Long-Term Follow-Up and Outcome of a Large Cohort of Patients with Common Variable Immunodeficiency

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies. WITHIN THE IPINET (Italian Primary Immunodeficiency Network) IPINET: De Mattia D, Martire B, Bari, Cossu F, Cagliari, Schirilló G, Catania, Castagnola E, Genova, Pietrogrande MC, Delle Piane RM, Milano, Putti C, Padova, Trizzino A, Amato GM, Palermo, Bertolini P, Parma, Zecca M, Pavia, Consolini R, Pisa, Moschese V, Rossi P, Cancrini C, Roma, Cazzola GA, Verona     

A New Algorithm for Closed-Loop Stimulation: A Feasibility Study

PIERAGNOLI, P., et al .: A New Algorithm for Closed-Loop Stimulation: A Feasibility Study. Closed-loop stimulation (CLS) is a physiological system for adaptive rate pacing based on monitoring and processing of the intracardiac impedance. The "standard" CLS algorithm (SCLS) requires continuous ventricular pacing. A new, enhanced CLS algorithm (ECLS) provides rate modulation during sensed and paced ventricular depolarizations. The aim of this study was to validate ECLS and to compare its effectiveness with that of SCLS. Ten patients received Inos²⁺ CLS pulse generators. SCLS and ECLS were uploaded to the device and evaluated in a randomized, crossover fashion at 30 and 45 days after pacemaker implantation. At each follow-up visit, ambulatory and posture tests were performed. Heart rate (HR) during daily activity was evaluated based on 24-hour Holter recordings. During all phases of the ambulatory test, both algorithms provided physiologically appropriate rates in all patients. The proportion of sensed ventricular events was significantly higher in ECLS (93.9%) than in SCLS (0.7%). The proportion of paced ventricular events during 24 hours was substantially lower with ECLS (25.7%) than with SCLS (98.4%). Postural changes did not influence HR with either algorithm. The Holter recordings indicated prompt, safe, and effective rate modulation appropriate to patient activity. In conclusion, analysis of these clinical data demonstrated the safety and effectiveness of the ECLS algorithm. Moreover, with this algorithm the ventricle is paced only when required, which may be expected to retard battery depletion and retain the natural ventricular activation pattern whenever possible. (PACE 2003; 26[Pt. II]:229–232)     

Hyperkalemic Distal Renal Tubular Acidosis in Salt-Losing Congenital Adrenal Hyperplasia

ABSTRACT. Functional indices of distal urinary acidification were assessed in two male infants, aged 1 and 3 months, with salt-losing congenital adrenal hyperplasia. In both cases the diagnosis was sustained by the presence of elevated plasma levels of 17-hydroxyprogesterone, hyponatremia, hyperkalemia, metabolic acidosis and increased plasma renin activity. Both patients were unable to lower urinary pH below 5.9 either during acute ammonium chloride-induced acidosis or after i.v. administration of furosemide. One patient also failed to decrease urine pH below 5.5 and to increase urinary potassium excretion during sodium sulfate infusion. Oral sodium bicarbonate loading was given to both patients but failed to induce a significant increase in the urine minus blood P_co2 gradient. This gradient remained low also after neutral phosphate administration. Repeated studies after acute administration of fludrocortisone in one case or after prolonged administration of hydrocortisone in the other resulted in complete normalization of all functional studies. We conclude that salt-losing congenital adrenal hyperplasia can lead to hyperkalemic distal renal tubular acidosis in early infancy. The defective renal secretion of hydrogen ion and potassium is probably related to the abolishment of the negative potential difference in the cortical collecting tubule induced by the impaired reabsorption of sodium.     

The structural role of high molecular weight tropomyosins in dipteran indirect flight muscle and the effect of phosphorylation

In Drosophila melanogaster two high molecular weight tropomyosin isoforms, historically named heavy troponins (TnH-33 and TnH-34), are encoded by the Tm1 tropomyosin gene. They are specifically expressed in the indirect flight muscles (IFM). Their N-termini are conventional and complete tropomyosin sequences, but their C-termini consist of different IFM-specific domains that are rich in proline, alanine, glycine and glutamate. The evidence indicates that in Diptera these IFM-specific isoforms are conserved and are not troponins, but heavy tropomyosins (TmH). We report here that they are post-translationally modified by several phosphorylations in their C-termini in mature flies, but not in recently emerged flies that are incapable of flight. From stoichiometric measurements of thin filament proteins and interactions of the TmH isoforms with the standard Drosophila IFM tropomyosin isoform (protein 129), we propose that the TmH N-termini are integrated into the thin filament structural unit as tropomyosin dimers. The phosphorylated C-termini remain unlocated and may be important in IFM stretch-activation. Comparison of the Tm1 and Tm2 gene sequences shows a complete conservation of gene organisation in other Drosophilidae, such as Drosophila pseudoobscura, while in Anopheles gambiae only one exon encodes a single C-terminal domain, though overall gene organization is maintained. Interestingly, in Apis mellifera (hymenopteran), while most of the Tm1 and Tm2 gene features are conserved, the gene lacks any C-terminal exons. Instead these sequences are found at the 3’ end of the troponin I gene. In this insect order, as in Lethocerus (hemipteran), the original designation of troponin H (TnH) should be retained. We discuss whether the insertion of the IFM-specific pro-ala-gly-glu-rich domain into the tropomyosin or troponin I genes in different insect orders may be related to proposals that the IFM stretch activation mechanism has evolved independently several times in higher insects.     

Transfemoral Pediatric Permanent Pacing:

COSTA, R., et al.: Transfemoral Pediatric Permanent Pacing: Long-term Results. The femoral vein has been used as an alternative conduit to implant pacemakers in children of any weight. Such method associates endocardial pacing and good cosmetics. The aim of this study was to evaluate prospectively, since 1981, the long-term follow-up of 99 children, from newborn to 13 years old (average   = 4.1 ± 3.6   years, 56 girls), who underwent the implantation of pacemakers via the femoral vein. Atrioventricular block was present in 88% of patients, of congenital etiology in 39% and postoperative in 54%. Single chamber pacemakers were implanted in 92% of patients. During a mean follow-up of 5.3 ± 5.0 years (maximum   = 18.2   years), 5 patients died of cardiac causes, 4 of infection, 2 suddenly, and 3 of unknown causes. The 5-, 10- and 15-year actuarial survival rates were 83.7%, 75.7%, and 75.7%, respectively. Transfemoral leads were used for a mean of 48.9 ± 44.0 months. Reasons for lead explantations were pacing failure in five patients, infection in eight, and elective in nine. The 2-, 5- and 10-year actuarial survivals of transfemoral leads were 87.6%, 73.8%, and 31.8%, respectively. The mean lead survival was 97 months. Overall, 105 reoperations were performed, 38 for battery depletion, 24 for body growth, 14 for infection or pocket revisions, and 27 for miscellaneous reasons. In conclusion, the durability and overall long-term performance of transfemoral leads were excellent. (PACE 2003; 26[Pt.II:487–491)     

A New Pacemaker for Paroxysmal Atrial Fibrillation Treated with Radiofrequency Ablation of the AV Junction

Atrial fibrillation is a relative contraindication to atrial synchronous pacing because of the risk of the tracking of rapid atrial rhythms by the pacemaker. In this study, we describe the clinical results of an AV synchronous rate responsive pacemaker with an original algorithm, which is able to sense pathological increments in atrial rate and automatically to switch into a non-AV synchronous mode of pacing. This pacemaker was implanted in 12 patients who had undergone radiofrequency ablation of the A V junction in order to cure severely symptomatic, drug refractory, paroxysmal atrial fibrillation. In an acute, intrapatient comparison between the standard AV synchronous mode and the automatic switching mode, ventricular tracking of atrial fibrillation occurred in 35% and 4% of total beats at rest and in 24% and 2% of total beats during exercise, respectively (P < 0.001). During 5 ± 4 months of follow-up, no further tachyarrhythmia related symptoms occurred. In conclusion, the standard DDDR mode is unable to eliminate ventricular tracking of atrial fibrillation, thus undermining the efficacy of AV junction ablation therapy. The automatic switching mode eliminates this adverse effect of dual chamber pacing.     

Age dependent impact of estimated glomerular filtration rate on long‐term survival after ischaemic stroke

Aims: Low estimated glomerular filtration rate (eGFR) is associated with high mortality after stroke. However, ageing can influence eGFR directly and limit this burden impact. We investigated if low eGFR can be a predictor of death in different age groups after ischaemic stroke. Methods: We evaluated and followed for 22 ± 14 months 871 unselected consecutive survivor patients more than 30 days after ischaemic stroke (55% men, mean age of 66 ± 13 years) recruited in a prospective Brazilian cohort study from March 2005 to December 2007. Traditional cardiovascular risk factors and eGFR by The Chronic Kidney Disease Epidemiology Collaboration formula were analyzed as predictors of mortality for the whole cohort population and stratified by age (younger or older than 65 years old) in a Cox proportional hazards regression model. Results: There were 119 (14%) deaths during follow up. The mean eGFR was 74 ± 23 mL/min per 1.73 m². Three hundred and sixteen patients (36%) presented eGFR lower than 60 mL/min per 1.73 m². For the whole population, eGFR lower than 60 mL/min per 1.73 m² was independently associated with death after stroke in the multivariate analysis. When stratified by age groups, low eGFR was the single and independent predictor of death just for individuals younger than 65 years‐old, as for older people just chronic atrial fibrillation, previous stroke and increase of age were associated with death. Conclusion: Low eGFR measured at the first day of hospital admission can be a simple and trustful predictor of death after ischaemic stroke in people younger than 65 years old.