The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors.

Context: The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective: We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods: We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results: Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion: We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.

Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics.

Cases in which bilateral adrenal 123I-Metaiodobenzylguanidine (123I-MIBG) scintigraphy accumulation is sometimes shown, with mildly elevated catecholamine (CA) or metanephrine (MN) levels (within 3 times the upper reference limit) are diagnostic dilemmas. We experienced 3 cases of adrenal incidentalomas with this dilemma in the differential diagnosis. The clinical diagnosis was subclinical Cushing's syndrome in 2 cases, and primary aldosteronism in 1. Despite suspected CA excess in clinical symptoms and imaging findings, the pathological findings of all these tumors were revealed to be cytochrome P450 family 11 subfamily B member 1 (CYP11B1) positive adrenocortical adenomas. Interestingly, adrenal medullary hyperplasia (AMH) was detected in the adrenal parenchyma of all those backgrounds. To clarify the clinical features of such cases, a cross-sectional study was conducted at the Kobe University Hospital from 2014 to 2020. One-hundred sixty-four patients who had undergone 123I-MIBG scintigraphy were recruited. Among them, 10 patients (6.1%) met the above criteria, including the presented 3 cases. Plasma adrenaline, noradrenaline, urinary metanephrine, and normetanephrine had values of 0.05 ± 0.05 ng/mL, 0.63 ± 0.32 ng/mL, 0.22 ± 0.05 mg/day, and 0.35 ± 0.16 mg/day, respectively. Nine cases were complicated with hypertension, and symptoms related to CA excess were observed. Half of them (5 cases) including presented 3 cases had unilateral adrenal tumors. These suggest that in cases of bilateral adrenal uptake on 123I-MIBG, AMH needs to be considered. Adrenocortical adenomas may be associated with AMH and further larger investigation is needed for this pathology.

Effects of L-carnitine supplementation on the quality of life in diabetic patients with muscle cramps.

Diabetic patients often suffer from muscle cramps. This study aimed to compare the quality of life (QOL) of diabetic patients with and without muscle cramps and to investigate the effect of L-carnitine supplementation in diabetic patients with muscle cramps. A total of 91 patients with diabetes were enrolled in this study: 69 patients with muscle cramps and 22 patients without muscle cramps. Muscle cramps and QOL were evaluated using the muscle cramp questionnaire and the Short Form 36 health survey version 2 (SF-36), respectively. Clinical characteristics were compared between diabetic patients with and without muscle cramps. In the prospective portion of the study, 25 diabetic patients with muscle cramps received L-carnitine supplementation (600 mg/day orally) for 4 months. The questionnaires were administered before and after supplementation. The SF-36 scores in diabetic patients with muscle cramps were lower than those in patients without muscle cramps on the subscales of physical function, role physical, bodily pain, vitality, general health, and social function. In the 25 patients with muscle cramps who received L-carnitine supplementation, the monthly frequency of muscle cramps and Wong-Baker FACES® Pain Rating Scale scores were significantly decreased. Scores on the following SF-36 subscales improved after L-carnitine supplementation: body pain, vitality, social function, and role emotional. This study demonstrated that muscle cramps decrease the QOL in patients with diabetes, and L-carnitine supplementation may improve the QOL by reducing the frequency and severity of muscle cramps in these patients.

Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: A comparison of anti-GAD antibody titers and time-dependent changes between neurologic disease and type I diabetes mellitus.

To determine clinical features of neurologic disorders associated with anti-glutamic acid decarboxylase antibodies (anti-GAD-Ab), we examined titers and time-dependent changes of anti-GAD-Ab. Six patients, stiff person syndrome (2), cerebellar ataxia (1), limbic encephalitis (1), epilepsy (1), brainstem encephalitis (1), were compared with 87 type I diabetes mellitus (T1DM) patients without neurologic disorders. Anti-GAD-Ab titers and index were higher in neurologic disorders than in T1DM, suggesting intrathecal antibody synthesis. Anti-GAD-Ab titers in T1DM decreased over time, whereas they remained high in neurologic disorders. Immunotherapy improved neurological disorders and anti-GAD-Ab titers and index provide clinically meaningful information about their diagnostic accuracy.

Impact of glycemic variability on the levels of endothelial progenitor cells in patients with type 1 diabetes.

OBJECTIVE: A reduction in endothelial progenitor cell (EPC) count is considered to correlate with cumulative cardiovascular risk factors including hyperglycemia. This study was conducted to elucidate the influence of glycemic variability on EPC count in patients with diabetes. METHODS: In study 1, we examined the number of EPCs in 57 patients with type 1 diabetes and 43 patients with type 2 diabetes. The number of EPCs (CD34+, CD34+CD133+, CD34+CD309+, and CD34+CD133+CD309+) was counted as the number of cells per 106 events. In study 2, we examined 37 outpatients with type 1 diabetes without macrovascular complications. We assessed associations between EPC count and seven parameters of glycemic variability (blood glucose standard deviation, mean amplitude of glycemic excursion, J index, M value, mean of daily differences, low blood glucose index, and high blood glucose index), as measured by continuous glucose monitoring. We further analyzed the correlation between EPC count and the carotid intima-media thickness (IMT) in 24 patients. RESULTS: In study 1, the number of circulating CD34+ and CD34+CD133+ cells was significantly decreased in patients with type 1 diabetes relative to that in patients with type 2 diabetes (p = 0.020 and 0.036, respectively). In study 2, a univariate analysis showed that the J index was negatively correlated with logCD34+ (r = -0.342, p = 0.039). LogCD34+ was significantly negatively associated with the max IMT (r = -0.486, p = 0.012) and the mean IMT (r = -0.503, p = 0.016). CONCLUSIONS: An increase in the J index, which reflects both hyperglycemia and glycemic variability, is associated with a reduction in the EPC count, which might result in the progression of diabetic vascular complications.

Association between Functional Capacity Decline and Nutritional Status Based on the Nutrition Screening Initiative Checklist: A 2-Year Cohort Study of Japanese Community-Dwelling Elderly.

AIM: To assess whether nutritional status based on the Nutrition Screening Initiative Checklist is useful for predicting functional capacity decline in community-dwelling Japanese elderly. METHODS: This two-year observational cohort study included 536 community-dwelling Japanese (65 years and older at baseline) who were independent in both activities and instrumental activities of daily living. Demographic attributes, chronic illness, lifestyle-related habits, nutritional status, functional capacity, and anthropometric measurements were assessed, with decline in functional capacity used as the outcome measure. RESULTS: Subjects were classified into three groups as follows based on the Nutrition Screening Initiative Checklist: low (59.5%), moderate (23.7%), and high (16.8%) nutritional risk. Significant differences were found between nutritional status and the following four baseline variables: age, hypertension, cerebrovascular diseases, and current smoking. However, no significant differences were evident between nutritional status and sex, body mass index, diabetes, drinking habit, or exercise habit. Logistic regression analysis adjusted for age, sex, body mass index, hypertension, cerebrovascular diseases and smoking habit showed that the high nutritional risk group was significantly associated with a decline in both activities of daily living (odds ratio: 4.96; 95% confidence interval (CI): 1.59-15.50) and instrumental activities of daily living (OR: 2.58; 95% CI: 1.31-5.06) compared with the low nutritional risk group. CONCLUSIONS: Poor nutritional status based on the Nutrition Screening Initiative Checklist was associated with a decline in functional capacity over a 2-year period in community-dwelling Japanese elderly. These results suggest that the Nutrition Screening Initiative Checklist is a suitable tool for predicting functional capacity decline in community-dwelling elderly.

Decreased ß-Cell Function Is Associated with Reduced Skeletal Muscle Mass in Japanese Subjects without Diabetes.

BACKGROUND: Decreased insulin secretion has a great impact on the incidence of type 2 diabetes in Japanese subjects. It is not clear whether ß-cell function is related to muscle mass in subjects without diabetes. We investigated the relationship between ß-cell function and skeletal muscle mass in Japanese subjects without diabetes. METHODS: The study included 1098 subjects (538 men and 560 women) aged 40 to 79 years, without diabetes (fasting glucose lower than 126 mg/dL and glycosylated hemoglobin lower than 6.5%), who consulted Osaka Medical College Health Science Clinic for a medical examination. Appendicular muscle mass was measured by bioelectrical impedance analysis. Appendicular muscle mass index was calculated as appendicular muscle mass divided by height squared (kg/m2). The homeostatic model assessment of ß-cell function was used to assess ß-cell function. The homeostatic model assessment of insulin resistance was used as a measure of insulin resistance. The association between appendicular muscle mass index and clinical parameters of ß-cell function and insulin resistance was examined. RESULTS: Log-transformed homeostatic model assessment of ß-cell function and Log-transformed homeostatic model assessment of insulin resistance showed a normal distribution. In both men and women, there was a significant positive correlation between appendicular muscle mass index and clinical parameters of ß-cell function and insulin resistance. Tertile analysis, following stratification according to appendicular muscle mass index, found that low appendicular muscle mass index was significantly associated with the Log homeostatic model assessment of ß-cell function and Log-transformed homeostatic model assessment of insulin resistance. CONCLUSION: This study shows that decreased ß cell function is associated with reduced skeletal muscle mass in Japanese subjects without diabetes.