胰腺内分泌肿瘤的诊断和外科治疗

目的：探讨胰腺内分泌肿瘤（pancreatic endocrine tumours, PET）的临床特点,藉以提高临床诊治水平。方法：对我院1973年1月至2006年12月收治的77例PET患者的临床、病理资料进行回顾性分析。结果：本组女性46例（59.7%）;功能性PET占72.7%;良性为81.8%。术前B超和CT检查发现65例（84.4%）有胰腺占位病变;单发肿瘤位于胰头、体、尾部,分别为18.2%、28.6%和45.5%;多发肿瘤6例。肿瘤最大径8 cm。所有病例均得到病理检查,显示胰岛素瘤43例（55.8%）,胃泌素瘤7例,胰高血糖素瘤5例,血管活性肠肽瘤1例,余21例为无功能PET。2例胃泌素瘤合并甲状旁腺瘤,为Ⅰ型多发性內分泌瘤。胰高血糖素瘤表现为游走性坏死性红斑、大泡性皮损和糖尿病。血管活性肠肽瘤表现为腹泻和低钾血症;无功能PET主要症状为反复中上腹隐痛。手术治疗PET的主要术式为肿瘤局部切除术（53例,68.8%）。手术后43例胰岛素瘤患者中,39例血糖恢复正常;胃泌素瘤、胰高血糖素瘤和血管活性肠肽瘤患者的术后症状均有缓解或完全消失。胰漏是主要的术后并发症。结论：PET发病隐匿,根据B超和CT检查可明确肿瘤的位置。最终诊断根据病理检查。本病预后明显好于胰腺癌,因此一旦明确诊断,应争取彻底切除肿瘤。恶性PET伴转移者的术后病死率较高。     

24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas

Summary Based on the known action of xanthine derivatives on the insulin secretion, the effect of pentoxifylline on carbohydrate homeostasis of type I (IDDM) and type II (NIDDM) diabetics was investigated. Pentoxifylline is known to exert a favorable influence on hemorheological disturbances in such patients. Twenty-four hour blood glucose pattern and insulin requirements were evaluated in type I and type II diabetics by the use of the artificial pancreas before and after a 14-day treatment with pentoxifylline 400 mg p.o. (Trental 400^?) t.i.d. During the stabilization period before treatment with pentoxifylline, NIDDM patients required 10.1±3.8 U of insulin and the IDDM 35±13.7 U. After 2 weeks on pentoxifylline, NIDDM required only 6.3±2.8 U (p<0.05) and IDDM 28.5±9.7 U (n.s.). Average blood glucose during the 24h decreased by 15.8±3.5% in NIDDM and by 10.3±2.5% in IDDM. Moreover, a significant smoothing of glucose fluctuations during the 24h was noted in both groups. It is concluded that pentoxifylline administered concurrently to any antidiabetic type of treatment leads to better blood glucose control as well as to prevention or delay of vascular complications. This work was supported by grants from the Social Ministry, Athens, Greece; Department of Internal Medicine I, University of Ulm, FRG;Deutsche Forschungsgemeinschaft SFB87 Endokrinologie, Ulm, FRG; the Alexander Onassis Foundation, Vaduz, Liechtenstein. Dedicated to Prof. Dr. med. h.c. Ernst F. Pfeiffer on the occasion of his 65th birthday anniversary.     

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

The large family of fibroblast growth factors (FGFs) has been known for its important roles in regulating critical cellular processes during embryonic development and homeostasis of normal tissues (1–3). While most FGFs act as cytokines or hormonelike proteins that mediate their pleiotropic cellular processes by binding to cell surface receptors endowed with intrinsic tyrosine kinase activity (FGFRs), a subfamily of FGFs (FGF 11–14) was shown to be uniquely expressed intracellularly. The mechanism of action and physiological roles of intracellular FGFs are poorly understood (4–6).In contrast to most receptor tyrosine kinases (RTKs) that are activated by a single ligand molecule that binds with high affinity to the extracellular domain of its cognate RTK with a dissociation constant in the subnanomolar range, the binding affinities of FGFs to FGFRs are, at least, 1,000–10,000 fold weaker with dissociation constants in the submicromolar range (7–9). The weak binding affinities toward FGFRs of the largest subfamily of FGF molecules designated canonical FGFs are offset by interactions with cell surface heparan sulfate proteoglycans (HSPGs). Both biochemical and structural studies revealed how multiple interactions between heparin or HSPG with both FGF and FGFR mediate tight association enabling robust receptor dimerization and tyrosine kinase activation (10, 11).The three endocrine FGFs, FGF19, 21, and 23 are part of an additional subfamily of FGF molecules. Endocrine FGFs function as circulating hormones that play essential roles in the control of various metabolic processes (12). In addition to the conserved FGF-domain found in all FGF ligands, endocrine FGFs contain unique C-terminal tails (CTs) composed of 46 (FGF19), 34 (FGF21), or 89 (FGF23) amino acids that serve as specific and high-affinity ligands for the two members of the Klotho family of surface receptors. It was shown that KLA serves as a high-affinity receptor for FGF23 while β-Klotho (KLB) functions as a high-affinity surface receptor for both FGF19 and FGF21 (13–16). Structural analyses of free and ligand-occupied Klotho proteins revealed the molecular basis underlying the specificity and high affinity of KLA and KLB toward endocrine FGFs. It also showed that Klotho proteins function as the primary receptors for endocrine FGFs whereas FGFR functions as a catalytic subunit that mediates cell signaling via its tyrosine kinase domain (8, 17, 18). Accordingly, endocrine FGFs stimulate their cellular responses by forming a ternary complex with Klotho proteins and FGFRs to induce receptor dimerization, tyrosine kinase activation, and cell signaling. Unlike FGFRs that are ubiquitously expressed, the expressions of KLA and KLB are restricted to specific tissues and organs to enable precise targeting of endocrine FGFs to stimulate their physiological responses in specific cells and tissues (19–22). The ability of endocrine FGFs to circulate is attributed to the loss of conserved heparin binding sites that are essential for the function of canonical FGFs (23).FGF23 is a 32-kDa glycoprotein, mainly produced in the bone by osteoblasts and osteocytes, that serve as a key hormone in regulating phosphate homeostasis, vitamin D, and calcium metabolism (24, 25). Circulating levels of physiologically active FGF23 are regulated by proteolytic cleavage to produce a FGF23 molecule lacking its unique CT (26, 27). The cleavage resulting in FGF23 inactivation prevents assembly and stimulation of the FGF23/FGFR/KLA complex. Additionally, the processing of FGF23 includes several posttranslational modifications which affect its stability and susceptibility toward proteolysis. Secreted FGF23 was shown to be O-glycosylated in its C-terminal cleavage site (28, 29) to protect the protein from C-terminal cleavage. In order for the cleavage site to be exposed, FGF23 has to be first phosphorylated in this region (30). Phosphorylation prevents glycosylation and exposes the cleavage site to proteolysis.In this paper, we demonstrate that the CT of FGF23 contains two tandem repeats and that each repeat binds with high affinity to KLA. This contrasts with FGF19 and FGF21, whose CTs contain a single binding site to KLB. Engineered FGF23 variants containing each of the two repeats individually or both repeats bind specifically to KLA and stimulate cell signaling to a similar extent. We also demonstrate that two cysteine residues flanking the second repeat form a disulfide bridge in FGF23 secreted by mammalian cells. However, both oxidized or unbridged forms of FGF23 exhibit similar KLA binding characteristics and similar cellular stimulatory activities. We also show that FGF23-WT induces mitogen-activated protein kinase (MAPK) activation in cells expressing chimeric KLA-FGFR proteins and use TIRFM imaging of individual KLA molecules on the cell surface to demonstrate that FGF23 has the capacity for simultaneous binding to two KLA molecules. These insights reveal the complexity of FGF23 regulation and its role in assembling the FGF23/FGFR/KLA signaling complex.     

性早熟女童血清中环境内分泌干扰物水平研究

[目的]了解女童血清中环境内分泌干扰物（EEDs）的水平及其与性早熟的关系。[方法]采用病例对照研究,以2011年杭州市某儿童医院内分泌科确诊为性早熟的女童219人为病例组,杭州市4所小学的健康女童271人为对照组,采用超高效液质联用技术测定女童血清中有机氯农药DDT的代谢产物DDE和20种邻苯二甲酸酯（DEHP、DBP、DIDP、DIBP、DNOP、DHXP、DEP、DAP等）,及其4种代谢产物（MEHP、MBP、MEP等）,以及2种洗涤剂的降解产物（4-OP、4-NP）和双酚A,共28种EEDs的含量。采用多元线性回归方法分析检出的EEDs与女童性早熟的相关性。[结果]病例组和对照组血清中检出14种EEDs,其中两组DDE、DEHP、DIBP、DBP、DIDP、MBP检出率均较高（50%～100%）。病例组DNOP（χ2=30.191,P〈0.001）和DIDP（χ2=71.100,P〈0.001）检出率显著高于对照组。病例组血清中DDE、DEHP、DNOP含量明显高于对照组（Z值分别为8.350、3.435、5.487,P〈0.001）;而DEP、DAP、DIBP、DBP、DHXP、MEHP、MBP、MEP含量则明显低于对照组（Z值分别为4.389、9.290、5.592、2.962、4.703、5.384、3.607、3.650,P〈0.01）;多元回归显示,DNOP（b=0.128,P〈0.001）和DDE（b=0.357,P〈0.001）的含量与性早熟呈正相关,而DAP（b=-0.183,P〈0.001）和MEP（b=-0.055,P〈0.01）的含量与性早熟呈负相关。[结论]两组女童血清都检出EEDs,DDE、DNOP的水平升高可能与女童性早熟的发生相关,DEP、DAP、DIBP、DBP、DHXP、MEHP、MBP、MEP存在低检出水平。     

Treating the primary in low burden metastatic prostate cancer: Where do we stand?

On the basis of endocrine therapy for patients with low burden metastatic prostate cancer (LBMP), the clinical efficacy and quality of life were compared between prostate-only directed radiotherapy (PODT) and prostate and metastasis radiotherapy (PMRT).From November 2009 to November 2015, total 91 patients newly diagnosed with LBMP were retrospectively analyzed, of which 52 patients received PODT and 39 patients received PMRT. The biochemical failure free interval (IBF), prostate specific survival (PCSS), and overall survival (OS) time were compared between the 2 groups, and expanded prostate cancer index composite (EPIC) scale was used to evaluate the difference in quality of life between the 2 groups.The median IBF of the PODT group was 31 months, which was significantly lower than the 39 months of the PMRT group (P < .05); the 5-year OS and PCSS were 58.9%, 65.3% in PODT group, and 58.9%, 71.79% in PMRT group, respectively. There was no significant between the 2 groups (P > .05); the side effects of acute radiotherapy in PMRT group were significantly higher than PODT group (P < .05), especially in bone marrow suppression and gastrointestinal reactions; The scores of urinary system function and intestinal system function in PMRT group were significantly higher than PODT group at the end of radiotherapy, 3 months after radiotherapy, and 6 months after radiotherapy (P < .05). The score of sexual function in PMRT group was significantly lower than that in PODT group after radiotherapy (P < .05), and higher than that in PORT group at other follow-up time points (P < .05). The hormone function was decreased at each follow-up time point in 2 groups, and there was no significant difference between the 2 groups (P > .05).Patients with LBMP receiving PMRT can improve IBF, but cannot increase PCSS and OS, and increase the incidence of acute radiation injury.     

Estradiol regulates responsiveness of the dorsal premammillary nucleus of the hypothalamus and affects fear‐ and anxiety‐like behaviors in female rats

Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E₂) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole‐cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E₂. Our results show that E₂ increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E₂ as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E₂ persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E₂ treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α‐ and β‐adrenoreceptors. In summary, our results implicate E₂ in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E₂ may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders.     

Zearalenone,an Estrogenic Mycotoxin,Is an Immunotoxic Compound

The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and their cellularities were evaluated. Moreover, acquired immune responses and macrophage activity were also assessed. ZEA promoted reduction in body weight gain, which is not fully explained by diminished food consumption. Despite no effect on haematological parameters, ZEA caused thymic atrophy with histological and thymocyte phenotype changes and decrease in the B cell percentage in the spleen. With respect to acquired and innate immune responses, no statistically significant differences in delayed-type hypersensitivity were noticed; however, in the ZEA-treated rats, antibody production and peroxide release by macrophages were impaired. The observed results could be related to ZEA activity on ERs; thus, ZEA is an immunotoxic compound similar to estrogen and some endocrine disruptors.     

Bilirubin as a signaling molecule

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.     

ANALYSIS OF THE RET PROTO-ONCOGENE IN SPORADIC PARATHYROID ADENOMAS

Missense germline mutations of the RET proto-oncogene have recently been identified in the hereditary cancer syndromes MEN2A, MEN2B, and FMTC, all characterized by medullary carcinoma, but also including phaeochromocytoma in MEN2A and MEN2B and parathyroid disease in MEN2A. In addition, somatic RET proto-oncogene mutations have been identified in a subset of sporadic medullary carcinomas and phaeochromocytomas. This study investigated the possibility that RET plays a role in sporadic parathyroid neoplasia. Firstly, normal and neoplastic parathyroid tissues were screened for expression of the RET proto-oncogene, using an RT-PCR approach on autopsy material. Secondly, 20 archival parathyroid adenomas were screened for somatic mutations in the transmembrane region of RET, the region associated with germline mutations in MEN2A and hence parathyroid disease, using a PCR–solid phase direct sequencing approach. RET expression was identified in all the parathyroid tissues analysed. However, no mutations were identified in any of the 20 adenomas, suggesting either that other mechanisms of RET activation occur, such as translocation, or that RET plays a more minor role in the growth control of the parathyroid cells than in C cells or phaeochromocytes.