Role of AMP-activated protein kinase activators in antiproliferative multi-drug pituitary tumour therapies: effects of combined treatments with compounds affecting the mTOR-p70S6 kinase axis in cultured pituitary tumour cells.

AMP-activated protein kinase (AMPK) is activated under conditions that deplete cellular ATP levels and elevate AMP levels. We have recently shown that AMPK can represent a valid target for improving the medical treatment of growth hormone (GH)-secreting pituitary adenomas and the effects of its activation or inhibition in pituitary tumour cells are worthy of further characterisation. We aimed to determine whether AMPK may have a role in combined antiproliferative therapies based on multiple drugs targeting cell anabolic functions at different levels in pituitary tumour cells to overcome the risk of cell growth escape phenomena. Accordingly, we tried to determine whether a rationale exists in combining compounds activating AMPK with compounds targeting the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR/p70S6K signalling pathway. AMPK down-regulation by specific small-interfering RNAs confirmed that activated AMPK had a role in restraining growth of GH3 cells. Hence, we compared the effects of compounds directly targeting the mTOR-p70S6K axis, namely the mTOR inhibitor rapamycin and the p70S6K inhibitor PF-4708671, with the effects of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on cell signalling and cell growth, in rat pituitary GH3 cells. AICAR was able to reduce growth factor-induced p70S6K activity, as shown by the decrease of phospho-p70S6K levels. However, it was far less effective than rapamycin and PF-4708671. We observed significant differences between the growth inhibitory effects of the three compounds in GH3 and GH1 cells. Interestingly, PF-4708671 was devoid of any effect. AICAR was at least as effective as rapamycin and the co-treatment was more effective than single treatments. AICAR induced apoptosis of GH3 cells, whereas rapamycin caused preferentially a decrease of cell proliferation. Finally, AICAR and rapamycin differed in their actions on growth factor-induced extracellular signal regulated kinase 1/2 phosphorylation. In conclusion, the results of the present study suggest the increased efficacy of combined antiproliferative therapies, including rapamycin analogues and AMPK activators in GH-secreting pituitary tumours, as a result of complementary and only partially overlapping mechanisms of action.

Hypopituitarism and antiphospholipid syndrome.

Vascular damage is a well known cause of hypopituitarism since Sheehan's report of postpartum pituitary necrosis; it has subsequently been reported that also sickle-cell anemia, eclampsia, pituitary apoplexy and other pathologies may induce failure of the anterior hypophysis through this mechanism. The antiphospholipid syndrome (APS) is characterized by widespread arterial and venous thrombosis with resulting different clinical features; Addison's disease due to adrenal thrombosis is the only endocrine involvement reported so far in this syndrome. We report here a case of global anterior pituitary insufficiency which developed soon after cerebral ischaemic stroke in a 62 year aged woman with Lupus aicoagulant activity (LAC) and large atrial thrombosis; underlying pathologies were excluded by appropriate investigations. Therefore in our opinion this is the first case in which anterior hypopituitarism is reported in the clinical constellation of APS and the second type of endocline involvement.

Coenzyme Q, Vitamin E and Apo-E alleles in Alzheimer Disease.

Neurodegenerative Diseases represent the most common cause of Dementia, about 5-10% of the population aged above 65 years and about 30% above 80 years. A study about Apo-E alleles, Coenzyme Q and Vitamins E as biological indicators was performed in plasma samples of patients aged from 30 to 85 years, affected by Neurodegenerative Diseases. The results were compared with control subjects of approximately the same ages as the reference group. A frequency of 21.7% of epsilon4 allele in control group was estimated, against 15.8% observed in patients. The frequency of epsilon2 and epsilon3 alleles was 13.0% and 65.2% in the control group against 10.5% and 73.7% in patients. No significant differences were observed between the frequency of epsilon3/epsilon3 genotype and epsilon3/epsilon4 genotype in the control group compared to patients' group. The frequencies observed in epsilon2/epsilon3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The epsilon2/epsilon2 and epsilon4/epsilon4 genotypes were not identified in any groups. Plasma CoQ10 concentrations were similar in patient and control groups and no differences were found even taking into account the distribution of male and female subjects in the two groups. Also, vitamin E did not provide evidence of any differences between groups and the analysis among sexes revealed that again vitamin E concentrations were similar in between subgroups.

Ataxic hemiparesis syndrome clinical and CT study of 20 new cases.

Twenty patients suffering from ataxic hemiparesis caused by lacunar infarcts were studied using computerized tomography. Supratentorial lesions were found in nineteen patients (95%) while subtentorial lesion was found in only one patient (5%). In all cases the lesions were localized along the corticopontine pathways, making the hypothesis of injury to this pathway the most valid explanation of ataxia.

Ataxic hemiparesis: further CT confirmation of an old localizing hypothesis.

4 cases of ataxic hemiparesis syndrome are supported by CT proof of a lesion confined to the posterior and superior part of the internal capsule, near the corona radiata. The site of lesion is usually held to be the basis pontis and rostral midbrain. We intend to furnish further evidence in support of an old hypothesis incriminating the corona radiata-internal capsule.

Penicillin CSF levels following intravenous therapy in syphilitic patients.

Serum and CSF levels of penicillin have been determined in 13 syphilitic patients treated with relatively high doses of penicillin G by the intravenous route. Wide individual variability in the CSF/serum concentration ratio was observed. In all patients the concentration of the antibiotic in the CSF was equal to or greater than 0.03 IU/ml., which is considered to be the minimal therapeutic concentration. The potential clinical usefulness of different therapeutic regimens in the treatment of neurosyphilis is discussed.

Pontomedullary encephalitis and basal meningitis due to Listeria monocytogenes: report of a case.

A case of CNS listeriosis in a 49-year-old man, previously in good health, is described. The illness showed a biphasic clinical pattern with a prodromal phase characterized by headache, fever and leukocytosis and subsequent development of pontomedullary cranial nerve paresis. The infection was rapidly progressive and fatal. Gram-positive rods, identified as Listeria monocytogenes, were detected in CSF samples only at the end stage of illness. Neuropathological abnormalities consisted of rhombencephalitis and basal meningitis. The major difficulties encountered in the early diagnosis of CNS listeriosis are discussed.

Cerebral mapping in subjects suffering from migraine with aura.

Cerebral mapping of the spontaneous electroencephalographic activity was performed in 31 subjects suffering from migraine with aura and the results were compared with those of a matched control group. All the patients were examined during the interictal period. While traditional visual interpretation of EEG records was negative in all but five cases (16.1%) spectral analysis showed an asymmetry in alpha total power over the posterior regions in 13 cases (41.9%) and an asymmetry in alpha band peak frequency in 17 (54.8%). By means of cerebral mapping and statistical significance probability mapping we were able to demonstrate a significant increase in alpha total power in 13 cases (41.9%) and a regional increase in delta and theta total power in 20 cases (64.5%). In comparison with the control group, the migraine patients showed a widespread increase in slow activity (theta and delta) mostly over the temporal regions.

Cerebral atrophy in motor neuron disease evaluated by computed tomography.

Thirty-two (64%) of 50 patients with motor neuron disease showed various patterns of cerebral atrophy (cortical, ventricular or both) at CT examination. The incidence of cerebral atrophy, particularly cortical atrophy, in motor neuron disease was greater than in a matched control group.

An ocular myopathy with glycogen storage and abnormal mitochondria in muscle fibres. Histochemical and ultrastructural findings.

The case of a 66-year-old woman with progressive external ophthalmoplegia and involvement of the proximal muscles of the upper and lower limbs is described. EMG examinations show signs of myopathic involvement. Histochemical and biochemical studies exclude a primary defect in glycogenolysis. The authors stress the peculiarity of the histochemical findings, characterized by the rare associated appearance of both mitochondrial changes and glycogen accumulation in muscle fibres. The most prominent ultrastructural findings are evidence of increased glycogen, usually present in vesicles or in mitochondria, and changes in number, size and structure of mitochondria. Quantitative biochemical examination of muscle homogenates confirmed the increased content of glycogen in muscle fibres.