Changes in Leptin to Adiponectin Ratio After Antiretroviral Therapy: A Pilot Observational Study.

AIM: Weight gain with the use of dolutegravir, bictegravir, and tenofovir alafenamide for antiretroviral therapy has been reported. However, studies on changes in body composition and the leptin/adiponectin ratio after antiretroviral therapy initiation are limited. These factors are important because they can be used as indicators of metabolic syndrome and cardiovascular disease risk. INTRODUCTION: This study aimed to investigate the changes in waist circumference, body composition, and adipokine levels after the initiation of antiretroviral therapy consisting of dolutegravir, bictegravir, and tenofovir alafenamide and evaluate the relationships between these parameters in Japanese patients living with human immunodeficiency virus. METHODS: This is a single-center, prospective, observational study. Waist circumference, body composition, and adipokine levels were measured at baseline and 12 months after antiretroviral therapy initiation in antiretroviral therapy-naive Japanese patients living with human immunodeficiency virus. Body composition was determined by bioelectrical impedance analysis. RESULTS: We included 11 patients (10 bictegravir/TAF/emtricitabine, 1 dolutegravir/lamivudine) in this study. The results showed no significant changes in waist circumference and body composition among the patients. The leptin/adiponectin ratio and serum leptin levels significantly increased after antiretroviral therapy initiation. Changes in waist circumference, fat mass, and visceral fat area showed a strong positive correlation. CONCLUSION: The leptin/adiponectin ratio increased following antiretroviral therapy initiation. The waist circumference measurement can be a simple, inexpensive, and useful method to identify changes in fat mass and visceral fat area after initiation of antiretroviral therapy.

Comparison between the impact of tenofovir alafenamide and that of abacavir on rapid kidney function decline: A retrospective observational study.

OBJECTIVES: To compare the impact of tenofovir alafenamide (TAF) on the slope of the estimated glomerular filtration rate (eGFR) with that of abacavir in Japanese patients living with HIV infection. METHODS: The participants in this single-centre, retrospective, observational study were Japanese patients with HIV infection who started antiretroviral therapy with TAF/emtricitabine or abacavir/lamivudine or were switched from tenofovir disoproxil fumarate/emtricitabine to TAF/emtricitabine or abacavir/lamivudine (anchor drugs remained constant) between January 2012 and December 2020. The eGFR slope was defined as the regression coefficient between eGFR and time. The study outcome was rapid kidney function decline (RKFD; eGFR slope < -5 mL/min/1.73 m2 /year). The adjusted effect of TAF on the eGFR slope was compared with that of abacavir using multivariate logistic regression analysis. RESULTS: The study included 184 patients (with 2835 eGFR data points). The median duration of exposure to TAF or abacavir was 2.6 years [interquartile range (IQR): 1.7-3.3], and the median eGFR slope was -4.1 mL/min/1.73 m2 /year (IQR: -6.4 to -1.2). In all, 72 patients (39%) experienced RKFD. Patients receiving TAF were more likely to experience RKFD (adjusted odds ratio = 3.74) than those receiving abacavir. There was a significant independent association between baseline eGFR and RKFD. CONCLUSIONS: These findings suggest that renal function should be monitored carefully after the initiation of TAF in Japanese patients with HIV infection.

Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on estimated glomerular filtration rate slope in patients with HIV: A retrospective observational study.

INTRODUCTION: There is limited data on the effects of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on estimated glomerular filtration rates (eGFR) slope in patients with human immunodeficiency virus (HIV) infection. This study aimed to compare the eGFR slope when administering TDF and TAF and to investigate the predictors of improvement in eGFR slope after switching from TDF to TAF. METHODS: We conducted a single-center, retrospective, observational study in Japanese patients with HIV infection who switched the antiretroviral drug from TDF to TAF. eGFR was calculated using serum cystatin C. The eGFR slope was defined as the regression coefficient between eGFR and time. Differences between eGFR slope during TDF and TAF administration were compared using Wilcoxon signed rank test. A stepwise logistic regression model was used to examine the associations between improvement of eGFR slope after switching from TDF to TAF and various parameters. RESULTS: Overall, 63 patients (656 eGFR) were included in the analysis. The median analyzed durations of TDF and TAF exposures were 1.6 and 1.5 years, respectively. There were no significant differences between eGFR slope during TDF and TAF periods (median: 0.6 vs. 4.0 mL/min/1.73 m2/year, p = 0.165). The eGFR slopes during the TDF period and while switching from TDF to TAF were independent predictors of improvement in eGFR slope after switching from TDF to TAF. CONCLUSIONS: The results suggest that patients with poor renal function and those with progressive worsening during TDF administration would benefit from switching to TAF.

Decrease in voriconazole concentration-to-dose ratio after letermovir initiation: a retrospective, observational study.

Letermovir is used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. Although this agent decreases voriconazole exposure in healthy individuals, the effect of coadministration of letermovir and voriconazole in HSCT recipients is unknown. This retrospective, observational, single-center study was conducted between January 2016 and July 2019 to examine the voriconazole concentration-to-dose ratio over three periods: (A) (days -7 to -1 [day 0: day of HCST]), (B) (days 4-10), and (C) (days 11-17). Forty-two HSCT recipients administered voriconazole were divided into the following two groups based on letermovir coadministration: letermovir (n = 15) and control (n = 27). The percent change (-33.2%, p < 0.05) in the voriconazole concentration-to-dose ratio from periods A to C in the letermovir group was significantly lower than that in the control group. Therefore, frequent therapeutic drug monitoring of voriconazole concentrations and subsequent dose adjustments should be performed regularly in HSCT recipients.

Tacrolimus Concentration after Letermovir Initiation in Hematopoietic Stem Cell Transplantation Recipients Receiving Voriconazole: A Retrospective, Observational Study.

Letermovir (LMV) is a new antiviral drug used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. It has been reported to increase tacrolimus (TAC) exposure and decrease voriconazole (VRCZ) exposure in healthy participants. However, VRCZ inhibits the metabolism of TAC. Thus, the effects of LMV on TAC exposure in patients receiving VRCZ are unknown. This retrospective, observational, single-center study was conducted between May 2018 and April 2019. The TAC concentration/dose (C/D) ratio, VRCZ concentration, and VRCZ C/D ratio for 7 days before and for the first and second 7-day periods after the initiation of LMV administration were evaluated. Fourteen HSCT recipients receiving VRCZ were enrolled. There was no significant difference in the TAC C/D ratio for 7 days before and for the first and second 7-day periods after initiating LMV administration (median: 866 [IQR: 653-953], 842 [IQR: 636-1031], and 906 [IQR: 824-1210] [ng/mL]/[mg/kg], respectively). In contrast, the VRCZ C/D ratio and concentration for the first and second 7-day periods after LMV initiation were significantly lower than those before initiating LMV administration (mean 1.11 ± 0.07, 0.12 ± 0.08, and 0.22 ± 0.12 [µg/mL]/[mg/kg] and 0.7 ± 0.5, 0.8 ± 0.5, and 1.3 ± 0.7 µg/mL, respectively; n = 12). This can be explained by the increase in TAC concentration caused by CYP3A4 inhibition due to LMV and by the decrease in TAC concentration ascribed to the decrease in VRCZ concentration by CYP2C19 induction due to LMV. These results suggest that it is unnecessary to adjust the dose of TAC based on LMV initiation; however, it is necessary to adjust the dose of TAC based on conventional TAC concentration measurements.

Utility of urinary liver-type fatty acid-binding protein as a predictor of renal dysfunction in Japanese patients with HIV receiving tenofovir disoproxil fumarate with low urinary ß2 microglobulin levels: a retrospective observational study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is known to reduce estimated glomerular filtration rate (eGFR). It is clinically important to identify patients at high risk for renal dysfunction as early as possible. Among the tubular markers, urinary ß2 microglobulin (Uß2MG) is a well-known biomarker of TDF-related tubulopathy. However, renal dysfunction has often been occurred in patients receiving TDF with low Uß2MG levels. Recently, urinary liver-type fatty acid-binding protein (UL-FABP) was suggested to be predictor of the progression of renal dysfunction. Thus, we focused on UL-FABP in patients receiving TDF with low Uß2MG levels. METHODS: A retrospective, observational, single-center study, between January 2013 and December 2016, was conducted. Two renal end points (> 25% decrement in eGFR and > 20 mL/min/1.73 m2 decrement relative to the baseline) were assessed. To estimate the effect of UL-FABP on time to the first event, log-rank test was performed. RESULTS: A total of 24 Japanese outpatients with human immunodeficiency virus receiving TDF were enrolled. The outcome each occurred in two patients during the follow-up period. UL-FABP levels ≥4.0 µg/g creatinine was significantly associated with > 25% decrement and > 20 mL/min/1.73 m2 decrement (p = 0.006 and 0.001, respectively). CONCLUSION: Based on our preliminary analysis, UL-FABP levels ≥4.0 µg/g creatinine predict renal dysfunction in patients receiving TDF with low Uß2MG levels.

Urinary liver-type fatty acid-binding protein levels as a potential risk factor for renal dysfunction in male HIV-infected Japanese patients receiving antiretroviral therapy: a pilot study.

Renal dysfunction is recognized with increasing frequency among the non-infectious co-morbidities associated with human immunodeficiency virus (HIV) infection. Recently, urinary liver-type fatty acid-binding protein (L-FABP) was suggested to be a predictor of the progression of renal dysfunction in patients without HIV. However, little is known regarding the utility of urinary L-FABP as a predictor of renal dysfunction in patients with HIV. A retrospective, observational, single-centre study was conducted between July 2014 and December 2016. The primary outcome was renal dysfunction defined as decrease in estimated glomerular filtration rate to less than 60 ml/min/1.73 m2. To estimate the effect of urinary L-FABP, proteinuria category, and urinary ß2 microglobulin (ß2MG) on the time to the first event, a log-rank test was performed. Accuracy, determined by area under the curve and calculated from receiver operating characteristic curves, was also assessed. Thirty Japanese outpatients with HIV receiving antiretroviral therapy (ART) were enrolled. The primary outcome occurred in five patients during the follow-up period. Urinary L-FABP level and proteinuria category were significantly associated with renal dysfunction (p = 0.045 and p = 0.037, respectively). In contrast, urinary ß2MG level was not significantly associated with renal dysfunction (p = 0.141). Urinary L-FABP was the most accurate predictor of renal dysfunction among the three urinary parameters. In conclusion, urinary L-FABP levels in HIV patients receiving ART were more accurate for predicting renal dysfunction than proteinuria and urinary ß2MG. In addition, urinary L-FABP helped to discriminate those patients with a higher risk for renal dysfunction.

[Early and Mid-term Outcomes of Surgical Treatment with Conservative Approach Using Adventitial Inversion Technique for an Acute Type A Aortic Dissection].

OBJECTIVE: This study was performed to assess the early and mid-term outcomes of surgical treatment with adventitial inversion technique for an acute type A aortic dissection. METHODS: From June 2008 to June 2015, 48 patients underwent emergent surgery for acute type A aortic dissection. Ascending aorta/hemiarch replacement was performed in 44/48(91.7%)patients, and total arch replacement in 4/48(8.3%)patients. The adventitial inversion technique was used for both proximal and distal stump constructions of the dissected aortic wall without the reinforcement of Teflon felt. Aortic regurgitation was treated with resuspention of aortic commissures. RESULTS: The operative mortality was 8.3%(4/48). There was no re-exploration in all patients. Postoperative computed tomography showed the obliteration of false lumen in aortic root in all of patients, and aortic arch and/or descending thoracic aorta in 80.9%(38/47)of patients. The actuarial survival rates at 5 years were 74.7%.The freedom from aortic or aortic valve event rate and reoperation rate at 5 year were 90.9% and 95.2%, respectively. CONCLUSION: The adventitial inversion technique provides excellent early and mid-term outcomes for the repair of acute type A aortic dissection.

A Case of External Compression of Femoral Vein by the Enlarged Iliopsoas Bursa with Long Term Edema.

The iliopsoas bursa is the largest bursa in the region of hip joint. It is unusual that these bursa become symptomatic. However the bursa can compress femoral vein, leading to lower extremity edema. A 58-year-old man was referred to our department for his unilateral leg edema which had been treated as deep vein thrombosis without any favorable response. Magnetic resonance angiography was performed, which demonstrated enlarged iliopsoas bursa compressing his femoral vein. Surgical removal of the bursa was performed. The postoperative course was uneventful, and the patient is free from symptoms with no evidence of recurrence.

Successful surgical exclusion of rapidly expanding kommerell diverticulum following a total arch replacement for an acute type a aortic dissection.

A 50-year-old man presented with an acute type A aortic dissection with an aberrant right subclavian artery. Emergent total arch replacement with an elephant trunk was performed. Intraoperatively, the origin of the aberrant right subclavian artery could not be resected because it was located too far from the distal arch. After two weeks, the patient became aware of dysphagia. Postoperative computed tomography showed the esophagus was compressed anteriorly by the aneurismal origin of this aberrant vessel (Kommerell diverticulum) with a patent false lumen. Additional replacement of the descending aorta via left thoracotomy was performed immediately to exclude a Kommerell diverticulum.

Phonological theory informs the analysis of intonational exaggeration in Japanese infant-directed speech.

To date, the intonation of infant-directed speech (IDS) has been analyzed without reference to its phonological structure. Intonational phonology should, however, inform IDS research, discovering important properties that have previously been overlooked. The present study investigated "intonational exaggeration" in Japanese IDS using the intonational phonological framework. Although intonational exaggeration, which is most often measured by pitch-range expansion, is one of the best-known characteristics of IDS, Japanese has been reported to lack such exaggeration. The present results demonstrated that intonational exaggeration is in fact present and observed most notably at the location of boundary pitch movements, and that the effects of lexical pitch accents in the remainder of the utterances superficially mask the exaggeration. These results not only reveal dynamic aspects of Japanese IDS, but also in turn contribute to the theory of intonational phonology, suggesting that paralinguistic pitch-range modifications most clearly emerge where the intonation system of a language allows maximum flexibility in varying intonational contours.

Thymidine phosphorylase inhibits vascular smooth muscle cell proliferation via upregulation of STAT3.

Dysregulated growth and motility of vascular smooth muscle cells (VSMC) play important role in obstructive vascular diseases. We previously reported that gene transfer of thymidine phosphorylase (TP) into rat VSMC inhibits cell proliferation and attenuates balloon injury induced neointimal hyperplasia; however, the mechanism remains unclear. The current study identified a signaling pathway that mediates effect of TP inhibited VSMC proliferation with a TP activity-dependent manner. Rat VSMC overexpressing human TP gene (C2) or control empty vector (PC) were used. Serum stimulation induced constitutive STAT3 phosphorylation at tyrosine705 in C2 cell but not in PC, which was independent of JAK2 signaling pathway. Inhibition of Src family kinases activity inhibited STAT3 phosphorylation in C2 cells. Lyn activity was higher in C2 cell than in PC. SiRNA based gene knockdown of Lyn significantly decreased serum induced STAT3 phosphorylation in C2 and dramatically increased proliferation of this cell, suggesting that Lyn plays a pivotal role in TP inhibited VSMC proliferation. Unphosphorylated STAT3 (U-STAT3) expression was significantly increased in C2 cells, which may be due to the increased STAT3 transcription. Gene transfection of mouse wild-type or Y705F mutant STAT3 into PC cell or mouse primary cultured VSMC significantly reduced proliferation of these cells, suggesting that overexpression of U-STAT3 inhibits VSMC proliferation. We conclude that Lyn mediates TP induced STAT3 activation, which subsequently contributes to upregulate expression of U-STAT3. The U-STAT3 plays a critical role in inhibiting VSMC proliferation.

Nafamostat mesilate, as a treatment for heparin resistance, is not associated with perioperative ischemic stroke in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: Nafamostat mesilate, a short-acting protease inhibitor, treats heparin resistance during cardiopulmonary bypass. This study tested whether nafamostat mesilate is associated with perioperative ischemic stroke. DESIGN: A retrospective observational study. PARTICIPANTS: A total of 870 adult cardiac surgery patients. INTERVENTION: The authors retrospectively identified the patients who received nafamostat mesilate and who suffered symptomatic ischemic stroke within 30 postoperative days. MEASUREMENTS AND MAIN RESULTS: The authors evaluated perioperative patient characteristics in association with perioperative ischemic stroke and death. The patients were identified as heparin resistant if they had an activated coagulation time of <480 seconds after the administration of heparin at 400 to 500 U/kg. Heparin-resistant patients received a 10- to 20-mg bolus plus 25 to 50 mg/h of nafamostat mesilate and heparin at 100 U/kg intravenously every 1.5 to 2.0 hours to maintain an activated coagulation time over 480 seconds. Of the 870 patients, 11 (1.3%) suffered a perioperative ischemic stroke. Of the 190 (21.8%) patients who received nafamostat mesilate, 1 (0.5%) suffered ischemic stroke compared with 10 (1.5%) in 680 patients without nafamostat mesilate (Fisher exact test; p = 0.47; regression analysis; odds ratio, 0.35; 95% confidence interval, 0.45-2.8; p = 0.32); 3 (1.6%) patients with nafamostat mesilate died postoperatively within 30 days compared with 11 (1.6%) without nafamostat mesilate (Fisher exact test; p > 0.99, regression analysis; odds ratio, 0.98; 95% confidence interval, 0.27-3.5; p = 0.97). CONCLUSIONS: No evidence was found that nafamostat mesilate was associated with perioperative ischemic stroke in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass.

Thrombosed abdominal aortic aneurysm associated with an extensively "shaggy" aorta repaired anatomically via a thoracoabdominal approach with supraceliac aortic clamping: report of a case.

A 76-year-old man with a history of multiple laparotomies and severe coronary artery disease was referred to our hospital after the sudden development of pain and numbness in the lower extremities. Computed tomography showed a thrombosed abdominal aortic aneurysm and diffuse aortic atherosclerosis; compatible with a "shaggy aorta." A good response to thrombolytic therapy permitted elective scheduling of abdominal aortic surgery after coronary artery bypass grafting. We operated via an extended left retroperitoneal approach through a thoracoabdominal incision. Epiaortic ultrasonography revealed that only the supraceliac aorta was free of mobile thrombi and had minimal plaque; we therefore placed a proximal aortic cross-clamp there. Anatomic aortic reconstruction was then performed successfully using an aorto-biiliac graft to restore adequate distal blood flow. There were no vital-organ ischemic complications, and the postoperative course was satisfactory.

Effects of nafamostat mesilate on coagulopathy with chronic aortic dissection.

A 65-year-old man with chronic aortic dissection experienced two massive subcutaneous hemorrhages. Laboratory data indicated disseminated intravascular coagulation, whereas a contrast computed tomographic scan revealed a dilatated aortic arch with a partial thrombosis at the false lumen. Because disseminated intravascular coagulation can be caused by chronic aortic dissection, and the aortic arch was 6 cm in diameter, we performed graft replacement from the ascending to the descending aorta in a single stage. Before graft replacement, nafamostat mesilate, a protease inhibitor, was administered and the disseminated intravascular coagulation improved. Nafamostat mesilate may be useful for managing disseminated intravascular coagulation associated with chronic aortic dissection.

Coronary arteries angiogenesis in ischemic myocardium: biocompatibility and biodegradability of various hydrogels.

To evaluate the biocompatibility and biodegradability of various hydrogels and choose suitable hydrogels for the coronary arteries angiogenesis in ischemic myocardium, we synthesized six kinds of hyaluronan hydrogels, fibrin hydrogel, poly(vinyl alcohol)-chitosan hydrogel, and obtained elastin hydrogels. We examined their degradation rates and cytotoxicity in vitro. Then, hydrogels were implanted into rat adductor muscles for 1, 2, or 4 weeks. Hydrogels and surrounding tissues were resected, followed by hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemical staining for measurements of degradation, immune response, and angiogenesis. 2-Iminothiolane grafted hyaluronan hydrogel and periodate oxidated hyaluronan hydrogel presented rapid degradation rates, low quantity of inflammation-mediating cells (12 +/- 3 and 12 +/- 4 per 2.5 x 10(-3) mm(2), respectively, at week 2), thin fibrous capsules (scores were 3.8 +/- 0.1 and 4.0 +/- 0.3 per 0.33 mm(2), respectively, at week 2) with dense blood vessels in the areas surrounding the implanted hydrogels. 2-Iminothiolane grafted hyaluronan and periodate oxidated hyaluronan hydrogels with appropriate degradation rates and low immune responses were suitable for coronary arteries angiogenesis in ischemic myocardium.

Measurement of glucose metabolism in rat spinal cord slices with dynamic positron autoradiography.

We attempted to measure the regional metabolic rate of glucose (MRglc) in sliced spinal cords in vitro. The thoracic spinal cord of a mature Wister rat was cut into 400-mum slices in oxygenated and cooled (1-4 degrees C) Krebs-Ringer solution. After at least 60 min of preincubation, the spinal cord slices were transferred into double polystyrene chambers and incubated in Krebs-Ringer solution at 36 degrees C, bubbled with 5% O(2)/5% CO(2) gas. To measure MRglc, we used the dynamic positron autoradiography technique (dPAT) with F-18-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) and the net influx constant of [(18)F]FDG as an index. Uptake curves of [(18)F]FDG were well fitted by straight lines for more than 7 h after the slicing of the spinal cord (linear regression coefficient, r=0.99), indicating a constant uptake of glucose by the spinal cord tissue. The slope (K), which denotes MRglc, is affected by tetrodotoxin, and high K(+) (50 mM) or Ca(2+)-free, high Mg(2+) solution. After 10 min of hypoxia, the K value following reoxygenation was similar to the unloaded control value, but after 45 min of hypoxia, the K value was markedly lower than the unloaded control value, and after >90 min of reoxygenation it was nearly 0. Our results indicate that the living spinal cord slices used retained an activity-dependent metabolism to some extent. This technique may provide a new approach for measuring MRglc in sliced living spinal cord tissue in vitro and for quantifying the dynamic changes in MRglc in response to various interventions such as hypoxia.

Hepatic ischemia-reperfusion increases vascular endothelial growth factor and cancer growth in rats.

BACKGROUND: In liver surgery, the hepatic pedicle often is clamped to reduce blood loss, and later unclamped, representing hepatic ischemia and reperfusion (I/R) with induction of hypoxia. Vascular endothelial growth factor (VEGF) expression reportedly is induced by hypoxia; further, some cancer cells express the VEGF receptor (flt-1, flk-1/KDR). We hypothesized that I/R-induced VEGF expression could enhance growth of microscopic tumor via VEGF receptors on tumor cells, thus promoting liver metastasis in a rat model. MATERIALS AND METHODS: Time-dependent VEGF expression in liver and plasma was determined by enzyme-linked immunosorbent assay in rats subjected to 60 min of 70% hepatic I/R (I/R group). Other rats given an intrasplenic inoculation of a rat colon adenocarcinoma cell line (RCH-H4) were divided 3 days later into three groups: group A, untreated; group B, sham operation; group C, 70% I/R for 60 min. Liver metastasis was evaluated on day 14. Expression of flt-1 and flk-1/KDR was examined in RCN-H4 cells, and effects of exogenous VEGF on RCN-H4 cell proliferation were determined by MTT assays. RESULTS: Hepatic VEGF expression increased significantly in the I/R group compared to the control group. Liver metastasis was more extensive in group C than in groups A and B. RCN-H4 cells expressed flt-1 and flk-1/KDR, while exogenous VEGF increased RCN-H4 cell proliferation. CONCLUSION: Hepatic ischemia reperfusion leads to induction of VEGF and this is associated with increased tumor burden in an animal model of colon cancer metastasis.