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Background: Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified., Aim: We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI., Methods: Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured., Results: Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane., Conclusions: Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI., (© 2024 Wiley Periodicals LLC.)

Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited., Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA., Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons., Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002)., Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality., (Published by Elsevier Inc.)

Background: Primary hyperparathyroidism (PHPT) caused by double adenoma may carry a higher risk of failure to cure. We compared outcomes in single adenoma (SA), double adenoma (DA) and four-gland hyperplasia (HP)., Methods: Patients undergoing initial parathyroidectomy for PHPT were categorized by diagnosis. The primary outcome was persistent/recurrent disease postoperatively., Results: Of 3408 patients, 81.3% had SA, 9.5% had DA, and 9.3% had HP. Rates of persistence/recurrence were 2.9%, 5.3%, and 4.5% in SA, DA, and HP, respectively (p = 0.281). Patients with persistence/recurrence had higher preoperative calcium (11.0 vs 10.7 mg/dl, p = 0.028) and PTH (96 vs 77 pg/ml, p = 0.015), and lower rates of IOPTH normalization (77% vs 96%, p < 0.001). On multivariable analysis, DA was associated with increased risk of persistent/recurrent disease (OR 3.0, p = 0.017)., Conclusions: Most patients with DA are cured with removal of two glands, but approximately 5% experience disease persistence/recurrence. Low-normal final IOPTH was associated with lower risk of persistent/recurrent disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Tertiary hyperparathyroidism associated with end-stage renal disease is characterized by progression from secondary hyperparathyroidism to an autonomous overproduction of parathyroid hormone that leads to adverse health outcomes. Rates of parathyroidectomy (PTX) have decreased with the use of calcimimetics. Optimal timing of PTX in relation to kidney transplant remains controversial. We aimed to identify the most cost-effective strategy for patients with tertiary hyperparathyroidism undergoing kidney transplant., Methods: We constructed a patient level state transition microsimulation to compare 3 management schemes: cinacalcet with kidney transplant, cinacalcet with PTX before kidney transplant, or cinacalcet with PTX after kidney transplant. Our base case was a 55-year-old on dialysis with tertiary hyperparathyroidism awaiting kidney transplant. Outcomes, including quality-adjusted life years, surgical complications, and mortality, were extracted from the literature, and costs were estimated using Medicare reimbursement data., Results: Our base case analysis demonstrated that cinacalcet with PTX before kidney transplant was dominant, with a lesser cost of $399,287 and greater quality-adjusted life years of 10.3 vs $497,813 for cinacalcet with PTX after kidney transplant (quality-adjusted life years 9.4) and $643,929 for cinacalcet with kidney transplant (quality-adjusted life years 7.4)., Conclusion: Cinacalcet alone with kidney transplant is the least cost-effective strategy. Patients with end-stage renal disease-related tertiary hyperparathyroidism should be referred for PTX, and it is most cost-effective if performed prior to kidney transplant., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A 59-year-old woman, a known case of hypertension, was incidentally diagnosed with a large right-sided adrenal mass. Investigations for a functional adrenal lesion resulted in very high preoperative norepinephrine levels. A right adrenalectomy was performed. Histology showed adrenal medullary hyperplasia (AMH). AMH is a rare diagnosis and its incidence is poorly documented in the literature. This is a benign entity which resembles pheochromocytoma (PCC) in both clinical and biochemical manner. AMH is usually bilateral and may occur in isolation or in association with PCC. In fact, some authors consider it to be a precursor to PCC. Thus, these patients need long-term follow-up in view of the risk of development of PCC later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Primary aldosteronism is a common cause of secondary hypertension. Primary aldosteronism is caused by an aldosterone-producing adenoma or bilateral hyperplasia that in some cases is asymmetrical with one adrenal dominating aldosterone secretion. Most patients with aldosterone-producing adenoma are biochemically cured by unilateral adrenalectomy, but patients with bilateral hyperplasia have a significant risk of residual or recurrent disease. Here, immunohistochemistry of CYP11B1 and B2 was used to investigate whether these markers could aid in the diagnostic workup of primary aldosteronism patients., Materials and Methods: A total of 39 patients with primary aldosteronism who underwent unilateral adrenalectomy for a presumed adenoma during 2013-2016 were included. Immunohistochemistry using monoclonal antibodies identifying the enzymes CYP11B1 and B2 was part of routine histopathological workup in 6 cases; in 33 cases, it was applied retrospectively. The hyperplasia diagnosis was suggested when there was no dominating nodule but immunoreactivity for CYP11B2 was seen in several nodules, which were also seen on routine sections. To distinguish between adenoma and hyperplasia, a ratio between the largest and second largest CYP11B2-positive nodules was calculated., Results: In all, 22 patients had an aldosterone-producing adenoma, while 13 patients were judged to have hyperplasia. In four cases, a final diagnosis could not be established, thus these were judged equivocal. Among the 33 cases investigated retrospectively, the primary histopathological diagnosis was altered from hyperplasia to aldosterone-producing adenoma in 9 cases (27%) after immunohistochemistry, and the immunohistochemically rectified adenoma group displayed improved clinical cure rates compared to the routine H&E-diagnosed cohort. Moreover, the B2 ratio was significantly higher in adenoma than in hyperplasia and equivocal cases., Conclusion: Immunohistochemistry detecting CYP11B1 and B2 expression is of great help in establishing a final histopathological diagnosis in patients with primary aldosteronism. This procedure should be part of the histopathological routine in all operated primary aldosteronism patients.

To study the effects of Tui Na therapy on patients with mammary gland hyperplasia.A total of 68 female patients with mammary gland hyperplasia were included in this retrospective study from May 2016 to May 2017 and assigned into control group (N = 34) treated with Rupixiao only (a proprietary Chinese medicine) or Tui Na group (N = 34) treated with Tui Na (Chinese massage) combined with Rupixiao. The pain intensity (visual analogous scale, VAS) and serum levels of luteinizing hormone (LH), estradiol (E2), prolactin (PRL), and progesterone (P) were examined before and after the treatment.The efficacies were 94.1% (32/34) in the Tui Na group and 76.5% (26/34) in the control group (P = .04). After treatment, VAS in Tui Na groups was significantly lower than that in control group (2.1 ± 1.1 vs 3.1 ± 1.1, P < .05). After follow-up for five months, the recurrence rates were 12.5% (4/32) in the Tui Na group and 23.1% (6/26) in the control group (P = .01). The levels of all 4 hormones in the Tui Na group increased significantly after treatment. In control group, only LH and E2 levels were significantly increased after treatment.In patients with mammary gland hyperplasia, Tui Na combined with Rupixiao could improve clinical symptoms, regulate sex hormone levels, and decrease the recurrence rate than Rupixiao alone. Our finding suggests that Tui Na can be potentially used for the treatment of mammary gland hyperplasia.

To evaluate safety and efficacy of one- vs. two-session radiofrequency ablation (RFA) of parathyroid hyperplasia for patients with secondary hyperparathyroidism (SHPT) and to compare the outcome of both methods on hypocalcemia. Patients with secondary hyperparathyroidism underwent ultrasound guided RFA of parathyroid hyperplasia. Patients were alternately assigned to either group 1 (n = 28) with RFA of all 4 glands in one session or group 2 (n = 28) with RFA of 2 glands in a first session and other 2 glands in a second session. Serum parathyroid hormone (PTH), calcium, phosphorus and alkaline phosphatase (ALP) values were measured at a series of time points after RFA. RFA parameters, including operation duration and ablation time and hospitalization length and cost, were compared between the two groups. Mean PTH decreased in group 1 from 1865.18 ± 828.93 pg/ml to 145.72 ± 119.27 pg/ml at 1 day after RFA and in group 2 from 2256.64 ± 1021.72 pg/ml to 1388.13 ± 890.15 pg/ml at 1 day after first RFA and to 137.26 ± 107.12 pg/ml at 1 day after second RFA. Group 1's calcium level decreased to 1.79 ± 0.31 mmol/L at day 1 after RFA and group 2 decreased to 1.89 ± 0.26 mmol/L at day 1 after second session RFA (P < 0.05). Multivariate analysis showed that hypocalcemia was related to serum ALP. Patients with ALP ≥ 566 U/L had lower calcium compared to patients with ALP < 566 U/L up to a month after RFA (P < 0.05). Group 1's RFA time and hospitalization were shorter and had lower cost compared with Group 2. US-guided RFA of parathyroid hyperplasia is a safe and effective method for treating secondary hyperparathyroidism. Single-session RFA was more cost-effective and resulted in a shorter hospital stay compared to two sessions. However, patients with two-session RFA had less hypocalcemia, especially those with high ALP.

Background & Aims: Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified., Methods: We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment)., Results: Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2 + isthmus progenitors, but not Hdc + mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r + Hdc - cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro., Conclusions: We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R + progenitors in the corpus. Gastrin-dependent function of CCK2R + progenitors is regulated by the extracellular signal-regulated kinase pathway., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.

Background/purpose: Gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid microsomal antibody (TMA) may be present in oral mucosal disease patients. This study mainly assessed the frequencies of serum GPCA, TGA, and TMA positivities in 131 oral precancer patients., Methods: Serum GPCA, TGA, and TMA levels were measured in 131 oral precancer patients including 96 oral leukoplakia, 26 oral erythroleukoplakia, and 9 oral verrucous hyperplasia patients and in 131 age- and sex-matched healthy control subjects., Results: We found that 131 oral precancer patients had higher frequencies of serum GPCA (10.7% vs. 2.3%, P = 0.012, statistically significant), TGA (4.6% vs. 2.3%, P = 0.498), and TMA (8.4% vs. 2.3%, P = 0.054, marginal significance) positivities than 131 healthy control subjects. We also found that 1 (0.8%), 6 (4.6%), and 16 (12.2%) oral precancer patients had the presence of three (GPCA + TGA + TMA), two (GPCA + TGA, GPCA + TMA, or TGA + TMA), or one (GPCA only, TGA only, or TMA only) autoantibody in their sera, respectively. Of 10 TGA/TMA-positive oral precancer patients whose serum thyroid-stimulating hormone (TSH) levels were measured, 80%, 10%, and 10% of these 10 TGA/TMA-positive oral precancer patients had normal, lower, and higher serum TSH levels, respectively. We also found a significantly higher GPCA positive rate in 26 smokers consuming >20 cigarettes per day than in 61 smokers consuming ≤20 cigarettes per day (P = 0.008)., Conclusion: Approximately 17.6% of 131 oral precancer patients have serum GPCA/TGA/TMA positivity. Only approximately 20% of TGA/TMA-positive oral precancer patients have either hypothyroidism or hyperthyroidism., (Copyright © 2019. Published by Elsevier B.V.)

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ , prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo ( P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL ( P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL ( P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 ( P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction., (©2019 American Association for Cancer Research.)

Plasma amino acids and their transporters constitute an important part of the feedback loop between the liver and pancreatic α-cell function, and glucagon regulates hepatic amino acid turnover. Disruption of hepatic glucagon receptor action activates the loop and results in high plasma amino acids and hypersecretion of glucagon associated with α-cell hyperplasia. In the present study, we report a technique to rescue implanted human pancreatic islets from the mouse kidney capsule. Using this model, we have demonstrated that expression of the amino acid transporter SLC38A4 increases in α-cells after administration of a glucagon receptor blocking antibody. The increase in SLC38A4 expression and associated α-cell proliferation was dependent on mechanistic target of rapamycin pathway. We confirmed increased α-cell proliferation and expression of SLC38A4 in pancreas sections from patients with glucagon cell hyperplasia and neoplasia (GCHN) with loss-of-function mutations in the glucagon receptor. Collectively, using a technique to rescue implanted human islets from the kidney capsule in mice and pancreas sections from patients with GCHN, we found that expression of SLC38A4 was increased under conditions of disrupted glucagon receptor signaling. These data provide support for the existence of a liver-human α-cell endocrine feedback loop., (Copyright © 2019 Endocrine Society.)

Background: Intimal hyperplasia is the major therapeutic concern after percutaneous coronary intervention. The aim of this study is to investigate effects of 2,3,4',5-tetrahydroxystilbene-2-O-β-D glucoside (TSG) on intimal hyperplasia and the underling mechanisms through attenuating the expressions of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1, and through promoting re-endothelialization with vascular endothelial growth factor (VEGF)., Method: Rats were operated with carotid artery balloon injury. The treatment groups were gavaged with 50 and 100 mg/kg/d of TSG. After 10 days of treatment, carotid artery pathological changes were evaluated by histology. Serum levels of SDF-1α, SCF, FKN and VEGF were detected by enzyme linked immunosorbent assay. The protein expressions of the receptors c-kit, CXCR4, CX3CR1, as well as CD34 and proliferating cell nuclear antigen (PCNA) were detected by immunochemistry., Results: TSG dose-dependently inhibited balloon injury-induced intimal hyperplasia, as evidenced by reducing neointima area (NIA), neointima area/media area (NIA/MA), neointima area/internal elastic area (NIA/IELA), and by decreasing the protein expression of PCNA. TSG reduced serum levels of SDF-1α, SCF and FKN, and it also decreased the expressions of the corresponding receptors c-kit, CXCR4, CX3CR1 in neointima. Importantly, the level of VEGF in peripheral blood and the expression of CD34 in vascular walls were increased to promote re-endothelialization., Conclusions: This study clearly demonstrated that TSG was effective in inhibiting intimal hyperplasia, and this effect was mediated, at least in part, through the SCF/c-kit, SDF-1α/CXCR4 and FKN/CX3CR1 axes. Importantly, TSG could increase VEGF and CD34 to promote endothelial repair., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: To study the relevance between serum sorting protein-related receptor containing the low-density lipoprotein receptor class A (SorLA) and intimal hyperplasia (IH) after carotid endarterectomy (CEA) operation., Methods: Seventy-nine carotid artery stenosis patients receiving CEA operation from September 2013 to March 2015 were included. Serum SorLA level was detected by enzyme linked immunosorbent assay method preoperatively. All the 79 patients received regular follow-up to diagnose the IH of target lesions, postoperatively. Based on the follow-up data, the patients were divided into IH group (n = 10) and non-IH group (n = 69). Serum SorLA levels were analyzed using t-test. Receiver-operating characteristic curve was applied to determine the value of serum SorLA to predict the occurrence of IH after CEA operation., Results: Patients in severe IH group had a higher level of serum SorLA than patients in non-IH group (1.648 ± 0.246 ng/mL vs. 1.278 ± 0.281 ng/mL, P < 0.001). When 1.44 ng/mL was designated as the cutoff value of serum SorLA, the predicting value had a sensitivity of 90% and a specificity of 73.5%., Conclusions: High serum SorLA level is related to IH after CEA operation. A serum SorLA level of 1.44 ng/mL can be used as a predicting index of postoperative IH., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To investigate the value of multiparameter joint analysis in the early diagnosis of gastric cancer (GC) in clinical practice., Methods: Concentrations of CEA, CA724 and three kinds of cytokines (TNF-α, IL-6 and IL-8) in 176 GC patients, 117 atypical hyperplasia patients, and 204 healthy control individuals were used for building the diagnostic model, then 58 GC patients, 41 atypical hyperplasia patients, and 66 healthy control individuals were enrolled independently. The joints of the indicators were analyzed by binary logistic regression analysis method., Results: For discriminating the healthy control group and the GC group, IL-6 had the best diagnostic value, and the area under curve (AUC) of joint analysis was 0.95 (0.93-0.97). For the early stage and advanced stage GC, the AUC were 0.95 (0.92-0.98) and 0.95 (0.92-0.97). For discriminating the atypical hyperplasia group and GC group, CA724 had the best diagnostic value, and the AUC of joint analysis was 0.97 (0.95-0.99). For the early stage and advanced stage GC groups, the AUC were 0.98 (0.96-0.99) and 0.96 (0.94-0.98). After evaluation, for discriminating the GC, early stage GC and advanced cancer group from the healthy control group, the diagnostic sensitivity was 89.66%, 84.21% and 92.31%, respectively, and the specificity was 92.42%, 90.91% and 90.91%. For discriminating the GC, early stage GC and advanced cancer groups from the atypical hyperplasia group, the diagnostic sensitivity was 87.93%, 78.95% and 92.31%, respectively, and the specificity was 87.80%, 85.37% and 90.24%., Conclusion: We have built a diagnostic model including CEA, CA724, IL-6, IL-8, and TNF-α. It may provide potential assistance as a screening method for the early detection of GC., Competing Interests: Conflict-of-interest statement: We declare that we have no financial or personal relationships with other individuals or organizations that can inappropriately influence our work and that there is no professional or other personal interest of any nature in any product, service and/or company that could be construed as influencing the position presented in or the review of the manuscript.

Objective: To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER) trial over a 3.5-5-year period., Research Design and Methods: Patients ( n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms., Results: At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients., Conclusions: There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group., (© 2017 by the American Diabetes Association.)

Introduction: Obesity and prostate cancer are related, but the causal relationship remains unknown. The aim of the study was to compare concentrations of leptin, adiponectin and chemerin in patients with prostate cancer and benign prostate hyperplasia and to examine associations of the adipokines with the grade of prostate cancer, interleukin-6 (IL-6), insulin resistance and anthropometric and metabolic variables., Material and Methods: The study group consisted of 140 men divided into two groups: I- prostate cancer (n=74) and II- with benign hyperplasia (n=66). Serum leptin, adiponectin, chemerin, IL-6 and metabolic profile were measured. Considering histological differentiation prostate cancer patients were divided into 3 subgroups: well differentiated (Gleason score ≤ 6), moderately differentiated subgroup (Gleason 7), and poorly differentiated (Gleason ≥8)., Results: There were no differences between groups in BMI, waist circumference, HOMA-I, serum levels of total cholesterol, glucose, triglycerides, adiponectin, leptin and chemerin. However, the concentrations of PSA, leptin-to-adiponectin ratio and IL-6 were significantly higher in cancer group compared with benign hyperplasia group. In the poorly differentiated cancer subgroup, subjects had higher PSA, leptin, chemerin, IL-6 and triglycerides concentrations. Overweight and obese men with prostate cancer were more likely to have moderately or poorly differentiated cancer than those with normal BMI. In the all men serum adiponectin was significantly correlated with HOMA-I, BMI, glucose, triglycerides, cHDL. There were significant correlations between leptin and BMI, HOMA-I, waist, glucose, triglycerides and cHDL. Among all the participants we observed associations between chemerin and waist as well as triglycerides. In prostate cancer patients chemerin correlated with IL-6 and leptin. We measured significant positive correlations between Gleason score and chemerin and leptin concentrations. There was a positive correlation between adiponectin and PSA levels in all men, as well as in cancer group., Conclusion: Leptin-to-adiponectin ratio and IL-6 were elevated in men with prostate cancer. Leptin, chemerin and IL-6 were associated with Gleason score. The relationships between leptin, chemerin and IL-6 were dependent on each other. Overweight and obese men had a higher Gleason score.

Objective: To investigate nodular regenerative hyperplasia (NRH) as a vascular complication of systemic sclerosis (SSc) with microvasculopathy as a common denominator., Methods: Cases of SSc-NRH were identified by systematic literature review and by screening the Zurich cohort. NRH had to be diagnosed by liver biopsy., Results: Literature review retrieved 22 cases. In our cohort, 1.4% of patients with SSc were diagnosed with NRH. Most had vasculopathy, were positive for anticentromere antibodies, had elevated alkaline phosphatase and gamma-glutamyl transferase levels, normal liver morphology on ultrasound yet increased stiffness on ultrasound elastography, and had portal hypertension., Conclusion: NRH might represent a rare yet potentially life-threatening vascular complication in SSc.

Our aim was to evaluate whether postnatal exposure to endosulfan (ENDO) modifies mammary gland (MG) development in pre- and post-pubertal male rats. From postnatal day 1 (PND1) to PND7, male rats were injected subcutaneously every 48h with either corn oil (vehicle) or 600μg ENDO/kg.bw. On PND21 and PND60, MG and blood samples were collected. Estradiol (E2) and testosterone (T) serum levels, MG histology, collagen fiber organization, proliferation index, and estrogen (ESR1) and androgen receptor (AR) expressions were evaluated. On PND21, E2 and T levels were similar between groups, whereas MG area, perimeter, number of terminal end buds and ESR1 expression were increased in ENDO-exposed rats. These changes were associated with alveolar development and increased organized collagen in the stroma. On PND60, a higher proliferation index in ENDO-exposed rats was correlated with a more developed lobuloalveolar structure. Hyperplastic alveoli and, hyperplastic ducts surrounded by a dense stroma were also observed in this group. T levels and ESR1 expression were similar between groups, whereas E2 levels and AR expression were decreased in ENDO-exposed rats. The exposure to ENDO in the first week of life interferes with the normal development of the MG and induces pre-malignant lesions in post-pubertal male rats., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The presence of virilizing signs associated with high serum androgen levels in postmenopausal women is rare. Virilizing ovarian tumors (VOTs) and ovarian stromal hyperthecosis (OH) are the most common etiologies in virilized postmenopausal women. The differential diagnosis between these two conditions is often difficult., Objective: To evaluate the contribution of clinical features, hormonal profiles and radiological studies to the differential diagnosis of VOT and OH., Design: A retrospective study., Setting: A tertiary center., Main Outcome Measures: Clinical data, hormonal status (T, E2, LH and FSH), pelvic images (transvaginal sonography and MRI) and anatomopathology were reviewed., Patients: Thirty-four postmenopausal women with a diagnosis of VOT (13 women) and OH (21 women) were evaluated retrospectively., Results: Clinical signs of hyperandrogenism were more prevalent in the VOT group than the OH group. Although the VOT group showed higher T and E2 levels and lower gonadotropin levels than the OH group, a great overlap occurred among the hormone levels. A pelvic MRI provided an accurate differentiation of these two conditions., Conclusion: In this group of patients, the main features contributing to the differential diagnosis of VOT and OH were serum levels of testosterone and gonadotropins and the presence of an ovarian nodule identified on the MRI. Although the association of clinical, hormonal and radiological features contributes to the differential diagnosis of these two conditions, histopathological analysis remains the gold standard for the diagnosis of ovarian hyperandrogenism in postmenopausal women., (© 2017 European Society of Endocrinology.)

Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4 -/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4 -/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.

Background: Intraoperative parathyroid hormone (IOPTH) monitoring is crucial in the treatment of primary hyperparathyroidism (PHPT). Often, the 5 min IOPTH levels fall, but not by the requisite 50 %. In such cases, the surgeon must decide whether to wait for additional levels or to continue exploration. This study aimed to evaluate the 5 min drop in IOPTH for distinguishing single adenomas (SA) from multigland disease., Methods: A retrospective analysis of a prospectively collected database was performed on PHPT patients who underwent initial curative parathyroidectomy between 2001 and 2013. Those with familial disease and those taking lithium or undergoing concomitant thyroidectomy were excluded from the analysis. For cases of double adenomas (DA) or hyperplasia (HA), the IOPTH values indicating additional glands were analyzed., Results: The inclusion criteria were met by 1021 patients: 817 patients with SA (82.2 %), 99 patients with DA (10 %), and 78 with HA (7.9 %). The SA patients exhibited a 56.6 ± 4.9 % decline in IOPTH at 5 min compared with 21.3 ± 4.5 % of the DA patients and 22.5 ± 4.3 % of the HA patients (p < 0.01). Post hoc comparisons showed that the 5 min decrease in the SA group was significantly greater than in either the DA group or the HA group (p < 0.01). A 5 min percentage decline of 35 % best distinguished SA from multiglandular disease (85.3 vs. 24.9 %)., Conclusion: The data suggest that when IOPTH level does not drop by at least 35 % at 5 min after excision, the surgeon should consider further exploration rather than wait for additional levels.

Background/aims: Chromogranin A is an important tool in the diagnosis of neuroendocrine tumors. Autoimmune gastritis is an autoimmune disorder marked by hypergastrinemia, which stimulates enterochromaffin-like cell proliferation. Chromogranin A is also elevated in autoimmune gastritis patients with a different level of increase in each patient. The goal of this study is to explore constituents that influence serum chromogranin A levels in autoimmune gastritis patients., Materials and Methods: One hundred and eighty-eight autoimmune gastritis patients and 20 patients with type I gastric carcinoid tumors were analyzed retrospectively and compared to 110 functional dyspepsia patients in terms of factors that might affect serum chromogranin A levels., Results: The mean serum chromogranin A level was 171.17±67.3 ng/mL in autoimmune gastritis patients (n=62) without enterochromaffin-like cell hyperplasia, and 303.3±102.82 ng/mL in patients (n=126) with enterochromaffin-like cell hyperplasia (p<0.001). The presence of corpus atrophy (p=0.026, OR: 5.03, CI 95%: 1.21-20.88, β=1.61) and presence of enterochromaffin-like cell hyperplasia (p=0.017, OR: 6.59, CI 95%: 1.4-31.08, β=1.88) were found as risk factors associated with serum chromogranin A level., Conclusion: Factors influencing raised serum chromogranin A levels in autoimmune gastritis were the presence of ECL cell hyperplasia and serum gastrin levels. Serum chromogranin A levels maybe helpful in distinguishing autoimmune gastritis patients and gastric carcinoid type I from the control group, but not useful in the differentiation of individuals with autoimmune gastritis from patients with gastric carcinoids.

Adipose tissue (AT) expansion is the result of two processes: hyperplasia and hypertrophy; and both, directly or indirectly, depend on the adipogenic potential of adipocyte precursor cells (APCs). Glucocorticoids (GCs) have a potent stimulatory effect on terminal adipogenesis; while their effects on early stages of adipogenesis are largely unknown. In the present work, we study, in a model of high GC levels, the adipogenic potential of APCs from retroperitoneal AT (RPAT) and its relationship with RPAT mass expansion. We employed a model of hyper-adiposity (30- and 60-day-old rats) due to high endogenous GC levels induced by neonatal treatment with l-monosodium glutamate (MSG). We found that the RPAT APCs from 30-day-old MSG rats showed an increased adipogenic capacity, depending on the APCs' competency, but not in their number. Analyses of RPAT adipocyte diameter revealed an increase in cell size, regardless of the rat age, indicating the prevalence of a hypertrophic process. Moreover, functional RPAT alterations worsened in 60-day-old rats, suggesting that the hyperplastic AT expansion found in 30-day-old animals might have a protective role. We conclude that GCs chronic excess affects APCs' adipogenic capacity, modifying their competency. This change would modulate the hyperplastic/hypertrophic balance determining healthy or unhealthy RPAT expansion and, therefore, its functionality.

The article considers the technique of high-performance liquid chromatography making it possible simultaneously detect cortisol, cortisone and secondary steroids in serum for consequent analysis of common reversed-phase high-performance liquid chromatography with ultraviolet under 240 nm. The liquid-liquid extraction from alkaline medium in diethyl ether The separation using column of 150x4.6 size ODS 3.5 mkm in isocratic mode. The eluent acetonitrile--0.02 M phosphate buffer pH 8.0--isopropanol (40:60:1). The application of proposed technique managed to separate cortisol, cortisone, dexamethasone, corticosterone, 11-desoxicortisol, testosterone, desoxicorticosterone, 17α-gidroxiprogesterone and androstendion in 20 minutes. The simplicity, reproducibility and sufficient selectivity and sensitivity of technique permit implement it in clinical practice for simultaneous diagnostic of inherent hyperplasia of adrenal glands type I and II.

There are few reports on parathyroid ultrasonography of multiple endocrine neoplasia type 1 (MEN1). This study investigated the ultrasonographic features of parathyroid glands in 10 patients with MEN1 who underwent preoperative neck ultrasonography and parathyroidectomy between 2006 and 2010 at Toranomon Hospital. We retrospectively analyzed clinical features, laboratory and ultrasonographic data, and pathological diagnosis. A total of 38 parathyroid glands were surgically removed (three to five glands from each patient). All removed parathyroids were pathologically diagnosed as hyperplasia. Seven cases (70.0 %) had adenomatous thyroid nodules. Twenty-five enlarged parathyroid glands (65.8 %) were detected by preoperative ultrasonography with a detection rate of 81.8 % (9/11) and 59.3 % (16/27) for patients without and with adenomatous nodules, respectively. Total parathyroid gland weight and potentially predictable total parathyroid volume by preoperative ultrasonography were significantly correlated with preoperative serum intact parathyroid hormone (iPTH) concentration (R = 0.97, P < 0.001 and R = 0.96, P < 0.001, respectively). The equation used for prediction of the total volume by ultrasonography was 15 × iPTH (pg/ml) - 1,000 and that for total weight was 20 × iPTH (pg/ml) - 1,400. Although adenomatous nodules often coexisted with MEN1 and made identification of enlarged parathyroid glands by ultrasonography difficult, the positive correlation between the predictable parathyroid volume by ultrasonography and serum iPTH suggests that their measurement is useful in the preoperative detection and localization of enlarged parathyroid glands in patients with MEN1. Furthermore, the presence of parathyroid glands that should be resected can be predicted before surgery using the equation proposed here.

Introduction: Primary hyperparathyroidism (PHPT) due to multigland hyperplasia is managed by subtotal parathyroidectomy (sPTX), with a partial gland left in situ. However, smaller, hyperplastic glands may be encountered intraoperatively, and it is unclear if leaving an intact gland is an equivalent alternative. This study evaluates the rates of permanent hypoparathyroidism and cure of PHPT patients with four-gland hyperplasia that were left with either a whole gland remnant (WGR) or a partial gland remnant (PGR) after sPTX., Methods: We reviewed the outcomes of PHPT patients with hyperplasia who underwent sPTX at an academic institution. Surgeon intraoperative judgment determined remnant size (a WGR vs. a PGR)., Results: Between 2002 and 2013, 172 patients underwent sPTX for PHPT. There were 108 patients (62.8%) who had a WGR. Another 64 patients (37.2%) had a PGR. Mean age was 60 ± 14 years. There were 82.6% female patients. Cases with positive family history for PHPT were more likely to have a PGR (12.5 vs. 3.7%; p = 0.03). Patients had similar preoperative and postoperative laboratories. Individuals with a PGR tended to have larger glands encountered by surgeons intraoperatively (525 ± 1,308 vs. 280 ± 341 mg; p = 0.02). One patient with a WGR developed permanent hypocalcemia. Overall, the cure rate was 97.1%. A mean of 29 ± 28.7 months follow-up revealed a recurrence rate of 5.2%. Disease persistence and recurrence rates were similar in patients., Conclusion: PHPT due to hyperplasia is managed by sPTX, leaving WGR without increased rates of disease persistence/recurrence. Patients without family history for hyperparathyroidism and those with smaller glands may be the best candidates for this approach.

Background: Aberrant expression of microRNAs is associated with neointimal hyperplasia (NIH) in type 2 diabetes. We prospectively compared the effects of pioglitazone on coronary NIH and changes in microRNAs according to NIH status in type 2 diabetic patients during 9-month follow-up., Methods and Results: Type 2 diabetic patients were randomly assigned to the pioglitazone (n=36) or control groups (n=36) after coronary stenting. Primary endpoint was the comparison of changes in neointimal volume on OCT and in the level of circulating microRNA-17,-24,-92a,-126 and -145 during 9-month follow-up. Secondary endpoint was the comparison of changes in brachial artery flow-mediated dilation and inflammatory markers such as IL-6, TNF-α, hsCRP, adiponectin, sICAM-1, and sVCAM-1 between the 2 groups. Neointimal volume was significantly lower in the pioglitazone group (25.02±17.78 mm(3)vs. 55.10±30.01 mm(3), P<0.001) with significant increases in circulating microRNA-24 (0.264±0.084 vs. 0.006±0.030, P<0.001) during follow-up. FMD was significantly greater in the pioglitazone than control group at 9 months (0.47±0.14 mm vs. 0.28±0.18 mm, P<0.05, respectively). Decreases in inflammatory markers such as IL-6, TNF-α, and sVCAM-1 were significantly greater in the pioglitazone than the control group during the follow-up., Conclusions: Pioglitazone significantly decreased NIH with increases in circulating microRNA-24 at 9-month follow-up. The decrease in microRNA-24 could be used as a potential predictor of increases in NIH in type 2 diabetic patients.

Background: Beckwith-Wiedemann syndrome (BWS) and hemihyperplasia (HH) are overgrowth conditions with predisposition to hepatoblastoma for which early diagnosis patients undergo cancer screening based on determination of the tumor marker α-fetoprotein (αFP). Repeated blood draws are a burden for patients with consequent compliance issues and poor adherence to surveillance protocol. We sought to analyze feasibility and reliability of αFP dosage using an analytical micromethod based on blood dried on filter paper (DBS)., Methods: Overall 143 coupled αFP determinations on plasma and DBS collected simultaneously were performed, of which 31 were in patients with hepatoblastoma predisposition syndromes and 112 were in controls. The plasma αFP dosage method was adapted to DBS adsorbed on paper matrix for newborn screening., Results: There was strong correlation between plasmatic and DBS αFP (r2 = 0.999, P < 0.001). Cohen's k coefficient for correlation was 0.96 for diagnostic cut-off of 10 U/ml (P < 0.001), commonly employed in clinical practice. The measurements on plasma and DBS were highly overlapping and consistent., Conclusion: The DBS method allowed to dose αFP reliably and consistently for the concentrations commonly employed in clinical settings for the screening of hepatoblastoma, opening new scenarios about conducting cancer screening in overgrowth syndromes.

Background: Primary hyperaldosteronism (PHA) is a cause of secondary arterial hypertension potentially curable by laparoscopic unilateral adrenalectomy. We describe the follow-up of these patients according to their medical or surgical treatment., Methods: We report a retrospective single-center study of 91 patients with PHA from 1998 to 2012. Treatment was guided by computed tomography (CT) scans. Preoperative adrenal vein sampling (AVS) was performed when the CT scan did not show single solitary unilateral nodules on the adrenal glands. During the follow-up, we considered hypertension to be cured in patients with normal blood pressure without antihypertensive medication (AM), and improvement was defined by a decrease in AM., Results: A total of 28 patients received only AM. Of the 62 patients who underwent a unilateral adrenalectomy, 46 (74 %) had an adrenal adenoma, 14 (22 %) a hyperplasia, and the adrenal gland was normal in two cases. Hypertension was cured in 24 cases (38 %), and 28 patients (45 %) showed improvement with a reduction in AM. Predictive factors for a cure were gender, age, number of preoperative AMs, preoperative arterial systolic blood pressure, and plasma renin activity. All patients who presented with hypokalemia were cured postoperatively. We performed 38 AVS and nine of these patients were operated on based on the AVS findings, with an improvement of 100 % of arterial blood pressure after surgery., Conclusion: Laparoscopic unilateral adrenalectomy for PHA cured or improved hypertension in 84 % of patients. Preoperative AVS is mandatory for surgical decision making if the CT scan shows bilateral or no lesions associated with PHA.

Objectives: Multiple, minimally invasive surgical techniques have been developed over the last few decades for the management of sporadic primary hyperparathyroidism (PHTP). However, in cases with multiglandular disease, bilateral cervical exploration remains the gold standard. Therefore, it is important to have an accurate estimation of the incidence of multiglandular disease in sporadic PHTP., Methodology: 698 patients were treated for PHTP between 1993 and 2010 at the University Hospitals Leuven, using the bilateral cervical exploration method. After excluding cases of multiple endocrine carcinoma syndrome, the incidences of double adenoma and multiple gland hyperplasia were investigated in these patients. Age, gender, imaging results, serum calcium and parathyroid hormone concentrations were analyzed and compared to the data of 50 randomly-selected, PHTP patients with solitary adenomas., Results: 6.6% and 2.4% of the patients with sporadic PHTP had double adenomas and multiple gland hyperplasia, respectively. The female/male ratio was 4.8 (38/8) and 1.8 (11/6), and the average age was 63 and 52 yrs for patients with double adenomas and multiple gland hyperplasia, respectively. The patients with solitary adenomas had a female/male ratio of 3.5, and an average age of 60 yrs. There were no significant differences in serum calcium or parathyroid hormone concentrations between patients with multiglandular disease and those with solitary adenomas., Conclusions: Multiglandular disease occurs in 9% of patients with sporadic PHTP, and cannot be excluded before surgery. This incidence must be considered when using minimally invasive techniques for treatment of sporadic PHTP. In cases of multiglandular disease, bilateral cervical exploration is indicated.

Aim: Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT., Methods: A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophagogastroduodenoscopy-obtained biopsies., Results: Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity × specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B12 levels (96.1% specificity)., Conclusion: Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up., (© 2014 S. Karger AG, Basel)

Background: An easy, reproducible and simple marker is needed to estimate phase of endometrial pathologic lesions such as hyperplasia and endometrial cancer and distinguish from pathologically normal results. We here aimed to clarify associations among neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), endometrial hyperplasia and cancer in patients with abnormal uterine bleeding., Materials and Methods: Patients (n=161) who were admitted with abnormal uterine bleeding and the presence of endometrial cells on cervical cytology or thick endometrium were investigated. The study constituted of three groups according to pathologic diagnosis. Group 1 included endometrial precancerous lesions like hyperplasia (n=63), group 2 included endometrial cancerous lesions (n=38) and group 3 was a pathologically normal group (n=60). Blood samples were obtained just before the curettage procedure and the NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count; similarly, PLR was defined as the absolute platelet count divided by the absolute lymphocyte count., Results: The white blood cell count was significantly higher in patients with cancer than in those with hyperplasia (p=0.005). The platelet count and neutrophil to lymphocyte ratio were significantly higher in patients with cancer than in control patients, but there was significantly no difference between patients with hyperplasia and other groups (p=0.001 and p=0.025 respectively). PLR was significantly lower in control subjects than in other groups (p<0.001), but there was no significant difference between patients with hyperplasia and those with cancer., Conclusions: PLR was significantly lower in control subjects than in other groups. Thus both hyperplasia and cancer may be differentiated from pathologically normal patients by using PLR. White blood cell count was significantly higher in patients with cancer than in those with hyperplasia and pathologically normal patients. Therefore white blood cell count may be used for discriminate hyperplasia to cancer. By using multiple inflammation parameters, discrimination may be possible among endometrial cancer, endometrial precancerous lesions and pathologically normal patients.

Background: The true association between breast cancer and vitamin D is currently under investigation. We compared serum 25-hydroxy-vitamin D levels in women with benign and malignant breast masses and controls., Materials and Methods: Levels of vitamin D were measured by electrochemiluminescense. Serum levels >35 ng/ml, 25-35 ng/ml, 12.5-25 ng/ml and <12.5 ng/ml were considered as normal, mild, moderate and severe vitamin D deficiency, respectively., Results: Overall, 364 women were included in the control, 172 in the benign and 136 in the malignant groups. The median serum vitamin D level was significantly lower in breast cancers than controls. Levels were also lower in malignant than benign cases and in benign cases than controls although statistically non-significant., Conclusions: Multinomial logistic regression analysis showed that severe vitamin D deficiency causes a three-fold increase in the risk of breast cancer while this was not the case for moderate and mild deficiency.

The present study was conducted to investigate the effects of gonadectomy on lung carcinogenesis in female and male mice, and to determine an association between sex hormone and lung carcinogenesis. Female and male A/J mice were divided into gonadectomized and unoperated control groups and all animals were treated intraperitoneally with 1 or 2 injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at the dose of 2 mg/mouse. The mice were sacrificed 18 or 56 weeks after surgery. Serum levels of estradiol in females and testosterone in males were confirmed to be decreased by gonadectomy. Lung white nodules were detected in all mice of all groups. In the control groups of 18- and 56-week studies, the multiplicities of lung nodules in females were significantly greater than in males. In males in the 56-week study, the multiplicity of macroscopical lung nodules, bronchiolo-alveolar hyperplasias, adenomas and tumors (adenomas and adenocarcinomas) showed significant increase with castration. In females in the 18-week study, the multiplicity of adenomas decreased significantly by ovariectomy. Based on the results of the present study, female A/J mice were confirmed to be more susceptible to NNK-induced lung carcinogenesis than males. Furthermore, it was suggested that the process is inhibited by testosterone and accelerated by estradiol. These findings indicate the possibility that sex hormones play important roles in determining sex differences in lung carcinogenesis in the A/J mice initiated by NNK.

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cardiac allograft vasculopathy (CAV) is the single most important long-term limitation to heart transplantation. This study aimed to assess the value of monitoring soluble human leukocyte antigen-G (sHLA-G) during the first year post-transplantation to predict the severity of CAV, in 21 out of 77 heart recipients assessed by intravascular ultrasound (IVUS). Serum sHLA-G concentration increased after transplant in recipients free of severe CAV, but decreased in recipients suffering from severe CAV, significant differences between these two groups were found 6 to 12 months post-transplantation. The optimal value of the change in post-transplant sHLA-G for identifying severe CAV was ≥0.062%, which maximized sensitivity (80%) and specificity (100%). Importantly, increases in post-transplant sHLA-G were inversely associated with severe CAV, but directly associated with human cytomegalovirus reactivation. In addition, recipients presenting non-severe CAV or an increased sHLA-G post-transplantation, showed higher numbers of CD8(+)CD28(-) T cells and a down-modulation of CD28 on CD4(+) lymphocytes, which typically identifies CD8(+) regulatory T cells and anergic/tolerogenic T helper cells, respectively. In conclusion, quantification of sHLA-G might offer a complementary non-invasive method for identifying recipients at risk of more severe CAV and who might benefit from earlier preventive therapies, although these results need to be confirmed in larger series., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of our study was to create a preoperative "index" that could predict the likelihood of additional hyperfunctioning parathyroid glands and let the surgeon determine whether to wait for the intraoperative parathyroid hormone (ioPTH) or to explore further., Background: During parathyroidectomy for primary hyperparathyroidism (PHPT), discovering a minimally "enlarged" parathyroid gland creates a dilemma for the surgeon regarding the need for further exploration. Although ioPTH testing can potentially solve this problem after a 20- to 30-minute period, several surgeons recognize that further operative exploration may be more effective., Methods: We analyzed a prospective database of 1235 consecutive patients who underwent parathyroidectomy for PHPT at our institution between March 2001 and August 2010. The Wisconsin Index (WIN) was defined as the multiplication of preoperative serum calcium by preoperative parathyroid hormone (PTH). Patients were divided into 3 WIN categories: low (<800), medium (801-1600), and high (>1600). The utility of the WIN was then validated on a subsequent cohort of 216 patients., Results: The median age of the patients was 61 years (range, 10-91), and 77% of the patients were female. The mean preoperative calcium and PTH levels were 11.0 ± 0 mg/dL and 127 ± 3 pg/mL, respectively. The mean WIN for the entire cohort was 1461 ± 38 and highly correlated with gland weight (P < 0.000001). A single adenoma was identified in 1000 patients (81%), double adenoma in 100 patients (8%), and hyperplasia in 135 patients (11%). The mean gland weights for the 3 WIN catagories were low = 370 ± 33 mg, medium = 532 ± 39 mg, and high = 985 ± 28 mg, respectively (P < 0.000001). A WIN nomogram, consisting of the combination of WIN and parathyroid gland weight, accurately predicted the likelihood of additional hyperfunctioning parathyroid glands. For example, for a WIN of less than 800 and a gland weight of 500 mg, there is a 9% chance for additional hyperfunctioning parathyroid glands based on the WIN nomogram. In contrast, for the same gland weight, if the WIN is 801 to 1600, these chances increase to 28%, and if the WIN is more than 1600, the chance of multigland disease is 61%. Comparison between the predicted chances for another gland with the actual chance in the validation cohort identified an R(2) value of 0.96., Conclusions: The WIN nomogram predicts the likelihood of additional hyperfunctioning parathyroid glands during parathyroidectomy. This simple intraoperative tool may be used to guide the decision of whether to wait for ioPTH results or to proceed with further neck exploration.

Background: Non-reactive platelet counts elevation occurs mainly in myeloproliferative disorders (MPDs), which have been reported to be closely associated with JAK2 V617F mutation. Complete blood cell count (CBC) is essential in diagnosis of MPDs, however, the impact of JAK2 V617F mutation on the patients' hemogram variation remains not clear., Methods: JAK2 V617F mutation was detected by allele specific real-time quantitative fluorescence PCR (AS-qPCR)., Results: Of the 402 non-reactive platelet elevating patients, JAK2 V617F mutation was detected in 222 (55.2%) patients. RBC counts, WBC counts, platelet-large contrast ratio (P-LCR), platelet distribution width (PDW) and mean platelet volume (MPV) were much higher in JAK2 V617F mutated patients, except platelet counts. In addition, when the patients were classified into subgroups by blood cell counts, it was found that JAK2 V617F mutation rate increased progressively with the increase of RBC counts and WBC counts, other than platelet counts. Furthermore, trilineage hyperplasia group showed highest JAK2 V617F mutation rate (93.26%), followed by the bilineage hyperplasia groups. Lastly, JAK2 V617F mutant allele burden was found much higher in polycythemia vera (PV) patients [median(P25-P75): 45.02%(35.12%-54.22%)] than in essential thrombocythemia (ET) patients [median(P25-P75): 28.23%(17.77%-41.66%)], and that it increased with WBC counts (r = 0.393, p = 0.000) and RBC counts(r = 0.215, p = 0.001), other than platelet counts (r = -0.051, p = 0.452). Further analysis revealed that in ET patients, JAK2 V617F mutant allele burden correlated with WBC counts and platelet counts positively, other than RBC counts, while in PV patients, it correlated with WBC counts and RBC counts positively, but not platelet counts., Conclusions: JAK2 V617F mutation occurs frequently in patients with non-reactive elevated platelet counts. The presence of JAK2 V617F mutation has great impact on hemogram variation, including RBC counts, WBC counts, platelet parameters and lineage hyperplasia, but not on platelet counts. Besides, JAK2 V617F mutant allele burden affects the blood cell proliferation pattern.

This study aimed to elucidate groups at high risk of developing cancer among patients with serologically identified Helicobacter pylori infection and nonatrophic stomach. Annual endoscopy was performed for a mean of 5.4 years in 496 asymptomatic middle-aged men who were H. pylori antibody-positive and pepsinogen (PG) test-negative. Subjects were stratified according to the activity of H. pylori-associated gastritis measured by serum levels of PG and H. pylori antibody, and/or by endoscopic findings of rugal hyperplastic gastritis (RHG), and cancer development was investigated. During the study period, seven cases of cancer developed in the cohort (incidence rate, 261/100,000 person-years), with 85.7% developing in the group showing a PGI/II ratio ≤ 3.0, reflecting active inflammation-based high PGII levels. Cancer incidence was significantly higher in this group (750/100,000 person-years) than in groups with less active gastritis. Furthermore, cancer incidence for this group was significantly higher in the subgroup with high H. pylori antibody titers than in the low-titer subgroup. Meanwhile, endoscopic findings revealed that 11.7% of subjects showed RHG reflecting localized highly active inflammation, and cancer risk was significantly higher in patients with RHG than in patients without. Combining the two serum tests and endoscopic examination for RHG allowed identification of subjects with more active gastritis and higher cancer risk. No cancer development was observed in these high-risk subjects after H. pylori eradication. Subjects with highly active gastritis identified by the two serological tests and endoscopic RHG constitute a group at high risk of cancer development with H. pylori-infected nonatrophic stomach., (Copyright © 2012 UICC.)

Background: In adolescents and young adults, primary hyperparathyroidism (PHPT) is an uncommon diagnosis. We compared the clinical characteristics of these patients to those of older adult patients with PHPT. We hypothesized that PHPT in adolescents and young adults is more often caused by single-gland disease and is amenable to minimally invasive parathyroidectomy (MIP)., Methods: We retrospectively reviewed the medical records of 452 consecutive patients who had surgery for PHPT. Patients ranged in age from 13 to 94 years and were dichotomized into younger (age <30 years, n = 17, 3.8%) and older (age ≥ 30 years, n = 435, 96.2%) patients. Continuous baseline and intraoperative and postoperative measures were not normally distributed and were summarized with medians and interquartile ranges (IQRs). Groups were compared using Wilcoxon rank sum test or Fisher exact test, and significance was set at P < .05., Results: Median [IQR] age was 24 [23-27] years for the younger group and 58 [51-66] years for the older group. Though not statistically significant, a smaller proportion of the younger patients compared with the older patients had a positive (99m)Tc-sestamibi scan (71%; 95% confidence interval [95% CI] = 44-90% vs. 83%; 95% CI = 79-86%) and showed a suspected parathyroid adenoma on ultrasound (65%; 95% CI = 38-86% vs. 80%; 95% CI = 76-83%). The younger and older age groups did not significantly differ on preoperative serum PTH levels (median [IQR]: 111 [76-145] pg/ml vs 110 [84-152] pg/ml; P = .73 respectively). The younger group had higher serum calcium levels (11.6 [11.1-12.2] mg/dl) compared with the older group (11.1 [10.7-11.5] mg/dl; P = .01). MIP was performed less frequently on the younger patients (70.6%) compared with older patients (88.7%; P = 0.04). Though the incidence of a single adenoma was somewhat more frequent in older patients (90%; 95% CI = 87-93%) than in younger patients (82%; 95% CI = 57-96%) it was the most frequent cause of PHPT in the younger patients. The younger and older groups did not significantly differ on percent drop from baseline for intraoperative PTH monitoring (81.7 vs 79.3%; P = .46), respectively., Conclusions: Younger patients with PHPT present with significantly higher serum calcium levels than older patients. However, younger patients are less likely to localize abnormal parathyroid glands on sestamibi or ultrasound. Though younger patients appear to have a higher incidence of hyperplasia compared with older patients, single gland disease is still the overall most frequent cause. Our data suggest that MIP should be more frequently considered in younger patients because of the high incidence of single gland disease.

Objective: To observe the effect of encircled needling plus electroacupuncture (EA) of the second pair of nipples on hyperplastic mammary glands, serum estradiol (E2), progesterone (P), prolactin (PRL) and testosterone (T) contents, estrogen receptor (ER) expression of the mammary glands in mammary hyperplasia rats., Methods: Forty Wistar rats were equally randomized into normal control, model, acupuncture and medication groups. Mammary gland hyperplasia model was established by intramuscular injection of diethylstilbestrol (0.5 mg/kg, once daily for 25 days) and progesterone (4 mg/kg, once daily for 5 days). For rats of the acupuncture group, 4 filiform needles were inserted into the surrounding tissues of the second pair of breasts, respectively, followed by giving the animal with EA stimulation for 30 min. Another one acupuncture needle was inserted into "Danzhong" (CV 17) and retained for 30 min. For rats of the medication group, tamoxifen solution (1.8 mg/kg) was given by gavage. Both medication and EA intervention were given once daily for 30 days. The diameter and height of the second pair of nipples were measured before and on the 10th, 20th and 30th days of the treatment. Serum E2, P, PRL and T levels were assayed by radioimmunoassay, and the tissues of the second pair of nipples were stained with H. E. method. Estrogen receptor immunoactivity of the breast tissue was detected by immunohistochemistry., Results: The diameter and height of the second pair of nipples, serum E2, PRL and T contents, and breast ER protein expression level were significantly higher in the model group than in the normal control group (P<0.05), while serum P content was remarkably lower in the model group than in the normal control group (P<0.05). In comparison with the model group, the diameter and height of the second pair of nipples, serum E2, PRL and T contents, and breast ER protein expression level were considerably lower in both acupuncture and medication groups (P<0.05), and serum P contents were significantly higher in the latter two groups (P<0.05). In addition, H.E. staining showed that the numbers of the lobule, alveolus and ducts of mammary glands were significantly increased, and the expansion of the acinar lumina and ducts was found in the model group. These pathological changes were relatively milder in both acupuncture and medication groups., Conclusion: Encircled needling plus EA stimulation of the surrounding tissues of the nipples can improve the hyperplasic nipples and pathological changes of the breast tissue in mammary gland hyperplasia rats, which is closely associated with its functions in lowering serum estradiol, prolactin, testosterone contents and estrogen receptor protein expression of the breast, and in increasing serum progesterone level.

Objectives: Soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) has been shown to exert protective action against atherosclerosis. The aim of this study was to investigate potential associations of coronary sTRAIL levels with indices of in-stent neointimal hyperplasia., Methods: 67 patients who underwent percutaneous coronary intervention with drug-eluting stent were followed up at approximately 12 months with determination of coronary sTRAIL concentration, angiography and intravascular ultrasound evaluation of the stent sites., Results: Mean sTRAIL concentration was 72.2 ± 2.8 pg/ml. sTRAIL was negatively correlated to indices of neointimal hyperplasia and positively correlated to in-stent minimum lumen area (p < 0.001). Neointimal obstruction and maximal in-stent cross-sectional neointima burden in patients in the upper sTRAIL quartile were 3.8 ± 1.2 and 12.6 ± 3.3%, respectively, versus 14.0 ± 0.7 and 49.8 ± 2.7% in the lower quartile (p < 0.001 for both). sTRAIL levels were significantly lower in patients with binary restenosis (48.7 ± 3.0 vs. 75.2 ± 2.9 pg/ml; p < 0.001). In the multivariate analysis, sTRAIL was an independent predictor of neointimal hyperplasia., Conclusion: This study demonstrates a negative association of sTRAIL to in-stent neointima formation. The potential pathophysiologic substrate of this effect implicates modulation of apoptosis in various cell types. These observations should prompt further evaluation of the link between sTRAIL and in-stent restenosis., (Copyright © 2012 S. Karger AG, Basel.)

Fibrosis in the parathyroid glands can be seen in adenomas, in carcinomas, and after fine needle aspiration of the thyroid gland. Fibrosis occurs in approximately 10% of typical adenomas and in all atypical adenomas. This is usually in the form of fibrous bands or trabeculae that intersect the hypercellular parenchyma. However, widespread diffuse fibrosis or sclerosis in either parathyroid gland hyperplasia or adenoma has not been reported before in the English medical literature. We report 3 cases of hyperparathyroidism (2 adenomas and 1 hyperplasia) with an unusual pattern of sclerosis. The hyalinized, eosinophilic fibrous tissue was diffusely distributed within and around the parathyroid parenchyma, often isolating groups of cells and single cells., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The sebaceous glands are susceptible to the effects of androgens. A benign proliferation of these hormones, i.e. hyperplasia, occurs with age., Objectives: This was a pilot study to demonstrate whether any correlation exists between circulating androgen levels and an increase in the incidence of sebaceous hyperplasia., Methods: Sixteen female patients with a diagnosis of sebaceous hyperplasia were compared to a control group of females of a similar age without the disease. Blood tests were performed on participants of both groups to measure circulating androgen levels (free and total testosterone and androstenedione levels). Results were tabulated for statistical analysis., Results: These data showed no statistically significant differences in circulating androgen levels between the patients with sebaceous hyperplasia and the control group., Conclusion: These data suggest that no significant changes occur in circulating androgen levels [free and total testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate] in patients with sebaceous hyperplasia.