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Objectives: Describe the details of the clinical presentation, diagnostic challenges, and management of a female neonate with neonatal severe hyperparathyroidism (NSHPT). Methods: This case report was developed from a retrospective chart review. The female infant was born to consanguineous parents—first cousins, with multiple prenatal concerns, including gestational diabetes, intrauterine growth restriction, polyhydramnios, and suspicion of a hypoplastic left atrium on prenatal echocardiogram (ECHO). Following a planned C‐section at 37 weeks gestation, the neonate exhibited moderate respiratory distress with subcostal retractions. On physical examination, craniotabes, a bell‐shaped chest, and a continuous machinery‐type murmur were noted. Results: Evaluation at birth revealed a large Patent Ductus Arteriosus and significant demineralization of skeletal structures with atypical rib morphology. Lab work at 24 h of life (HOL) showed elevated serum calcium level (14.3 mg/dL), ionized calcium—iCal (2.32 mmol/L), and normal 25‐OH Vitamin D (54.2 ng/mL). A comprehensive skeletal survey uncovered generalized osteopenia, metaphyseal lucencies, and evidence of healing fractures. Repeat lab work at 43 HOL, showed serum calcium of 18.0 mg/dL, iCal 2.67 mmol/L, and elevated parathyroid hormone (PTH) of 2116 pg/mL. Diagnosis of NSHPT was established based on laboratory findings. Molecular testing confirmed a homozygous variant (c.1744T >A; p.Cys582Ser) in the calcium‐sensing receptor (CaSR) gene which confirmed the diagnosis of NSHPT. NSHPT, a rare genetic disorder associated with high mortality rates, is often caused by inactivating CaSR gene variants. The patient's family history revealed a strong correlation with familial hypocalciuric hypercalcemia (FHH), a benign condition associated with asymptomatic hypercalcemia, normal to minimally elevated parathyroid level, and hypocalciuria, it is caused by heterozygous inactivating mutations in the CaSR gene. Treatment of NSHPT typically involves total or subtotal parathyroidectomy; however, initial medical intervention is often necessary. In this case, the neonate underwent medical treatment with calcitonin, furosemide to help facilitate renal clearance of calcium, and intravenous fluids before a successful parathyroidectomy. Conclusions: This case accentuates the importance of considering rare genetic disorders in neonates with complex clinical presentations and affirms the need for comprehensive counseling and education, particularly in consanguineous parents, to address familial implications and guide appropriate interventions. [ABSTRACT FROM AUTHOR]

Myxedema coma is a rare life‐threatening form of hypothyroidism that manifests as neuropsychiatric, metabolic, respiratory, and cardiovascular dysfunction. From 2010 to 2022, our hospital managed three cases of myxedema coma. While the overall characteristics of these cases were similar to those in previous reports, we noticed that all cases were negative for thyroid autoantibodies and an autopsy in one of the cases exhibited end‐stage thyroiditis. During a systematic review of cases from 1999 to 2022, we also noticed that a significant proportion of myxedema coma was caused by seronegative primary hypothyroidism especially in Japan. [ABSTRACT FROM AUTHOR]

A 24‐year‐old Indigenous Australian female with long‐standing, poorly controlled type 1 diabetes mellitus (T1DM) presented with 3 months' history of unilateral thigh swelling and pain. Her laboratory investigations showed evidence of a persistent inflammatory state with normal creatine kinase. Infectious and autoimmune investigations were negative. Imaging demonstrated evidence of muscular oedema and atrophy. Muscular pain and swelling have a broad list of differential diagnoses. This case highlights a rare but potentially debilitating complication of diabetes mellitus—diabetic myonecrosis with its challenges in reaching a definitive diagnosis due to non‐specific symptomology and laboratory findings. However, it is an important differential of leg pain and swelling to consider, particularly in those with long‐standing diabetes and pre‐existing microvascular complications. Glycaemic control is paramount in preventing this potentially severe diabetic complication. [ABSTRACT FROM AUTHOR]

Background: Several cases of severe hypocalcemia in the setting of COVID‐19 have been reported. The proposed mechanisms include direct viral interaction with ACE2 receptors in the parathyroid gland, viral chelation of calcium, worsening hypovitaminosis D, critical illness leading to unbound fatty acids binding calcium, and inflammatory cytokines leading to PTH resistance. Given the life‐threatening nature of hypocalcemia, this underrecognized phenomenon should be on the forefront of the clinician's attention. This case highlights a rare manifestation of COVID‐19 and further complicated by the patient's reimplanted parathyroid gland. Presentation: A 73‐year‐old female with primary hyperparathyroidism status post parathyroidectomy with reimplantation in the left forearm presented with 4 days of viral syndrome, found to have tetany and Chvostek's sign on physical exam. Pertinent laboratory abnormalities included calcium 5.3 mg/dL, ionized calcium 0.44 mmol/L, magnesium 1.4 mg/dL, phosphorous 5.5 mg/dL, PTH 242 pg/mL, and 25‐OH vitamin D 56 ng/mL. Chest CT revealed multifocal pneumonia consistent with positive COVID‐19 testing. She was subsequently admitted to the ICU for severe, symptomatic hypocalcemia and was initiated on a continuous calcium infusion, remdesivir, baricitinib, and steroids. Tetany resolved after 9 g calcium repletion, and she was transferred to the medical floor with an ionized calcium of 0.83 mmol/L. On hospital day 3, repeat ionized calcium was 0.78 mmol/L despite ongoing repletion. Given the persistence of hypocalcemia, a repeat PTH level was obtained which remained high at 487 pg/mL, suggesting ongoing PTH interference in the setting of COVID‐19. PTH was obtained from the right (nonimplanted) arm which was normal at 74 pg/mL. This indicated an appropriate PTH response from the reimplanted gland, and that ongoing hypocalcemia may be due to insufficient PTH function to maintain systemic calcium levels or a peripheral interference with PTH level. With continued calcium supplementation and treatment of COVID‐19, the patient's calcium stabilized at 8.6 mg/dL. She was discharged on oral calcium supplementation with endocrinology follow‐up. Conclusion: Acute hypocalcemia strongly correlates with a profound inflammatory response in COVID‐19 patients. This case corroborates the cytokine/PTH hypothesis. This patient had a high PTH sampled near the reimplanted gland but an inappropriately normal PTH from the nonimplanted arm, indicating that direct viral interaction interfering with PTH release is an unlikely mechanism. This case represents a scenario where PTH can be sampled directly from the source and this type of model could aid in the process of determining the etiology of hypocalcemia in COVID‐19. [ABSTRACT FROM AUTHOR]

This case report presents a unique clinical scenario of a 58‐year‐old male suffering from severe refractory myasthenia gravis and concurrent alopecia areata postthymectomy. Myasthenia gravis, a common autoimmune disorder, is characterized by muscle weakness due to autoantibodies targeting neuromuscular junction proteins. Alopecia areata, another autoimmune disease, is often seen in individuals with myasthenia gravis, suggesting a shared immunological basis. The patient's condition was resistant to conventional treatment, and he developed alopecia areata following thymectomy. Despite the challenges in managing refractory myasthenia gravis and the associated alopecia areata, significant improvements were observed following a cortisone taper. This case highlights the potential therapeutic role of cortisone tapering in managing refractory myasthenia gravis and associated alopecia areata. This case also prompts further exploration into the immunological shifts following thymectomy, particularly its potential role in triggering alopecia areata. [ABSTRACT FROM AUTHOR]

Summary. Disorders of sexual differentiation are defined as congenital alterations between chromosomal, gonadal, and phenotypic sex. The principal cause of these disorders is an adrenal origin; however, there are infrequent causes, such as congenital lipoid adrenal hyperplasia. Case. We present the case of a woman who, during the neonatal period, presented salt‐losing adrenal insufficiency associated with 46 XY gonadal dysgenesis. The genetic study found a steroidogenic acute regulatory protein (StAR) mutation. Conclusion. Mutations in StAR result in a nonfunctional protein, which clinically translates into congenital adrenal hyperplasia and, in the case of patients with 46 XY karyotype, is accompanied by gonadal dysgenesis characterized by androgen deficiency, without alterations in anti‐Müllerian hormone. [ABSTRACT FROM AUTHOR]

Background. Primary adrenal insufficiency is an uncommon condition that manifests as nonspecific symptoms such as fatigue, weight loss, salt craving, and hyperpigmentation. Common cardiovascular presentations of AI are hypotension, arrhythmias, and syncope. However, acute heart failure is an uncommon presentation. Case Presentation. Here, a 26‐year‐old man was hospitalized with vasopressor‐resistant cardiogenic shock, which was finally attributed to an adrenal crisis. His past medical history was notable for Hashimoto's disease, controlled with oral levothyroxine. Conclusion. AI should be considered among patients with cardiogenic shock who are unresponsive to conventional inotropes. Additionally, a history of autoimmune diseases may increase the suspicion of AI. Although the presentation of cardiogenic shock in a patient with undiagnosed AI is considered a rarity, delay in prompt treatment can lead to life‐threatening conditions. [ABSTRACT FROM AUTHOR]

Background and Aim: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). Methods: This was a multicenter, double‐blind, placebo‐controlled phase 2a trial that evaluated 24 patients with biologic‐resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. Results: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin‐treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin‐treated groups at 24 weeks (P = 0.043) in the mixed‐effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. Conclusion: In this trial, we observed a long‐lasting (24 weeks) decrease in CDAI in the adrenomedullin‐treated groups. Adrenomedullin might be beneficial for biologic‐resistant CD, but further research is needed. [ABSTRACT FROM AUTHOR]

The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study. [ABSTRACT FROM AUTHOR]

Isolation studies on the peptides in human urine reveal the presence of uroguanylin, a unique peptide that resembles guanylin in functional behavior. The peptide possesses guanylate cyclase C stimulatory activity and is present in large amounts. Uroguanylin possibly regulates renal electroylte balance, while guanylin is involved in the intestinal region.

Background andObjective: Seasonal variation of blood pressure (BP) is well known, and a relationship between increases in BP and the incidence of cardiovascular accidents (CVAs) in the winter has been reported. Parameters of arterial stiffness may exhibit seasonal variation; however, available data are currently limited. Novel arterial stiffness indexes, namely the arterial velocity pulse index (AVI) and arterial pressure–volume index (API), can be determined through usual maneuver for BP measurement during the regular examination in the outpatient clinic.The present study assessed the seasonal variation of AVI and API in 59 hypertensive patients undergoing stable treatment and regularly visiting our outpatient clinic over a period of 30 months. Methods: BP, pulse rate (PR), AVI, and API were measured using the AVE-1500 (Pasesa) in the sitting position. Six time frames of assessment were established. All measurements (average: 17.9 measurements per person) were sorted using these six time frames, and their averages were used for analysis. Results: Significant seasonal variations in PR (P < 0.001) and AVI (P < 0.001), along with weak variation in systolic BP (SBP) (P = 0.047) and marginal variation in API (P = 0.055), were confirmed by repeated analysis of variance. SBP, API, and PR were decreased, whereas AVI was increased in the summer. Coefficient variations were SBP 5.1%, PR 4.9%, AVI 12.6%, and API 10.6%. Conclusion: AVI was associated with reflected wave like as augmentation index. Thus, a high AVI may suggest increased central wave reflection. Although the significance of seasonal variation of AVI remains unknown, AVI may influence seasonal variations in the incidence of CVA. [ABSTRACT FROM AUTHOR]

Kita, Toshihiro, Kazuo Kitamura, Junichiro Sakata, and Tanenao Eto. Marked increase of guanylin secretion in response to salt loading in the rat small intestine. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G960-G966, 1999.--Guanylin and uroguanylin are intestinal peptides that stimulate guanylate cyclase C and cause chloride secretion. These peptides show topological instability due to two disulfide bonds. The disulfide bonds were reduced and S-carboxymethylated to cleave the bonds and obtain stable and sole derivatives. We established a new and reliable RIA system for the stable derivatives from both peptides. With the use of this system, the response of the peptides to salt loading of the rat small intestine was evaluated. The lumen of the small intestines of Sprague-Dawley rats was perfused in vivo with Krebs-Ringer solution containing different concentrations of salt or mannitol. Mature guanylin, proguanylin, and mature uroguanylin were found in the perfusate in the basal state. The highest salt loading (200 mM NaCl for 20 min) increased the guanylin secretion about threefold (1.9 [+ or -] 0.2 vs. 5.4 [+ or -] 0.5 pmol/min), with the effect lasting for 60 min. The uroguanylin secretion was less affected. Hyperosmolar mannitol also caused a significant but smaller increase of guanylin secretion. Increased guanylin could lead to increased salt and water secretion of the intestine; thus members of the guanylin family have potential roles in the regulation of water and salt metabolism in the small intestine. uroguanylin; radioimmunoassay; chloride secretion; reductive S-carboxymethylation

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles. [ABSTRACT FROM AUTHOR]

Although blockade of the renin-angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly ( p < 0.001). Attainment of the target office BP ( p = 0.0014) and 24-h BP levels ( p = 0.0296) also improved significantly. Subgroup analysis indicated that the reduction of 24-h systolic BP was larger in patients treated with diuretics than those without ( p = 0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect. [ABSTRACT FROM AUTHOR]

Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1 -year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension. [ABSTRACT FROM AUTHOR]

Dietary K+ intake may increase renal K+ excretion via increasing plasma [K+] and/or activating a mechanism independent of plasma [K+]. We evaluated these mechanisms during normal dietary K+ intake. After an overnight fast, [K+] and renal K+ excretion were measured in rats fed either 0% K+ or the normal 1% K+ diet. In a third group, rats were fed with the 0% K+ diet, and KCl was infused to match plasma [K+] profile to that of the 1% K+ diet group. The 1% K+ feeding significantly increased renal K+ excretion, associated with slight increases in plasma [K+], whereas the 0% K+ diet decreased K+ excretion, associated with decreases in plasma [K+]. In the KCl-infused 0% K+ diet group, renal K+ excretion was significantly less than that of the 1% K+ group, despite matched plasma [K+] profiles. We also examined whether dietary K+ alters plasma profiles of gut peptides, such as guanylin, uroguanylin, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, pituitary peptides, such as AVP, α-MSH, and γ-MSH, or aldosterone. Our data do not support a role for these hormones in the stimulation of renal K+ excretion during normal K+ intake. In conclusion, postprandial increases in renal K+ excretion cannot be fully accounted for by changes in plasma [K+] and that gut sensing of dietary K+ is an important component of the regulation of renal K+ excretion. Our studies on gut and pituitary peptide hormones suggest that there may be previously unknown humoral factors that stimulate renal K+ excretion during dietary K+ intake. [ABSTRACT FROM AUTHOR]

Cardiovascular accidents related to atherosclerosis are the leading cause of death among hemodialysis patients, which makes continuous monitoring of their cardiovascular status crucial. Recently, a handy device for monitoring the augmentation index (AIx) in the radial artery was introduced in Japan, enabling the use of the AIx in addition to pulse wave velocity (PWV) in the management of hemodialysis patients. In this study the AIx, PWV, abdominal aortic calcification index (ACI), and left ventricular mass index (LVMI) were serially assessed in 108 hemodialysis patients. The radial AIx was monitored using a newly introduced tonometer (HEM-9010AI), and the interrelationships among the measured parameters and their contributions to the risk of cardiovascular accidents were evaluated. The radial AIx was significantly higher in hemodialysis patients than in healthy subjects ( N = 50) and was well correlated with risk markers such as LVMI ( r = 0.30, P = 0.019) and ACI ( r = 0.38, P < 0.001), but not with PWV. Multiregression analysis showed that radial AIx was also significantly associated with LVMI, ACI and blood pressure; PWV was associated with other parameters such as age, blood pressure, and ACI. The AIx and ACI were both significantly increased in patients with cardiovascular complications. Although PWV was strongly increased in the hemodialysis patients, it failed to discriminate between these subgroups of high-risk patients. The radial AIx is closely associated with aortic calcification, cardiac hypertrophy, and a history of cardiovascular accidents in hemodialysis patients, and could be a useful marker for management of these patients. [ABSTRACT FROM AUTHOR]

This paper presents numerical results on bifurcations and chaotic behavior in a fundamental power system model, a single-machine infinite-bus system model with generator excitation control by the first-order lag AVR. The numerical analysis mainly focuses on revealing the parameter value region where the chaotic behavior is observed. It is shown that the partially linearized model, which is derived by linearizing all of the nonlinear elements except the AVR limiter, exhibits similar bifurcations and chaos. Several simulation results indicate that the mechanisms producing the chaotic behaviors and the bifurcations are the same both in the linearized model and in the original single-machine infinite-bus system model for parameter value variation which does not move the equilibrium point from the reference point used for the linearization. © 2002 Wiley Periodicals, Inc. Electr Eng Jpn, 142(2): 21–28, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10090 [ABSTRACT FROM AUTHOR]

Background: The novel peptide, uroguanylin, is mainly produced in the intestine and causes natriuresis via cyclic GMP (cGMP) activation. Uroguanylin plays an important role in sodium transport in the gastrointestinal tract and functions as an intestinal natriuretic hormone during oral salt load. However, the role and behavior of uroguanylin in the kidneys during high salt load remains unknown. Methods: We measured the uroguanylin concentrations in the urine and plasma of rats fed with low or high salt diets for 1 week, using a sensitive radioimmunoassay (RIA). Urinary cGMP and electrolyte excretion was also measured. Intestinal and renal expression of uroguanylin mRNA was evaluated by Northern blotting and by reverse transcription-polymerase chain reaction (RT-PCR). Results: The urinary excretion of immunoreactive (ir-) uroguanylin in rats on the high salt diet was significantly higher than that in the low salt group (425 ± 107 vs. 128 ± 8.5 pmol/day, p < 0.01) and significantly correlated with urinary Na[sup +] and cGMP excretion. Plasma ir-uroguanylin levels between the two groups did not significantly differ. Uroguanylin mRNA expression was increased both in the intestine and kidneys of rats on the high salt diet. Conclusion: These findings suggest that uroguanylin regulates sodium metabolism in the intestine and kidneys during oral salt load in an autocrine and paracrine manner.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn's disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment. [ABSTRACT FROM AUTHOR]

A 35-year-old man with refractory Crohn's disease showed a loss of response to infliximab after requiring treatment with infliximab at 10 mg/kg together with steroid to maintain remission. His symptoms recurred, and colonoscopy showed extensive active ulcers in the colon. Adrenomedullin therapy was started in addition to the conventional infliximab therapy. A few days after, his symptoms went into remission. Endoscopy at 2 and 7 weeks revealed significant mucosal remission without steroid therapy. Adrenomedullin promoted mucosal healing and led to the re-induction of remission in Crohn's disease in a patient with a loss of response to infliximab.