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The new Italy -- Greece HVDC link is at 1000m the deepest submarine link in existence, and includes one of the longest underground sections in the world. Proving it involved [...]

The Ross procedure for aortic valve replacement was introduced at two paediatric cardiac centres (Freeman Hospital, Newcastle, and Royal Liverpool Children's Hospital) where surgeons had no previous experience of this [...]

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Inadvertent placement of an introducer sheath in an artery during central venous cannulation is rare and can result in devastating complications. Although traditional closure devices have been employed as prompt and adequate treatment, more innovative devices such as collagen plugs are being studied for their efficacy. We report a case of inadvertent insertion of an 8 French sheath into the right carotid artery which occurred in the electrophysiological laboratory during scheduled transjugular measurement of portal pressure gradient. The consultant neuroradiologist successfully removed the arterial sheath and the puncture site was sealed with a collagen-based vascular closure device (Angio-Seal STS Plus). Accidental insertion of an arterial sheath is an uncommon but potentially serious complication of jugular venous catheterization. When the carotid artery is inadvertently cannulated, sheath removal can be complicated by significant hemorrhage and acute dyspnea due to location of the vessel near the upper airways. Although traditional manual compression and closure devices have been effective at restoring hemostasis, collagen seals or plugs may be more viable to treat this precarious situation. This averted an otherwise emergent open surgical procedure to remove the sheath and repair the carotid artery in a high-risk patient.

Peritoneal dialysis (PD) represents a treatment opportunity for patients with end-stage renal failure, but it has particular complications that sometimes force cessation of this procedure (1–9). These complications are due to the presence of the peritoneal catheter and of dialysis solution within the peritoneal cavity. Infections are the most common complications of PD, followed by mechanical complications.Diagnostic imaging of the complications of PD is important because such an evaluation can aid in the diagnosis and in the decision making process about the treatment. In this review we present the main radiologic investigations employed: plain radiograph, US, peritoneography, computed tomography peritoneography, magnetic resonance peritoneography, peritoneal scintigraphy.To diagnose catheter-related problems plain radiograph, ultrasonography and peritoneography can be useful. US is useful in diagnosing and following-up exit-site and tunnel infections. Peritoneography and C T-peritoneography, alone or in combination, can be recommended as gold standard investigation to assess mechanical peritoneal dialysis complications, such as catheter malfunction, leaks, hernias and sclerosing peritonitis. Newer methods, such as MR peritoneography or scintigraphy could be useful in selected patients, on center-based experience. An appropriate use of radiology may significantly improve technique survival, morbidity and mortality of patients treated with PD.

Hepatitis C virus (HCV) variability is mainly attributed to the ability of the virus to respond to host immune pressure, acting as a driving force for the evolution of quasispecies. This study was aimed at studying the changes in HVR-1 heterogeneity and the evolution of HCV quasispecies in HIV/HCV-coinfected patients according to the pattern of response to highly active antiretroviral therapy (HAART).Sixteen HIV/HCV-coinfected patients harbouring HCV genotype 1 and who had been on HAART for at least 1 year, 8 showing increasing CD4+T-cell counts (immunological responders) and 8 showing a stable or decreasing CD4+T-cell counts (immunological non-responders), were selected from a prospective cohort study.After 1 year of HAART, 11 patients showed HIV viral load <2.6 log10cp/ml (virological responders), and 5 showed HIV viral load above this value (virological non-responders). Plasma samples, collected before starting therapy and after 1 year of HAART, underwent clonal sequence analysis for HVR-1 region of HCV. Non-synonymous/synonymous substitutions ratio (Ka/Ks), aminoacidic complexity (normalized Shannon entropy) and diversity (p-distance), were considered as parameters of quasispecies heterogeneity. After 1 year of HAART, heterogeneity of HVR-1 quasispecies significantly decreased in virological non-responders, whereas the heterogeneity tended to increase in virological responders. The differences in the evolution were less stringent, when considering immunological response. On the other hand, profound qualitative modifications of HVR-1 quasispecies were observed only in patients with both immunological and virological HAART response.On the whole, these findings suggest that, in patients undergoing HAART, the extent of HCV variability and the evolution of HVR-1 quasispecies is influenced by the pattern of response to antiretroviral therapy.

The prognostic role of GB virus type C (GBV-C) viraemia in HIV-infected subjects treated with highly active antiretroviral therapy (HAART) is still undefined, The aim of this analysis is to assess the relationship between GBV-C infection and response to antiretroviral therapy among HIV-infected subjects initiating HAART when antiretroviral-naive.A prospective, observational study of 400 HIV-infected patients with measurements of GBV-C RNA, hepatitis C virus (HCV) antibodies and HCV RNA determined from plasma stored prior to HAART initiation, Time to virological (achieving HIV RNA =500 copies/ml) and immunological success (a CD4+ count increase of =200cells/µl), and the time to virological relapse (confirmed HIV RNA >500 copies/ml) were assessed by Kaplan-Meier methods and Cox proportional hazard regression model.Of the subjects, 117 (29.3%) were GBV-C positive and, overall, 351 (87.8%) patients achieved virological success, After controlling for a number of confounders including HCV RNA, GBV-C viraemic patients experienced a significantly lower risk of HIV rebound than those who were GBV-C negative [relative hazard (RH)=0.56, 95% CI: 0.34–0.93, P=0.03], Conversely, the probability of achieving initial virological success or CD4+ count response after HAART did not differ between GBV-C-negative and -positive subjects, These results suggest that GBV-C coinfection may play a role in determining the rate of HIV rebound possibly by competing with HIV replication after HIV load has been successfully suppressed by HAART.

We examined the impact of a lamivudine-containing highly active antiretroviral therapy (HAART) regimen on 164 hepatitis B virus/HIV co-infected individuals starting their first HAART. Lamivudine-treated patients (accounting for 73% of the study population) showed a significantly lower level of alanine aminotransferase over follow-up [–81.1 mU/ml mean difference; 95% confidence intervals (95% CI): –30.3; –131.7, P=0.003] and a significantly reduced risk of liver-related morbidity/mortality [Relative hazard (RH)=0.07; 95% CI: 0.01–0.38, P=0.002] than those starting a lamivudine sparing-regimen.

High level HIV-1 drug resistance in recently infected treatment-naive individuals correlates with sub-optimal virological responses to highly active antiretroviral therapy (HAART). To determine whether genotypic HIV-1 drug resistance in chronic naive patients, as interpreted by various systems, could predict the virological outcomes of HAART, isolates from patients enrolled in a prospective observational cohort (ICoNA) prior to treatment start were genotyped. Genotypic susceptibility scores (GSS) assigned to the initial HAART regimens using the interpretations of pre-therapy resistance mutations by 13 systems were related to virological outcomes. Of 415 patients, 42 (10%) had at least one major resistance mutation. According to the different interpretations, 1.9–20.5% of patients had some level of resistance to at least one drug in the initial regimen. In multivariable analysis, GSS from two systems significantly predicted the time to virological success: Rega 5.5, for each unit increase in GSS adjusted relative hazard (RH) 1.86 [95% confidence intervals (95% CI): 1.15–3.02] and hivresistanceWeb v3, RH 1.87 (95% CI: 1.00–3.48). With three other systems, GSS showed a trend towards a significant prediction of success: Retrogram 1.6, RH 2.33 (95% CI: 0.98–5.53), Menéndez 2002, RH 2.36 (95% CI: 0.97–5.72) and Stanford hivdb, RH 2.06 (95% CI: 0.94–4.49). Genotypic resistance testing coupled with adequate interpretation in chronic naive patients can usefully identify those at risk of sub-optimal virological response to HAART.

Mechanical circulatory support (MCS) is increasingly used after cardiotomy in children when conventional medical treatment fails. Poor overall survival and long-term outcome have been reported. We report our experience of post-cardiotomy MCS using a conventional bypass circuit.

OBJECTIVE: To evaluate the efficacy and safety of prostaglandin (PG) E1alpha-cyclodextrin for Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc) and its effect on variables of immune activation and endothelial injury in SSc such as tumor necrosis factor-alpha (TNF-alpha), soluble interleukin 2 receptor (sIL-2R), circulating intercellular adhesion molecule-1 (cICAM-1), von Willebrand factor (vWF), and tissue-type plasminogen activator (t-PA). METHODS: We studied 36 women with SSc, 24 of them given three 60 microg intravenous PGE1alpha-cyclodextrin infusions on 5 consecutive days at 6 week intervals during the winter. RP symptoms and healing of digital lesions were evaluated. Twenty age matched healthy women were the controls. TNF-alpha, sIL-2R, cICAM-1, vWF, and t-PA were measured after the first and last infusion of PGEE1alpha-cyclodextrin and correlated with clinical features. RESULTS: RP symptoms improved in 87% of the patients. The benefit of each 5 day cycle lasted 4 or more weeks in 75%. PGE1alpha-cyclodextrin reduced the daily frequency of RP symptoms by 20% (p < 0.05), 41% (p < 0.005), and 53% (p < 0.0005) from baseline after the 1st, 2nd, and 3rd infusions, respectively. The severity of the attacks was reduced to a limited degree. In 12 of the 14 patients with digital lesions, these healed completely. Ten patients had mild side effects during treatment (headache, increased intestinal motility, flushing). TNF-alpha, sIL-2R, cICAM-1, vWF, and t-PA plasma concentrations were significantly higher in patients with SSc than controls (p < 0.05, p < 0.001). TNF-alpha, sIL-2R, and cICAM-1 were higher in diffuse SSc and patients with lung involvement. The plasma levels of cICAM-1 and t-PA were significantly reduced after the 1st infusion of PGE1alpha-cyclodextrin (both p < 0.005) and further reduced after the last (p < 0.0005 and p < 0.005). CONCLUSION: PGE1alpha-cyclodextrin reduces RP symptoms and plasma levels of the markers of endothelial injury in SSc, suggesting that an improvement of endothelial dysfunction contributes to its prolonged therapeutic effect.

Enoximone and enoximone sulphoxide concentrations were measured in plasma of 20 infants, median age 6.0 (range 0.6-49.7) weeks, during and after prolonged continuous infusions. Patients were given enoximone 1 mg kg-1 and an infusion at 10 micrograms kg-1 min-1 just before being weaned from cardiopulmonary bypass (CPB). The infusion was stopped when clinically indicated, after a median 97 (range 24-572) h. Arterial blood samples were taken 30 min and 12 h after CPB, every 24 h during the infusion, and then 2, 4, 8, 12 and 24 h after the infusion was stopped. Pharmacokinetic non-compartmental analysis was performed using TOPFIT software. Fourteen patients who retained normal hepatic function had a median (95% confidence intervals) clearance of 9.7 (6.3-14.1) ml min-1 kg-1, elimination half-life of 5.2 (2.4-6.8) h and a volume of distribution of 3.6 (2.0-5.7) litre kg-1. The six patients with significant hepatic dysfunction had a lower clearance, 5.7 (2.4-14.5) ml min-1 kg-1, and significantly longer elimination half-life, 7.6 (6.5-10.9) h (P = 0.02). Enoximone sulphoxide elimination half-life was significantly prolonged in three patients with renal dysfunction, 16.2 (10.5-17.7) h versus 6.9 (6.1-9.4) h (P = 0.03). These results confirm that enoximone pharmacokinetics in infants is similar to that found in adults. The infusion rate of enoximone should be reduced if hepatic or renal dysfunction supervenes.

The optimal management of tetralogy of Fallot is still under debate, particularly with respect to surgical approach and the age of operation. In recent times a transatrial-transpulmonary approach and primary repair in younger patients is favoured. The purpose of the present study was to analyze the result of our current surgical management by assessing the perioperative and intermediate term follow up in order to define the optimal strategy and timing of operation for our institution.

Piezoelectric actuators can develop large forces very quickly and with high efficiency. The need for high-voltage power supplies has been overcome with stack or multilayer actuators, but the available displacements are still minute. This has limited their use to specialist optical and micro-positioning systems. In order to obtain useful strokes for more general engineering applications, their output displacement must (and can) be amplified. One way of achieving this is by direct mechanical amplification-typically using flexure hinged structures or hydraulic amplifiers. This method is described in the paper.

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We used a laser Doppler probe to measure gastric mucosal blood flow (flux) and a paediatric tonometer to intermittently calculate gastric-arterial PCO2 difference (PrCO2-PaCO2 gap) in 50 infants aged 0.3-52 weeks who required hypothermic cardiopulmonary bypass (CPB). During CPB, patients in group 2 (n = 25) were given dopexamine 1.0 mg kg-1 over 5 min, followed by an infusion of 2 micrograms kg-1 min-1. Patients in group 1 (n = 25) received an equal volume of saline. Drug allocation was random and blinded. Measurements of flux, PrCO2-PaCO2 gap and mean femoral arterial pressure (MAP) were made over 5 min during steady state before and after cooling on CPB to 18-24 degrees C. MAP and blood lactate concentrations were similar in both groups throughout CPB. Mean flux decreased from 182 (SD 60) at the beginning of CPB to 158 (51) after rewarming on CPB in group 1, whereas it increased from 180 (56) to 196 (49) in group 2. This post-rewarm flux was significantly greater in group 2 than in group 1 (P = 0.01). Similarly, mean PrCO2-PaCO2 gap increased significantly from 3.6 (6.3) to 8.2 (6.7) in group 1 (P = 0.01) compared with a significant decrease from 5.8 (5.5) to 2.1 (5.5) in group 2 (P = 0.02). Mean PrCO2-PaCO2 gap after rewarming in group 2 was significantly higher than that in group 1 (P = 0.001). These data indicate that dopexamine may be useful in maintaining normal gut perfusion in infants requiring hypothermic CPB.

Atrioventricular septal defects were repaired in 87 patients from 1981 to 1988. Interventricular communications were present in 73 patients, and major associated anomalies were present in 17 (tetralogy of Fallot in four, double-outlet right ventricle in two, multiple ventricular septal defects in 11). Five deaths occurred in the hospital (5.7%; 70% confidence limits, 3.2% to 9.7%). A preoperative New York Heart Association class V functional condition was the only incremental risk factor (p = 0.02) for death in the hospital. No patient (0%; 70% confidence limits, 0% to 2.15%) had complete heart block. Actuarial survival rate at 80 months was 81.4%. The only incremental risk factor (p = 0.005) leading to reoperation was a preoperative valve incompetence. Actuarial rate at 80 months for freedom from reoperation was 84.2% in the overall group of patients after repair of atrioventricular septal defect We conclude that an improvement in survival and success rates should be found when a policy of earlier repair is followed.

DNA nuclear content was evaluated on 46 paraffin-embedded blocks of vulvar cancer by means of flow cytometry. Fifteen of 44 evaluable samples (34%) were found to have an aneuploid DNA pattern. Aneuplody showed a statistically significant relationship with tumor grading (P= 0.0004) and defined a subset of patients who have pathological characteristics of high risk, such as advanced stage of disease, deepest stromal invasion, or positive inguinal nodes. However, when a multivariate regression model was used, ploidy status did not have any prognostic role, while FIGO staging system was confirmed to be the strongest independent prognostic factor (P= 0.009). The integration of a panel of cell kinetic parameters with traditional features is worth investigating on a larger population.

The control of synchronous machines is usually performed by means of PID-based control loops. However, in underexcitation condition (negative reactive power), dangerous non-linear oscillations may arise. To avoid them, an additional control loop is introduced in this paper with the purpose of making the overall system to approximately match a linear time-invariant model, while keeping unchanged the existing standard PID-based control structure. Such an additional loop is implemented via a structured neural network.

AimsTo investigate the effectiveness of long term, low dose azithromycin treatment for chronic cryptosporidiosis in patients with AIDS.MethodsAzithromycin was administered as initial daily treatment to 13 patients with AIDS: 6 patients received 500 mg for 30 to 40 days (mean 35); 3 patients received 1000 mg for 21 to 50 days (mean 37); and 4 patients received 1500 mg for 20 days. Nine of the 13 patients were also given low dose maintenance treatment with different schedules of azithromycin for 30 to 360 days (mean 129). Patients were monitored, during and after treatment, for parasite shedding in stool and for daily stool frequency and body weight. All but one patient had severe immunodeficiency.ResultsLong term, low dose maintenance treatment was associated with major clinical and parasitological benefits: there was probable eradication of infection in 2 patients, and 7 patients showed a complete response with persistent high decrease (5 patients) or clearance (2 patients) of parasite in stool. The drug was well tolerated, and there was no relapse either during treatment or during follow up (up to 21 months). These results were more impressive than those observed after the short term initial course of azithromycin, which was unable at any tested dose to achieve parasite clearance in stool (except in the patient with less advanced immunodeficiency) or to prevent relapse in 3 patients who discontinued treatment. Reversible side effects occurred with the 1500 mg daily dose.ConclusionsLong term, low dose azithromycin is well tolerated and may induce stable remission of chronic crypto-sporidiosis in patients with AIDS. It may lead to probable eradication of the infection in some patients, even those with severe immunodeficiency.

AimTo investigate morphological changes in Enterocytozoon bieneusi and the duration of symptomatic relief after combination treatment with furazolidone and albendazole in AIDS patients.MethodsFour severely immunocompromised AIDS patients with symptomatic E bieneusi infection of the gut received an 18 day course of combined furazolidone and albendazole (500 + 800 mg daily). All patients were monitored for parasite shedding in stool by light microscopy at the end of treatment and monthly during follow up. At the end of treatment, duodenal biopsy specimens obtained from three patients were studied by transmission electron microscopy by two pathologists blind to the patients' treatment or clinical outcome. Duodenal biopsy specimens obtained from one of the patients two months after completion of treatment were also studied electronmicroscopically.ResultsAll patients had long lasting symptomatic relief, with a major decrease--or transient absence--of spore shedding in stools from completion of treatment. After treatment, changes in faecal spores were persistently found by light microscopy in all cases, and there was evidence of both a substantial decrease in parasite load and ultrastructural damage in the parasite in all biopsy specimens. The treatment was well tolerated, and no patient had clinical or parasitological relapse during follow up (up to 15 months).ConclusionsThe long lasting symptomatic relief observed in all four treated patients correlated with the persistent decrease in parasite load both in tissue and in stool, and with the morphological changes observed in the life cycle of the protozoan. These data suggest that combined treatment with furazolidone and albendazole is active against E bieneusi and may result in lasting remission even in severely immunocompromised patients.

The variable-region (V) genes of the murine T-cell receptor beta chain exist largely as single-element subfamilies. The V beta 5 and V beta 8 genes belong to the only two known three-member V beta subfamilies. We present studies on the linkage of these six genes and show that the genomic organization is that of alternating V beta 5 and V beta 8 genes. Our analysis suggests that these genes were tandemly duplicated, the unit of duplication being a pair of V beta 5 and V beta 8 genes. This tandem organization permits transcripts to initiate from the promoter of an unrearranged V beta located upstream of the rearranged V beta gene. These transcripts can generate functional beta-chain gene messages by novel RNA splicing of the upstream leader exon to the V beta coding exon of the downstream rearranged gene. We extend the analysis of the T-cell receptor genomic organization to include 12 V beta genes and suggest that all V beta genes are closely linked on chromosome 6. In addition, we discuss the possible implications of the close linkage of the V beta genes on the development of the T-cell receptor beta-chain gene repertoire.

AbstractCopyright © 2003 S. Karger AG, Basel

GASTROENTEROLOGY 2000;118:986-987

In the last two decades new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. Aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs.