Impact of renal function on mid-term outcomes in heart failure patients treated with tolvaptan.

BACKGROUND:: Although tolvaptan, an electrolyte-free water diuretic for congestive heart failure (HF), is reported to have no effect on long-term mortality or HF-related morbidity, there may exist some subgroups of patients who may receive beneficial effect of tolvaptan. The purpose of this study was to identify clinical factors associated with mid-term effect of tolvaptan on clinical outcomes of patients who discharged after acute HF. METHODS:: We retrospectively analyzed 140 patients (88 male; mean age, 77.1 ± 11.0 years) with acute HF who received tolvaptan (initial dose 8.6 ± 3.6 mg/day) during their hospitalization. They were divided into two groups according to how the tolvaptan was used at discharge; 77 in the tolvaptan-continued group and 63 in the discontinued group. RESULTS:: The Cox proportional hazards model revealed that eGFR was the only independent predictor for the occurrence of mid-term cardiac events (composite of re-hospitalization due to HF and all-cause death; aHR = 0.9870, p = 0.02597). The Kaplan-Meier survival curves of the two groups demonstrated no difference in cumulative event-free rates. In the subgroup with preserved renal function at admission (eGFR ⩾ 30 ml/min/1.73 m2), the continuous use of tolvaptan increased composite events (aHR = 2.130, p = 0.02549). CONCLUSIONS:: The continuous use of tolvaptan after discharge did not affect mid-term cardiac events of HF overall but may be associated with increased cardiac events in the subgroup with preserved renal function. These findings suggest that the tolvaptan administration might need to be limited to treatment of in-hospital acute HF.

[Orthographic similarity or semantic relation? The origin of orthographic neighborhood size effects on the lexical decision to Japanese kanji words].

It is known that lexical decisions to Japanese kanji words get faster as the orthographic neighborhood size of the words grows. This study aimed to show that this facilitative effect of orthographic neighborhood size is due not only to orthographic similarity but also to semantic relationships between words and their neighbors. In the experiment, common and proper nouns each composed of two kanji characters were used as stimuli, the latter having no semantic relation to their neighbors. Lexical decision times for each type of noun were measured with large and small orthographic neighborhoods. The results showed that lexical decision times for both common and proper nouns with large neighborhoods were shorter than those with small neighborhoods, and that the difference was prominent for common nouns sharing their first characters with neighbors. These results suggest that the semantic relatedness of the first characters of Japanese kanji words and their neighbors also facilitates their lexical decision. Finally, variance of neighborhood effects on lexical decision among writing systems and the need to consider various kanji-specific factors are discussed.

Microdose pharmacogenetic study of ¹4C-tolbutamide in healthy subjects with accelerator mass spectrometry to examine the effects of CYP2C9∗3 on its pharmacokinetics and metabolism.

Microdose study enables us to understand the pharmacokinetic profiles of drugs in humans prior to the conventional clinical trials. The advantage of microdose study is that the unexpected pharmacological/toxicological effects of drugs caused by drug interactions or genetic polymorphisms of metabolic enzymes/transporters can be avoided due to the limited dose. With a combination use of accelerator mass spectrometry (AMS) and (14)C-labaled compounds, the pharmacokinetics of both parent drug and its metabolites can be sensitively monitored. Thus, to demonstrate the usability of microdose study with AMS for the prediction of the impact of genetic polymorphisms of CYP enzyme on the pharmacokinetics of unchanged drugs and metabolites, we performed microdose pharmacogenetic study using tolbutamide as a CYP2C9 probe drug. A microdose of (14)C-tolbutamide (100 µg) was administered orally to healthy volunteers with the CYP2C9(∗)1/(∗)1 or CYP2C9(∗)1/(∗)3 diplotype. Area under the plasma concentration-time curve for the (14)C-radioactivity, determined by AMS, or that for the parent drug, determined by liquid chromatography/mass spectrometry, was about 1.6 times or 1.7 times greater in the CYP2C9(∗)1/(∗)3 than in the CYP2C9(∗)1/(∗)1 group, which was comparable to the previous reports at therapeutic dose. In the plasma and urine, tolbutamide, carboxytolbutamide, and 4-hydroxytolbutamide were detected and practically no other metabolites could be found in both diplotype groups. The fraction of metabolites in plasma radioactivity was slightly lower in the CYP2C9(∗)1/(∗)3 group. Microdose study can be used for the prediction of the effects of genetic polymorphisms of enzymes on the pharmacokinetics and metabolic profiles of drugs with minimal care of their pharmacological/toxicological effects.

The effect of temporal uncertainty on negative priming.

The purpose of this study was to assess whether the temporal uncertainty of stimuli appearance influences negative priming. A simple reaction time measure of temporal uncertainty was introduced and showed that temporal uncertainty varied according to the response-stimulus interval (RSI). Using a design introduced by Conway in 1999 for manipulating RSIs, temporal uncertainty was shown to be measurably different for different RSI conditions, even across conditions which previous research had assumed to be equal in temporal uncertainty. This difference in temporal uncertainty partially accounted for differences in negative priming between conditions. An important implication is that research in negative priming generally should take account of temporal uncertainty, for example, by using the simple reaction time measure used here.

Recovery of corneal sensation after myopic correction by laser in situ keratomileusis with a nasal or superior hinge.

PURPOSE: To measure corneal sensitivity after laser in situ keratomileusis (LASIK) to determine the time required for recovery of this parameter. SETTING: Ohshima Hospital of Ophthalmology, Fukuoka, Japan. METHODS: Corneal sensation was measured with a Cochet-Bonnet-type esthesiometer in 75 patients before and 1, 3, 6, and 12 months after correction of myopia by photorefractive keratectomy (n = 21) or LASIK (n = 54). RESULTS: Photorefractive keratectomy did not affect corneal sensation. In the LASIK group, a large and significant decrease in corneal sensitivity was apparent at 1 month (P<.05). Although corneal sensitivity appeared to have recovered slightly at 3 months, it remained significantly decreased (P<.05). By 6 or 12 months, the corneal sensitivity in LASIK patients was not statistically different from the preoperative values in the study patients. A significantly greater decrease in corneal sensitivity was apparent in the LASIK patients with a nasal hinge than in those with a superior hinge (F = 7.54, P<.01). Corneal sensitivity was in the normal range in 31.5% of LASIK patients at 3 months and in 57.4% and 82.1% at 6 and 12 months, respectively. CONCLUSION: Recovery of corneal sensation had begun 3 months after LASIK and appeared complete after 12 months.

An analysis of BIGH3 mutations in patients with corneal dystrophies in the Kyushu district of Japan.

PURPOSE: To assess the involvement of BIGH3 in corneal dystrophies (CD) with an autosomal dominant trait, in patients referred to a hospital in the Kyushu district of Japan. METHODS: Forty-five CD patients from 44 families were studied. Genomic DNA was extracted from peripheral blood, and exons 4 and 12 of the BIGH3 gene were amplified by polymerase chain reaction followed by direct sequencing. RESULTS: In exon 4, an R124H mutation associated with Avellino corneal dystrophy (ACD) was found in 39/44 families (86.4%) and an R124C mutation associated with lattice corneal dystrophy type 1 (LCD1) was detected in 2/44 families (4.5%). In exon 12, an R555W mutation associated with granular corneal dystrophy (GCD) was detected in 4/44 families (9.1%). CONCLUSIONS: Codons R124 and R555 of the BIGH3 gene represent mutational hotspots in the genomes of Japanese patients with autosomal-dominant CD.

Two brothers with gelatinous drop-like dystrophy at different stages of the disease: role of mutational analysis.

PURPOSE: A report of two Japanese brothers with gelatinous drop-like corneal dystrophy, one with and one without the typical gelatinous drop-like region. DESIGN: Interventional case report and observational case report. METHODS: After penetrating keratoplasty, the corneal button, right eye, of the elder brother, 39 years of age, was stained and examined by microscopy. The M1S1 and BIGH3 genes were examined for mutations using the polymerase chain reaction and direct sequencing. Corneal abnormalities in the younger brother, 37 years of age, were observed. RESULTS: The elder brother had bilateral gelatinous prominences and band-shaped corneal opacities, whereas the younger brother had only bilateral band-shaped opacities. Histologically, corneal deposits beneath the epithelium stained with Congo red. Molecular genetic analysis revealed that M1S1 was homozygously mutated in both brothers (Q118X). CONCLUSION: The Q118X mutation of the M1S1 gene can produce either a gelatinous drop-like region or band-shaped opacities.