Relationship of plasma 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentration with OATP1B activity in patients with chronic kidney disease.

Organic anion-transporting polypeptides (OATP)1B are drug transporters mainly expressed in the sinusoidal membrane. Many studies have suggested that OATP1B activity is affected by genetic factor, the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Coproporphyrin-I (CP-I) is spotlighted as a highly accurate endogenous substrate of OATP1B. We previously reported a positive correlation between plasma CMPF and CP-I concentrations in patients with chronic kidney disease (CKD). The present study evaluated the impact of genetic polymorphisms, CMPF, IL-6, TNF-α, and estimated glomerular filtration rate (eGFR) on individual differences in OATP1B activity in patients with CKD. Seventy-three patients with CKD who received kidney transplant at least 3 months earlier were analyzed. Plasma CP-I concentration was higher in OATP1B1*15 carriers than in non-carriers. In all patients, CP-I did not correlate significantly with CMPF, IL-6, TNF-α, or eGFR. However, when the dataset was cut off at CMPF concentration of 8 and 7 µg/mL, 4 µg/mL, 3 µg/mL or 2 µg/mL, CMPF correlated positively with CP-I, and correlation coefficient tended to be higher as plasma CMPF concentration was lower. In conclusion, OATP1B1*15 impacted OATP1B activity in patients with CKD, but IL-6 and TNF-α did not. However, the impact of CMPF on OATP1B activity was limited to low CMPF concentrations, and the effect could be saturated at high concentrations. When prescribing an OATP1B substrate drug for patients with CKD, the OATP1B1*15 carrier status and plasma CMPF concentration may need to be considered to decide the dose regimen.

Usefulness of Belimumab in Adult Patients With Systemic Lupus Erythematosus Evaluated Using Single Indexes: A Meta-Analysis and Systematic Review.

Background: Belimumab is the first antibody drug approved for systemic lupus erythematosus (SLE), and is a fully human monoclonal antibody that inhibits soluble B lymphocyte stimulator protein. In clinical trials, a composite index was used to assess efficacy of belimumab. However, clinical guidelines on SLE treatment currently use single efficacy indexes. Objective: The main objective of this study was to perform a meta-analysis to evaluate the efficacy of belimumab utilizing single indexes used in routine clinical practice, rather than the composite efficacy index used in clinical trials during the development phase. As a secondary endpoint, safety was also evaluated. Methods: Several databases were searched to identify reports published up to December 1, 2021 on randomized controlled trials examining the efficacy of belimumab in adult patients with SLE. From the clinical trial data, efficacy was evaluated using single indexes including the SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index, and Physician Global Assessment. Safety was also assessed. Data were synthesized and analyzed using Review Manager 5.4. This study protocol was registered in the UMIN Clinical Trials Registry (Registration number: UMIN000052846). Results: The search identified 12 reports that met the inclusion criteria. Five reports were included in efficacy evaluation and 9 in safety evaluation. The primary endpoint was SLEDAI. Significantly more belimumab-treated patients achieved a ≥4-point reduction in SLEDAI (relative risk 1.28; 95% confidence interval, 1.16-1.40; P < 0.00001) compared with placebo. Other efficacy endpoints were also improved significantly in the belimumab group. No difference in safety was found between belimumab and placebo. Conclusions: The present meta-analysis evaluating clinical trial data using various single indexes recommended by clinical guidelines for SLE verifies that addition of belimumab to standard of care is efficacious for moderate-to-severe SLE.

Evaluation of the usefulness of plasma 4ß-hydroxycholesterol concentration normalized by 4α-hydroxycholesterol for accurate CYP3A phenotyping.

Plasma 4ß-hydroxycholesterol (OHC) has drawn attention as an endogenous substrate indicating CYP3A activity. Plasma 4ß-OHC is produced by hydroxylation by CYP3A4 and CYP3A5 and by cholesterol autoxidation. Plasma 4α-OHC is produced by cholesterol autoxidation and not affected by CYP3A activity. This study aimed to evaluate the usefulness of plasma 4ß-OHC concentration minus plasma 4α-OHC concentration (4ß-OHC-4α-OHC) compared with plasma 4ß-OHC concentration and 4ß-OHC/total cholesterol (TC) ratio in cross-sectional evaluation of CYP3A activity. Four hundred sixteen general adults were divided into 191 CYP3A5*1 carriers and 225 non-carriers. Twenty-six patients with chronic kidney disease (CKD) with CYP3A5*1 allele were divided into 14 with CKD stage 3 and 12 with stage 4-5D. Area under the receiver operating characteristic curve (AUC) for the three indices were evaluated for predicting presence or absence of CYP3A5*1 allele in general adults, and for predicting CKD stage 3 or stage 4-5D in patients with CKD. There was no significant difference between AUC of 4ß-OHC-4α-OHC and AUC of plasma 4ß-OHC concentration in general adults and in patients with CKD. AUC of 4ß-OHC-4α-OHC was significantly smaller than that of 4ß-OHC/TC ratio in general adults (p = 0.025), but the two indices did not differ in patients with CKD. In conclusion, in the present cross-sectional evaluation of CYP3A activity in general adults and in patients with CKD with CYP3A5*1 allele, the usefulness of 4ß-OHC-4α-OHC was not different from plasma 4ß-OHC concentration or 4ß-OHC/TC ratio. However, because of the limitations in study design and subject selection of this research, these findings require verification in further studies.

Rapid and simple quantification of belimumab in human plasma using ultra-high performance liquid chromatography with tandem mass spectrometry.

OBJECTIVE: Belimumab is a monoclonal antibody against the B-lymphocyte stimulating factor and is approved for the treatment of patients with systemic lupus erythematosus (SLE) not responding adequately to existing therapies. In this study, we established and validated an assay for quantifying belimumab in human plasma. METHODS: From the peptides generated by trypsin digestion of belimumab, in silico analysis was used to search for unique peptides to determine the surrogate peptides. Samples were trypsin digested, pretreated with solid phase extraction, and analyzed by ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) to quantify the surrogate peptide in the samples. The assay was validated according to the Food and Drug Administration (FDA) bioanalytical method validation guidance. We used the established assay to quantify plasma belimumab concentrations in two SLE patients treated with belimumab. RESULTS: Among the unique peptides identified by the in silico analysis, the peptide with the best peak shape when measured by UHPLC-MS/MS was selected as the surrogate peptide. The validation results of this assay met the acceptable criteria recommended by the FDA guidance. The lower limit of quantification (LLOQ) for belimumab was 2 µg/mL. Recovery rates and matrix effects when corrected for internal standards were 91.5-114.3 % and 96.9-108.4 %, respectively. Plasma concentrations of belimumab were measured in 12 samples from two belimumab-treated SLE patients. All concentrations were within the calibration range. CONCLUSIONS: We have established and validated a method for measuring plasma belimumab concentrations using UHPLC/MS-MS. By measuring plasma belimumab concentrations in more patients, this method is expected to contribute to appropriate use of belimumab.

Optimizing the Approach to STA-MCA Bypass Surgery and Reducing Wound Complications.

BACKGROUND AND OBJECTIVES: The treatment of complex intracranial aneurysms with bypass surgery using 2 branches of the superficial temporal artery (STA) proves to be an effective surgical option. However, the harvest of these 2 STA branches, combined with a pterional craniotomy, carries the potential risk of delayed wound healing of the skin flap. This study undertook a retrospective analysis to examine and identify the factors associated with this delayed wound healing. METHODS: A total of 56 consecutive cases, including both ruptured and unruptured complex intracranial aneurysms, that underwent bypass surgery with 2 branches of the STA, were analyzed retrospectively. RESULTS: Major delayed wound healing was observed in 6 (10.7%) cases. Univariate analysis demonstrated significant associations with the following factors: rupture (P = 0.023), presence of diabetes mellitus (P = 0.028), large craniotomy size (P = 0.012), and the type of skin incision (P ≤ 0.001). Age (P = 0.283), sex (P = 0.558), body mass index (P = 0.221), and other blood test parameters did not demonstrate any statistical significance. Similarly, the presence of a dominant frontal branch (P = 0.515) or a low-positioned frontal branch (P = 0.622) did not reveal statistically significant results. CONCLUSIONS: In the treatment of complex intracranial aneurysms, where harvesting of the 2 STA branches is involved with a pterional craniotomy, producing a smaller skin flap (L- or T-shaped incision) is effective in minimizing the risk of delayed wound healing. The process of harvesting the STA and closing the wound demands meticulous care, taking into consideration the normal anatomical structures and the subdermal vascular plexus of the scalp.

Bypass Surgery for Vertebral Artery and Posterior Inferior Cerebellar Artery Fusiform Aneurysms: Surgical Technique and Key Lessons.

Fusiform vertebral artery (VA) aneurysms are challenging to treat due to their pathophysiology, morphology, and anatomic location.1,2 Endovascular treatments are considered to be a widely adopted safe option for this pathology.1 Open microsurgical treatment is considered for complex anatomy, important branch involvement, poor collateral flow, or failed endovascular therapy.3-7 This report aims to show the flow-replacement strategy and bypass technique for a VA aneurysm with complex anatomy and branch involvement. A 24-year-old man presented to our clinic with a bilateral fusiform VA aneurysm discovered during workup of progressive headaches. Further investigation revealed that the left-side aneurysm was mostly thrombosed and the posterior inferior cerebellar artery arose from the aneurysm dome with a fusiform enlargement within a few millimeters from the branching point. After evaluating all management options, the patient decided on surgical treatment of the left VA aneurysm. We performed an occipital artery to posterior inferior cerebellar artery end-to-side anastomosis distal to the fusiform enlargement, followed by trapping of the aneurysm and dome resection (Video 1). Antegrade flow to the distal VA was reestablished using a radial artery interposition graft, thus preventing any flow alterations that may cause growth or rupture of the contralateral aneurysm caused by increased hemodynamic stress if the ipsilateral VA flow is not preserved.8 After in-hospital physical rehabilitation, the patient was discharged with a modified Rankin Scale score of 1. The contralateral aneurysm is managed with serial imaging and treatment will ensue if there is clinical-radiologic evolution. The patient consented to the procedure and publication of his image.

Prevalence of iron-deficient but non-anemic university athletes in Japan: an observational cohort study.

BACKGROUND: Iron deficiency (ID) and iron deficiency anemia (IDA) are long-standing health problems in athletes, affecting both performance and health. ID prevalence in young athletes remains high and a matter of concern. ID and IDA can lead to fatigue, reduced endurance, and decreased oxygen transport, potentially compromising athletic performance. We hypothesized that ID would still be a major health concern in university athletes across sports clubs in Japan. PURPOSE: The study aimed to investigate the prevalence of ID and IDA in athletes participating in Kendo, badminton, baseball, and handball at the University of Tsukuba (Tsukuba, Ibaraki Prefecture, Japan). The study also examined the correlation between hypoferritinemia and other variables, such as previous use of iron supplements, body mass index (BMI), energy intake, and years of athletics. METHODS: Between January and December 2019, 126 university athletes, consisting of 79 males and 47 females, underwent physical measurements and blood tests. The blood test included complete blood count, levels of serum ferritin, serum iron, and total iron-binding capacity. The anemia was defined in accordance with the WHO criteria. Daily energy and iron intake were estimated with the food frequency questionnaire in Japanese (FFQg). Thirty-four female athletes responded to a survey about their menstruation and low-dose estrogen-progestin (LEP) usage. RESULTS: While none of the athletes had anemia, 22 (47%) female athletes exhibited serum ferritin levels of 30 ng/mL or less, defining them as hypoferritinemia. The multivariate logistic regression model revealed that a shorter duration of the athletic experience (adjusted odd ratio [95% confidence interval]: 0.62 [0.43-0.90]), lower energy intake (0.994 [0.989-0.999]), and higher dietary iron intake (4.40 [1.12-17.26]) were associated with hypoferritinemia. Seventeen (50%) female athletes reported a decline in subjective performance during menstruation, albeit two took LEP regularly. CONCLUSIONS: This study reveals that ID is a prevalent health concern among young female athletes across sports clubs. It underscores the need for their education on the importance of assessing ID status. Limitation includes the nature of single-site and observational study, the absence of hepcidin measurement, and an unspecified amount of exercise. Comprehensive investigations are needed to elucidate the causes and optimal treatments for ID in young athletes.

Characteristics of Top-Searched Individuals in Japan's Yen for Docs Conflicts of Interest Database During the COVID-19 Pandemic.

Purpose Transparency in healthcare has led to increased public disclosure of doctors' conflicts of interest, with the "Yen for Docs Database" in Japan emerging as a pivotal source. Nevertheless, there remains ambiguity regarding the backgrounds and influence of highly-searched persons, especially during the COVID-19 pandemic. The primary objective of this study was to examine if the database was utilized for its intended purpose in 2021, a year marked by the introduction of vaccines and treatments, the addition of new COVID-19-related data, and the frequent appearances of expert statements in various media outlets. Methods We conducted a descriptive analysis on the 10 most frequently searched individuals in the "Yen for Docs Database" between August 27 and September 23, 2021, and determined the amount of money they received from pharmaceutical companies and other organizations over the four-year period between 2016 and 2019. To characterize frequently searched individuals' academic profiles and appearances in the mass media, we identified their h-index and affiliation, their activity on Twitter, and the number of TV appearances. Results There were 72,904 searches during the study period, with the top person accounting for 4,905 of those searches. All top 10 were male, mostly affiliated with universities and specialists in infectious diseases or related fields. Their median number of COVID-19 articles was five, and the median h-index was 34. Four of these top 10 had Twitter accounts, with followers ranging from 12,000 to 195,000. The median amount received from pharmaceutical entities over four years was $154,930, ranging from $809 to $705,502. Conclusions In the Yen for Docs Database, a significant portion of searches during the COVID-19 pandemic was concentrated on a selected group of healthcare professionals with considerable payments over the years, and they exhibited prominent academic and media profiles. These observations highlight the need for more transparent conflicts of interest disclosure among physicians with public visibility.

Evaluation of effects of indoxyl sulfate and parathyroid hormone on CYP3A activity considering the influence of CYP3A5 gene polymorphisms.

AIMS: Indoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4ß-Hydroxycholesterol (4ß-OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4ß-OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α-hydroxycholesterol (4α-OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact-PTH concentrations on plasma 4ß-OHC concentration, 4ß-OHC/total cholesterol ratio and 4ß-OHC-4α-OHC, with consideration of the influence of CYP3A5 polymorphism. METHODS: Sixty-three CKD patients were analysed and divided into CYP3A5 carrier group (n = 26) and non-carrier group (n = 37). RESULTS: Plasma indoxyl sulfate significantly correlated inversely with 4ß-OHC concentration and with 4ß-OHC-4α-OHC in both the CYP3A5*1 carrier group (r = -0.42, P = .034; r = -0.39, P = .050, respectively) and the non-carrier group (r = -0.45, P = .0054; r = -0.39, P = .019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact-PTH concentration and any of the CYP3A activity indices. CONCLUSIONS: The present results suggest that plasma indoxyl sulfate and intact-PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD.

Dome Resection and End-to-End Reanastomosis for a Middle Cerebral Artery Fusiform Aneurysm of the M1 Segment: 2-Dimensional Operative Video.

Fusiform aneurysms of the middle cerebral artery (MCA) are both relatively uncommon and challenging to treat given their pathophysiology, morphology, and anatomy (e.g., perforating arteries involvement).1,2 Endovascular treatment of fusiform MCA aneurysms can achieve good outcomes in well-selected cases.3,4 Open microsurgical strategies are effective in a case of fusiform MCA aneurysms with complex anatomy or perforator involvement.2,5,6 We demonstrate the bypass strategy for resection of a fusiform M1 MCA aneurysm (Video 1). A 48-year-old female was referred for the treatment of a growing incidental right M1 MCA fusiform aneurysm. Imaging showed a tortuous M1 segment with no apparent perforator involvement, which we considered a candidate for resection and reanastomosis. A modified minipterional transsylvian approach was performed as described earlier.7,8 A double superficial temporal artery to middle cerebral artery bypass was performed to maintain flow to MCA territory and distal perforators in anticipation of a long temporary flow arrest due to complex aneurysmal dissection and reanastomosis and also to serve as long-term protective insurance. Resection and end-to-end reanastomosis will preserve the antegrade flow and prevent the risk stump thrombosis carried by a simple trapping.9,10 We cover the nuances of this technique including key steps to an efficient aneurysmal resection and complication avoidance. The patient tolerated the procedure well, and postoperative imaging showed no aneurysmal remnant and flow restoration with no evidence of stroke. We discharged the patient home with a modified Rankin scale of 0. The patient consented to the procedure and publication of his or her image.

Reverse Suction Decompression Using the Superior Thyroid Artery During Clipping of a Complex Anterior Choroidal Artery Aneurysm.

Direct aneurysmal suction decompression was first described by Dr. Flamm in 1981 to improve safety and ease clipping of complex aneurysms by deflating their dome.1 This technique evolved over the following decade, from direct aneurysmal puncture to indirect-reverse-suction decompression (RSD).2,3 The conventional technique for RSD involves a cannulation of the internal (ICA) or common (CCA) carotid arteries.2-9 Direct puncture of either the CCA or ICA carry risk of arterial wall damage (e.g., dissection), which may result in significant morbidity.10,11 We routinely cannulate the superior thyroidal artery (SThA) as the vascular access to perform RSD. This subtle technical nuance prevents dissection of either the CCA or ICA while providing a reliable source for RSD.12 In this operative video, the SThA was cannulated to apply reverse suction decompression, which allowed releasing perforating arteries from the dome of an anterior choroidal artery aneurysm in a 68-year-old lady. The patient tolerated the procedure well, was discharged without neurologic deficits, and resumed normal life with no aneurysm remnant. The patient consented to the procedure and video/photography publication. RSD is an optimal technique to enhance efficiency and safety when dissecting around the dome of a complex intradural ICA aneurysm. The use of the SThA avoids the risk of ICA or CCA wall damage due to access, which defeats the protective purpose of RSD itself. Video 1 provides an educational example of the SThA cannulation technique for RSD during dissection and clipping of a complex anterior choroidal artery aneurysm.

A case of facial nerve palsy caused by severe head injury treated by translabyrinthine approach.

Background: Several treatments for traumatic facial paralysis have been reported, but the role of surgery is still controversial. Case Description: A 57-year-old man was admitted to our hospital with head trauma due to a fall injury. A total body computed tomography (CT) scan showed a left frontal acute epidural hematoma associated with a left optic canal and petrous bone fractures with the disappearance of the light reflex. Hematoma removal and optic nerve decompression were performed immediately. The initial treatment was successful with complete recovery of consciousness and vision. The facial nerve paralysis (House and Brackmann scale grade 6) did not improve after medical therapy, and thus, surgical reconstruction was performed 3 months after the injury. The left hearing was lost entirely, and the facial nerve was surgically exposed from the internal auditory canal to the stylomastoid foramen through the translabyrinthine approach. The facial nerve's fracture line and damaged portion were recognized intraoperatively near the geniculate ganglion. The facial nerve was reconstructed using a greater auricular nerve graft. Functional recovery was observed at the 6-months follow-up (House and Brackmann grade 4), with significant recovery in the orbicularis oris muscle. Conclusion: Interventions tend to be delayed, but it is possible to select a treatment method of the translabyrinthine approach.

A case of anterior choroidal artery occlusion test under MEP monitoring for a recurrent internal carotid artery-anterior choroidal artery bifurcation aneurysm clipping.

A 59-year-old female with recurrent Anterior Choroidal Artery (AchA) aneurysm was elected for surgery at our institution through a standard pterional approach. Two thin perforating branches were found to origin from the dome of the aneurysm during operation, and therefore complete aneurysm clipping preserving these branches was not feasible. These perforating branches were temporarily occluded under motor-evoked potential (MEP) monitoring. The MEPs remained stable during 10 min of temporary clipping, and we concluded that these branches could be sacrificed, and therefore neck clipping was performed occluding these tiny AchA perforators. Although postoperative magnetic resonance imaging with diffusion-weighted images showed ischemic signs in left AchA territory after the operation, the patient remained asymptomatic and was discharged home with mRS 0.

ZLN005 improves the survival of polymicrobial sepsis by increasing the bacterial killing via inducing lysosomal acidification and biogenesis in phagocytes.

Polymicrobial sepsis still has a high mortality rate despite the development of antimicrobial agents, elaborate strategies to protect major organs, and the investment of numerous medical resources. Mitochondrial dysfunction, which acts as the center of energy metabolism, is clearly the basis of pathogenesis. Drugs that act on PGC1α, the master regulator of mitochondrial biosynthesis, have shown useful effects in the treatment of sepsis; therefore, we investigated the efficacy of ZLN005, a PGC1α agonist, and found significant improvement in overall survival in an animal model. The mode of action of this effect was examined, and it was shown that the respiratory capacity of mitochondria was enhanced immediately after administration and that the function of TFEB, a transcriptional regulator that promotes lysosome biosynthesis and mutually enhances PGC1α, was enhanced, as was the physical contact between mitochondria and lysosomes. ZLN005 strongly supported immune defense in early sepsis by increasing lysosome volume and acidity and enhancing cargo degradation, resulting in a significant reduction in bacterial load. ZLN005 rapidly acted on two organelles, mitochondria and lysosomes, against sepsis and interactively linked the two to improve the pathogenesis. This is the first demonstration that acidification of lysosomes by a small molecule is a mechanism of action in the therapeutic strategy for sepsis, which will have a significant impact on future drug discovery.

Blueberry Leaf Extract Prevents Lacrimal Hyposecretion in Sjögren's Syndrome-like Model of Non-obese Diabetic Mice.

BACKGROUND/AIM: This study evaluated the effect of blueberry leaf hot water extract (BLEx) on Sjögren's syndrome (SS)-like lacrimal hyposecretion in male non-obese diabetic (NOD) mice. MATERIALS AND METHODS: NOD or BALB/c mice were fed 1% BLEx or control (AIN-93G) for 2 weeks from the age of 4 to 6 weeks. Pilocarpine-induced tear volume was measured using a phenol red-impregnated thread. The lacrimal glands were evaluated histologically by H&E staining. The IL-1ß and TNF-α levels in the lacrimal gland tissue were measured by ELISA. The mRNA expression levels of secretion-related proteins were measured by real-time PCR. LC3 I/II and arginase 1 expression levels were measured by western blot. RESULTS: After feeding with BLEx, pilocarpine-induced tear secretion in NOD mice was increased. In contrast, the mRNA expression levels of the cholinergic muscarinic M3 receptor, aquaporin 5, and ion channels related to lacrimal secretion were not changed by BLEx administration. In addition, the protein expression of arginase 1, which was recently reported to be involved in tear hyposecretion in NOD mice, was also not improved by BLEx administration. Although infiltration in the lacrimal gland of NOD mice was not decreased, the levels of TNF-α and the autophagy-related protein LC3 were significantly suppressed by BLEx treatment. CONCLUSION: BLEx treatment may ameliorate lacrimal hyposecretion in NOD mice by delaying the progression of autoimmune disease by suppressing autophagy in lacrimal glands.