Supplementary Material for: Dapsone-induced granulomatous cholestatic hepatitis unmasked by steroid taper: a case report

Introduction: Dapsone is known to cause drug induced liver injury (DILI) but can rarely induce the formation of hepatic granulomas. In this case, we describe a patient with jaundice who demonstrated granulomas on liver biopsy in response to dapsone. Her symptoms were only evident once steroids, used to also treat her pyoderma gangrenosum, had been tapered. Case: A 67-year-old female was hospitalized due to one day of jaundice. She had started dapsone and prednisone concurrently seven weeks ago to treat her pyoderma gangrenosum. Steroids were discontinued four days prior to symptoms. Her labs were notable for newly elevated alkaline phosphatase (756 U/L), aspartate transaminase (199 U/L), alanine transaminase (273 U/L), and total bilirubin (12.6 mg/dL). Dapsone was held due to suspicion for DILI. A liver biopsy was performed and disclosed non-necrotizing hepatic granulomas. After infectious and autoimmune causes were excluded, dapsone was determined to be the cause of her hepatic granulomas. Her bilirubin and liver enzymes steadily normalized over the next four weeks following discontinuation of dapsone. Conclusion: Dapsone-related liver injury may present following a steroid taper if dapsone and steroids had been initially started together. Hepatic granulomas, though rare, can be seen when dapsone causes DILI

Supplementary Material for: Distal Pancreatectomy Utilizing a Flexible Stapler Closure Eliminates the Risk of Pancreas-Related Factors for Postoperative Pancreatic Fistula

<b><i>Objectives:</i></b> To identify the risk factors for clinically relevant pancreatic fistula after distal pancreatectomy with a flexible cartridge stapler, TL60. <b><i>Methods:</i></b> Forty consecutive patients who underwent a distal pancreatectomy by the TL60 stapler were retrospectively reviewed in association with postoperative complications. <b><i>Results:</i></b> The overall morbidity rate was 43% (17 patients), and mortality was null. Pancreatic fistula was the most frequent postoperative complication, seen in 11 patients (27.5%): grade A in 4 (10%) and grade B in 7 (17.5%). No grade C pancreatic fistula was observed. Univariate analyses of risk factors demonstrated that pancreas-related factors, including diabetes mellitus, thickness and texture of the pancreatic parenchyma, transection line for the pancreas, pancreatic duct ligation, and use of artificial patches had no impact on the occurrence of pancreatic fistula. A multivariable logistic regression analysis identified operative time (≥300 min) as the only notable predictor of clinically relevant pancreatic fistula (odds ratio = 3.253, 95% confidence interval 1.739-5.752; p = 0.031). <b><i>Conclusion:</i></b> Distal pancreatectomy with the use of the TL60 stapler eliminated the risk of pancreas-related factors for the occurrence of clinically relevant pancreatic fistula

Supplementary Material for: Classification of Uniparental Isodisomy Patterns That Cause Autosomal Recessive Disorders: Proposed Mechanisms of Different Proportions and Parental Origin in Each Pattern

<p>Patients with autosomal recessive (AR) disorders are usually born to parents both of whom are heterozygous carriers of the disease. However, in some instances only one of the parents is a carrier and a mutation is segregated to the patient through uniparental isodisomy (UPiD). Recently, an increasing number of such case reports has been published, and it has become clear that there are several different UPiD patterns that cause AR disorders. In this article, we report 3 remarkable patients with different patterns of UPiD. We then review 85 cases collected in the literature. We realized that they can be classified into 3 patterns: UPiD of the whole chromosome, segmental UPiD with uniparental heterodisomy (UPhD), and segmental UPiD caused by post-zygotic mitotic recombination (MiRe). Whole chromosomal UPiD accounted for the majority of cases, with paternal origin accounting for approximately twice as many cases as maternal origin. Most cases of segmental UPiD with UPhD were of maternal origin, with a dominancy of nondisjunction in meiosis I, while segmental UPiD through MiRe is the smallest pattern with equal parental origin. These differences in proportion and parental origin in each pattern can be explained by considering nondisjunction during oogenesis as the starting point and UPiD as subsequent events.</p

Supplementary Material for: Intracranial Cerebral Artery Dissection of Anterior Circulation as a Cause of Convexity Subarachnoid Hemorrhage

<b><i>Background:</i></b> Convexity subarachnoid hemorrhage (cSAH), defined as intrasulcal bleeding restricted to hemispheric convexities, has several etiologies: reversible cerebral vasoconstriction syndrome, cerebral amyloid angiopathy, and internal carotid artery (ICA) stenosis or occlusion. However, it remains unknown whether cerebral artery dissection causes cSAH. <b><i>Methods:</i></b> We retrospectively investigated patients admitted to our hospital between 2005 and 2013 with ischemic stroke or transient ischemic attack caused by cerebral artery dissection. Cerebral artery dissection was diagnosed by cervical or cerebral magnetic resonance imaging (MRI) or computed tomography (CT) showing a wall hematoma. CT angiography, ultrasonography, or intra-arterial digital-subtraction angiography detected cerebral artery dissection if a double lumen, string sign, intimal flap, or dissecting aneurysm was observed at a nonbifurcation site. We used CT or MRI to detect cSAH, which was defined as blood collection restricted to one or few cerebral sulci without extending to the basal cisterns, ventricles, or Sylvian and interhemispheric fissures. Demographic, neuroimaging, treatment, and prognostic data were collected. <b><i>Results:</i></b> In total, 82 patients were diagnosed with ischemic stroke caused by cerebral artery dissection. The following arteries were affected: the ICA (9 patients), anterior cerebral artery (ACA; 12 patients), middle cerebral artery (MCA; 12 patients), vertebral artery (37 patients), basilar artery (5 patients), posterior cerebral artery (2 patients), and posterior inferior cerebellar artery (4 patients). In addition, 1 patient presented with simultaneous dissection in both the vertebral and internal carotid arteries, and 6 patients (7%) presented with cSAH (3 men and 3 women, age 39-67 years). The MCA was dissected in four cases and the ACA in two cases, with cSAH frequencies of 33 (4 of 12) and 17% (2 of 12), respectively, in those vessels. Artery dissection in the vertebrobasilar artery system was not responsible for cSAH (0 of 48). In all the MCA dissection cases, cSAH occurred in the arterial border zone between the ACA and MCA territories. Although 2 patients showed early reperfusion with temporary cSAH enlargement, cSAH was self-limiting. Antithrombotic treatment did not complicate the clinical course when used in 4 patients during acute or subacute phases. All patients achieved a 3-month poststroke modified Rankin Scale of 0-2. <b><i>Conclusion:</i></b> Our data suggest that cSAH caused by intracranial cerebral artery dissection is not rare. Further investigations are needed to elucidate the precise mechanism underlying cSAH in cerebral artery dissection

Supplementary Material for: A Novel Evaluation for Predicting Aortic Complicated Lesions Using Calcification on Chest X-ray

<p><b><i>Background:</i></b> The aorta is a significant source of cerebral thromboembolisms. Aortic complicated lesions (ACLs) are key findings on transesophageal echocardiography (TEE) for assessing aortic sources of emboli to the brain. TEE is sometimes avoided due to its invasiveness. However, few reports have examined alternative methods for predicting ACLs. We investigated relationships between aortic arch calcification (AAC) on chest X-ray and ACLs. <b><i>Methods:</i></b> Participants comprised 300 patients with acute ischemic stroke or transient ischemic attack who underwent TEE for the evaluation of the aortic arch and heart. A postero-anterior plain chest X-ray in the recumbent position was evaluated on admission for each patient. AAC was evaluated using 4 grades (0-3) and “AAC thickness” defined as the distance from the inner margin of the most distant AAC to the outer margin of the aortic vessel wall. ACLs were defined by intima-media thickness (IMT) ≥4.0 mm or presence of ulcerated or mobile plaques. Carotid maximum IMT on ultrasonography was also evaluated. Comparison of the diagnostic ability to predict ACL was performed between AAC grades and AAC thickness or AAC thickness and carotid maximum IMT using the Delong method. <b><i>Results:</i></b> ACLs were identified in 71 patients (23.7%), including ACLs with ulcerated plaques in 24 (8.0%) and ACLs with mobile plaques in 9 (3.0%). Plaque thickness was greater in higher AAC grades or higher quartiles of AAC thickness (<i>p</i> for trend <0.001 each). The Cochran-Armitage test showed that both higher AAC grade and higher quartile of AAC thickness were significantly associated with the presence of ACLs, as well as the presence of ulcerated or mobile plaques (<i>p</i> for trend < 0.001 each). Receiver-operating characteristic (ROC) analysis showed optimal cut-off values for AAC thickness of 5.6 mm for ACLs and 6.0 mm for ulcerated or mobile plaques. Multivariate logistic regression revealed a higher grade of AAC (grades 2-3) and AAC thickness (≥6 mm) as significantly associated with ACLs and ulcerated or mobile plaques (<i>p</i> < 0.001 each). ROC curve comparisons showed that AAC thickness offered a better marker of ACLs than AAC grade (<i>p</i> = 0.019), although no significant difference was evident between AAC thickness and carotid maximum IMT (<i>p</i> = 0.567). <b><i>Conclusions:</i></b> AAC on chest X-ray, evaluated by both AAC grade and AAC thickness to the outer aortic vessel wall, was significantly associated with ACLs on TEE. AAC thickness was suggested as more useful than AAC grade and equivalent to carotid IMT in predicting ACLs.</p

Supplementary Material for: Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

<p><b><i>Background:</i></b> Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. <b><i>Methods:</i></b> We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. <b><i>Results:</i></b> Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. <b><i>Conclusion:</i></b> We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.</p

Supplementary Material for: The Effects of Chronic Subcutaneous Administration of an Investigational Kisspeptin Analog, TAK-683, on Gonadotropin-Releasing Hormone Pulse Generator Activity in Goats

The continuous activation of the kisspeptin receptor by its agonists causes the abrogation of kisspeptin signaling, leading to decreased pulsatile luteinizing hormone (LH) secretion. Employing this phenomenon as a tool for probing kisspeptin action, this study aimed to clarify the role of kisspeptin in gonadotropin-releasing hormone (GnRH) pulse generation in goats. We examined the effects of chronic administration of TAK-683, an investigational kisspeptin analog, on LH secretion, GnRH immunostaining, pituitary responses to exogenous GnRH, and GnRH pulse generator activity, reflected by a characteristic increase in multiple-unit activity (MUA volley). An osmotic pump containing TAK-683 was subcutaneously implanted on day 0. TAK-683 treatment dose-dependently suppressed pulsatile LH secretion on day 1. Higher doses of chronic TAK-683 profoundly suppressed pulsatile LH secretion but had little effect on GnRH immunostaining patterns and pituitary responses to GnRH on day 5. In ovariectomized goats, MUA volleys occurred at approximately every 30 min on day -1. On day 5 of chronic TAK-683 administration, pulsatile LH secretion was markedly suppressed, whereas MUA volleys were similar to those observed on day -1. Male pheromones and senktide (neurokinin B receptor agonist) induced an MUA volley but had no effect on LH secretion during chronic TAK-683 administration. The results indicate that the chronic administration of a kisspeptin analog profoundly suppresses pulsatile LH secretion without affecting GnRH content, pituitary function or GnRH pulse generator activity, and they suggest an indispensable role for kisspeptin signaling in the cascade driving GnRH/LH pulses by the GnRH pulse generator

Supplementary Material for: Social Anxiety/Taijin-Kyofu Scale (SATS): Development and Psychometric Evaluation of a New Instrument

<i>Background:</i> Taijin-kyofu (TK), especially the ‘convinced' subtype of TK (c-TK; also known as the ‘offensive' subtype of TK), is described as a Japanese culture-bound syndrome similar to social anxiety disorder (SAD). Recently, in Western countries, the symptoms of c-TK have been investigated in patients with SAD. We developed the Social Anxiety/Taijin-Kyofu Scale (SATS), a 12-item structured clinician-rated instrument designed to rate the severity of TK symptoms, and examined its reliability and validity. <i>Methods:</i> The SATS was administered to 15 patients with c-TK diagnosed using the traditional Japanese TK criteria. Interviews used to score patients' symptoms were recorded on videotape. Additionally, the Clinical Global Impression-Severity Scale (CGI-S) was administered to assess convergent validity. Interrater reliability was assessed on 15 videotaped interviews; the interviews were independently rated by 10 other raters. Test-retest re-liability was assessed on 15 videotaped interviews by the same rater at an interval of more than 4 weeks. <i>Results:</i> The SATS had high internal consistency (Cronbach's α = 0.97) and good interrater reliability (ICC = 0.88-0.93) and test-retest reliability (ICC = 0.94-0.99). The SATS total score correlated with the CGI-S scores (r = 0.77, p < 0.0001). <i>Conclusion:</i> The SATS appears to be a reliable and valid measure of the symptoms of TK

Supplementary Material for: Prognostic Value of Pre- and Postoperative Anti-p53 Antibody Levels in Colorectal Cancer Patients: A Retrospective Study

<p><b><i>Objective:</i></b> To determine the utility of the post-/preoperative anti-p53 antibody (p53 Ab) ratio as a prognostic factor for colorectal cancer (CRC) recurrence. <b><i>Methods:</i></b> A total of 737 nonmetastatic CRC patients who had undergone R0 resection were retrospectively analyzed. p53 Ab levels were measured within 1 month prior to and at least every 3 months after surgery. Post-/preoperative p53 Ab ratios were calculated, and the optimal ratio cutoff values for predicting recurrence were determined using the Kaplan-Meier method and the log-rank test. <b><i>Results:</i></b> Preoperative p53 Ab elevation was observed in 194 patients (pre-p53 high). Preoperative p53 Ab levels correlated with TNM stage. Re-elevation of p53 Ab levels occurred on recurrence in the pre-p53 high group, but not in the pre-p53 low group (n = 543). In the pre-p53 high group, patients who experienced tumor recurrence exhibited a slow postoperative reduction of p53 Ab levels, and a post-/preoperative p53 Ab ratio >0.4 at postoperative 3 months predicted relapse-free survival. In other words, a p53 Ab level remaining higher than 40% of the preoperative level was an independent and strong risk factor for recurrence in multivariate analyses. <b><i>Conclusion:</i></b> In CRC patients with preoperative p53 Ab elevation, the rate of p53 Ab reduction in the early postsurgical period is a promising prognostic factor for recurrence.</p

Supplementary Material for: Serum Proteomic Signatures of Common Health Outcomes among Older Adults

Introduction: In aging populations, the coexistence of multiple health comorbidities represents a significant challenge for clinicians and researchers. Leveraging advances in omics techniques to characterize these health conditions may provide insight into disease pathogenesis as well as reveal biomarkers for monitoring, prognostication, and diagnosis. Researchers have previously established the utility of big data approaches with respect to comprehensive health outcome measurements in younger populations, identifying protein markers that may provide significant health information with a single blood sample. Methods: Here, we employed a similar approach in two cohorts of older adults, the Baltimore Longitudinal Study of Aging (mean age = 76.12 years) and InCHIANTI Study (mean age = 66.05 years), examining the relationship between levels of serum proteins and 5 key health outcomes: kidney function, fasting glucose, physical activity, lean body mass, and percent body fat. Results: Correlations between proteins and health outcomes were primarily shared across both older adult cohorts. We further identified that most proteins associated with health outcomes in the older adult cohorts were not associated with the same outcomes in a prior study of a younger population. A subset of proteins, adiponectin, MIC-1, and NCAM-120, were associated with at least three health outcomes in both older adult cohorts but not in the previously published younger cohort, suggesting that they may represent plausible markers of general health in older adult populations. Conclusion: Taken together, these findings suggest that comprehensive protein health markers have utility in aging populations and are distinct from those identified in younger adults, indicating unique mechanisms of disease with aging