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Background: Anatomical abnormalities in the pulmonary vessels have long aroused great interest among thoracic surgeons, and numerous variations of pulmonary vessels have been reported. Heterotaxy syndrome is an anatomical abnormality in which typically asymmetrical organs, including the lungs, develop symmetrically. We report the case of a 71-year-old man with heterotaxy syndrome undergoing radical lobectomy in the treatment of non-small cell lung cancer., Case Presentation: Computed tomography (CT) revealed an irregular nodule 25 mm in diameter in the right middle lobe. Two months later, at his first visit to our University Hospital, CT revealed a rapidly growing tumor 60 mm in diameter. In addition, three-dimensional (3D) CT revealed the upper and middle lobar bronchi forming a common trunk with the mediastinal type of the right pulmonary artery (PA). The patient underwent video-assisted right middle lobectomy + systematic complete hilar and mediastinal lymph node dissection. The interlobar fissure between the right upper and middle lobes was incomplete, and the common trunk formed by the upper-middle bronchus emerged from an area between the right PA (A 1+3 ) and the right superior pulmonary vein., Conclusion: The finding of A 4+5 branching from the right main PA and descending posterior to the right upper-middle bronchus, which formed a common trunk, resembled a mirror image of the normal left lung. To our knowledge, a common trunk with the mediastinal type of the right PA has never been reported during video-assisted right middle lobectomy. In patients with heterotaxy syndrome, 3D-CT to preoperatively understand their anatomy is essential., Competing Interests: Declarations. Ethics approval and consent to participate: Not needed. IRB Protocol No. 2679 allows collection of tissue and medical records with consent or waiver of consent when no personalized health information is required, as was the case in this case report. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To assess the risk factors for thrombosis in the pulmonary vein stump (PVT) and the efficacy of proximal ligation in preventing PVT after lobectomy., Methods: In total, 649 surgical patients with lung cancer were retrospectively reviewed. To compare the clinical effectiveness of PV proximal ligation, the simple stapler group (290 patients) and the proximal ligation group (359 patients who underwent thread ligation at the pericardial reflection with/without a stapler) were analyzed., Results: In the simple stapler group, 12 of 290 patients (4.1%) developed PVT. Among these, 9 of 58 underwent left upper lobectomy (LUL). In contrast, 5 of the 359 patients (1.4%) in the proximal ligation group developed PVT. All five patients received LUL. The incidence of PVT in the proximal ligation group was significantly lower than that in the simple stapler group (p = 0.0295) as well as in the analysis by LUL alone (p = 0.0263). A logistic regression analysis indicated that higher BMI and LUL were associated with the development of PVT (p = 0.0031, p < 0.0001), and PV proximal ligation reduced PVT (p = 0.0055)., Conclusion: Proximal ligation of the PV has the potential to prevent PVT, especially after LUL., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

When a mass occurs at the staple line following lung resection, it can be difficult to distinguish between local cancer recurrence and granuloma. We present a case of a staple-line granuloma with 18F-fluorodeoxyglucose-positron emission tomography uptake and elevated serum carbohydrate antigen 19-9 (CA19-9) in a patient with ovarian cancer lung metastasis. After granuloma resection, serum CA19-9 levels normalized, and CA19-9 positive cells were identified in the resected tumor. Therefore, serum CA19-9 elevation does not rule out a staple-line granuloma. Whereas granulomas on computed tomography (CT) scans tend to show smooth shadows along the staple line unilaterally, detailed CT evaluation may help diagnostic differentiation. Differentiation based on imaging and tumor markers has limitations. However, core needle biopsy has the risk of misdiagnosis and tumor cell dissemination, therefore surgical resection should be considered when comprehensive findings indicate a potential recurrence., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Accurate clinical staging is crucial for selection of optimal oncological treatment strategies in non-small cell lung cancer (NSCLC). Although brain MRI, bone scintigraphy and whole-body PET/CT play important roles in detecting distant metastases, there is a lack of evidence regarding the indication for metastatic staging in early NSCLCs, especially ground-grass nodules (GGNs). Our aim was to determine whether checking for distant metastasis is required in cases of clinical T1N0 GGN., Methods: This was a retrospective study of initial staging using imaging tests in patients who had undergone complete surgical R0 resection for clinical T1N0 Stage IA NSCLC., Results: A total of 273 patients with cT1N0 GGNs (n = 183) or cT1N0 solid tumors (STs, n = 90) were deemed eligible. No cases of distant metastasis were detected on initial routine imaging evaluations. Among all cT1N0M0 cases, there were 191 incidental findings on various modalities (128 in the GGN). Most frequently detected on brain MRI was cerebral leukoaraiosis, which was found in 98/273 (35.9%) patients, while cerebral infarction was detected in 12/273 (4.4%) patients. Treatable neoplasms, including brain meningioma and thyroid, gastric, renal and colon cancers were also detected on PET/CT (and/or MRI). Among those, 19 patients were diagnosed with a treatable disease, including other-site cancers curable with surgery., Conclusions: Extensive staging (MRI, scintigraphy, PET/CT etc.) for distant metastasis is not required for patients diagnosed with clinical T1N0 GGNs, though various imaging modalities revealed the presence of adventitious diseases with the potential to increase surgical risks, lead to separate management, and worsen patient outcomes, especially in elderly patients. If clinically feasible, it could be considered to complement staging with whole-body procedures including PET/CT., (© 2024. The Author(s).)

Introduction: Determining a surgical strategy for early-stage lung cancer requires an accurate histologic diagnosis. Immunohistochemistry (IHC) enables reliable diagnosis of histological types but requires more time and more tumor tissue slides than hematoxylin and eosin staining. We aimed to assess the clinical validity of a new rapid multiplex IHC technique utilizing alternating current (AC) mixing for intraoperative lung cancer diagnosis., Methods: Forty-three patients who underwent radical resection of lung cancers were enrolled in a retrospective observational study. Frozen sections were prepared from lung tumor samples, and rapid IHC employing AC mixing was implemented alongside a multiplex IHC protocol targeting thyroid transcription factor-1 + cytokeratin 5, desmoglein 3 + Napsin A, and p63 + tripartite motif containing 29. We then evaluated the concordance between intraoperative diagnoses derived from rapid multiplex IHC and final pathology., Results: The concordance rate between the pathological diagnosis made with added rapid multiplex IHC and the final pathology was 93.0% (Cohen's 𝜅 coefficient = 0.860 and 95% CI: 0.727-0.993). When considering only adenocarcinoma and squamous cell carcinoma, the diagnoses were in agreement for all cases., Conclusions: We suggest rapid multiplex IHC as a promising tool for determining surgical strategies for lung tumors., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Tracheobronchial injury (TBI) is a rare but potentially life-threatening trauma that requires prompt diagnosis and treatment. We present a case in which a patient with COVID-19 infection was successfully treated for a TBI through surgical repair and intensive care with extracorporeal membrane oxygenation (ECMO) support., Case Presentation: This is the case of a 31-year-old man transported to a peripheral hospital following a car crash. Tracheal intubation was performed for severe hypoxia and subcutaneous emphysema. Chest computed tomography showed bilateral lung contusion, hemopneumothorax, and penetration of the endotracheal tube beyond the tracheal bifurcation. A TBI was suspected; moreover, his COVID-19 polymerase chain reaction screening test was positive. Requiring emergency surgery, the patient was transferred to a private negative pressure room in our intensive care unit. Due to persistent hypoxia and in preparation for repair, the patient was started on veno-venous ECMO. With ECMO support, tracheobronchial injury repair was performed without intraoperative ventilation. In accordance with the surgery manual for COVID-19 patients in our hospital, all medical staff who treated this patient used personal protective equipment. Partial transection of the tracheal bifurcation membranous wall was detected and repaired using 4-0 monofilament absorbable sutures. The patient was discharged on the 29th postoperative day without postoperative complications., Conclusions: ECMO support for traumatic TBI in this patient with COVID-19 reduced mortality risk while preventing aerosol exposure to the virus., (© 2023. The Author(s).)

Objectives: The division of inferior pulmonary ligament (IPL) during upper lobectomy (UL) was believed to be mandatory to dilate the remaining lung sufficiently. However, the benefits, especially postoperative pulmonary function, remain controversial. This study aimed to evaluate whether IPL division leads to pulmonary dysfunction., Methods: This retrospective study included 213 patients who underwent UL between 2005 and 2018. They were categorized into an IPL division group (D group, n = 106) and a preservation group (P group, n = 107). Postoperative dead space at the lung apex, pulmonary function and complications were assessed using chest X-rays and spirometry. Changes in bronchial angle, cross-sectional area and circumference of the narrowed bronchus on the excised side were measured on three-dimensional computed tomography., Results: There was no significant difference in the postoperative complication rate, the dead space area, forced vital capacity (FVC), or forced expiratory volume in 1 s (FEV1) between the 2 groups after right UL (FVC; P = 0.838, FEV1; P = 0.693). By contrast, after left UL pulmonary function was significantly better in the P than in the D group (FVC; P = 0.038, FEV1; P = 0.027). Changes in bronchial angle did not significantly differ between the 2 groups. The narrowed bronchus's cross-sectional area (P = 0.021) and circumference (P = 0.009) were significantly smaller in the D group than in the P group after left UL., Conclusions: IPL division during left UL caused postoperative pulmonary dysfunction and airflow limitation due to bronchial kinking. IPL preservation may have a beneficial impact on postoperative pulmonary function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: Locoregional recurrence of non-small cell lung cancer (NSCLC) occurs even among patients with stage I disease, as a result of tumor proliferative activity. The aim of this study was to evaluate the clinical reliability of a new rapid immunohistochemistry (IHC) technique for assessing malignant potential through detection of tumoral Ki-67 expression., Materials and Methods: The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within 20 min during surgery. First, to investigate the association between clinical outcomes and tumoral Ki-67 labeling with rapid IHC, 21 pairs of surgical patients treated between 2012 and 2020 for pStage IA1-3 NSCLC with/without recurrence were retrospectively reviewed. Second, 40 frozen section (FS) samples in patients with NSCLC for whom radical surgery was planned between April 2021 and February 2022 were deemed eligible for comparison of the clinical performance of conventional IHC and intraoperative rapid Ki-67 IHC with FS., Results: Detection of tumoral Ki-67 expression using rapid IHC with formalin-fixed, paraffin-embedded (FFPE) blocks was significantly associated with clinical outcomes in R0 pStage IA NSCLC surgical patients, including overall and recurrence-free survival (P = 0.0043 and P &lt; 0.0001, respectively). Levels of Ki-67 expression among resectable NSCLC patients detected using rapid IHC with FS significantly correlated with those detected using conventional FFPE-IHC (p &lt; 0.001). An intraoperative cut-off of &gt; 7.5 % tumor cell Ki-67 positivity accurately predicted pathological stage more advanced than IA3 [P = 0.0185, Odds ratio = 20.477, 95 % confidence interval (CI): 1.660-252.55]., Conclusion: Rapid Ki-67 IHC with AC mixing could potentially serve as a clinical tool for intraoperative determination of tumor malignancy status. The present study suggests that segmentectomy for early small NSCLCs is oncologically safe and a reasonable alternative to lobectomy, but only when there is adequate intraoperative selection for primary tumors with low-grade malignancy, which could be verified using intraoperative rapid Ki-67 IHC with FS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The options for lung cancer treatment have increased due to the development of immune checkpoint inhibitors, but there has been no report of inoperable cases whereby the treatment effects rendered the case operable, an operation was subsequently performed, and histological assessment of the surgical specimen was carried out. Here, we report a 67-year-old man who was given pembrolizumab for T3N0 lung squamous cell carcinoma suspected of pericardial infiltration and judged inoperable. Treatment effect was evaluated after four courses. Computed tomography indicated a partial response, and operability was feasible. Therefore, thoracoscopic left upper lobectomy was performed after six courses of pembrolizumab, and histological assessment of the treatment effect was determined to be Ef 3, a complete response. The postoperative course was uneventful and he was discharged on the third postoperative day. We encountered a case that could be surgically treated after pembrolizumab administration. This treatment was safe and effective for advanced lung cancer., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Secondary spontaneous pneumothorax (SSP) is difficult to treat by itself and due to its association with serious underlying diseases. It has a high rate of recurrence and often requires extended hospitalization. Therefore, we evaluated the outcome and risk factors associated with recurrence and extended hospitalization., Methods: We retrospectively examined 61 patients with SSP, and evaluated the patients' characteristics, underlying diseases, introduction of home oxygen therapy, Brinkman index, and X-ray imaging findings to determine the risk factors for recurrence and extended hospitalization., Results: There were 28 patients (46.0%) with chronic obstructive pulmonary disease, 8 (13.1%) with interstitial pneumonia, 16 (26.2%) with massive emphysema, and 9 (14.8%) with other diseases. Adhesion and mediastinal shift visualized by X-ray imaging were observed in 37 (37.9%) and 25 patients (40.1%), respectively. Recurrence occurred in 25 patients (40.9%) and the average hospitalization duration was 14.5 days (±11.2). A multivariate analysis showed that adhesion on X-ray imaging was a significant risk factor for recurrence (odds ratio 4.90, 95% confidence interval 1.38-21.44) and mediastinal shift on X-ray imaging was a significant risk factor for extended hospitalization (odds ratio 6.05, 95% confidence interval 1.44-31.06)., Conclusions: Findings from X-ray imaging, and not underlying diseases, are risk factors for recurrence and extended hospitalization.

Background/aim: Transient leukopenia during hemodialysis due to neutrophil activation is attributed to bioincompatibility of the dialysis membrane, but the mechanism remains unclear. We studied the mechanism of neutrophilic activation by comparing a vitamin E modified membrane (CLEE) and a regular cellulose membrane (CLSS)., Methods: (1) CLSS and CLEE membranes were used in a crossover clinical study in 7 chronic hemodialysis patients. Neutropenia, CD11b expression, and plasma C3a and myeloperoxidase concentrations were compared between the two dialyzer membranes. (2) Normal blood was circulated through CLEE and CLSS minimodels, and the same parameters were compared. (3) Blood samples with modified complement activities (EDTA: both classical and alternative pathways inactivated; EGTA+Mg: classical pathway inactivated; heating: alternative pathway inactivated; control: no modification) were incubated in the CLSS minimodel, and the neutrophilic activation was compared., Results: In clinical hemodialysis, neutropenia, CD11b expression, and C3a and myeloperoxidase levels were significantly lower when CLEE membranes were used. The same tendency was observed in minimodels. However, the degrees of inhibition in clinical dialysis, especially at the venous line, were significantly higher than in minimodels. As compared with controls, CD11b expression and myeloperoxidase level were significantly lower when both classical and alternative pathways were inactivated or when the classical pathway alone was inactivated, but were not significantly different when the alternative pathway alone was inactivated., Conclusions: Vitamin E modification of the dialyzer reduces some reactions of neutrophilic activation, such as CD11b expression and myeloperoxidase release, more effectively in the clinical situation than in ex vivo models, suggesting a possible effect of vitamin E in inhibiting bioreactions due to pyrogen in the dialysate. The classical complement pathway is required in membrane-induced neutrophilic activation, at least during the initial stage., (Copyright 2000 S. Karger AG, Basel)

Although heme oxygenase (HO) has been suggested to be involved in the regulation of cardiovascular function through production of carbon monoxide (CO), the pathophysiological significance of HO in hypertensive organ damage remains unknown. We examined the effects of inducing HO-1 mRNA by stannous chloride (SnCl2) on cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). Chronic administration of SnCl2 resulted in a significant decrease in left ventricular (LV) weight/body weight ratio and LV brain natriuretic peptide (BNP) mRNA levels as a marker of cardiac hypertrophy and a significant increase in LV HO-1 mRNA levels and LV cGMP contents in SHR-SP/Izm, while there was no significant change in systemic blood pressure. These results provide the first evidence that induction of HO in the heart attenuates cardiac hypertrophy in load-independent mechanism in genetically hypertensive rats.

A patient with malignant cardiac pheochromocytoma with bone metastases is described. The primary tumor was located between the pulmonary trunk and the left atrium, while metastatic lesions were found in the iliac bones. Treatments with antihypertensive agents, alpha-methylparatyrosine, and combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine partially improved the patient's symptoms, catecholamine levels, and the metastatic lesion of the iliac bones. However, the primary tumor in the heart progressively increased in size and the patient died of disseminated intravascular coagulation and other various complications about 4 years after the diagnosis of the disease.

We studied target organ-protective effects of aracepril, an angiotensin-converting enzyme inhibitor, and the expression of endothelin-1 (ET-1) and nitric oxide synthase (NOS) mRNA. Aracepril (30 mg/kg) was administered orally to Izumo strain of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) for 8 weeks from 4 weeks of age and for 4 weeks from 8 weeks of age. The expression of ET-1 and endothelial NOS (eNOS) mRNA in the heart, aorta, kidneys, and brain cortex, and the expression of neuronal NOS (bNOS) mRNA in brain cortex, were analyzed by RT-PCR/Southern blotting or RNase protection analysis. Administration of aracepril markedly lowered blood pressure and decreased left ventricular weight in SHR-SP/Izm. Expression of ET-1 mRNA in the heart, kidneys, and brain was significantly enhanced in SHR/SP/Izm compared with that in WKY/Izm. Aracepril significantly decreased the expression of ET-1 mRNA, whereas there was no significant change of that in the aorta. Although expression of eNOS mRNA in the heart, aorta, and kidneys did not show any significant difference between the two strains of rats, administration of aracepril for 8 weeks significantly decreased the expression of eNOS and bNOS mRNA in brain tissue. These results suggested that aracepril may protect major target organs by modifying the expression of ET-1 and NOS mRNA, in addition to its hypotensive effect.

The functional significance of angiotensin II (Ang II) receptor subtypes in adrenals remains unknown. Ang II receptor type 1a (AT1a) expression was localized by in situ hybridization to the zona glomerulosa and zona fasciculata, while AT1b was localized to the zona glomerulosa. Plasma aldosterone and corticosterone levels were measured after injection with Ang II or the type 2 receptor (AT2) agonist CGP-42112 in wild-type and AT1a deficient mice. Aldosterone and corticosterone levels were lower in AT1a deficient mice. Ang II increased plasma aldosterone levels in AT1a deficient mice, but to a lesser extent in mice pretreated with nonselective AT1a/AT1b antagonist, CV-11974. CGP-42112 did not affect aldosterone levels. Ang II increased corticosterone levels in wild-type mice but not in AT1a deficient mice. Results suggest Ang II stimulates aldosterone secretion via AT1a and AT1b in the zona glomerulosa and corticosterone secretion via AT1a in the zona fasciculata, and provide first evidence for differential roles of AT1a and AT1b in the adrenals.

Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.

We determined functional and morphological changes of the heart by 2-dimensional and pulse Doppler echocardiography in 20 patients with primary aldosteronism and compared the results with those in 50 healthy normotensive subjects, 12 patients with Cushing's syndrome, 9 patients with pheochromocytoma, and 47 patients with essential hypertension. All hypertensive groups had greater left ventricular mass indexes than did the normotensive group (76.9 +/- 17.2 g/m2). Despite similar age distribution, blood pressure during antihypertensive treatment, and duration of hypertension, the primary aldosteronism group had a significantly greater left ventricular mass index (152.5 +/- 42.5 g/m2) than did the Cushing's syndrome (103.4 +/- 37.5 g/m2), pheochromocytoma (122.4 +/- 28.5 g/m2), and essential hypertension (101.4 +/- 32.8 g/m2) groups. The left ventricular posterior wall thickness and interventricular septal wall thickness were significantly greater in the hypertensive groups than in the normotensive group and also significantly greater in the primary aldosteronism group than in any of the other hypertensive groups. By contrast, there were no significant differences among the four hypertensive groups in any variable of systolic or diastolic function of the heart. The results suggest that left ventricular hypertrophy is more pronounced in patients with primary aldosteronism than in patients with other forms of hypertension. It is therefore important to echocardiographically evaluate cardiac hypertrophy as a risk factor of morbidity and mortality in patients with this low renin hypertension.

Inhibins and activins have been known to modify the secretion of various pituitary hormones. To study whether inhibins and activins are present in human pituitary tissues, immunohistochemical studies with antisera to activin A and inhibin alpha subunit were performed on 9 human pituitary adenoma tissue specimens and one sample of normal pituitary tissue adjacent to one adenoma. Activin immunoreactivities were demonstrated in the cytoplasms of one GH and one PRL and two non-functioning adenomas and one normal pituitary tissue, but they were negative in one PRL, one ACTH, one FSH and two non-functioning adenomas. Thus, the presence and absence of activin in the same type of adenoma in regard to hormone production, suggested that the difference in immunostaining simply reflected the difference in the activin concentration. In contrast to this, inhibin alpha subunit immunoreactivity was not found in any of the tissues studied. These data suggested a local synthesis of activin in the normal pituitary as well as various kinds of pituitary adenoma tissues and its local role in the human pituitary gland.

Recent studies have demonstrated that inhibins and activins both play not only endocrine roles but also local regulatory roles in gonadotoropin secretion. There has been controversy as to the subtype of rat pituitary inhibin/activin. We studied the levels of inhibin alpha, beta A and beta B subunit mRNAs by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) and the changes in their levels by adding inhibin alpha, beta A and beta B mRNA antisense oligonucleotides and inhibin A, activin A or GnRH to cultured rat anterior pituitary cells. This study demonstrated the level of 3 mRNAs to be 1.6 x 10(-2), 0.75 and 3.4 x 10(-2) molecules/cell with a molar ratio of 1:50:2. A stimulatory role for activin B in FSH secretion was suggested as beta B mRNA antisense oligonucleotide decreased FSH secretion. The beta B mRNA level tended to be decreased by the addition of activin A, but the decrease was not statistically significant. GnRH did not affect alpha and beta B mRNA levels when administered singly. The level of beta A mRNA was not changed by any of the above treatments. In conclusion, the presence of inhibin alpha, beta A and beta B subunit mRNAs in the rat anterior pituitary with the greatest abundance of beta A was demonstrated by using RT-PCR. Activin B or activin AB may play important roles in FSH secretion in an autocrine or a paracrine fashion, and activin A may play an indirect role in FSH secretion.

Inhibin alpha and beta A subunit messenger ribonucleic acid (mRNA) levels were measured quantitatively by reverse transcription-polymerase chain reaction (RT-PCR) in human pituitary adenomas. The inhibin alpha subunit mRNA levels were undetectably low in cultured adenoma tissues, but beta A mRNA were 0.383 +/- 0.074 in 3 GH adenomas, 0.672 +/- 0.140 in 3 prolactinomas and 0.957 +/- 0.414 molecules/cell in 3 non-functioning adenomas. The addition of 10(-8) M activin A decreased the beta A mRNA levels within 4 h in 1 of 3 GH adenomas, 2 of 3 prolactinomas and 2 of 3 non-functioning adenomas, though the decreases were not statistically significant. The results showed an abundance of beta A subunit mRNA compared with alpha subunit mRNA in all human pituitary adenomas and a local role for activin in its own production through inhibin beta A mRNA subunit expression.

We describe a 31-year-old man. Although the plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were elevated, computed tomography and rapid sequence pyelography disclosed no abnormality. However, based on the findings of the small tumor (8 x 8 mm) in the kidney visualized by magnetic resonance imaging (MRI) and excessive PRA in the right renal vein, tumor resection was performed. The positive immunohistochemical staining of renin and the visualization of renin mRNA by in situ hybridization provided evidence supporting the diagnosis of juxtaglomerular cell tumor. Blood pressure, PRA, and PAC were normalized after the surgery. The observations suggest that MRI is a powerful diagnostic procedure in small juxtaglomerular cell tumor.

Although atrial and brain natriuretic peptides are well known to be involved in the regulation of cardiovascular and endocrine functions as circulating hormones, the roles of the C-type natriuretic peptide (CNP) remain unknown. We examined the effects of CNP on the secretion of aldosterone and cyclic nucleotides from bovine adrenal zona glomerulosa cells in culture. CNP produced a dose-dependent increase in the basal secretion of cGMP, with an EC50 of 3.8 x 10(-10)M. CNP significantly inhibited the ACTH-induced increase in aldosterone and cAMP in a dose-related manner, with an IC50 of 3.6 x 10(-10)M. Although ACTH itself did not increase cGMP secretion, the addition of CNP elicited a significant increase in cGMP secretion. The effects of CNP on the basal secretion of cGMP and the ACTH-induced secretion of aldosterone were significantly reversed by a nonpeptide natriuretic peptide receptor antagonist, HS-142-1. CNP immunoreactivity was localized in the zona glomerulosa by immunohistochemical staining. In addition, expression of CNP messenger RNA and natriuretic peptide B receptor messenger RNA was demonstrated by RT-PCR in the zona glomerulosa tissue and cells in culture. These findings suggest that CNP is a local factor regulating ACTH-induced aldosterone secretion through a guanylyl cyclase-cGMP pathway.

Although aldosterone (Aldo.) secretion is regulated by various humoral factors, evidence has accumulated to support an involvement of dopaminergic system in its regulation. The pathophysiological significance of the dopaminergic system in primary aldosteronism (PA) however remains unknown. In the present study, we examined the effects of metoclopramide (MCP) on Aldo. secretion in normal subjects (n = 11) and patients with essential hypertension (EH, n = 8), aldosterone-producing adenoma (APA, n = 10), and idiopathic hyperaldosteronism (IHA, n = 6). Plasma Aldo., prolactin (PRL), renin, cortisol, serum sodium, and serum potassium levels were determined before and 30 min after i.v. bolus injection of 10 mg MCP at 9 a.m. Plasma Aldo. showed a significant increase after MCP in normal subjects, EH, and APA, but not in IHA. The incremental response of plasma Aldo. was largest in APA and smallest in IHA. The percentage increase in plasma Aldo. from the basal level was significantly attenuated in IHA, while no significant difference was seen among other groups. Although plasma PRL showed a significant increase in response to MCP, no difference of the change was seen among the groups. There was no significant change in plasma cortisol, renin, serum sodium, and serum potassium levels in response to MCP. In addition, the response of Aldo. to MCP was normalized in APA after unilateral adrenalectomy, while that of PRL did not change. These results indicate that the adrenal dopaminergic activity is enhanced in APA and attenuated in IHA and suggest an involvement of the dopaminergic system in the pathogenesis of IHA.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibin and activin were initially isolated as regulators of pituitary or gonadal hormone and are now known to be growth factors belonging to the TGF-beta family with diverse influences on the differentiation and proliferation of various tissues. To investigate the role of inhibin and activin in human brain tumors, the expression of inhibin alpha, and beta A mRNA as well as activin type II receptor (ACTR II) mRNA were studied in various human brain tumors. The tumors were divided into the following 4 groups: 3 Rathke's cleft cysts and 2 craniopharyngiomas (group 1), 8 meningiomas (group 2), 8 malignant gliomas (group 3), and various other tumors including 1 each of germinoma, astrocytoma, hemangioblastoma, and osteochondroma as well as 2 malignant lymphomas and 2 metastatic squamous cell carcinomas (group 4). Immediately after resection, tumor tissues were homogenized in guanidine thyiocyanate to extract total RNA. PCR was then performed with reverse-transcribed cDNA and the respective amplification primers. DNA bands were obtained by agarose gel electrophoresis. Messenger RNA for the inhibin beta A subunit was demonstrated in all of the tissues studied. In contrast, inhibin alpha subunit mRNA was expressed in 60%, 50%, 75%, and 75% of the tumors in groups 1, 2, 3 and 4, respectively, whereas ACTR II mRNA was demonstrated in 20%, 37.5%, 62.5% and 50% of the tumors in each group. Coexpression of mRNAs for the inhibin alpha, and beta A subunits and ACTR II occurred in some brain tumors. The levels of inhibin alpha and ACTR II mRNA tended to be higher in the tumors with a higher grade of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibin and activin are known to be involved in the pituitary hormone secretion as well as proliferation of the pituitary. We studied the expression of inhibin alpha, and beta A subunit and activin type II receptor (ACTR 2) mRNAs in human pituitary adenomas to determine the significance of inhibin and activin in pituitary hormone secretion. Tumor tissues were homogenized immediately after resection in guanidinium thiocyanate to extract total RNA. PCR was performed with reversely transcripted cDNA and respective amplification primers. DNA bands obtained for inhibin alpha, beta A and ACTR 2 by agarose gel-electrophoresis were 367, 285, and 389 bp, respectively. Messenger RNAs for inhibin beta A were demonstrated in all of the pituitary tissues studied, namely in 3 GH, 2 ACTH, 6 PRL and 1 FSH producing adenomas and 17 non-functioning adenomas. Inhibin alpha mRNAs were detected in 10 of 12 functioning adenomas and 15 of 17 non-functioning adenomas. ACTR 2 mRNAs were found in 11 out of 17 non-functioning adenomas, but only found in 3 out of 12 functioning adenomas. These results suggested local production of activin, a homodimer of beta-subunits, and inhibin, a heterodimer of alpha and beta subunits, in most of the pituitary adenomas regardless of their hormone secretion. On the other hand, a significantly higher incidence of ACTR 2 in non-functioning adenomas than in functioning adenomas suggested that activin had its main site of action in non-functioning adenomas, which could be potential gonadotropinomas.

Follistatin-free activin and inhibin levels were measured in the culture medium of porcine granulosa cells by a competitive protein binding assay and N-fragment RIA, respectively. Cultures were maintained for 6 days in MEM containing 10% fetal calf serum. FSH and HCG (1-1,000 IU/L) were added on day 2 to cultures containing 1 x 10(5) cells/ml and the medium was changed every 2 days. Granulosa cells secreted a large amount of progesterone, which indicated their luteinization. Activin and inhibin were both secreted throughout the 6 day culture period. Both of them increased equally in response to FSH and HCG in a dose-dependent manner on day 4, but their responses became discrepant on day 6, when the activin response decreased while the response of inhibin increased. This study demonstrated that cultured porcine granulosa cells secrete both activin and inhibin under the control of FSH and LH. The activin response was lost before that of inhibin, suggesting the role of activin at an earlier stage of luteinization.

The role of inhibin in gonadal function and reproduction has been confirmed by the measurement of plasma inhibin levels, but there has been no clinical data available on activin because of the lack of a good assay method. We measured plasma free activin levels during the normal menstrual cycle using a newly developed competitive protein binding assay with follistatin as the binding protein. Plasma inhibin levels were measured simultaneously using an alpha-subunit N-terminal fragment RIA with recombinant inhibin as the reference standard. Four normal women, aged 23-29 years, were investigated by obtaining plasma at 3-day intervals. Plasma inhibin levels showed some variation during the follicular phase, but a parallel rise in inhibin and progesterone was observed during the luteal phase. These findings confirmed those of previous studies. In contrast, plasma free activin levels did not show any substantial changes during the menstrual cycle. This study suggests that activin has no endocrine role in modulating the pituitary-gonadal axis during the normal menstrual cycle, while changes of inhibin reflect cyclic gonadal function and indicate an endocrine role for this protein in modulating gonadal activity.

Endothelin (ET), originally discovered in vascular endothelial cells, has also been demonstrated in nonvascular tissues. The present study was undertaken to elucidate the presence of ET in the human pituitary. The avidin-biotin complex method with antiserum to ET-1 (and ET-2) or ET-3 was used to identify ET in human pituitaries obtained by autopsy. ET-3 immunoreactivity was found in the cytoplasm of large ovoid cells of the anterior pituitary. Using the double staining method, the cells containing ET-3 immunoreactivity were differentiated from cells containing ACTH, TSH beta, GH, PRL, and protein S-100. By staining with anti-LH beta antiserum in adjacent sections and using the double staining method, the cells were identified as gonadotrophs. No staining was observed in the posterior pituitary. In addition, no ET-1 (and ET-2) immunoreactivity was detected. The specific localization of ET-3 immunoreactivity in the gonadotrophs of the human pituitary suggests a possible role of ET-3 in the regulation of anterior pituitary function.

A patient with a rare combination of prolactinoma and aldosterone producing adrenal adenoma (APA) was reported in relation to studies concerning dopaminergic regulation of PRL and aldosterone secretion. The patient is a 38-year-old female with plasma PRL and aldosterone concentrations (PAC) of 563 ng/ml and 54 ng/dl, respectively. A bolus of 10 mg of metoclopramide significantly increased plasma PRL in 6 normal subjects and in 4 patients with APA, whereas the responses were blunted in 7 patients with prolactinoma and in our patient. The response of aldosterone to metoclopramide was less than that of PRL, but similar in all studied subjects, indicating that the dopaminergic inhibition of aldosterone secretion is less than that of PRL in normal subjects and did not change in patients with APA or prolactinoma. Oral administration of 2.5 mg of bromocriptine suppressed plasma PRL significantly in all the subjects studied, but did not produce any consistent changes in PAC. Discrepancies in the response of PRL and aldosterone to metoclopramide and to bromocriptine suggest a difference in the dopaminergic regulation of PRL and aldosterone secretion in both normal subjects and patients with prolactinoma and APA. It is unlikely that reduced dopaminergic inhibition is the basis for hypersecretion of PRL and aldosterone in our patient.

Plasma immunoreactive (IR)-7B2 was measured in four patients with gonadotropin-producing pituitary adenomas. The basal level of plasma IR-7B2 was elevated in one of the four patients. Hyperresponse of plasma IR-7B2 to LHRH or LHRH/TRH was noted in two patients tested. 7B2 was positively stained in a paraffin-embedded section of gonadotropin-producing pituitary adenoma obtained at surgery. These findings suggest that 7B2 is produced in gonadotropin-producing pituitary adenomas and secreted into the blood stream under certain conditions. 7B2 may be a useful marker for gonadotropin-producing pituitary adenomas.

A 73-yr-old patient with idiopathic hypoparathyroidism was admitted to our hospital in May 1981. The immunoreactive PTH (iPTH) level determined by RIA using antiserum specific for the C-terminal region of PTH-(65-69) was in the upper normal range (0.6 ng/mL) and over the next 7 yr increased gradually to 6 ng/mL. Since iPTH levels determined using other commercial RIA kits remained constantly decreased or in the undetectable range, we studied the mechanism of false elevation of iPTH in this patient. The patient's serum contained no binding protein to the tracer ([125I]) [Tyr45] human PTH-(46-84)), nor was any heterophilic antibody to the first [guinea pig immunoglobulin G (IgG)] or the second antibody (goat IgG) detected. Consistent with these findings, the dilution curve of the serum was parallel with that of standard bovine PTH-(1-84). Gel filtration analysis revealed that the iPTH-like substance was eluted in the void volume (apparent mol wt, greater than 70,000). Almost all of the iPTH-like substance was adsorbod by a protein-A-Sepharose column. When the IgG fraction purified by protein-A-Sepharose affinity chromatography was applied to an antihuman IgG lambda-Sepharose column, 72% of the iPTH-like substance was detected in the IgG lambda. These results suggest that the falsely elevated iPTH in the patient's serum was due to IgGs (mainly IgG lambda), which were cross-reactive with the antiserum highly specific for the C-terminal region of human PTH-(65-69).

Pyrolysates of cyanocobalamin, thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, and ascorbic acid were tested for mutagenicity in the histidine-requiring mutants Salmonella typhimurium TA98 and TA100. Each vitamin was sealed in a glass tube and heated at 100-600 degrees C in a muffle furnace. Methanol-chloroform extracts of the pyrolysate of each vitamin tested did not show any mutagenicity in either TA98 or TA100 without rat liver 9000 x g supernatant fraction (S9) added. In the presence of S9, the B-group vitamins (cyanocobalamin, thiamine hydrochloride, riboflavin, and pyridoxine hydrochloride) were all mutagenic in TA98 and TA100, with the highest activity among the vitamins tested found in the pyrolysate of cyanocobalamin. The pyrolysate of 0.25 mumole cyanocobalamin produced 3200 revertants, while the pyrolysates of 0.25 mumole thiamine hydrochloride and riboflavin produced only 910 revertants, and the pyrolysate of pyridoxine hydrochloride did not show any mutagenicity at that amount. The mutagenicity was generally more active to TA98 than to TA100, indicating that frameshift-type mutagens were contained in the pyrolysates. The pyrolysate of ascorbic acid did not show any mutagenic activity in either TA98 or TA100 under the present experimental conditions.

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.

To investigate a mode and a site of action of inhibin on FSH and LH secretion, in vivo and in vitro effects of porcine follicular fluid (PFF) on FSH and LH secretion were studied in male rats. PFF administered i.v. suppressed basal FSH levels for 1-8 hr, but did not alter LH levels. On the contrary, PFF given either 1 or 6 hr in advance, suppressed LH-RH stimulated LH responses as well as LH-RH induced FSH responses. In cultured pituitary cells PFF exerted a partial suppressive effect on LH release. PFF suppressed LH release only under the maximal stimulation with 10(-10) M LH-RH and 0.1 mM 3-isobutyl-1-metylxanthine (IBMX) to a lesser degree compared with uniform and greater suppression on FSH release regardless of the experimental conditions. Above results showed a selective suppressive effect of PFF on FSH release and synthesis with a less inhibitory effect on LH release mainly at the pituitary level.

Basal levels of sex steroids, and the responses of LH and FSH to LH-RH were studied in twenty-five female patients with Cushing's syndrome (17 Cushing's disease and 8 adrenocortical adenoma). Only two patients had a regular menstrual cycle. Amenorrhea or oligomenorrhea had been of long duration in the other cases except for three postmenopausal patients. In patients with Cushing's disease, basal estradiol was low or below normal in 86%. Progesterone was normal in 83%, but testosterone was high in half of the cases. The response of LH to LH-RH in patients with Cushing's disease was normal in 35%, low in 35% and high in 29% of the cases. FSH response to LH-RH was normal in 23.5%, low in 23.5% and high in 53%. In patients with adrenocortical adenoma, basal of estradiol was low or below normal, but progesterone and testosterone were normal in all cases. The response of LH and FSH to LH-RH in all patients with adrenocortical adenoma was higher than normal. In three postmenopausal women, a higher response of LH and FSH to LH-RH was seen in two cases and suppressed in one case. These data suggest that the main site of suppression of the gonadal axis in patients with adrenocortical adenoma is the gonad rather than the pituitary gland or hypothalamus, though the mechanism of hypogonadism in patients with Cushing's disease is heterogeneous.