Adriano Stella

Intense Antiextracellular Adaptive Immune Response to Human Cytomegalovirus in Very Old Subjects with Impaired Health and Cognitive and Functional Status

Human aging is characterized by expanded and altered adaptive immune responses to human CMV (HCMV). It is unclear whether this expansion has its origins in age-related homeostatic disturbances or viral reactivation, whether anti-CMV immune surveillance may still be effective, and what are the consequences of this expanded immune response for health and longevity. We conducted an observational cross-sectional study in groups of HCMV-seropositive subjects aged ≥65 y of variable health status to compare the intensity of Ab responses against HCMV with those against EBV and with CD4+ and CD8+ T cell proinflammatory effector responses directed to HCMV-derived pp65 and immediate-early protein 1 synthetic peptides. Ab responses to HCMV, but not to EBV, and anti-HCMV CD4+, but not CD8+, T cell responses were more intense in elderly subjects aged ≥85 y in poor health and were inversely correlated with markers of functional activity and cognitive function. Therefore, humoral and CD4+ T cell anti-HCMV responses were specifically intensified in advanced aging associated with comorbidity and cognitive and functional impairments. Such a distinctive pattern of adaptive immunity indicates that immune responses targeting the extracellular phase of HCMV are increased in these elderly subjects and could represent an indirect effect of localized and undetectable HCMV reactivation. This study demonstrates that the oldest subjects in poor health with physical and mental impairment express intense functional immune responses to extracellular HCMV and suggests that they may be at risk for direct pathogenic effects by HCMV reactivation as well as indirect pathogenic effects linked to proinflammatory anti-HCMV effector responses.

Oxytocin does not modify GH, ACTH, cortisol and prolactin responses to Ghrelin in normal men.

BACKGROUND In order to test the possible effect of Oxytocin (OT) on Ghrelin-stimulated GH, PRL, ACTH and cortisol, ten healthy normal men were studied. METHODS TESTS Ghrelin (0.2 μg/kg body weight (BW)) as an iv bolus; Ghrelin plus OT (2 IU as bolus plus 0.07 IU/min administered for 90 min). RESULTS The administration of OT did not change GH, PRL, ACTH and cortisol release induced by Ghrelin. CONCLUSIONS The data suggests that in humans OT did not modulate the GH, PRL, ACTH and cortisol response to Ghrelin.

Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Alprazolam (ALP), a benzodiazepine activating GABAergic receptors, is involved in ACTH secretion. WHAT THIS STUDY ADDS • This study demonstrates a partial opioid influence in the inhibitory effect of ALP on the release of ACTH/cortisol during physical exercise. AIMS To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise. METHODS Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time -90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests. RESULTS ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P ≤ 0.01 vs. baseline) for ACTH and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P ≤ 0.02 vs. control test for ACTH, and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial. CONCLUSIONS These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol.

Stimulatory effect of naloxone on plasma cortisol in human: Possible direct stimulatory action at the adrenal cortex.

UNLABELLED The purpose of the present study was to gain a better insight in the mechanism of naloxone underlying the regulation of adrenal cortisol secretion in humans in vivo; therefore, the stimulatory effect of naloxone on cortisol secretion was assessed in a group of patients with hypothalamo-pituitary disconnection. Patients with hypothalamo-pituitary disconnection because of various pathologies (craniopharingioma, cordoma, suprasellar meningioma, or pituitary macroadenoma) participated in the study. RESULTS Circulating cortisol, but not adrenocorticotropin (ACTH) levels were significantly higher after naloxone administration than after saline. CONCLUSION Besides the well-known hypothalamo-pituitary stimulatory action on ACTH release in normal humans, the results of the present study suggest that naloxone exerts direct effects on cortisol secretion at the adrenal gland level; another possibility is that naloxone stimulation of cortisol secretion is mediated by other factor than ACTH.

Naloxone decreases the inhibitory effect of somatostatin on GH release induced by cigarette smoking in man

To establish whether somatostatin (SRIH) exerts its inhibitory effect on the nicotine-induced release of GH by interacting with an opioid pathway, normal volunteers were treated with naloxone during (2 no-filter) cigarettes smoking and with SRIH. Nicotine significantly increased serum GH levels about 3.5 fold. Naloxone alone did not change GH rise induced by cigarette smoking. The stimulatory effect of GH by nicotine was completely blocked by SRIH. In the presence of both SRIH and naloxone, GH levels rose 1.5 fold in response to nicotine. Since naloxone only partially reversed the inhibiting action of SRIH, only a partial involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opiates might produce this inhibiting effect on GH rise in response to cigarette smoking through independent pathways.

Inhibitory effect of somatostatin on the NPY response to insulin-induced hypoglycemia and the role of endogenous opioids

The present study was undertaken in order to establish whether somatostatin (SRIH) is able to modify the neuropeptide Y (NPY) response to insulin-induced hypoglycemia during insulin tolerance test (ITT) in man. In addition, the possible involvement of opioid peptides in the mediation of hypoglycemia and/or SRIH action was investigated. Subjects were injected intravenously with 0.15IU/kg insulin alone (control test) or with SRIH (4.1μg/min/90min), naloxone (10mg in an iv bolus) or the combination of the two substances. Plasma NPY concentrations rose significantly during ITT. The NPY response was significantly reduced by the treatment with SRIH. The administration of naloxone did not modify NPY levels whereas when both SRIH and naloxone were given, NPY response to hypoglycemia did not differ from that observed in the control test. These data demonstrate that SRIH inhibits the NPY response to hypoglycemia. Naloxone-sensitive endogenous opiates do not seem to be involved in the control of hypoglycemia-induced NPY release. In contrast, since naloxone reversed the inhibiting effect of SRIH, an involvement of opioid peptides in the SRIH action may be supposed.

Increased arginine-vasopressin response to hypertonic stimulation and upright posture in idiopathic hyperprolactinemia☆

To evaluate the possible influence of idiopathic hyperprolactinemia on the arginine-vasopressin (AVP) response to osmotic and pressure-volumetric stimuli, 14 idiopathic hyperprolactinemic women and 13 normoprolactinemic women were studied during a hypertonic saline infusion test (0.51M NaCl infusion for 2h) and an orthostatic test (standing upright and maintaining an orthostatic position for 20min). In both experimental conditions, the AVP response was significantly higher in women with idiopathic hyperprolactinemia than in normal normoprolactinemic women. These results indicate that in women hyperprolactinemia influences the AVP response to hyperosmotic and hypovolemic stimuli.

Glucoreceptors located in the brain mediate NPY release induced by hypoglycemia in normal men

The NPY secretory pattern after an insulin tolerance test (ITT) (0.15 IU/kg body weight) was evaluated in 8 normal men. They were infused with normal saline (control test), glucose or fructose. Insulin-induced hypoglycemia produced a significant increment in serum NPY in the control test. The infusion of fructose was unable to change the NPY secretory pattern during insulin-induced hypoglycemia. In contrast, the NPY increase during ITT was completely abolished when the concomitant infusion of glucose prevented insulin-induced hypoglycemia. These results exclude a direct role of hyperinsulinemia in the mechanism underlying the stimulation of NPY secretion during ITT. Furthermore, since glucose but not fructose crosses the blood-brain-barrier (BBB), the NPY increase during ITT appears to be generated by low glucose concentrations at the level of glucosensitive areas located inside the brain.

Completely reversible agranulocytosis in a multiple myeloma patient treated with thalidomide-dexamethasone

Dr. Francesca Magalini, Prof. Paolo Sansoni: We report a 67-year-old man admitted to our Department of Internal Medicine because of severe lumbosacral pain. On admission, laboratory tests showed a white cell count of 4,420/mm with 55% of neutrophils, Hb 9.5 g/dl and a platelet count of 141,000/mm. Serum tests showed an increase in total protein (10.9 g%), c-globulin 39.5% with IgA 6,440 mg/dl IgG 407 mg/dl and IgM 5 mg/dl, b2-microglobulin (5.6 mg/dl), PCR (5.25 mg/dl) and hypercalcemia (10.9 mg/dl). A CT scan revealed: ‘‘in the axillary right region, a homogeneous and ovoidal formation of 66 9 35 mm with contrast enhancement infiltrating the rib and surrounding tissues; multiple osteolytic lesions involving ribs, pelvis, femurs and the body of D12’’. A bone marrow aspiration demonstrated a plasma cell infiltration of about 50% of nucleated bone marrow cells. Because of severe lumbosacral pain, the patient was started on phenthanyl (25 mcg/72 h) together with roentgentherapy (10 Gy) along with bisphosphonate therapy (pamidronate 90 mg). Shortly thereafter, because of the persistence of the symptoms, the patient underwent vertebroplastic treatment on D12–L1–L2 with rapid disappearance of all symptoms. Subsequently, we started thalidomide–dexamethasone (TD–Dex) therapy (TD 100 mg/day for 2 weeks then 200 mg/day, Dex 40 mg on days 1–4, 9–12, 17–20 at odd cycles and on days 1–4 at even cycles). Because of somnolence and cognitive impairment on day 9, the patient was started with plasmapheresis (four times in 1 week). The paraprotein level dropped from pretherapy values of 6,440 to 770 mg/dl after 28 days of treatment. We noticed after 3 weeks of therapy that the total leukocyte count decreased from 4,420 to 3,200/mm and the absolute number of neutrophils from 2,431 to 1,184 (Fig. 1). Concomitantly, the hemoglobin level increased from 9.5 g% (before treatment) to 12.5 g% and the platelet counts from 141,000 to 229,000/mm, respectively (Fig. 1). After 4 weeks of TD–Dex therapy, the number of neutrophils dropped to very low counts (20/mm) when the TD–Dex was stopped and G-CSF started at a dosage of 30 MU a day with concomitant antibiotic prophylaxis with moxifloxacine (400 mg/day). At that time, the patient refused the consent for bone marrow biopsy. After 4 days of G-CSF treatment, the neutrophils increased to 2,136/mm, and after 1 week the G-CSF treatment was discontinued when values of neutrophils [5,000/mm were reached. Thereafter, the absolute number of neutrophils increased to 8,700/mm and remained[4,000/mm for the following 2 weeks; the search for antibodies against neutrophils (p-ANCA and c-ANCA) was negative and the complement fractions (C3–C4) were within the normal range. As regards the clinical response to TD–Dex therapy, we observed a profound reduction of the plasma and urinary paraprotein level together with normalization of calcemia, b2 microglobulin and PCR.