Antisenescence effect of REAC biomodulation to counteract the evolution of myelodysplastic syndrome.

About 30 percent of patients diagnosed with myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML). The senescence of bone marrow?derived mesenchymal stem cells (BMSCs) seems to be one of the determining factors in inducing this drift. Research is continuously looking for new methodologies and technologies that can use bioelectric signals to act on senescence and cell differentiation towards the phenotype of interest. The Radio Electric Asymmetric Conveyer (REAC) technology, aimed at reorganizing the endogenous bioelectric activity, has already shown to be able to determine direct cell reprogramming effects and counteract the senescence mechanisms in stem cells. Aim of the present study was to prove if the anti-senescence results previously obtained in different kind of stem cells with the REAC Tissue optimization - regenerative (TO-RGN) treatment, could also be observed in BMSCs, evaluating cell viability, telomerase activity, p19ARF, P21, P53, and hTERT gene expression. The results show that the REAC TO-RGN treatment may be a useful tool to counteract the BMSCs senescence which can be the basis of AML drift. Nevertheless, further clinical studies on humans are needed to confirm this hypothesis.

Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage.

Frizzled receptors are the mediators of the wnt canonical and non-canonical pathways, which play fundamental roles in cell differentiation and organism development. A large body of work indicates that dysregulation of wnt signalling is a feature of oncogenic transformation, but most of the studies published so far focus on the assessment of the consequences of aberrations of the canonical pathway in human cancer. In this review, we discuss the emerging role of the wnt non-canonical pathway regulated by frizzled receptor 6 (Fzd6) in the pathogenesis of different types of human malignancies. The function played by Fzd6 in the physiology of normal and cancer cells has been highlighted in the view that an increased knowledge of the signalling pathways upstream and downstream of this receptor could ultimately result in the identification of new targets for cancer therapy.

Thyroid and celiac disease: clinical, serological, and echographic study.

OBJECTIVE: We sought to reevaluate the prevalence of thyroid dysfunction and thyroid autoimmunity in 47 patients with celiac disease; 91 healthy subjects were studied as controls. Both patients and controls were from Sardinia, Italy. METHODS: Diagnosis of celiac disease was made on the basis of clinical history, presence of positive antigliadin IgA (AGA-A) and IgG (AGA-G) antibodies, antireticulin antibodies (ARA), antiendomysium antibodies (EMA), and was confirmed by jejunal biopsy. HLA class II typing for DQB1 and DQA1 alleles was performed in 36/47 celiac patients. Thyroid was evaluated by palpation and echography; serum free thyroid hormones (FT4, FT3), thyrotropic hormone (TSH), and antithyroid peroxidase autoantibodies (anti-TPO) were assayed by radioimmunoassays. RESULTS: The prevalence of anti-TPO was higher in celiac patients (29.7%) than in healthy controls (9.6%) (p < 0.001) and thyroid echography frequently displayed (42.5%) a hypoechogenic pattern. Five anti-TPO-positive celiac patients were hypothyroid (two overt, three subclinical). A higher but not significantly different prevalence of anti-TPO (3/7 = 42.8%) was found in celiac patients displaying the DQB1*0502 genotype, when compared with the remaining patients (8/29 = 27.6%). CONCLUSIONS: An elevated prevalence of clinical and subclinical autoimmune thyroid autoimmunity was found in Sardinian celiac patients, especially in those displaying the DQB1*0502 genotype; this finding could be related to a particular genetic background of the Sardinian population.

Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party.

Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts of < or = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG-CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion-independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.

Mechanocardiographic effects of an elevated central venous pressure.

Since 1985 we demonstrated that the increase of left ventricular mean diastolic pressure shortens the interval existing between the onset of the electrocardiographic P-wave and the onset of the left apexcardiographic "a"-wave (Aubert et al., 1981; Mortarino et al., 1985). In particular we showed that left P-"a" time interval shortens below 100 msec when left ventricular mean diastolic pressure rises above 12 mmHg. Our results thus substantiated the previous reports related to the P-4th heart sound shortening and 4th heart sound--1st heart sound increase occurring in patients with left ventricular failure (Shapira et al., 1982). In that same period, Kesteloot and collaborators showed a direct relationship between the velocity of appearance of the right internal jugular pulse (JVP) waves and the value of central venous pressure (CVP) (Minten et al., 1985). Moreover the range of variability of the right P-"a" interval (which is the time elapsing between the onset of the electrocardiographic P-wave and the onset of the "a"-wave on the JVP tracing) is, in adult subjects, of similar magnitude of the left P-"a" interval (respectively 60-140 msec (Fishleder, 1968) and 80-160 msec (Mortarino et al., 1985) suggesting a symmetric effect of an elevation of diastolic pressure on left and right P-"a" intervals. We therefore decided to test this hypothesis in a group of patients.

Mechanocardiographic effects of ACE-inhibitors.

Twenty-one subjects who suffered a recent medium sized anterior myocardial infarction conditioning a mild congestive heart failure were randomly allocated to treatment with captopril (25 mg b.i.d., 10 pts) or placebo (11 pts). After 2 months of therapy the group on the active treatment showed a significant increase of apexcardiographic protodiastolic filling period duration reflecting a clear cut decrease of mean pulmonary capillary wedge pressure (from 14 +/- 2 to 7 +/- 3 mm Hg) while patients on placebo did not show any difference in respect to baseline. Neither treatment significantly modified the PEP/LVET ratio despite a significant increase of left ventricular ejection fraction in patients receiving captopril (from 37 +/- 4% to 43 +/- 5%). Cardiac response to ACE-inhibitors can thus be noninvasively monitored by apexcardiography.

Abnormalities of sodium transport by sodium, potassium-activated adenosine triphosphatase in erythrocytes from obese children.

1. Intracellular Na+ concentration [Na+]i and Na+ extrusion catalysed by sodium potassium-activated adenosine triphosphatase (Na+, K+-pump) were evaluated in erythrocytes from 21 obese children and 20 normal weight- and age-matched controls. 2. Obese children showed a significantly decreased Vmax. for Na+, K+-pump-mediated Na+ efflux (5638 +/- 338 vs 7597 +/- 335 mumol h-1 litre-1 of cells mean +/- SEM, P = 0.01), while [Na+]i (9.3 +/- 0.3 vs 9.1 +/- 0.5 mmol/litre of cells, mean +/- SEM, NS) and Na+ efflux in fresh cells (2380 +/- 153 vs 2533 +/- 180 mumol h-1 litre-1 of cells, mean +/- SEM, NS) were similar in both groups. 3. Mean diastolic blood pressure was significantly higher in obese children than in controls, although both groups were normotensive (73.8 +/- 1.3 vs 66.2 +/- 1.9 mmHg, mean +/- SEM, P = 0.009). 4. Abnormal Na+, K+-pump activity is present in individuals with idiopathic obesity. 5. The possible link between obesity and blood pressure regulation may be mediated through modifications in Na+,K+-pump activity.

Quantitative and functional abnormalities of total T lymphocytes in relatives of patients with Hodgkin's disease.

Seven patients, long-term survivors of Hodgkin's disease, and 24 of their relatives (parents, siblings and children), together with normal controls were studied for percentages, absolute counts and mitogen-proliferative responses by means of monoclonal antibodies, E rosette technique and in vitro cultures with PHA, ConA and PWM. The aim of the study was to ascertain whether the impaired cell-mediated immunity of Hodgkin's patients was also present in relatives in order to elucidate the still debated etiology of the defect and of the disease (congenital? environmental? infectious?). The results show that both Hodgkin's patients and their relatives have a significant decrease of total T cells (as T3+, T11+ and E rosette-forming cells) in peripheral blood and a significant impairment of polyclonal responses to all the mitogens employed. The Leu-7+ cells (i.e. a consistent amount of natural killer cells) are significantly increased only in the Hodgkin's patients but not in their relatives. The T cell subpopulations (T4 and T8), B cells and monocytes do not show any difference between the patients, their relatives and normal controls. Our results seem to support, at least in part, the presence of a common defect of T cell lineage both in patients and in their relatives, but its etiology still remains uncertain (genetic? environmental?).

Calcitonin stimulates maturation of mammalian growth plate cartilage.

To determine whether calcitonin (CT) might effect maturation of mammalian growth plate cartilage, we administered salmon CT (sCT) to young rats and used the growth plate from the distal metatarsal as our in vivo growth plate model. Growth plate alkaline phosphatase activity and histological examination were assessed after 3 days of sCT treatment. Alkaline phosphatase activity, a marker of hypertrophied chondrocytes, increased 85%, and the zone of maturation enlarged in rats receiving sCT. In addition, sCT treatment was associated with an increased growth plate 35SO4 incorporation 84% above animals receiving buffer alone. We tested whether this might be a direct effect of CT by using an in vitro model, the growth plate from the fetal pig scapula. Organ culture of these cartilages in serum-free medium with and without sCT (1 U/ml) was performed for 3 days. sCT stimulated alkaline phosphatase activity 49% above growth plates incubated in medium alone. Furthermore, sCT treatment increased the number of hypertrophied chondrocytes leading to widening of the zone of maturation. These studies suggest that CT might have a role growing mammals by promoting maturation of growth plate cartilage.

Homologous and heterologous growth hormones fail to stimulate avian cartilage growth in vitro.

Recent reports that GH has a direct effect on growing cartilage have raised questions as to the role of somatomedins (Sm) in cartilage growth. To test the hypothesis that GH directly stimulates cartilage growth, we added homologous and heterologous GHs to organ cultures of embryonic chick pelvic cartilage. Pelvic rudiments from 9-day-old chick embryos were incubated in serum-free medium for 3 days in medium alone or medium containing chicken GH, turkey GH, bovine GH, human GH, and bovine GH produced by recombinant DNA methodology. None of the GH preparations studied stimulated avian cartilage growth in vitro. However, cartilage wet weight increased in response to sera from normal and growth hormone-treated hypophysectomized rats. In addition, 20 ng/ml purified Sm-C caused a 78% increase in cartilage weight above that of cartilage incubated in medium alone. Insulin also caused an increase in cartilage weight, but in concentrations 50,000-100,000 times that of Sm-C. Our studies demonstrate that homologous and heterologous GH have no effect on growing avian cartilage and support the hypothesis that Sm directly mediate cartilage growth.