41; p = .007). CONCLUSIONS: The absence of S4 on phonocardiography was associated with impaired exercise tolerance and adverse cardiac events in HCM patients with sinus rhythm.

Simple Phonocardiography with the Ankle-Brachial Index Measurement System as a Tool for Detecting Fourth Heart Sounds of Hypertrophic Cardiomyopathy.

Conventional phonocardiography is useful for objective assessment of cardiac auscultation, but its availability is limited. More recently, an ankle-brachial index (ABI) measurement system equipped with simple phonocardiography has become widely used for diagnosing peripheral artery disease, however, whether this simple phonocardiography can be an alternative to conventional phonocardiography remains unclear.This retrospective study consisted of 48 patients with hypertrophic cardiomyopathy (HCM) and 107 controls. The presence of the fourth sound (S4) was assessed by conventional phonocardiography, in addition to apexcardiography and auscultation, in all patients with HCM. S4 was also estimated by the ABI measurement system with the phonocardiographic microphone on the sternum (the standard method) or at the apex (the apex method) in HCM patients and controls.S4 on conventional phonocardiography was detected in 42 of 48 patients (88%) with HCM. Auscultation for the detection of S4 had a sensitivity of 0.78, specificity of 0.57, and accuracy of 0.75. These diagnostic values were generally superior to those of the standard method using the ABI measurement system, whereas the apex method using the ABI measurement system had better diagnostic values, with an excellent specificity of 1.0, sensitivity of 0.77, and accuracy of 0.80. No significant differences were observed in low ABI defined as < 0.9.Simple phonocardiography equipped with the ABI measurement system may be an alternative to conventional phonocardiography for the detection of S4 in patients with HCM when the phonocardiographic microphone is moved from the sternum to the apex.

Serum polyethylene glycol-specific IgE and IgG in patients with hypersensitivity to COVID-19 mRNA vaccines.

BACKGROUND: The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies. METHODS: Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls. RESULTS: Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG. CONCLUSIONS: The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.

Physical Restraints in Critically Ill Children: A Multicenter Longitudinal Point Prevalence Study.

OBJECTIVES: We elucidate to investigate the prevalence of and factors associated with the use of physical restraints among critically ill or injured children in PICUs. DESIGN: This was a multicenter, longitudinal point prevalence study. SETTING: We included 26 PICUs in Japan. PATIENTS: Included children were 1 month to 10 years old. We screened all admitted patients in the PICUs on three study dates (in March, June, and September 2019). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We collected prevalence and demographic characteristics of critically ill or injured children with physical restraints, as well as details of physical restraints, including indications and treatments provided. A total of 398 children were screened in the participating PICUs on the three data collection dates. The prevalence of children with physical restraints was 53% (211/398). Wrist restraint bands were the most frequently used means (55%, 117/211) for potential contingent events. The adjusted odds of using physical restraint in patients 1-2 years old was 2.3 (95% CI, 1.3-4.0) compared with children less than 1 year old. When looking at the individual hospital effect, units without a prespecified practice policy for physical restraints management or those with more than 10 beds were more likely to use physical restraints. CONCLUSIONS: The prevalence of physical restraints in critically ill or injured children was high, and significant variation was observed among PICUs. Our study findings suggested that patient age, unit size, and practice policy of physical restraint could be associated with more frequent use of physical restraints.

Investigation of Fluorescent Substrates and Substrate-Dependent Interactions of a Drug Transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1).

PURPOSE: In this study, we investigated organic anion transporting polypeptide 2B1 (OATP2B1)-mediated uptake of fluorescent anions to better identify fluorescent substrates for in vitro OATP2B1 assays. The OATP2B1 is involved in the intestinal absorption and one of the pharmacokinetic determinants of orally administered drugs. METHODS: A microplate reader was used to determine the cellular accumulation of the fluorescent compounds into the OATP2B1 or the empty vector-transfected HEK293 cells. RESULTS: Two types of derivatives were found to be OATP2B1 substrates: heavy halogenated derivatives, such as 4',5'-dibromofluorescein (DBF), and carboxylated derivatives, such as 5-carboxyfluorescein (5-CF). The DBF and 5-CF were transported in a time and concentration-dependent manner. The DBF was transported at a broad pH (pH 6.5-8.0) while 5-CF was transported at an acidic pH (pH 5.5-6.5). The Km values were 0.818 ± 0.067 µM at pH 7.4 for DBF and 8.56 ± 0.41 µM at pH 5.5 for 5-CF. The OATP2B1 inhibitors, including atorvastatin, bromosulfophthalein, glibenclamide, sulfasalazine, talinolol, and estrone 3-sulfate, inhibited the DBF and the 5-CF transport. Contrastively, testosterone, dehydroepiandrosterone sulfate, and progesterone inhibited the DBF transport but stimulated the 5-CF transport. Natural flavonoid aglycones, such as naringenin and baicalein, also exhibited substrate-dependent effects in this manner. CONCLUSION: We found two fluorescein analogs, DBF and 5-CF as the OATP2B1 substrates that exhibited substrate-dependent interactions.

The Bezold-Jarisch reflex in a patient with coronary spastic angina.

Acute inferior myocardial damage can induce transient bradycardia and hypotension-the Bezold-Jarisch reflex, which is explained by the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a 76-year-old man who showed a perfusion defect in the inferior wall with redistribution on exercise scintigraphy with thallium-201. Of note, during exercise at an intensity of 100 watts, the patient's heart rate transiently decreased from 122 to 95 bpm in sinus rhythm, accompanied by ST-segment depression. A diagnosis of coronary spastic angina was made since no stenotic lesions were observed on conventional coronary angiography.

Ventricular late potentials and myocardial fibrosis in hypertrophic cardiomyopathy.

AIMS: Ventricular late potentials (VLPs) represent delayed conduction due in part to myocardial fibrosis. We sought to examine the relationship of signal-averaged electrocardiography findings with myocardial fibrosis as assessed by cardiac magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM). METHODS: This study consisted of 41 HCM patients with sinus rhythm who had undergone risk assessment including CMR and signal-averaged electrocardiography such as VLPs, filtered QRS duration, low amplitude signal duration of the terminal filtered QRS below 40 µV (LAS), and root mean square voltage of the late 40 ms of the filtered QRS (RMS). The concordance rate between VLPs and myocardial fibrosis as assessed by CMR was examined. RESULTS: Late gadolinium enhancement (LGE) on CMR was detected in 13 patients, and VLPs were detected in 14. Filtered QRS duration, LAS, RMS, and VLPs were not associated with LGE. The results of LGE and VLPs were concordant in 26 patients, whereas 15 exhibited discordance. Patients with discordance had a higher maximum wall thickness (24.1 ±â€¯4.0 mm versus 21.0 ±â€¯5.9 mm, p < 0.05), higher LGE volume (2.3 ±â€¯1.2 g/cm versus 0.0 ±â€¯0.8 g/cm, p < 0.01), lower LGE volume/the total number of sites with LGE (1.5 ±â€¯0.7 versus 3.1 ±â€¯2.8, p < 0.01), and predominant LGE location of the interventricular septum and anterior wall (60% versus 8%, p < 0.01) than patients with concordance. CONCLUSION: VLPs were not a reliable marker for the detection of myocardial fibrosis as assessed by LGE on CMR in our cohort of patients with HCM. CONDENSED ABSTRACT: Ventricular late potentials on signal-averaged electrocardiography represent delayed conduction due in part to myocardial fibrosis but were not an alternative to cardiac magnetic resonance for detecting myocardial fibrosis in patients with hypertrophic cardiomyopathy.

The Bezold-Jarisch Reflex in a Patient With Stanford Type A Acute Aortic Dissection.

BACKGROUND: The Bezold-Jarisch reflex is a depressor reflex of the heart due to the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a case of Stanford type A acute aortic dissection, in which coronary spastic angina caused the Bezold-Jarisch reflex in the acute phase. CASE REPORT: A 53-year-old man presented with left chest pain and cold sweating. An electrocardiogram was normal and the high-sensitivity cardiac troponin T level was negative. A diagnosis of Stanford type A acute aortic dissection was made based on computed tomography (CT); there was no evidence of ischemic heart disease on coronary CT angiogram obtained simultaneously. While waiting for emergency surgical repair, chest pain worsened, followed by bradycardia and hypotension, along with ST-segment elevations in the inferior leads, all of which were resolved by conservative treatment. During surgery, no evidence to suggest an extension of the dissection to the ostium of the right coronary artery was observed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The present case highlights the importance of recognizing the Bezold-Jarisch reflex because this depressor reflex may require different management than other conditions.

Insight into the Time Course of Type III Kounis Syndrome: A Case Report.

BACKGROUND: Kounis syndrome is a rare condition that is characterized by the coexistence of acute coronary syndrome and allergic reactions; however, its time course remains unclear. We report a case of anaphylactic shock with subsequent development of ST-segment elevation myocardial infarction. CASE REPORT: A 47-year-old man with food allergies presented to the emergency department of our hospital with breathing difficulties after eating bread. He had a history of angina and underwent stent implantation 3 years earlier. On examination, he was lethargic, disoriented, and in shock. He had a rash on his face and anterior chest wall, as well as severe itching and sweating. Anaphylaxis was diagnosed and, 3 min after presentation, 0.5 mg epinephrine was injected intramuscularly into the right thigh. Electrocardiography, which was recorded 2 min after the administration of epinephrine, was normal; however, chest pain developed suddenly 18 min later. Repeat electrocardiography showed ST-segment elevations, and emergency coronary angiography revealed total occlusion of the left anterior descending coronary artery (i.e., the previous stenting site). Recanalization of the left anterior descending coronary artery was achieved after repeated thrombus aspiration with difficulty, followed by stent implantation inside of the stent under the support of intra-aortic balloon pumping. The clinical course was uneventful. He was discharged and advised to avoid eating wheat and carry an epinephrine self-injection kit for anaphylaxis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The present case highlights the importance of recognizing Kounis syndrome in the management of anaphylactic shock because treatment may be difficult, particularly in patients with type III Kounis syndrome.

[Fundamental Study of Inflation Pressure Resistance in an Angiographical Tube].

This study was designed to clarify the relation between the pressure resistance of an angiographical tube and the amount of contrast medium injected under a connected microcatheter used for interventional radiology (IVR). We investigated the injection pressure and the expansion rate at the center of the tube during contrast enhancement by setting the power injector to 1200 PSI pressure, with 2.0 ml/s injection speed, 10 ml injection volume, 5.0 s injection time, and 0 s rise time for tubes with different pressure resistance performance (low or high). Then we examined the amount of contrast medium material discharged from the microcatheter. The low-pressure resistant tube (less than 140 PSI) injection pressure exceeded the pressure performance. The expansion rate increased to 49%, presenting a risk of rupture. The injection pressure of the high-pressure resistant tube (less than 1200 PSI) was within the pressure-resistance performance. The expansion rate increased to 38%. However, when the contrast medium discharge amount contributing to the image was measured within the injection time under the condition of 10 ml injection for 5.0 s, the former was 2.3 ml and the latter was 4.2 ml. The entire amount was not discharged during the injection period. It became apparent that it is discharged in drips after some time. Results show that the tube expansion caused retention of the contrast medium inside, which decreases the actual amount of the injected contrast medium. From the results, we infer the possibility of preventing reduction of the injected contrast medium amount attributable to expansion.

Third and Fourth Heart Sounds and Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

BACKGROUND: The 4th heart sound (S4) is commonly heard in patients with hypertrophic cardiomyopathy (HCM). The 3rd heart sound (S3) is also audible in HCM patients regardless of the presence or absence of heart failure. These extra heart sounds may be associated with myocardial fibrosis because myocardial fibrosis has been suggested to affect left ventricular compliance.Methods and Results:The present retrospective study evaluated 53 consecutive HCM patients with sinus rhythm who had no symptoms of heart failure and underwent an initial assessment including phonocardiography, echocardiography, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). S3 was detected on phonocardiography in 13% of all patients, and S4 was recorded in 75% of patients. Patients with S3 had a higher incidence of LGE and larger LGE volumes (86% and 11.5±2.4 g/cm, respectively) than patients without S3 (33% and 2.5±0.8 g/cm, respectively; P=0.02 and P=0.002). The presence of S4 was not associated with MRI findings, including the incidence of LGE and LGE volume. The diagnostic value of S3 for the detection of LGE was highly specific (97%), with a low sensitivity (29%). CONCLUSIONS: Myocardial fibrosis, as assessed by LGE, was associated with S3 but not with S4 in patients with HCM. These results may contribute to the risk stratification of patients with HCM.

Electrocardiographic changes as a marker of improved subendocardial ischemia in a patient with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) patients sometimes develop subendocardial ischemia without coronary artery stenosis. We report a case of non-obstructive HCM, in which electrocardiographic changes were observed with improvement of subendocardial ischemia. A 76-year-old man presented with chest pain on exertion. The electrocardiogram revealed left ventricular (LV) hypertrophy with repolarization abnormalities. No coronary stenosis was found on computed tomography angiography, but thallium-201 exercise scintigraphy revealed transient LV cavity dilation after exercise, consistent with subendocardial ischemia. His chest symptoms disappeared after starting verapamil. Transient LV cavity dilation improved without a reduction in exercise tolerance, as did electrocardiographic abnormalities without any changes on echocardiography.

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium-phosphate cotransporter as a cause.

We previously reported the contribution of sodium-phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25 mg/kg, 2.5 mg/kg and 25 mg/kg was intravenously injected as a bolus, the areas under the plasma concentration-time curve of lithium until 60 minutes were calculated to be 6.23 mEq·min/l, 8.77 mEq·min/l and 64.6 mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25 mg/kg group (r = 0.840) and 2.5 mg/kg group (r = 0.773), whereas this correlation was weak in the 25 mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium-phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5 mg/kg, but did not affect it in rats administered 25 mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium-phosphate cotransporter potentially being involved.

Effect of renal ischemia on urinary excretion of lithium in rats.

Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 min or 90 min. After intravenous injection of lithium chloride at 25 mg/kg, the pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49 ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43.4%. Renal ischemia inhibited the renal excretion of lithium, and did not affect its fractional excretion. The urinary pH of rats with renal ischemia for 90 min was significantly higher than those of the other groups, and the linear regression with the fractional excretion of lithium in rats with renal ischemia showed a moderate correlation (r = 0.650, p = 0.00193). This study demonstrated the effect of renal ischemia on the renal excretion of lithium in rats. It was suggested that not only glomerular filtration but also the reabsorption of lithium was impaired by renal ischemia.