An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Variables influencing patient satisfaction for hypnotics: difference between zolpidem and brotizolam.

WHAT IS KNOWN AND OBJECTIVE: The pharmacokinetics of zolpidem and brotizolam is affected by gender and age, that is, increased clearance in males taking zolpidem and younger subjects taking brotizolam. The purpose of this study was to determine the variables including gender and age influencing patient satisfaction for hypnotics, zolpidem and brotizolam. METHODS: The study included 329 patients who were treated with zolpidem (n = 172) and brotizolam (n = 157) for insomnia. Patients were interviewed to evaluate individual satisfaction and drug efficacy. The factors associated with dissatisfaction of zolpidem and brotizolam were identified using multiple logistic analysis. RESULTS AND DISCUSSION: Of the participating patients, 40 (23%) and 41 (26%) complained of dissatisfaction with zolpidem and brotizolam, respectively. An insufficient amount of sleep (<6 h) and the number of awakenings were common factors cited for dissatisfaction for both drugs. Males were found to report a higher rate of dissatisfaction for zolpidem, whereas patients younger than 65 years and those receiving corticosteroid therapy reported a higher rate of dissatisfaction with brotizolam. WHAT IS NEW AND CONCLUSION: These results suggested that patient satisfaction was different between zolpidem and brotizolam in terms of gender for zolpidem and age and corticosteroid co-administration for brotizolam, which could be used to help choose a better drug among the two in patients with insomnia.

Long-term observation of renal function on combination therapy with prostaglandin and angiotensin-converting enzyme inhibitor for chronic kidney disease.

AIMS: Recently, we reported the effectiveness of PAC therapy, a combination therapy with prostaglandin (PG) and angiotensin-converting enzyme inhibitor (ACE-I), as a new tool for the prevention of chronic kidney disease. In the current study, we continually treated these patients with or without PG and analyzed the survival rate of renal function by Kaplan-Meier method and Cox regression analysis. MATERIAL AND METHODS: 52 patients (serum creatinine 2.9 A+/- 1.9 mg/dl) were followed-up for 48 months. 26 patients continued to receive ACE-I monotherapy and the remaining 26 patients were treated by PAC therapy. Primary end-point was defined as a decrease in 1/Cr by 0.2 (dl/mg), initiation of renal replacement therapy or death. RESULTS: At the end of the study, PAC therapy significantly reduced the risk for the decline in renal function compared to ACE-I monotherapy by 54%. Survival time was longer in PAC group (21.7 A+/- 2.2 and 35.1 A+/- 3.9 months, in ACE-I monotherapy and PAC therapy, p < 0.05). Cox regression analysis indicated that age, sex and blood pressure except urinary protein excretion did not relate to the risk reduction by PAC therapy. CONCLUSION: PAC therapy was proved to reduce the progression of end-stage renal failure.

Assessment of hypnotic effects and patient satisfaction in empirical use of sleep medicines.

OBJECTIVE: We assessed the hypnotic effects of and patient satisfaction with three types of hypnotics prescribed empirically: ultra-short-acting (US-a), short-acting (S-a), and intermediate- and long-acting (IL-a) agents. METHODS: We studied 310 insomniac patients (age 60.5 +/- 15.0 years) treated with US-a (n = 124), S-a (n = 149) or IL-a (n = 37) agents. Patients were interviewed to evaluate individual satisfaction and drug efficacy. Efficacy, as assessed by total sleep time (TST) and sleep latency time (SLT), was compared between satisfied and dissatisfied patient groups. Nocturnal awaking curve for each hypnotic was used for comparing the effects between satisfied and dissatisfied patient groups in each type of hypnotics. RESULTS: Thirty-two patients (25.8%) were dissatisfied with US-a, 35 (23.5%) with S-a and 11 (29.7%) with IL-a. TST differed significantly between satisfied and dissatisfied groups: 424 +/- 88 vs. 345 +/- 101 min for US-a (P < 0.001), 440 +/- 84 vs. 359 +/- 111 min for S-a (P < 0.001) and 453 +/- 96 vs. 345 +/- 125 min for IL-a (P < 0.01), respectively. With IL-a agents, the SLT of dissatisfied patients was longer than in satisfied ones (81 +/- 52 vs. 33 +/- 22 min, P < 0.05). Twenty (62.5%) dissatisfied patients taking US-a agents awoke before 05:00 hours - a rate significantly higher than satisfied patients (n = 23, 25.0%, P < 0.001). These characteristics of dissatisfied patients were reflected by the patterns of nocturnal awaking curves, although the patterns for satisfied patients were similar among the three types of hypnotics. CONCLUSION: Between 24% and 30% of patients were dissatisfied with their hypnotics. Shorter TST was common in dissatisfied patients receiving any agent, for reasons differing among hypnotics (longer SLT with IL-a agents and early awakening with US-a). Drug efficacy and patient satisfaction in empirical use of hypnotics can be assessed by nocturnal awaking curves for each hypnotic.

Blood ribavirin concentration in high-dose ribavirin for adenovirus-induced haemorrhagic cystitis - a case report.

Blood ribavirin concentration was monitored after the administration of high-dose oral ribavirin in a case of adenovirus-induced haemorrhagic cystitis post-stem-cell transplantation. Combination use of intravenous gamma immunoglobulin (15 g/3 days) and high-dose ribavirin (RBV; 9000 mg/4 days) provided plasma ribavirin concentration of 24.3 microM and achieved virus eradication. High level of erythrocyte ribavirin (1085 microM; mostly as phosphorylated metabolites) with long half-life (15 days) caused severe anaemia, which required several blood transfusions for 2 weeks after the cessation of the ribavirin treatment. It was suggested that blood transfusion and intensive haemoglobin level monitoring is necessary for at least 4 weeks after the RBV, because of the high accumulation of phosphorylated ribavirin in erythrocytes even after stopping ribavirin administration.

Low-responders to angiotensin II receptor blockers and genetic polymorphism in angiotensin-converting enzyme.

AIMS: The existence of low-responders to angiotensin II receptor blockers (ARBs) in terms of the preservation of renal function is reported here. We investigated the relationship between the responsiveness to ARBs and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. METHODS: The effects of ARBs on proteinuria and the progression of chronic renal failure were examined in 113 patients with chronic kidney disease for 34 months before and 27 months after the addition of ARBs. RESULTS: Although a decrease in blood pressure was seen in the II, DI and DD patient subgroups of the ACE gene, the decrease in proteinuria and the amelioration of loss of renal function were observed in the II and DI but not in the DD patients. Kaplan-Meier analysis was employed with a decrease of the reciprocal of serum creatinine of more than 0.2, the induction of renal replacement therapy or death as endpoints. The analysis comparing the periods before and after the addition of ARBs revealed the extension of time to an end-point by the addition of ARBs in all groups together (II + DI + DD), in Group II, and Group DI but not in the DD patient Group. CONCLUSIONS: These data suggest that DD patients with ACE gene demonstrate diminished response to ARBs in terms of renoprotection and that ACE gene polymorphism needs to be taken into account when using ARBs as a means of renoprotective therapy.

Impact of serum flecainide level on control of atrial fibrillation in a case treated with cardiac resynchronization therapy.

A 72-year-old male patient with dilated cardiomyopathy was treated with oral flecainide (100 mg/day) for persistent atrial fibrillation (AF) that could not be converted to sinus rhythm by electrical cardioversion. Initiation of flecainide treatment provided sinus rhythm without prolongation of QRS and QTc, bradycardia and first-degree atrioventricular block at a serum flecainide level of 438 ng/mL. Then, he received cardiac resynchronization therapy (CRT). Dose reduction to 50 mg/day because of stabilization of heart rate after CRT produced AF at a serum flecainide level of 270 ng/mL. Electrical cardioversion did not restore the AF to a sinus or pacing rhythm. Dose escalation of flecainide (to 100 mg/day) restored the pacing rhythm at a serum flecainide level of 401 ng/mL. This case suggests that in the Japanese population, serum flecainide level should be maintained at >300 ng/mL to control AF even after effective CRT.

Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.

The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.

Angiotensin-converting enzyme inhibitor withdrawal and ACE gene polymorphism.

AIMS: Withdrawal of angiotensin-converting enzyme (ACE) inhibitors may affect the progression of chronic renal failure and an insertion/deletion (I/D) polymorphism of the ACE gene may influence it. METHODS: We retrospectively collected patients with chronic glomerulonephritis and benign nephrosclerosis who discontinued ACE inhibitor use. The relationship between the decline of renal function after the withdrawal and the influencing factors such as ACE gene polymorphism, blood pressure and proteinuria were evaluated using multiple regression analysis. RESULTS: Forty-two patients (initial serum creatinine 0.5 - 6.5 mg/dl) had been treated and discontinued ACE inhibitor use. Only patients with the II or DI genotypes of the ACE gene developed the deterioration of renal function, starting at 2 months after the withdrawal. Stepwise regression analysis revealed that the level of proteinuria after the withdrawal, presence of the insertion of ACE gene and serum creatinine level at the time of withdrawal mainly influenced the decline of renal function after the withdrawal (adjusted R2 = 0.48). CONCLUSION: Withdrawal of ACE inhibitor causes the deterioration of renal function in patients with the II or DI genotypes, high proteinuria after the withdrawal, and high serum creatinine level at the withdrawal, which probably causes the rebound increase in serum ACE activity.

Chromatographic determination of free lidocaine and its active metabolites in plasma from patients under epidural anesthesia.

OBJECTIVE: We developed a simple and selective assay method for simultaneous determination of free lidocaine (LDC) and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX) in plasma, by using high-performance liquid chromatography (HPLC). The method was applied to the plasma concentration monitoring in continuous epidural anesthesia with LDC. MATERIALS AND METHODS: Free fraction was separated from plasma by using an ultrafiltration technique. Free and total LDC, MEGX and GX in plasma were analyzed by HPLC equipped with ordinary octadecylsilyl silica (ODS) column and ultraviolet (UV) detector. PATIENTS: Five male patients with cancer who received epidural injection of 1.5% LDC for 5 hours in elective thoracic surgery, were enrolled to determine the plasma levels of total and free LDC, MEGX and GX. RESULTS AND DISCUSSION: The calibration curve for free LDC, MEGX and GX were linear at the concentration of 25 to 1,000 ng ml(-1) (r = 0.9998 - 0.9999). The recoveries for LDC, MEGX and GX from plasma water were ranged 73.2-89.1%. The coefficient variations for intra- and inter-day assay for LDC, MEGX and GX were less than 4.1%. The detection limit ofeach drug was 20 ng ml(-1). Plasma-free MEGX after 180 min epidural injection was higher than free LDC, even though the total concentration of MEGX was 4 times lower than that of LDC. The percentages of free fraction for LDC, MEGX and GX were 11.7, 48.5 and 78.3% after 5-hour epidural administration of LDC. Since the free fraction of MEGX and GX increases and exceeds the concentration of free LDC during continuous epidural anesthesia, accumulation of these toxic metabolites should be carefully monitored as well as LDC. CONCLUSION: The present method is a reliable technique and can be applied to monitoring free LDC, MEGX and GX, which provide us beneficial information as to the LDC metabolism and toxicity.

Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury.

BACKGROUND: Acute renal failure (ARF) is caused by ischemic and nephrotoxic insults acting alone or in combination. Anti-inflammatory agents have been shown to decrease renal ischemia-reperfusion and cisplatin-induced injury and leukocyte infiltration. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits inflammatory and cytotoxic pathways implicated in acute renal injury. Therefore, we sought to determine if IL-10 inhibits acute renal injury. METHODS: The effects of IL-10 were studied in mice following cisplatin administration and bilateral renal ischemia-reperfusion, in a rat model of renal transplantation, and in cultured mouse cortical tubule cells. RESULTS: IL-10 significantly decreased renal injury following cisplatin administration and following renal ischemia/reperfusion. Delay of IL-10 treatment for one hour after cisplatin also significantly inhibited renal damage. IL-10 and alpha-melanocyte stimulating hormone (alpha-MSH) increased recovery following transplantation of a kidney subjected to warm ischemia. To explore the mechanism of action of IL-10, its effects were measured on mediators of leukocyte trafficking and inducible nitric oxide synthase (NOS-II). IL-10 inhibited cisplatin and ischemia-induced increases in mRNA for tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), and NOS-II. IL-10 also inhibited staining for markers of apoptosis and cell cycle activity following cisplatin administration, and nitric oxide production in cultured mouse cortical tubules. CONCLUSIONS: IL-10 protects against renal ischemic and cisplatin-induced injury. IL-10 may act, in part, by inhibiting the maladaptive activation of genes that cause leukocyte activation and adhesion, and induction of iNOS.

Plasma lidocaine concentrations during continuous thoracic epidural anesthesia after clonidine premedication in children.

UNLABELLED: There is no report concerning oral clonidine's effects on epidural lidocaine in children. Therefore, we performed a study to assess the concentrations of plasma lidocaine and its major metabolite (monoethylglycinexylidide [MEGX]) in children receiving continuous thoracic epidural anesthesia after oral clonidine premedication. Ten pediatric patients, aged 1-9 yr, were randomly allocated to the Control or Clonidine 4 microg/kg group (n = 5 each). Anesthesia was induced and maintained with sevoflurane in oxygen and air (FIO2 40%). Epidural puncture and tubing were carefully performed at the Th11-12 intervertebral space. An initial dose of 1% lidocaine (5 mg/kg) was injected through a catheter into the epidural space, followed by 2.5 mg x kg(-1) x h(-1). Plasma concentrations of lidocaine and MEGX were measured at 15 min, 30 min, and every 60 min for 4 h after the initiation of continuous epidural injection. The concentrations of lidocaine and MEGX were measured using high-pressure liquid chromatography with ultraviolet detection. Hemodynamic variables were similar between members of the Control and Clonidine groups during anesthesia. The Clonidine group showed significantly smaller lidocaine concentrations (p < 0.05) and the concentration of MEGX tended to be smaller in the plasma of the Clonidine group for the initial 4 h after the initiation of epidural infusion. In conclusion, oral clonidine preanesthetic medication at a dose of 4 microg/kg decreases plasma lidocaine concentration in children. IMPLICATIONS: Oral clonidine decreases the plasma lidocaine concentration in children. Our finding may have clinical implications in patients receiving continuous epidural anesthesia. Additionally, perhaps an additional margin of safety regarding lidocaine toxicity is gained through the use of oral clonidine in children who will receive epidural lidocaine.

Protein binding of glufosinate and factors affecting it revealed by an equilibrium dialysis technique.

We investigated the protein binding of glufosinate ammonium (GLF) and several factors affecting this binding using human serum albumin (HSA) and human volunteer serum under various conditions. The mean ratios of the free GLF (RFr-GLF) to 4% HSA were examined in the sera of patients described elsewhere at GLF levels from 1 microg/mL to 500 microg/mL; the range was found to be only from 0.80 to 0.88. Neither the incubation temperature nor buffers containing different chloride ion concentrations had any effect on the RFr-GLF to HSA. Moreover, the addition of heparin, glycoprotein-alpha1-acid (AAG), and sodium azide had no effect on the RFr-GLF. However, pH of the isotonic phosphate buffer and the addition of palmitic or oleic acid were seen to have an effect. In this study, the mean RFr-GLF to healthy human serum was 0.99. This high value was evidenced that GLF was rapidly excreted through the renal route.

Intranephron localization and regulation of the V1a vasopressin receptor during chronic metabolic acidosis and dehydration in rats.

The intrarenal localization and role of the V1a vasopressin receptor in body fluid homeostasis are unclear. We investigated the intranephron localization of V1a receptor mRNA and protein using reverse transcription (RT)-competitive polymerase chain reaction (PCR) and immunohistochemistry with a specific polyclonal antibody. To determine whether the V1a receptor is involved in the regulation of acid-base balance, we also examined the effects of acute and chronic metabolic acidosis and dehydration on V1a receptor expression. V1a mRNA was expressed most abundantly in the cortical collecting ducts (CCD) and decreased in the deeper CD. Expression in the glomeruli and thick ascending limbs was low. The immunohistochemical study revealed the presence of the V1a receptor in the glomeruli, the thick ascending limbs and the CD. Dehydration decreased V1a mRNA expression in the CD. Chronic metabolic acidosis increased V1a receptor mRNA expression in the CD but decreased V2 receptor mRNA expression. Western blot analysis revealed up-regulation of the V1a receptor protein in chronic metabolic acidosis. Incubation of microdissected CCD or outer medullary CD (OMCD) in a low-pH (or or low-HCO3-) medium increased the levels of V1a receptor mRNA but decreased V2 receptor mRNA expression. Incubating OMCD with arginine vasopressin (AVP) and the V1a receptor antagonist (OPC21268) increased V2 receptor mRNA expression compared with incubation with AVP alone. These data suggest that V1a receptors are present primarily in the principal and intercalated cells in the CD and that these receptors are involved in the regulation of water and acid-base balance.

Modulation by cyclic AMP and phorbol myristate acetate of cephaloridine-induced injury in rat renal cortical slices.

Intracellular signaling pathways of cAMP and protein kinase C (PKC) have been suggested to modulate the generation of free radicals. We investigated the effects of cAMP and phorbol myristate acetate (PMA), a PKC activator, on cephaloridine (CER)-induced renal cell injury, which has been reported to be due to the generation of free radicals. Incubation of rat renal cortical slices with CER resulted in increases in lipid peroxidation and lactate dehydrogenase (LDH) release and in decreases in gluconeogenesis and p-aminohippurate (PAH) accumulation in rat renal cortical slices, suggesting free radical-induced injury in slices exposed to CER. A derivative of cAMP ameliorated not only the increase in lipid peroxidation but also the renal cell damage induced by CER. This amelioration by a cAMP derivative of lipid peroxidation and renal cell damage caused by CER was blocked by KT 5720, a protein kinase A (PKA) inhibitor. Lipid peroxidation and the indices of cell injury were increased by PMA. PMA also enhanced CER-induced lipid peroxidation and cell damage in the slices. This enhancement by PMA of CER-induced injury was blocked by H-7, a PKC inhibitor. These results indicated that intracellular signaling pathways of cAMP and PKC modulate free radical-mediated nephrotoxicity induced by CER.

Effect of ascites on tacrolimus disposition in a liver transplant recipient.

To examine the effects of ascites on tacrolimus disposition, the authors measured tacrolimus concentration in blood and ascitic fluid from a patient with a living related liver transplant recipient who required removal of 500 to 2400 mL ascitic fluid daily. Tacrolimus levels in ascitic fluid ranged from 0.07 to 0.29 ng/mL and in whole blood from 7.5 to 20.3 ng/mL. The tacrolimus concentration in ascitic fluid positively correlated with that in whole blood ( r = 0.878, P <0.0001). Because the amounts of tacrolimus excreted into the ascitic fluid corresponded to only 0.01% to 0.09% of the dose administered, the authors concluded that the effects of ascites on tacrolimus disposition were negligible even though large amounts of ascitic fluid were drained regularly.

Reduction in standard MAC and MAC for intubation after clonidine premedication in children.

We examined the relative effects of different doses of oral clonidine on the MAC for endotracheal intubation (MACEI) and the MAC for skin incision (MAC) in children. We studied 90 children (15 in each group) (age range 2-8 yr, weight 10-27 kg, height 89-124 cm) who received one of three preanaesthetic medications: placebo (control), oral clonidine 2 micrograms kg-1, or oral clonidine 4 micrograms kg-1 100 min before anaesthesia. Anaesthesia was induced and maintained with sevoflurane in oxygen and air without i.v. anesthetics and neuromuscular relaxants. The end-tidal sevoflurane concentration was kept constant for > or = 15 min before tracheal intubation or skin incision. MACs were determined using Dixon's 'up-and-down method'. Mean (SD) MACEIs of sevoflurane were 2.9 (0.1)%, 2.5 (0.1)% and 1.9 (0.1)% (P < 0.05), and MACs were 2.3 (0.1)%, 1.8 (0.1)% and 1.3 (0.1)% (P < 0.05), respectively, in control, clonidine 2 micrograms kg-1 and clonidine 4 micrograms kg-1 groups. The MACEIs and MACs decreased dose-dependently. The MACEI/MAC ratio (1.4) was not affected by clonidine.