Mammosomatotroph adenoma of the pituitary associated with gigantism and hyperprolactinemia. A morphological study including immunoelectron microscopy

Summary A 29-year old giantess with growth hormone excess and hyperprolactinemia underwent transsphenoidal surgery to remove her pituitary tumor. Electron microscopy revealed a mammosomatotroph adenoma composed of one cell type. Immunoelectron microscopy, using the immunogold technique, demonstrated predominantly growth hormone or prolactin or a varying mixture of both growth hormone and prolactin in the adenoma cells. The presence of growth hormone and prolactin was found not only in the cytoplasm of the same adenoma cells but also in the same secretory granules. In the nontumorous adenohypophysis, somatotrophs and lactotrophs showed ultrastructural signs of hyperactivity. This finding is in contrast with the presence of suppressed somatotrophs and lactotrophs seen in nontumorous portions of adult pituitaries harboring growth hormone or prolactin-secreting adenomas. Our morphological study reinforces the view that growth hormone-producing pituitary tumors, originating in childhood, are different from those of the adult gland.Supported in part by Grant MT-6349 of the Medical Research Council of Canada     

A significant role of leukemia inhibitory factor in the brain and periphery in endotoxin stimulation of adrenocorticotropin secretion in the rat

Leukemia inhibitory factor (LIF) is considered as another important cytokine regulating the activity of the hypothalamo-pituitary-adrenal axis. In this study, we examined the effects of intravenous (iv) and intracerebroventricular (icv) administrations of anti-LIF antibody on plasma adrenocorticotropin (ACTH) responses induced by intraperitoneal administration of lipopolysaccharide (LPS, 250 μg/kg) in male rats. Fifteen minutes before the LPS injection, anti-rat LIF antibody or control serum was given iv or icv. The antibody was administered at two different concentrations, i.e. undiluted and five-times diluted. Irrespective of the route of administration, the anti-LIF antibody partially but significantly suppressed ACTH responses to LPS, and its suppressive effect was similar between its two different concentrations. These results indicate that the anti-LIF antibody already exerted its maximal effects at its diluted preparation, and hence that the role of LIF in LPS-stimulated ACTH secretion is essentially partial. This is the first study to demonstrate in vivo that LIF in both the brain and general circulation plays a significant role in mediating endotoxin-stimulated ACTH secretion in the rat.     

Vascular factors in the neurotoxic damage caused by 1, 3-dinitrobenzene in the rat

Using a 3 x 10 mg/kg dose schedule of 1,3-dinitrobenzene (DNB) over two days in Fischer rats, we have found the following changes in vascular function and structure during the early phase of the symmetrical brain stem lesions. 1. Marked increase in cerebral blood flow generally but especially in the inferior colliculi, from 6 h after the final dose of DNB. 2. Increasing incidence of petechial haemorrhages in inferior colliculi, cerebellar roof, vestibular and superior olivary nuclei from 12 h. 3. Focal leakage of horseradish peroxidase and many sleeve-like arteriolar haemorrhages seen in vibratome sections and by scanning electron microscopy (SEM) in these regions from 12 h. 4. Periarteriolar oedema and protein leakage present in step-serial sections in these regions from 12 h, with astrocyte swelling and occasional small infarcts. These changes suggest that the vascular bed may play an important role in the pathogenesis of these lesions, perhaps in parallel with early astroglial damage. They are discussed in relation to (i) the known presence of xanthine oxidase in the vascular bed of the brain and the likelihood of "useless redox cycling' with free radical generation from this enzyme's interaction with nitroheterocyclic compounds, and (ii) the possible role of free radical damage to endothelial cells in this intoxication and in the analogous lesions of natural and experimental Wernicke's encephalopathy.     

Suppression of Theiler''s murine encephalomyelitis virus induced demyelinating disease by administration of gangliosides

The distribution of leukemia inhibitory factor receptor (LIFR) mRNA in the adult rat brain was examined by in situ hybridization technique. The intense signals of LIFR mRNA were restricted to specific brain regions relevant to the motor and sensory systems. The moderate expression of LIFR mRNA was observed in several brain regions, including the cerebral cortex, hippocampus, thalamus, hypothalamus and cerebellum. Most of the signals of LIFR mRNA were detected on likely neuronal cells. These findings suggest the possibility that LIF has potential actions on the neuronal cells in the central nervous system of the adult rat.     

Differential adaptations of insulin-like growth factor-I, basic fibroblast growth factor, and leukemia inhibitory factor in the plantaris muscle of rats by mechanical overloading: an immunohistochemical study

We investigated changes in several growth factors in the rat plantaris muscle produced by mechanical overloading by ablation of synergists using immunohistochemistry. At 1 and 3 days post surgery, the insulin-like growth factor-I (IGF-I) level was slightly increased in the cytosol and markedly increased in the invading cells of the extracellular space. Thereafter, the IGF-I immunoreactivity evoked by overloading rapidly decreased to the normal level. The level of leukemia inhibitory factor (LIF), which was not shown to change at 1 day post surgery, was increased in the cytosol at 3, 5, 7 and 10 days and at 2 weeks. Basic fibroblast growth factor (bFGF) immunoreactivity did not change during the entire period of overloading (1 day–3 weeks post surgery). These results indicate that the elevations of the levels of IGF-I and LIF show differential time course in the plantaris muscle subjected to functional overload. Furthermore, bFGF appears not to be related to the compensatory hypertrophy produced by overloading. Received: 20 June 1997 / Revised, accepted: 8 September 1997     

Large and giant pituitary adenoma resection by microscopic trans-sphenoidal surgery: Surgical outcomes and complications in 123 consecutive patients

To evaluate surgical outcomes and complications of patients who underwent microscopic trans-sphenoidal surgery (MTS) for large and giant pituitary adenomas (PAs). A retrospective study of electively operated cases of PA over a six year period was performed. Surgical outcomes and complications of 64 patients with large PAs (≥3 cm) and 59 patients with giant PAs (>4 cm), who underwent MTS at same period, were reviewed. Medical reports of all selected patients were assessed to collect demographic information such as age, sex, clinical symptoms, PA size, the extent of PA extension and resection, outcomes and complications. Patients with large PAs had improvement in visual improvement (78.1%; 50/64), gross total resection (84.4%; 54/64) compared to patients with giant PAs who had improvement in visual (71.2%; 42/59) and gross total resection (74.6%; 44/59). The rate of CSF leakage was 7.8% and 23.7% for large and giant PAs (p = 0.0399). After a mean follow-up period of 40.8 (6−75) months, 10 (15.6%) patients with large PAs experienced tumor recurrence, while 2 giant PA patients (3.4%) experienced tumor recurrence after a mean follow-up period of 40.6 (3−70) months (p = 0.0314). Resection of both large and giant pituitary adenomas by microscopic trans-sphenoidal surgery may be safe and effective surgical technique with low morbidity and mortality.     

Transsphenoidal surgery assisted by a new guidance device: results of a series of 747 cases

Objective

The objective of this study is to report the efficacy and safety of microsurgical transsphenoidal surgery using a frame for sella guidance in a series of patients with untreated pituitary adenoma.

Methods

In this study, seven hundred and forty-seven patients undergoing transsphenoidal resection of a pituitary adenoma involving use of the frame were included. Follow-up of twelve to one hundred months was performed in all patients.

Results

During the procedures using the frame, pituitary adenomas were fully exposed, and no cavernous sinus haemorrhage due to anteroposterior displacement or internal carotid artery lesion due to right-and-left deviation occurred. The duration of the surgical procedure ranged from 28 min to 87 min with a mean of 44 min. The most frequent tumour type was prolactin-secreting adenoma (32.4%), followed by clinically non-functioning adenoma (NFPA) (28.5%), growth hormone-secreting adenoma (25.0%), and adrenocorticotropin-secreting adenoma (13.7%). Normalisation of visual defects occurred in 226 (42.2%) of the 535 patients with visual disturbances. Normalisation of hormone occurred in 458 of 551 patients with endocrine-active tumour in the follow-up period. Two patients died as a consequence of surgery.

Conclusion

The endonasal transsphenoidal technique is a safe, quick, and effective approach to pituitary adenomas. Our guidance frame allows the surgeon to open and close the wound rapidly, which avoids trajectory deviation and shortens the duration of the surgical procedure.     

Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis

Leukemia inhibitory factor (LIF) is a survival factor for motoneurons. In this study we investigated whether intense systemic LIF therapy prevents the loss of lumbar motoneurons in the transgenic SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. Treatment involved daily 25 microg/kg intraperitoneal injection for a period of 6 weeks starting at 70 days of age. Using the unbiased optical dissector technique, significant rescue of motoneurons in the LIF-treated group (3809+/-455) was found compared to the vehicle group (1085+/-140).     

Cyanidin suppresses amyloid beta-induced neurotoxicity by inhibiting reactive oxygen species-mediated DNA damage and apoptosis in PC12 cells

Amyloid beta(Aβ)-induced oxidative stress is a major pathologic hallmark of Alzheimer's disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aβ-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aβ-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aβ, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aβ-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aβ-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aβ neurotoxicity.     

炒麦芽含药血清对MMQ大鼠垂体瘤细胞NGF、PRL分泌的影响

目的了解炒麦芽含药血清对体外培养的MMQ大鼠垂体瘤细胞神经生长因子（NGF）、催乳素（PRL）分泌表达的影响。方法应用血清药理学的方法，以不同剂量、15％给药比例的家兔炒麦芽含药血清和阳性对照药物溴隐停含药血清及正常血清对体外培养的MMQ大鼠垂体瘤细胞进行干预，连续检测4d，以放射免疫法检测细胞培养液上清中NGF和PRL分泌量，并对实验结果进行统计分析。结果炒麦芽各剂量含药血清组、溴隐停组与空白对照组相比培养液中NGF和PRL含量具有显著性差异（P〈0．05），其中，正常血清组和空白对照组之间无统计学意义（P〉0．05）。随炒麦芽含药血清剂量的增加，MMQ垂体瘤细胞NGF分泌量逐渐升高，并伴随着PRL分泌量逐渐下降，炒麦芽剂量、NGF、PRL分泌量三者间呈显著相关（P〈0．05）；阳性对照药物溴隐停含药血清对NGF和PRL的分泌均具有抑制作用（P〈0．01）。结论低剂量炒麦芽促进PRL分泌和高剂量炒麦芽抑制PRL分泌的双向调控机制可能是通过影响NGF分泌实现的．溴隐停抑制PRL激素分泌的原因可能与NGF分泌无关。     

Regulation of luteinizing hormone secretion by neuropeptide Y in rats: hypothalamic and pituitary actions

Previous studies have suggested that the stimulatory effect of neuropeptide Y (NPY) on the release of luteinizing hormone (LH) in rats may be due to a central action of the peptide that promotes the release of LH-releasing hormone (LHRH) from the hypothalamus, and to an action in the pituitary gland, to potentiate the release of LH induced by LHRH. The objectives of the present experiments were to test 1) whether NPY stimulation of LHRH release requires extracellular Ca++, and 2) whether NPY can exert direct stimulatory effects on the release of LH from anterior pituitary cells. The in vitro release of LHRH from medial basal hypothalamic fragments induced by KCl depolarization (56 mM), but not the basal release, was blocked by omission of Ca++ and addition of 0.1 mM EGTA to the incubation medium and also by cobalt (1 mM). Depolarization-induced release of the peptide was unaffected by nifedipine, diltiazem, or lanthanum. However, the stimulation of LHRH release by NPY (1 microM) still occurred in Ca++ free/EGTA medium. In a second set of experiments, 10 min pulses of NPY (1-100 nM) alone were ineffective in stimulating the release of LH from dispersed, perifused anterior pituitary cells obtained from ovariectomized, untreated or ovariectomized, estrogen-treated rats, under conditions where pulses of LHRH (0.1-10 nM) were consistently effective. A brief increase in LH release was observed during a 30 min exposure to 100 nM NPY in estrogen-pretreated cells, but not from untreated cells, and the effect was not as marked as that produced by LHRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

The stimulation of prolactin secretion by taurine: Studies on the site of action

Taurine's site of action within the central nervous system was localized by studying its effect on prolactin secretion following the microinfusion of 125 nmoles of this amino acid into discrete regions of the brain. Taurine was found to stimulate prolactin secretion only when microinfused into the arcuate nucleus of the hypothalamus. Taurine was not effective in other areas of the hypothalamus or in several extra-hypothalamic sites. Mannitol infusions (125 nmoles) into the arcuate nucleus, used as a control, were without effect on prolactin secretion. These studies extend previous observations on the prolactin-releasing action of centrally administered taurine and suggest further that the arcuate nucleus is one target site for this action.     

Surgical outcome and prognostic factors of pediatric epilepsy caused by cortical dysplasia

Objects We analyzed 30 patients with cortical dysplasia (CD) and epilepsy to evaluate the clinical characteristics and surgical outcome of both epilepsy control and neurocognition.Materials and methods The mean ages at seizure onset and at the time of the operation were 3.6 years (range, 1 month–12.6 years) and 10.3 years (range, 1.5–18.3 years), respectively. The mean follow-up period was 3.2 years (range, 1–5.3 years). ¹⁸FDG-positron emission tomography was the most sensitive and magnetic resonance imaging was the most specific in localizing the lesion. Developmental/intellectual delay was predominant in the early-onset group (n=18, seizure onset <3 years), with intelligence tending to be normal in the late-onset group (n=12, seizure onset ≥3 years). Mild CD predominated in the late-onset epilepsy group and moderate or severe CD in the early-onset group (p=0.005). The surgical success rate of epilepsy control was 87%. A better outcome was obtained if the lesion was confined to the temporal lobe. School performance was favorable in 43%. The age at seizure onset and preoperative developmental/intellectual delay were the important prognostic factors in school performance as well as the epilepsy control. A total of 77% of patients had relatively good social adaptation. Successful epilepsy control and good school performance were affirmative conditions precedent to social adaptation.Conclusions Due to the favorable control of epilepsy and its effect on school performance and social adaptation, surgical treatment is strongly recommended for cortical dysplasia and intractable epilepsy.     

Skeletal muscle weakness caused by carrageenan-induced inflammation

Introduction: The skeletal muscle weakness associated with many chronic diseases has been attributed to the catabolic effect of pro-inflammatory cytokines. We aimed to determine if local muscle inflammation has direct affects on contractile function and contributes to muscle weakness independent of muscle atrophy or mechanical injury. Methods: Local muscle inflammation was induced by injecting an algal-derived polysaccharide, carrageenan (10 mg/kg), into the right tibialis anterior muscle in healthy ARC mice. The contralateral muscle was injected with sterile isotonic saline, and the muscles were removed after 24 h for measurement of contractile function and cytokine concentration. Results: Carrageenan significantly reduced maximum specific force, decreased the maximum rate of force development, altered the force-frequency relationship, and increased intramuscular levels of pro-inflammatory cytokines and chemokines. Conclusions: These results indicate that carrageenan directly affects contractile function and causes skeletal muscle weakness. Local muscle inflammation may contribute to the weakness observed in inflammatory related disorders. Muscle Nerve 46: 413-420, 2012.     

外伤性颅底骨折所致脑脊液漏的处理及预后因素分析

目的分析影响外伤性颅底骨折所致脑脊液漏愈合的相关因素,以探索外伤性脑脊液漏更好的治疗策略。方法回顾性分析2000年2月至2009年4月期间收治的外伤后颅底骨折所致的脑脊液漏患者的临床资料,收集患者基本信息,入院时GCS评分,脑脊液漏的类型(鼻漏、耳漏)、治疗方式(保守治疗、腰大池引流、手术),有无颅内感染、脑脊液漏预后状况等相关临床资料,采用SPSS软件统计分析可能影响脑脊液漏愈合的相关因素。结果 83例脑脊液漏患者中,男性患者55名,女性患者28名,年龄16~73岁,平均43.8±17.3岁。其中11例患者因颅内合并伤(颅内血肿、神经损伤等)、广泛性颅底骨折、严重的脑脊液漏等行急诊手术治疗,39例患者采用保守治疗脑脊液漏愈合,31例采用腰大池置管引流愈合,2例经保守观察及腰大池引流治疗后仍未治愈行开颅手术修补后愈合。治疗效果满意,无死亡病例,仅1例颅内感染病例。影响脑脊液漏愈合相关因素包括:患者年龄、入院时GCS评分、脑脊液漏的类型。结论多数外伤性脑脊液漏经保守治疗或腰大池置管引流治疗后可愈合,因合并伤需要手术、颅骨广泛性骨折、脑脊液漏严重者需尽早手术治疗。     

由缺血缺氧性脑病导致的意识障碍患者意识恢复的相关因素分析

目的 探讨由缺血缺氧性脑病导致的意识障碍患者的临床特点及影响意识康复的相关因素。方法 回顾性分析2013年10月至2018年10月在南部战区总医院神经康复一科住院的46例由缺血缺氧性脑病导致慢性意识障碍患者的临床资料,采用二元logistic回归方法对可能影响意识恢复的相关因素进行分析。结果 单因素分析显示植物状态持续时间（P<0.001）、发病至神经康复时间（P=0.001）、（CRS-R）评分（P=0.016）、性别（P=0.034）、阵发性交感神经过度兴奋（P=0.016）、体感诱发电位（P=0.002）和脑电图（P=0.003）与意识恢复相关,差异具有统计学意义（P<0.05）。logistic回归分析显示,植物状态持续时间（OR=1.077,95%CI：1.009~1.148,P=0.025）、阵发性交感神经过度兴奋（OR=15.511,95%CI：1.210~198.833,P=0.035）是意识恢复的独立影响因素。结论 植物状态持续时间过长、阵发性交感神经过度兴奋的出现是影响缺血缺氧性脑病慢性意识障碍患者意识恢复的临床指标。     

Peptide- and transmitter-containing neurons in the mediobasal hypothalamus and their relation to GABAergic systems: possible roles in control of prolactin and growth hormone secretion

Indirect immunofluorescence histochemistry was used to study the relation among GABAergic, catecholaminergic, cholinergic, and peptidergic neurons in the rat mediobasal hypothalamus. By employing a direct double-labelling procedure using sheep antiserum against glutamic acid decarboxylase (GAD), mouse monoclonal and rabbit antibodies to neurotensin (NT) and rabbit antisera to tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), galanin (GAL), growth hormone-releasing factor (GRF), or somatostatin (SOM), it was demonstrated that GAD-positive fibers and terminals in the external part of the median eminence co-contained immunoreactivity for TH, NT, GAL or GRF, but not for SOM. In the internal part of the median eminence-infundibular stalk, GAD-positive/NT-, GAL-, and GRF-negative and GAD-positive/TH-positive fiber plexa were shown. When a recently developed direct triple-labelling procedure with biotin-conjugated mouse secondary antibodies in conjunction with diethylaminocoumarin (DAMC)-conjugated avidin was employed, presence of GAD/GAL/NT- as well as GAD/GRF/NT-containing varicosities could be demonstrated close to hypophysial portal vessels. In colchicine-pretreated animals, GAD was shown to coexist with TH, NT, or GAL in cell bodies in both the dorsomedial and ventrolateral domains of the arcuate nucleus, but with GRF only in the ventrolateral division. ChAT-positive neurons in the ventrolateral region were also TH-positive. In the ventrolateral arcuate nucleus, triple-labelling followed by elution-restaining showed GAD/NT/GAL/TH-immunoreactivities in the same cells. Similarly, double-labelling with two following elution-restaining steps showed several NT/GAL/GRF/TH-containing cell bodies in this part of the arcuate nucleus. GAD-positive cells in the anterior hypothalamic periventricular area and fibers in the pituitary neurointermediate lobe were also TH-positive. The results demonstrate complex patterns of storage of chemical messengers in neurons of the arcuate nucleus-median eminence complex. Possible neuroendocrine interactions of these systems in the control of prolactin and growth hormone secretion are discussed.     

Activation of epileptic foci by transcranial magnetic stimulation: effects on secretion of prolactin and luteinizing hormone

Summary Transient elevation of serum levels of prolactin has been observed following several types of epileptic seizures and after electrical stimulation of limbic temporal lobe structures via implanted electrodes. Transcranial magnetic stimulation has been found to selectively induce epileptiform afterdischarges in the epileptic focus of candidates for epilepsy surgery who suffered from temporal lobe epilepsy. Lateralized serial transcranial magnetic stimulation was therefore used and serum levels of prolactin or luteinizing hormone were measured to find if it could be used as a non-invasive diagnostic tool. The investigation was performed on six patients and five healthy volunteers. In the patients the induction of epileptiform potentials was continuously monitored via subdural electrodes. A transient surge of prolactin and luteinizing hormone was found in only one patient, in whom a complex partial seizure was induced. Thus, transcranial magnetic stimulation appeared not to be helpful for the lateralization of the (primary) epileptic focus during presurgical evaluation.     

Effects of Δ-THC on VIP-induced prolactin secretion in anterior pituitary cultures: evidence for the presence of functional cannabinoid CB1 receptors in pituitary cells

Peripheral administration of cannabinoid CB₁ receptor agonists to laboratory rats induce a brief rise in plasma prolactin (PRL) levels followed by a prolonged decrease in PRL secretion from the pituitary. While the inhibitory component of this biphasic response depends on the cannabinoid-induced activation of dopamine release from hypothalamic terminals located in the median eminence, the neurobiological mechanisms underlying the activation phase of PRL release remains to be explained. In the present study the possible direct effect of the cannabinoid receptor agonist Δ⁹-Tetrahydrocannabinol (THC) on prolactin secretion and cAMP accumulation was examined in anterior pituitary cultures. THC (0.1 and 1 μM) increased cAMP levels, and induced PRL release (1 and 10 μ). THC did not affect vasoactive intestinal peptide (VIP, 0.5 μM) induced cAMP accumulation in pituitary cultures, showing additive effects at THC 1 μM concentration. However, THC did prevent VIP-dependent increases in prolactin secretion. These results indicate that THC, through a direct pituitary action, activates both the synthesis of cAMP and PRL release and interferes with intracellular mechanisms involved in PRL secretion by VIP. These actions could be mediated through cannabinoid CB₁ receptors which were found to be present in anterior pituitary cells, including lactotrophs, as revealed by immunocytochemistry with a specific polyclonal antibody raised against the CB₁ receptor protein.