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Microbubble testing using transcranial Doppler (TCD) is an important screening tool for diagnosing paradoxical cerebral embolism with high-risk PFO. However, little is known about the association between the microbubble test by TCD and the features of high-risk PFO evaluated by transesophageal echocardiography (TEE). We studied 101 consecutive patients at Showa University, from April 2019 to October 2020, who underwent both TCD and TEE with a sufficient Valsalva maneuver and who were strongly suspected by neurologists as cryptogenic stroke. According to the appearance of microbubbles as high-intensity transient signals (HITS), the TCD grade was stratified into three categories based on the criteria (A: none, no HITS, B: small; 1-10 HITS, and C: large; 10 HITS, or an uncountable number of HITS). Among patients with RLS through the PFO in TEE, high-risk morphological features of PFO for cerebral embolism were evaluated as follows: (1) tunnel height, (2) tunnel length, (3) total excursion distance of the atrial septum into the right and left atrium, (4) existence of Eustachian valve or Chiari network, (5) angle of PFO from the inferior vena cava, and (6) large shunt (20 or more microbubbles). Of 101 patients (TCD grade; Group A = 49, Group B = 26, Group C = 26), RLS through PFO was detected in 37 patients (grade A = 8, grade B = 6, grade C = 23) by TEE. Among PFO-positive patients, tunnel height, length, total excursion distance into the right and left atria, angle of PFO from the inferior vena cava, and frequency of large shunt in TEE were significantly larger in grade C than in grade A and B (p 0.05). Additionally, grade C patients had significantly more forms of high-risk PFOs than those in grades A and B when the six features of high-risk PFO were compared. A multivariate logistic regression demonstrated that the tunnel length of PFO and the presence of large shunt in TEE were independently associated with large HITS in TCD (odds ratio: 1.18 and 49.5, 95% confidence interval 1.043-1.337 and 10.05-244.3, p = 0.0086 and p 0.0001, respectively). In conclusion, the existence of a large HITS detected by TCD may have a screening advantage in predicting the high-risk morphologies of PFO that can cause paradoxical cerebral embolism.

Tricuspid regurgitation (TR) is a common condition that is independently associated with high mortality rates in patients with heart failure (HF). Several studies have demonstrated the clinical efficacy of add-on tolvaptan in patients hospitalized for HF. However, the effects of add-on tolvaptan in patients with significant TR are less well understood. Among the patients with moderate-to-severe TR assessed by transthoracic echocardiography during hospitalization for congestive HF, 39 patients who could complete the clinical course after starting add-on tolvaptan were included in the study. Rehospitalization due to HF and cardiac death were defined as adverse cardiac events in this study. We investigated the presence or absence of cardiac events within 2 years following the introduction of tolvaptan and evaluated echocardiographic functional parameters associated with cardiac events. The average patient age was 75 ± 14 years, and 23 patients (59%) experienced adverse cardiac events within 2 years after add-on tolvaptan administration. Serum creatinine (mg/dL) and brain natriuretic peptide (pg/mL) concentrations at discharge were significantly higher in patients with cardiac events than in those without cardiac events {1.48 [1.02-1.58] vs. 1.07 [0.79-1.41], p = 0.03; 526 [414-1044] vs. 185 [104-476], p = 0.01, respectively}. The presence or absence of past hospitalization for HF was also significantly higher in the event-positive group compared to event-free group (78 vs. 44%, p = 0.04). Comparison of echocardiographic parameters revealed that patients with cardiac events had a significantly lower left ventricular ejection fraction (40 ± 16 vs. 49 ± 15%, p = 0.049) and lower right ventricular fractional area change (RVFAC) (35 ± 12 vs. 45 ± 10%, p = 0.008) than those without cardiac events. Multiple logistic regression analysis revealed that RVFAC and past hospitalization for HF were independently associated with cardiac events following the introduction of tolvaptan (odds ratio, 0.934 and 4.992; p = 0.048 and 0.04, respectively). Right ventricular contractility as well as past history of admission for HF, left ventricular ejection fraction, renal function, and brain natriuretic peptide level at discharge may reflect the clinical outcomes after HF hospitalization in patients with significant TR who were treated with tolvaptan.

Aspiration pneumonia is a common complication of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome. However, the detailed clinical course of aspiration pneumonia in neonates and infants diagnosed with this disorder remains unclear. We report a case of a 2-yr-old girl diagnosed with MIRAGE syndrome during the early neonatal period. The patient developed 3 episodes of aspiration pneumonia until 4 mo of age, and this complication was attributed to esophageal hypoperistalsis secondary to achalasia and gastroesophageal reflux. Enteral feeding via a duodenal tube effectively prevented further episodes of aspiration pneumonia in this patient.

Hypertension is one of the most serious side effects of glucocorticoid therapy. We retrospectively investigated the frequency of hypertension during treatment of adrenal crisis and analyzed the factors associated with its development. Patients who were admitted for primary hypoadrenalism due to diagnosed or suspected adrenal crisis were included. In the analysis, the subjects were divided into two groups: the hypertensive group (group H) and non-hypertensive group (group Non-H). The primary endpoint was the difference in the hourly therapeutic hydrocortisone (HDC) dosage between the two groups. The hourly therapeutic HDC dose in the two groups was defined as the hourly HDC dose from the start of HDC infusion until the development of hypertension in group H or until the last blood pressure measurement in group Non-H. Nine of 19 crises led to hypertension. There was no significant difference in the therapeutic HDC dosage between the groups (p = 0.108). In conclusion, hypertension developed in some patients during treatment for adrenal crisis. There was no significant difference in the therapeutic HDC dosage between groups H and Non-H.

There are as yet no cohort studies of hypoglycemia in type 1 diabetes before starting insulin therapy. Our aim was to determine the frequency and clinical features of hypoglycemia in patients with type 1A diabetes prior to commencing insulin therapy.Eighty-seven patients with type 1A diabetes were enrolled, and a retrospective chart review of the patients was conducted.Hypoglycemia before insulin therapy occurred in six of 87 patients (6.9%). The HbA1c levels at the diagnosis of type 1A diabetes in the hypoglycemia group were lower than in the non-hypoglycemia group (median: 7.3% (56 mmol/mol) vs. 11.9% (106 mmol/mol), p 0.0001). Similarly, the 24-hour urinary C-peptide (UCPR) levels of the former group were higher than those of the latter group (16.5 μg/day/mWe demonstrated that some patients with type 1A diabetes experience hypoglycemic episodes before insulin therapy. Patients with early-stage type 1A diabetes with relatively low HbA1c or high UCPR have a risk of hypoglycemia. These findings may impact when and how insulin is introduced in the treatment of early-stage type 1A diabetes.

Familial hypercholesterolemia (FH, OMIM number #143890) is an autosomal dominant disorder, resulting in low-density lipoprotein (LDL) receptor dysfunction. The prevalence of FH is estimated to be approximately, 1 in 200 and 1 in 170,000 among heterozygotes and homozygotes, respectively (1). Since FH patients develop severe coronary-artery disease (CAD) due to hypercholesterolemia in early adult life, lipid-lowering treatments must be started at childhood (2). Although pediatric FH is clinically diagnosed based on the serum LDL cholesterol (LDL-C) levels and a family history of hypercholesterolemia, genetic analysis is useful for a definitive diagnosis, as it can predict the risk stratification of CAD (3, 4) and assist in early diagnosis and intervention, leading to improved prognosis. Here, we present a novel mutation in the LDLR gene, in a patient with heterozygous FH (HeFH).

Context Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings. Objective To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients. Methods We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics. Results We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency. Conclusions Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.

Chronic inflammation is a molecular element of the metabolic syndrome and type 2 diabetes. Saturated fatty acids (SFAs) are considered to be an important proinflammatory factor. However, it is still incompletely understood how SFAs induce proinflammatory cytokine expression. Hereby we report that activating transcription factor (ATF) 4, a transcription factor that is induced downstream of metabolic stresses including endoplasmic reticulum (ER) stress, plays critical roles in SFA-induced interleukin-6 (Il6) expression. DNA microarray analysis using primary macrophages revealed that the ATF4 pathway is activated by SFAs. Haploinsufficiency and short hairpin RNA–based knockdown of ATF4 in macrophages markedly inhibited SFA- and metabolic stress–induced Il6 expression. Conversely, pharmacological activation of the ATF4 pathway and overexpression of ATF4 resulted in enhanced Il6 expression. Moreover, ATF4 acts in synergy with the Toll-like receptor-4 signaling pathway, which is known to be activated by SFAs. At a molecular level, we found that ATF4 exerts its proinflammatory effects through at least two different mechanisms: ATF4 is involved in SFA-induced nuclear factor-κB activation; and ATF4 directly activates the Il6 promoter. These findings provide evidence suggesting that ATF4 links metabolic stress and Il6 expression in macrophages.

Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

Context: Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide. Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity, and its functional significance in vivo is currently unknown.Objective: We examined the functional significance of a novel NPR-B KHD mutation in humans.Patients and Methods: A 28-yr-old Japanese male presented with marked short stature (118.5 cm, −9.3 sd). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z-scores of −2.75 and −0.98 (his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and wild type allele was investigated by the titration experiments.Results: We identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for C-type natriuretic peptide but no discernible ligand-induced cGMP production. Furthermore, L658F mutant impaired wild-type NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant-negative effect.Conclusions: This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development.

Androgen insensitivity syndrome (AIS) is an X-linked recessive disorder caused by mutation in the gene for the androgen receptor (AR) with 46,XY karyotype (OMIM 300068). The clinical phenotype of AIS is complete or partial. Complete AIS is characterized by a consistent phenotype: unambiguous female external genitalia, breast development at pubertal age, blind-ending vagina, absence of uterus, absent or scant pubic and axillary hair, and presence of normally differentiated testes in a girl or woman. However, the clinical features of partial AIS are variable: ambiguous external genitalia in a girl or woman, undervirilized external genitalia in a boy or man, or azospermia with unambiguous male external genitalia in a man (1,2,3,4). So far more than 300 mutations in all exons of the AR gene have been reported in complete AIS (5). We report a novel mutation of the AR gene in a patient with complete AIS.

Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation. Obese adipose tissue is characterized by dynamic changes in cellular composition and function, which may be referred to as “adipose tissue remodeling”. Among stromal cells in the adipose tissue, infiltrated macrophages play an important role in adipose tissue inflammation and systemic insulin resistance. We have demonstrated that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 complex, thereby activating macrophages. Such a sustained interaction between endogenous ligands derived from parenchymal cells and pathogen sensors expressed in stromal immune cells should lead to chronic inflammatory responses ranging from the basal homeostatic state to diseased tissue remodeling, which may be referred to as “homeostatic inflammation”. We, therefore, postulate that adipose tissue remodeling may represent a prototypic example of homeostatic inflammation. Understanding the molecular mechanism underlying homeostatic inflammation may lead to the identification of novel therapeutic strategies to prevent or treat obesity-related complications.

IMAGe association is a recently recognized multi-system disorder of unknown etiology. IMAGe is a mnemonic acronym that stands for Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies (OMIM 300290). Suspicion for the disorder is readily raised by the distinctive clinical and endocrinological constellation, and radiological identification of metaphyseal dysplasia is crucial for the diagnosis. However, knowledge of the onset, evolution, severity, and variation of the metaphyseal dysplasia is currently limited. We illustrate the radiological evolution of an affected girl from her premature birth to early childhood. Her initial skeletal changes included thin ribs, delayed ossification of the juxtatruncal bones, and delayed epiphyseal ossification. The former two became less conspicuous during infancy. Metaphyseal dysplasia was not discerned at birth. However, mild metaphyseal cupping, sclerosis and longitudinal striations became manifest in late infancy, and then progressed with age. It is thought that the skeletal alterations in IMAGe association encompass retarded endochondral ossification normalized later on and mild metaphyseal dysplasia of postnatal onset.

Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder characterized by renal tubular insensitivity to antidiuretic hormone, resulting in an inability to concentrate urine. We report on an infant boy with CNDI who showed growth failure during treatment with sodium restriction. At the age of 4 mo, he was diagnosed as having CNDI, judging from fever with hypernatremia (serum Na 153 mEq/L), diluted urine (urine osmolarity 193 mOsm/kg), high antidiuretic hormone (plasma antidiuretic hormone 53 pg/mL), and normal renal function (serum creatinine 0.3 mg/dL). His length and weight were mean +0.4 and -1.1 SD, respectively, at that time. He was treated with sodium restriction (sodium intake; 0.53 mEq/kg/day) using low sodium formula in addition to trichlormethiazide, spironolactone, and mefenamic acid. Growth failure developed: his length and weight were mean -2.4 and -3.3 SD, respectively, at the age of 10 mo. After withdrawal of sodium restriction to 1.5 mEq/kg/day of sodium intake without any change of caloric intake and medication, catch-up growth was observed. At the age of 39 mo, the patient's height and weight were mean -0.8 and -0.6 SD, respectively. We conclude that excessive sodium restriction can cause growth failure in infants with CNDI.