Cranial osteolytic metastases as the only recurrence of gastric carcinoma.

The purpose of this case report is to increase the knowledge about bone metastatic pattern in gastric cancer. A 59-year-old man presented with headache three years after a total gastrectomy for signet-ring cell carcinoma. Head computed tomography and magnetic resonance imaging showed multiple osteolytic lesions of the cranial vault and base, consistent with metastatic or haematological disease. Bone scintigraphy confirmed areas of accumulation only in the skull. An extensive search didn't show any other tumor. Bone biopsy revealed metastatic signet-ring cell carcinoma. In gastric cancer, bone metastases are generally associated with metastases in lymph nodes, liver, and lung, and have a higher frequency in the thoracolumbar spine. However, cranial bone metastases presenting with headache may be the only manifestation of gastric cancer recurrence.

Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with Systemic Sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study.

Raynaud?s phenomenon (RP) and cutaneous fibrosis are the distinctive manifestations of scleroderma, in which Endothelin-1 plays a fundamental pathogenetic role. Bosentan, an Endothelin-1 receptor antagonist used for the treatment of pulmonary arterial hypertension, retards the beginning of new sclerodermic digital ulcers (DU). This open-label, observational, retrospective study verified the effect of Bosentan on RP and skin fibrosis in sclerodermic outpatients affected by pulmonary arterial hypertension without DU. Fourteen subjects (13 women, 1 man; mean age 60 ± 7.5 years; ten with limited and four with diffuse scleroderma) were observed at baseline (T0) and after four (T1), twelve (T2), twenty-four (T3) and forty-eight (T4) weeks during treatment with Bosentan. They were evaluated for daily quantity and duration of RP attacks and skin thickness (using modified Rodnan total skin score, MRSS). Videocapillaroscopic evaluation was performed at T0 and T4. Bosentan decreased significantly the number and duration of RP attacks, beginning at T2 (p<0.05). Videocapillaroscopy showed significant improvement of microcirculatory patterns at T4 (p<0.05). MRSS decreased throughout the study, reaching the statistical significance at T3 and T4 (p<0.01) in the whole cohort. The present data suggest that Bosentan is effective in stabilizing the microcirculation involvement and in improving skin fibrosis irrespective of scleroderma patterns.

Long-term plasma levels of leptin and adiponectin in Rett syndrome.

OBJECTIVE: Rett syndrome is a progressive neurological disorder affecting almost exclusively females after age 6 months and characterised by acquired microcephaly, psychomotor retardation, growth failure, purposeless hand movements, autistic-like behaviour and wide-based and stiff legged gait. Leptin and adiponectin, peptides secreted by adipose tissue, are involved in the regulation of body weight and energy expenditure. DESIGN AND PATIENTS: We investigated in patients with Rett syndrome the variations of plasma leptin and adiponectin and their relation over a 2-year period. Sixteen female patients, mean age at the basal time 9.4 +/- 4.3 years, with classical Rett syndrome were enrolled. Controls were 16 healthy female subjects, mean age at the basal time 9.9 +/- 3.4 years. MEASUREMENTS: Blood samples were withdrawn in the morning at the baseline, 12 months after and 24 months after; plasma leptin and adiponectin concentrations were detected by ELISA. RESULTS: In patients, leptin concentrations significantly increased, while adiponectin concentrations significantly decreased. Both leptin and adiponectin values were significantly higher than those found in controls at each time. Leptin significantly correlated with adiponectin in patients, while there was not a significant correlation in controls. CONCLUSION: Since all patients were not obese, we might hypothesize that in Rett syndrome leptin and adiponectin might participate to clinical manifestations other than weight balance.

Myelodysplasia and Good syndrome. A case report.

Good syndrome (GS) is a rare adult-onset immunodeficiency disease characterised by hypogammaglobulinaemia and thymoma. Here we describe a 72-year-old male patient who was diagnosed with GS when he was 62, after a two-year history of recurrent respiratory infections. A chest CT scan showed a mediastinal mass which was surgically removed; its histology revealed a thymoma. The patient was hypogammaglobulinaemic and his clinical condition dramatically improved after starting an appropriate dosage of IVIG. Two years ago he developed a normochromic normocytic anaemia requiring several transfusions. A bone marrow biopsy revealed a myelodysplastic syndrome. The patient started cyclosporine and the anaemia gradually improved, achieving transfusion independence.

Extracorporeal photopheresis affects co-stimulatory molecule expression and interleukin-10 production by dendritic cells in graft-versus-host disease patients.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photochemotherapy (ECP) has been introduced as an alternative treatment for GVHD refractory to conventional immunosuppressive treatment, although its mechanism of action is not yet clear. We investigated, in seven GVHD patients, the effects of ECP on dendritic cell maturation and cytokine production in an in vitro model that could mimic the potential in vivo effect of reinfusion of ECP-treated peripheral blood mononuclear cells. The model was based on co-culture of ECP-treated lymphocytes with monocyte-derived dendritic cells (DCs) of the same patient. We found that the co-culture of ECP-treated lymphocytes with immature DCs reduced CD54, CD40 and CD86 mean fluorescence intensity (MFI) significantly after lipopolysaccharide (LPS) stimulation, without affecting human leucocyte antigen D-related and CD80 MFI. In the same co-culture model, DCs produced increased amounts of interleukin (IL)-10 when co-cultured with ECP-treated lymphocytes and stimulated with LPS, while IL-12 and tumour necrosis factor-alpha production were not affected. These results suggest that reinfusion of large numbers of autologous apoptotic lymphocytes is significant for the therapeutic outcome of ECP through down-regulation of co-stimulatory molecules on DCs, inducing non-fully mature DCs with a low signal 2 and up-regulation of IL-10, which is an immunosuppressive cytokine.

Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia.

BACKGROUND: Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized-low-density lipoprotein cholesterol (ox-LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox-LDL lectin-like receptor-1 (LOX-1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment. MATERIALS AND METHODS: A prospective 4-year study involving 1039 event-free subjects (643 males, 396 females) treated with atorvastatin (10-40 mg day(-1)) to reach the appropriate Adult Treatment Panel-III LDL target of 3.36 mmol L(-1). Enrolled subjects were evaluated every 6 months or at a clinical event. LOX-1 3'UTR/T-C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic-colorimetric method, ox-LDL by enzyme linked immunosorbent assay, platelet activation by P-selectin (P-sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C-reactive protein (CRP) by sensitive nephelometric technique. RESULTS: LOX-1 3'UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4.90, 95% CI 3.19-6.98, P < 0.00001). Smoking influenced events in LDL-targeted subjects (P < 0.0001). Ox-LDL and P-sel were better indicators than LDL or other variables according to 3'UTR/C genotype regardless of the magnitude of LDL reduction (OR 4.21, 95% CI 2.29-6.70 P < 0.0001). CONCLUSIONS: LOX-1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.

Increased TNF-alpha production by peripheral blood mononuclear cells in patients with Krabbe's disease: effect of psychosine.

BACKGROUND: Inflammatory and/or immune activation occurs both in animal models (twitcher mice) and in the brain of patients with Globoid cell leukodystrophy (GLD) or Krabbe's disease (KD). In this study we evaluated in vitro the cytokine profile of KD patients and the effect of psychosine, the toxic metabolite which plays a role in the demyelination process in these patients. MATERIALS AND METHODS: We studied cytokine production by peripheral blood mononuclear cells (PBMCs) isolated from four KD patients, diagnosed on the basis of clinical criteria. Cells were cultured and stimulated with appropriate agents and the supernatants collected before and after the addition of psychosine. Tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and monocyte chemoattractant factor (MCP)-1) production was evaluated (ELISA method) and compared with a group of 10 normal subjects. RESULTS: We found a significant increase of TNF-alpha release by PBMCs of KD patients compared with healthy subjects; TNF-alpha production was significantly increased after LPS addition. Psychosine was able to induce a further significant increase (P < 0.05) only in cells obtained from KD patients and not from control subjects. No changes were found in IL-8 and MCP-1 production. CONCLUSIONS: The increased TNF-alpha production permits us to confirm the presence of an inflammatory-immune stimulus in KD patients, which may be induced and potentiated by the pathogenetic metabolite psychosine.

Rett syndrome and plasma leptin levels.

OBJECTIVE: To describe in patients with Rett syndrome (classic and preserved-speech variant) plasma leptin levels and their relationship to BMI (body mass index) and age. STUDY DESIGN: Female patients (n = 48; age range 3-20 years) affected by classic Rett syndrome were enrolled into the study. Eleven female patients, age range 3 to 20 years, with preserved-speech variant Rett syndrome were included in the study. Controls were 24 healthy female subjects, age range 3 to 20 years. Blood samples (3 mL) were withdrawn from an antecubital vein in the morning; plasma leptin concentrations were detected by enzyme-linked immunosorbent assay method. RESULTS: Patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Leptin concentrations did not significantly differ between patients with classic Rett and preserved-speech variant. Leptin values positively correlated with age and BMI. CONCLUSIONS: Because in all patients the increased leptin concentrations were not associated to obesity, we hypothesize that in patients with Rett syndrome leptin might participate to clinical manifestations other than weight balance.

Lectin-like oxidized-LDL receptor-1 (LOX-1) polymorphisms influence cardiovascular events rate during statin treatment.

BACKGROUND: Oxidized-LDL (ox-LDL) are involved in atherothrombosis by induction of endothelial dysfunction and thrombosis. The specific receptor lectin-like oxidized-LDL receptor-1 (LOX-1) is expressed in endothelial cells, monocytes and platelets. LOX-1 gene allelic variants (3'UTR/T) have been related with cardiovascular events and reduced anti-platelet activity induced by statins. OBJECTIVES: To detect whether LOX-1 polymorphisms could affect statins effectiveness in cardiovascular prevention. PATIENTS/METHODS: The present was a retrospective study performed in 751 white hypercholesterolemic subjects treated with increasing doses of atorvastatin (n=382, 247 male, 135 female) or simvastatin (n=369, 244 male, 125 female) up to 4 years, whose LDL target was 3.36 mmol/L according to the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATPIII). Single nucleotide polymorphism were evaluated by allelic discrimination assays (PCR), lipid profile by enzymatic-colorimetric methods and C-reactive protein (CRP) by a nephelometric technique. RESULTS: Twenty-three non-ST elevation (NSTEMI) and eleven ST-elevation myocardial infarction (STEMI) were encountered in the observational period without differences between treatments (p=0.175) and sex (p=0.139). Each symptomatic subject (10 reaching the appropriate LDL target and 24 with still undesirable LDL) had the 3'UTR/T allelic variant (adjusted O.R. 4.63, 95% C.I. 3.46-6.70, p<0.0001). Among patients not reaching LDL target the C allele resulted protective with respect to T carriers (p<0.00001). Also, similar changes of CRP resulted in different event rate between T and C carriers (p<0.001) in the whole cohort. CONCLUSIONS: In the studied population LOX-1 genetic variants influence cardiovascular risk reduction induced by statins also in patients not reaching the LDL target. The previously described LOX-1-related antithrombotic actions of both statins employed could have a specific role in what observed, suggesting a genetic influence in statins LDL-lowering partially related actions.

Inhibition of maturation of human monocyte-derived dendritic cells in a patient with Mycobacterium avium infection.

Mycobacterium avium complex is a facultative intracellular pathogen that can cause pulmonary disease in immunocompromised individuals. Dendritic cells (DCs) play a central role in protective immunity against mycobacteria. Mycobacterium avium complex infects DCs but does not impair in vitro infected monocytes differentiation into DCs. A 54-year old woman affected by chronic graft-versus-host-disease (cGVHD) was referred to our Division of Dermatology. Immature DCs were generated from her monocytes. One week later she was hospitalized due to a lung infection with Mycobacterium avium complex. Monocyte-derived DCs during Mycobacterium avium infection expressed low levels of CD1a and CD80 as determined by flow cytometry. They also expressed high levels of CD83 and CD86, and when stimulated with LPS for 24 hrs they slightly up-regulated CD83 and did not produce IL12. When monocyte-derived DCs were obtained from the patient after having recovered from the Mycobacterium avium complex infection, they expressed normal levels of CD1a and CD80 and were negative both for CD83 and for CD86. IL12 production in response to LPS was restored. Inhibition of DC maturation by the in vivo infection with Mycobacterium avium may be an immune-evasion mechanism used by the pathogen because incompletely matured DCs may not activate effector T cells efficiently in vivo.

Variations of peripheral markers of serotoninergic system in selected vascular patients.

BACKGROUND AND AIM: Serotonin (5-HT), a decarboxylated derivative of tryptophan, is synthesized in the enterochromaffin cells and released into blood stream to be incorporated into platelets. At the site of endothelial lesions, platelets aggregate and secrete 5-HT that presents several vascular actions involved in thrombosis and atherogenesis. In fact, 5-HT may induce vasoconstriction in the presence of endothelial injury, aggregation of platelets, and mitogenesis of arterial smooth muscle cells and endothelial cells. It may also contribute to the vascular inflammation associated with atherogenesis by increasing the synthesis of Interleukin-6 in vascular smooth muscle cells. We evaluated serotonin levels in plasma and platelets of patients with unstable angina and ischemic stroke, to identify an association between serotonin and atherosclerosis of coronary and cerebral arteries. METHODS AND RESULTS: Twenty patients (14 men, 6 women, mean age 69 +/- 10 years) with unstable angina and 15 patients (7 men, 8 women, mean age 81 +/- 10 years) with ischemic stroke were included in the study. Twenty-four healthy subjects matched for age and sex constituted the control group. Blood samples were drawn in the morning to determine plasma and platelet concentrations of serotonin. In patients with unstable angina serotonin levels in platelets were significantly lower (p < 0.001) than those observed in controls, while serotonin concentrations in plasma did not significantly differ from those found in controls. In patients affected by stroke serotonin levels in plasma and in platelets did not significantly differ from those found in normal subjects. CONCLUSIONS: Our findings may contribute to the knowledge to different mechanisms involved in the pathogenesis of cardiac and cerebral ischemia.

Pro-inflammatory/anti-inflammatory cytokine imbalance in acute coronary syndromes.

The aim of this study was to evaluate the presence of an imbalance between proinflammatory and anti-inflammatory mediators in patients affected by acute coronary syndromes (ACS). We considered two groups of 26 and 28 patients with acute myocardial infarction (AMI) and unstable angina (UA) respectively, compared with a group of 30 patients with stable angina and 30 healthy volunteers. We evaluated the production in cultured and stimulated lymphomonocytes of interferon (IFN)gamma and tumour necrosis factor (TNF)alpha, which are well known to possess proinflammatory effects, and of interleukin (IL)10, which has been shown to have a protective anti-inflammatory activity. We also assessed the clinical characteristics of groups and, particularly, we evaluated the circulating levels of C-reactive protein (hs-CRP). We found a significant increase of IFNgamma and TNFalpha production (P<0.01) and a significant decrease of IL10 production (P<0.05) in cultures of lymphomonocytes taken from patients with AMI and UA compared with SA patients and controls. No significant changes where found between AMI and UA patients and SA patients and controls. Circulating levels of hs-CRP were significantly increased (P<0.01) in patients with ACS compared with the other control groups. Our data showed an increased production of proinflammatory mediators in ACS that may be detectable both in circulating blood and in cell cultures where it is possible to evaluate in a better way the functional state of cells; this finding was associated with a reduced production of the antiinflammatory cytokine IL10. In conclusion, a relevant imbalance is present in ACS and this fact could contribute to plaque instability and clinical manifestations.

Cytokines in acute coronary syndromes.

The aim of this study was to show the presence of an imbalance between pro-inflammatory and anti-inflammatory mediators in patients affected by acute coronary syndromes (ACS). We evaluated the production in cultured and stimulated lymphomonocytes of interferon (IFN)gamma and tumor necrosis factor (TNF)alpha, which are well known to possess pro-inflammatory effects, and of interleukin (IL)10, which has been shown to have a protective anti-inflammatory activity, in two groups of 30 patients affected by acute myocardial infarction (AMI) and unstable angina (UA), compared with two equivalent groups of patients with stable angina (SA) and of healthy volunteers. We found a significant increase of IFNgamma and TNFalpha production (p<0.01) and a significant decrease of IL-10 production (p<0.01) in cultures of lymphomonocytes taken from patients with AMI and UA compared with SA patients and controls. No significant changes were found between AMI and UA patients and SA patients and controls. We conclude that a relevant imbalance in cytokine release is present in ACS, markedly favoring pro-inflammatory effects.

Iloprost treatment reduces TNF-alpha production and TNF-RII expression in critical limb ischemia patients without affecting IL6.

Iloprost, a stable prostacyclin analogue, regulates expression of genes that are involved in inflammation and in cell growth and inhibits the in vitro production of cytokines. We evaluated the effect of an in vivo weekly iloprost treatment on TNF-alpha and IL6 monocyte production (evaluated by ELISA), on monocyte apoptosis (Annexin V/uptake of propidium iodide by flow cytometry) and on peripheral blood mononuclear cell (PBMC) TNF-alpha receptors (TNF-RI and TNF-RII) mRNA expression (RT-PCR) in 14 atherosclerotic critical limb ischemia patients. PBMC were stimulated with LPS for 24h. TNF-alpha production was significantly reduced by iloprost whereas IL6 production was not affected. Iloprost did not accelerate monocyte apoptosis. TNF-RI mRNA expression was not modified by iloprost, whereas TNF-RII mRNA expression was significantly reduced. Our data show that iloprost may have anti-inflammatory effects in addition to the well-known vasodilatatory and anti-aggregant ones.

Extracorporeal photopheresis affects interleukin (IL)-10 and IL-12 production by monocytes in patients with chronic graft-versus-host disease.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photopheresis (ECP) has recently been introduced as an alternative treatment for cases of cGVHD refractory to conventional immunosuppressive treatment, but its mechanism of action is not yet clear. OBJECTIVES: To investigate in seven patients with cGVHD the effects of ECP on resistance of monocytes to apoptosis and on monocyte cytokine production. METHODS: We designed an in vitro model that could mimic the potential in vivo effect of reinfusion of peripheral blood mononuclear cells treated by ECP. The model was based on coculture of ECP-treated lymphocytes with untreated monocytes from the same patient. RESULTS: ECP did not accelerate spontaneous apoptosis of monocytes. However, ECP-treated monocytes produced increased amounts of interleukin (IL)-12. In contrast, IL-12 production by monocytes did not increase in cocultures, but IL-10 production was upregulated. CONCLUSIONS: These results suggest that reinfusion of large numbers of autologous apoptotic lymphocytes is significant for the therapeutic outcome of ECP through upregulation of IL-10, which is an immunosuppressive cytokine.

Structural and functional abnormality of systemic microvessels in cardiac syndrome X.

BACKGROUND AND AIM: Microvascular damage of coronary bed has been considered the main pathogenetic factor of cardiac syndrome X (chest pain, exercise-induced ischemic ST-segment changes and angiographically normal coronary arteries). Previous studies have demonstrated that vascular abnormalities are not confined to the heart, suggesting a peripheral vascular dysfunction. On the hypothesis of a generalized microvascular disturbance in cardiac syndrome X, we performed a morphologic and functional study of systemic microcirculation in patients with syndrome X compared to normal subjects. METHODS AND RESULTS: Microvessels were evaluated with intravital videocapillaroscopy (VCP) executed in peripheral and conjunctival observation sites which explore micro and paramicrocirculation; biohumoral study included markers of inflammation and of endothelial function, coagulative-fibrinolytic system and lipid metabolism. Videocapillaroscopy showed several morphologic changes (present in high percent of patients with syndrome X and not in controls) and significant quantitative alterations (capillary density, granular flow score, alterations of vessel profile, length of capillary loop branches and of arteriole/venule diameter) which indicated a severe alteration of whole vessel structure and an important rearrangement of microvascular disposition. In a similar way, the humoral study showed some significant changes of endothelial (vWF, ICAM-1, E-sel, PAI-1), inflammatory (C-reactive protein (CRP), fibrinogen) and metabolic factors (HDL-chol) which are commonly associated with inflammatory response. CONCLUSIONS: We conclude that patients with cardiac syndrome X exhibited some structural and functional alterations of systemic microvasculature; the pattern is similar to that detected in systemic inflammatory diseases and suggests a vascular lesion of inflammatory type. The same changes could be operating also in coronary microvessels of patients with syndrome X.

Short-term and long-term effects of one-week treatment with intravenous iloprost in critical limb ischemia patients (Leriche-Fontaine stage III and IV).

AIM: Iloprost, usually administered through intravenous infusion for 6 hours per day for at least 21 days, is the main medical treatment for critical limb ischemia in patients unsuitable for surgical or endovascular approach. We evaluated the tolerance and the short-term and long-term effects of a single 1-week treatment in critical limb ischemia patients. METHODS: Twenty-nine patients in Leriche-Fontaine III and IV stage were treated with iloprost infusions for 16 hours per day for 7 days, achieving a maximal dose of 1.5 ng/kg/min. Tolerance and clinical assessment after treatment discontinuation and after 1 and 6 months were recorded; clinical evaluation (rest pain, trophic lesions), ankle/brachial pressure index (ABPI) and treadmill exercise test were performed before, immediately after treatment and after 1 and 6 months. RESULTS: No discontinuation of treatment occurred because of intolerance to iloprost. At the end of the treatment 69% of patients were responders, 55.2% at 1 month, 37.9% after 6 months. ABPI and treadmill maximum walking distance were improved by the treatment at every timepoint. After 6 months 10.3% mortality and 3.4% major amputation rates were recorded. There was a higher percentage of non-responders amongst women vs men, in diabetic patients vs non diabetic and in stage IV patients vs stage III. CONCLUSIONS: One-week treatment with iloprost is safe and effective in both Leriche-Fontaine stage III and IV patients. Clinical effects are persistent over time, often lasting up to the 6th month, similarly to the commonly used 28-day treatment, with clear implications in terms of patient's compliance and medical cost containment.