Anticardiolipin antibodies in children and adolescents with insulin-dependent diabetes mellitus

Anticardiolipin antibodies were determined in 29 diabetic children and adolescents, aged 3.9–26.8 years, with disease duration from 1 month to 19 years. Anti-islet cell antibodies (ICA-IgG and CF-ICA), anti-insulin antibodies (IAA), antithyroid antibodies and non organ-specifc (NOSA) antibodies were also determined. Patients were grouped according to insulin-dependent diabetes mellitus (IDDM) duration: group I (n=11)<6 months, and group II (n=18)>5 years. Eleven of group II patients showed precocious signs of micro-angiopathic complications. Forty-two age- and sex-matched healthy subjects served as controls. IgG and IgM anticardiolipin antibodies were evaluated by ELISA and their results expressed as arbitrary units (AU). IgG anticardiolipin antibodies were found in 7 patients (24%), while IgM anticardiolipin antibodies were absent in all. IgG anticardiolipin antibodies were more frequent in IDDM patients than in controls (P<0.005) and group I (in 6 out of 11 patients; 54.5%) than in group II (in 1 out of 18 patients; 5.5%) (P<0.025). In five out of six group I patients with IgG anticardiolipin antibodies, ICA-IgG and/or CF-ICA were also found. No correlation was observed between anticardiolipin and other auto-antibodies, micro-angiopatic complications, and HLA typing.     

Verapamil in the cardioversion of atrial fibrillation. Clinical study

BACKGROUND: Prolonged periods of atrial fibrillation (AF) or high frequency atrial pacing lead to a significant shortening of atrial refractory periods. This time-dependent electric remodelling is reduced significantly by the administration of verapamil. METHODS: The present series consists of 24 patients all suffering from atrial fibrillation (33% acute AF and 66% chronic recurrent AF) admitted to our Cardiology Department (Rome University). Group G1 (13 patients) received i.v. verapamil (50 mg in 500 cc saline solution at 40 ml/hr). Group G2 (11 patients) received amiodarone i.v. (300 mg in bolus form followed by the infusion of 900 mg in 500 cc 5% glucosate solution, 33 ml/hr for 6 hours and subsequently 18 ml/hr). All patients received non-fractionated heparin i.v. at the same time. RESULTS: No statistically significant difference was observed in the percentage of pharmacological cardioversions in the two groups: G1=61% vs G2=54% p=0.94). The patients who were not cardioverted pharmacologically were done so electrically (external DC shock). CONCLUSIONS: Albeit in this small population of patients verapamil proved to possess anti-arrhythmic effects on a par with that of standard amiodarone antiarrhythmic treatment. This antiarrhythmic potential of verapamil should be demonstrated in a broader randomised study.     

Cadaveric renal transplantation with quadruple immunosuppression in patients with a positive antiglobulin crossmatch

The significance of the antiglobulin crossmatch in the cyclosporine era remains controversial. Over an 11-month period, 124 recipients of cadaveric renal allografts (109 primary, 15 nonprimary) were retrospectively crossmatched via the antiglobulin technique. Criteria for recipient selection for transplantation included a negative T lymphocytotoxic (CDC) crossmatch for current and historical sera. Fourteen patients (11.3%) underwent transplantation in the setting of a negative T and positive antiglobulin crossmatch. The patient group included 10 female and 4 male patients with a mean age of 43.8 years. All but one patient received a primary transplant, and current sera were positive in the antiglobulin crossmatch in all cases. The mean HLA-ABDR match was 1.4 (range 0-4). Preoperative PRA titers ranged from 0 to 80% (mean 18.3%). All patients underwent successful renal transplantation with quadruple immunosuppression consisting of prednisone, azathioprine, and the sequential use of MALG/cyclosporine. There were no episodes of hyperacute rejection. However, 10 patients (71.4%) experienced acute rejection, including 7 episodes within 4 days of transplant. Early rejection was significantly more common in patients with a positive antiglobulin test (50% vs. 20.9%, P less than 0.05). The mean one-month serum creatinine was 1.7 mg/dl. Actual patient and allograft survival are 92.9% and 85.7%, respectively. Risk factors for a positive antiglobulin crossmatch included female sex and prior sensitization as measured by PRA. Although these patients represent a high-risk group for early rejection, no adverse effect on patient or graft survival was noted with quadruple immunotherapy. In conclusion, a positive antiglobulin crossmatch is no longer a contraindication to renal transplantation with current immunosuppressive strategies.     

Increased levels of circulating endothelial cells in chronic periaortitis as a marker of active disease

BACKGROUND: The pathogenesis of chronic periaortitis (CP) has not been clarified. The histologic features and the association with autoimmune diseases suggest an immune-mediated disorder with marked inflammatory vascular and perivascular lesions. To clarify the role of vascular damage we looked for the presence and the surface phenotype of circulating endothelial cells (CECs) in the peripheral blood of patients with chronic periaortitis. METHODS: Eleven patients with CP were evaluated for the presence of CECs; 9 patients had active and 2 inactive disease. Three patients with active disease were also evaluated 3 months after therapy. Ten atherosclerotic patients, 10 patients with renal insufficiency of variable degree and etiology, and 40 healthy subjects were evaluated as controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31, P1H12, and CD36 positive, and activated CECs as CD45 negative and P1H12, CD62 positive. RESULTS: The median number of CECs in patients with CP (10(6) cells/mL) was significantly higher than in healthy controls (16 cells/mL, P= 0.0004) and atherosclerotic patients (25 cells/mL, P= 0.0005) Two patients with inactive disease had a CEC count comparable to that of normal subjects. In 2 of the 3 patients reevaluated, 3 months after therapy CEC numbers normalized. Almost all CECs were microvascular in origin and showed an activated phenotype. CONCLUSION: The presence of a high number of CECs in the active phase of chronic periaortitis and their normalization during inactive disease suggest that endothelial damage may play a role in the pathogenesis of the disease.     

Comparative analysis of the DST and Imuran-plus-DST protocols for live donor renal transplantation

We have done a comparative analysis of two consecutive clinical trials at our center: the first in 56 patients who received blood transfusions from their prospective donors (DST group), and the second in 36 patients who received such transfusions while they were taking Imuran in an attempt to reduce the incidence of sensitization against the donor (IM + DST group). The major findings of our study are: (1) Imuran significantly (P less than .05) reduced the rate of sensitization from 27% to 11%; (2) Patients who had prolonged dialysis before entering one of these protocols were significantly more likely to become sensitized against their living donors, and had significantly higher sensitization against the leukocyte panel, although panel-reactive antibodies were not significantly changed by transfusions from the live donor; (3) MLC reactivity against the living donor was not significantly altered by donor transfusions, and was also not different for sensitized and transplanted patients; (4) Results of transplantation were excellent in both patient groups, with only two grafts and two patients lost in 68 transplants (actuarial one-year survival of 97% and 93% of patients alive and with functional grafts at one year in the DST and IM + DST groups, respectively); (5) Rejection episodes occurred in about 50% of each group, but were of a special type (DST-type rejection) in about 30% of the DST patients and 10% of the IM + DST patients (P = .07); (6) The probability of transplantation, and the results of transplantation after unsuccessful entry into one of these protocols was not adversely affected. We think that primarily because of the low rate of sensitization the IM + DST protocol is superior to the DST protocol. Both, however, are established clinical tools that have increased our clinical transplant volume by a large number of highly successful transplants.     

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein. Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.     

Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers

The bioavailability of drotaverine (CAS 14009-24-6) was investigated after oral administration of a drotaverine capsule preparation (20 mg Droxa mite) and compared to that of a reference tablet preparation. The preparations were investigated in 23 healthy volunteers, aged between 20 and 27 years, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of drotaverine plasma concentrations were collected at pre-defined time points up to 30 h following drug administration. A washout period of two weeks separated both treatment periods. Drotaverine plasma concentrations were determined by means of a validated HPLC method (UV detector, imipramine HCl salt as an internal standard). The limit of detection was 6 ng/ml. Values of 1593.92 +/- 949.70 ng x h/l (95% confidence interval (CI): 1183.20-2004.60) for the test and 1705.48 +/- 737.78 ng x h/l (95% CI: 1386.40-2024.50) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax of 121.89 +/- 37.03 ng/ml (95% CI: 104.05-139.80) and 121.85 +/- 37.97 ng/ml (95% CI: 107.09-135.74) and time to reach maximum plasma concentration--Tmax of 1.29 +/- 0.42 h (95% CI: 1.11-1.48) and 1.14 +/- 0.34 h (95% CI: 0.99-1.29) achieved for the test and reference preparations did not differ significantly. The relative bioavailability (AUC(0-infinity) ratio test/reference) and Cmax ratio test/reference were 103.15% (90% CI: 81.68-124.60) and 103.74% (90% CI: 94.10-113.38), respectively. AUC was calculated using two different methods. There were no significant differences between the obtained values. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the European Agency for the Evalution of Medicinal Products (CPMP) and the Food and Drug Administration, it is concluded that the new drotaverine capsule formulation is therapeutically equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.     

The tumor-specific de2-7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR

Mutations of the epidermal growth factor receptor (EGFR) gene are found at a relatively high frequency in glioma, with the most common being the de2-7 EGFR (or EGFRvIII). This mutation arises from an in-frame deletion of exons 2-7, which removes 267 amino acids from the extracellular domain of the receptor. Despite being unable to bind ligand, the de2-7 EGFR is constitutively active and imparts a significant in vivo growth advantage to glioma cells. In order to examine the signalling pathways activated by the de2-7 EGFR and its biological effects in an in vitro system, the de2-7 EGFR gene was transfected into the murine IL-3-dependent pro-B-cell line BaF/3. Expression of the de2-7 EGFR enhanced the survival of BaF/3 cells in the absence of IL-3 by reducing apoptosis in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. Interestingly, while de2-7 EGFR also enhanced proliferation of BaF/3 cells in low levels of IL-3, this effect was independent of PI3-K. Survival and proliferation were further enhanced when BaF/3 cells were cotransfected with the de2-7 and wt EGFR. This was due to heterodimerization between the de2-7 and wt EGFR leading to trans-phosphorylation of the wt EGFR. This observation is directly relevant to glioma where de2-7 and wt EGFR appear to be coexpressed. Thus, expression of de2-7 EGFR in BaF/3 cells provides an in vitro model for evaluating the signalling pathways activated by this receptor.     

Right hemispheric dysfunction in a case of pure progressive aphemia: fusion of multimodal neuroimaging

This article describes the unusual case of a 60-year-old woman suffering from pure progressive aphemia. The fusion of multimodal neuroimaging (MRI, perfusion SPECT) implicated the right frontal lobe, especially the inferior frontal gyrus. This area also showed the greatest functional MRI activation during the performance of a covert phonemic fluency task. Results are discussed in terms of bihemispheric language representation. The fusion of three sets of neuroimages has aided in the interpretation of the patient's cognitive brain dysfunction.