Renal physiological regenerative medicine to prevent chronic renal failure: should we start at birth?

With the incidence of end-stage renal disease increasing dramatically during the last ten years, its prevalence rising about 8% per year, chronic kidney disease (CKD) represents one of the most problematic public health problems worldwide. CKD represents a growing clinical problem that, in its terminal stages, requires renal replacement therapy. Kidney transplant has been proposed as the definitive therapy able to address the growing clinical, social and economic problems related to the increasing prevalence of end-stage kidney disease (ESKD). Traditional stem cell-based regenerative medicine, when applied to kidneys disrupted by end-stage renal disease, has been shown to be unable to regenerate the damaged organ. The theme of this work is to hypothesize a new approach to the prevention of CKD, based on the management of the huge amount of stem/progenitor cells physiologically present in the kidney of preterm babies at birth. Here a new concept of primary prevention of renal disease is suggested: a true primary prevention, starting in the perinatal period aimed at increasing the number of functioning glomeruli. This approach has been defined as "physiological regenerative medicine", in order to underline the use of physiological tools, including endogenous renal stem cells and stem cell stimulators physiologically expressed in our cells.

The wet solidus of silica: predictions from the scaled particle theory and polarized continuum model.

We present an application of the Scaling Particle Theory (SPT) coupled with an ab initio assessment of the electronic, dispersive, and repulsive energy terms based on the Polarized Continuum Model (PCM) aimed at reproducing the observed solubility behavior of OH2 over the entire compositional range from pure molten silica to pure water and wide pressure and temperature regimes. It is shown that the solution energy is dominated by cavitation terms, mainly entropic in nature, which cause a large negative solution entropy and a consequent marked increase of gas phase fugacity with increasing temperatures. Besides, the solution enthalpy is negative and dominated by electrostatic terms which depict a pseudopotential well whose minimum occurs at a low water fraction (XH2O) of about 6 mol. %. The fine tuning of the solute-solvent interaction is achieved through very limited adjustments of the electrostatic scaling factor γel which, in pure water, is slightly higher than the nominal value (i.e., γel = 1.224 against 1.2), it attains its minimum at low H2O content (γel = 0.9958) and then rises again at infinite dilution (γel = 1.0945). The complex solution behavior is interpreted as due to the formation of energetically efficient hydrogen bonding when OH functionals are in appropriate amount and relative positioning with respect to the discrete OH2 molecules, reinforcing in this way the nominal solute-solvent inductive interaction. The interaction energy derived from the SPT-PCM calculations is then recast in terms of a sub-regular Redlich-Kister expansion of appropriate order whereas the thermodynamic properties of the H2O component at its standard state (1-molal solution referred to infinite dilution) are calculated from partial differentiation of the solution energy over the intensive variables.

Melting of α-Al2O3 and vitrification of the undercooled alumina liquid: ab initio vibrational calculations and their thermodynamic implications.

We present the results of a computational investigation of the structure-energy and vibrational properties of alumina under various aggregation states (crystalline, glassy, and liquid) with ab initio procedures. IV-fold, V-fold, and VI-fold oxygen-coordinated aluminum monomeric forms in a dielectric continuum with dielectric constant ε = 4.575 were investigated through DFT/B3LYP gas-phase calculations coupled with a Polarized Continuum Model approach and those of the periodical structure D(6)(3d) (R-3c) which leads to the α-Al(2)O(3) polymorph of alumina, when subjected to symmetry operations, were investigated with the same functional within the LCAO approximation and in the framework of Bloch's theorem. Based on the computed energies and vibrational features, an aggregate of the D(6)(3d) positively charged cluster [Al(12)O(11)](14+) contoured by [AlO(4)](5-) units in an approximate 1:3 proportion to achieve neutrality satisfactorily reproduce the heat capacity of the liquid within experimental uncertainty. The glass is seen as a wrong accretionary form induced by fast cooling rates and subjected to steric forces that locally modify the coordination state of the central atom. Cessation of rotational and translational movements, only partly counterbalanced by acoustic sine-wave-dispersed and excess phonons, gives rise to the huge heat-capacity gap observed at the glass transition (~5.3R). When cooling rates are sufficiently slow, the accretion around the D(6)(3d) seeds follows the structural constraints and the heat capacity of α-alumina is almost perfectly reproduced by the 27 Einstein oscillators coupled with the 3 acoustic terms and the anharmonic corrections.

Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective randomized open-label study (EpIC Project).

BACKGROUND: Strokes are the leading cause of epileptic seizures in adults and account for 50% of seizures in those over the age of 65 years. The use of antiepileptic drugs to prevent recurrent poststroke seizures is recommended. METHODS: One hundred and twenty-eight patients with poststroke seizures were randomly allocated to treatment with either levetiracetam (LEV) or sustained-release carbamazepine (CBZ) in a multicenter randomized open-label study. After a titration study phase (2 weeks), the optimal individual dose of trial medication was determined and treatment was continued for another 52 weeks. The primary endpoint was defined as the proportion of seizure-free patients; the secondary endpoints were: evaluation of time recurrence to the first seizure, EEG tracings, cognitive functions and side effects. RESULTS: Of 128 patients, 22 discontinued the trial prematurely; thus a total of 106 patients (52 treated with LEV and 54 treated with CBZ) were included in the analysis. The results of the study were as follows: no significant difference in number of seizure-free patients between LEV and CBZ (p = 0.08); time to the first recurrence tended to be longer among patients on LEV; there was no correlation between the therapeutic effect and the EEG findings in either treatment group; LEV caused significantly fewer (p = 0.02) side effects than CBZ; attention deficit, frontal executive functions and functional scales (Activities of Daily Living and Instrumental Activities of Daily Living indices) were significantly worse in the CBZ group. CONCLUSIONS: This trial suggests that LEV may be a valid alternative to CBZ in poststroke seizures, particularly in terms of efficacy and safety. In addition, our results show that LEV has significant advantages over CBZ on cognitive functions. This trial also indicates that LEV in monotherapy is a safe and effective therapeutic option in elderly patients who have suffered epileptic seizures following a stroke.

A developmental approach to drug-induced liver injury in newborns and children.

The liver represents the major site of drug metabolism in humans. The developmental changes that occur in the liver's metabolic activity during fetal life and in the perinatal period are at the basis of the varied sensitivity of human newborns to many drugs. The decreased capacity of the fetal and newborn liver to metabolize, detoxify, and excrete drugs--total cytochrome P450 content in the fetal liver being 30% to 60% of adult values--may explain the prolonged actions of many drugs in the newborn, as well as less their potential toxicity. On the other hand, the low levels of phase I (activation) enzymes, producing more polar reactive and often toxic metabolites, could explain the lower incidence of adverse effects of some drugs reported in newborns. Moreover, the greater capacity of newborns to synthesize glutathione is at the basis of their ability in inactivating many toxic metabolites. Here we review the acute and chronic liver toxicity due to the most widely used drugs in the neonate. We will discuss in detail the biochemical profile of the fetal and neonatal liver, and the toxic metabolites formed during the metabolism of the most widely used drugs in the neonate. The histological picture of liver disease related to the therapeutic use of drugs will be discussed, with particular emphasis on the mode of cell death involved in hepatitis induced by different drugs most frequently utilized in the neonatal intensive care units.

Invasive and non-invasive long-term mechanical ventilation in Italian children.

BACKGROUND: To date, few studies have been published regarding the number of children in Italy who require long-term mechanical ventilation (LTV) and their underlying diagnoses, ventilatory needs and hospital discharge rate. METHODS: A preliminary national postal survey was conducted and identified 535 children from 57 centers. Detailed data were then obtained for 378 children from 30 centers. RESULTS: The estimated prevalence in Italy of this population was 4.3/100000. The majority of children (72.2%) were followed in pediatric units. The primary physicians who cared for these patients were either pediatric intensivists or pediatric pulmonologists. Neurological patients (78.2% of cases) represented the principal disorder category. 57.2% of the patients were non-invasively ventilated, with a nasal mask being the most common interface (85% of cases). The presence of clinical symptoms that were associated with abnormal findings on diagnostic testing was the primary indication for ventilatory support, whereas weaning failure was the primary indication for tracheotomy. Invasive ventilation was significantly related to younger age, longer daily hours on ventilation and cerebral palsy. Ventilatory modes with guaranteed minimal tidal volume were more often used in patients with tracheotomy. Despite their age, illness severity and need for technological care, 98% of the study population were successfully home discharged. CONCLUSION: Managing pediatric home LTV requires tremendous effort on the part of the patient's family and places a significant strain on community financial resources. In particular, neurological patients require more health care than patients in other categories. To further improve the quality of care for these patients, it is essential to establish a dedicated national database.

T cell therapy for nasopharyngeal carcinoma.

Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.

Long-term home ventilation of children in Italy: a national survey.

BACKGROUND: Improved technology, as well as professional and parental awareness, enable many ventilator-dependent children to live at home. However, the profile of this growing population, the quality and adequacy of home care, and patients' needs still require thorough assessment. OBJECTIVES: To define the characteristics of Italian children receiving long-term home mechanical ventilation (HMV) in Italy. METHODS: A detailed questionnaire was sent to 302 National Health Service hospitals potentially involved in the care of HVM in children (aged <17 years). Information was collected on patient characteristics, type of ventilation, and home respiratory care. RESULTS: A total of 362 HMV children was identified. The prevalence was 4.2 per 100,000 (95% CI: 3.8-4.6), median age was 8 years (interquartile range 4-14), median age at starting mechanical ventilation was 4 years (1-11), and 56% were male. The most frequent diagnostic categories were neuromuscular disorders (49%), lung and upper respiratory tract diseases (18%), hypoxic (ischemic) encephalopathy (13%), and abnormal ventilation control (12%). Medical professionals with nurses (for 62% of children) and physiotherapists (20%) participated in the patients' discharge from hospital, though parents were the primary care giver, and in 47% of cases, the sole care giver. Invasive ventilation was used in 41% and was significantly related to young age, southern regional residence, longer time spent under mechanical ventilation, neuromuscular disorders, or hypoxic (ischemic) encephalopathy. CONCLUSIONS: Care and technical assistance of long-term HMV children need assessment, planning, and resources. A wide variability in pattern of HMV was found throughout Italy. An Italian national ventilation program, as well as a national registry, could be useful in improving the care of these often critically ill children.

Ultrasonography and neonatal urinary tract infections.

B-mode ultrasonography and the power-Doppler are methods for studies by images in rapid technological evolution. Their applications and limits in the study of infections of the urinary tract in the neonatal period are pointed out.

The vibrational behavior of silica clusters at the glass transition: Ab initio calculations and thermodynamic implications.

We present the results of a computational investigation with ab initio procedures of the structure-energy and vibrational properties of silica clusters in a dielectric continuum with dielectric constant ε=3.8, through density functional theory/B3LYP gas phase calculations coupled with a polarized continuum model approach [integral equation formalism applied to a polarized continuum (IEFPCM)] and those of the periodical structure D(6h) which leads to the α-cristobalite polymorph of silica when subjected to symmetry operations with the same functional within the linear combination of atomic orbitals (LCAO) approximation and in the framework of Bloch's theorem. Based on the computed energies and vibrational features, an aggregate of the D(6h) network and the monomer locally ordered in the short-medium range and both present in the glass in a mutual arrangement lacking of spatial continuity reproduces satisfactorily the experimentally observed low T heat capacity and the deviation from the Debye T(3) law. Above T(g), the experimental heat capacity of the liquid is perfectly reproduced summing to the internal modes the translational and rotational contributions to the bulk heat capacity and subtracting the (acoustic) terms arising from coherent motion (no longer existent).

Parental role in the Intensive Care Unit for children affected by Werdnig Hoffmann disease.

AIM: The aim of this study was to determine the role of parents after extubation of their children affected by Spinal Muscular Atrophy Type 1 (SMA1) in the Pediatric Intensive Care Unit. Currently, children affected by SMA1 are often treated with non-invasive mechanical ventilation and mechanical support of cough. During the first two or three years of life they frequently present severe respiratory failure requiring intubation. Extubation may be at severe risk of failure even because of inadequate care. METHODS: Parents of SMA1 children were offered an early education on the most critical aspects and a training in non-invasive respiratory support after diagnosis. They were asked and allowed to stay as longer as possible with their child after extubation. Quality and quantity of care given by parents during the first 24 hours after extubation were recorded. RESULTS: All parents participated to the success of the weaning procedure: they gave continuous care and all children could be extubated. CONCLUSION: The presence of parents after extubation of SMA1 patients is important for the success of the procedure; otherwise, the presence of a skilled nurse is needed, with a nurse-patient ratio of 1:1.

Congenital central hypoventilation syndrome: genotype-phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation.

Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder. Although most CCHS associated PHOX2B mutations occur de novo, about 10% of the cases are inherited from apparently asymptomatic parents, thus confirming variable expressivity and incomplete penetrance of PHOX2B mutations. Three asymptomatic parents of children affected with CCHS, and found to carry the same PHOX2B expansion mutations as their siblings, were studied by overnight polysomnography and somatic mosaicism analysis. In one case, significant sleep breathing control anomalies were detected, while the other two resulted in normal. In tissue-specific allele studies, mosaicism with a comparatively low mutant allele proportion was showed in the two unaffected adult carriers. Accurate polysomnography and assessment of the degree of somatic mosaicism should be conducted in asymptomatic carriers of PHOX2B mutations, as they may unmask subclinical but significant anomalies.

Noninvasive ventilation with positive airway pressure in paediatric intensive care.

AIM: The aim of the present study is to retrospectively evaluate the effectiveness of noninvasive pressure ventilation in the 24-bed Pediatric Intensive Care Unit (PICU) of the G. Gaslini Institute during a 24-month period. METHODS: A retrospective analysis of the characteristics (pH, CO2, SpO2, respiratory rate, oxygen requirement) of patients treated with noninvasive mechanical ventilation for different acute pathologies has been performed. RESULTS: Twenty patients (mean age 7.4+/-0.28 years) with acute respiratory failure due to different pathologies were treated with noninvasive mechanical ventilation. They were divided into 2 groups: the hypoxic group, suffering from pulmonary diseases, and the hypercapnic group, presenting a failure of the mechanical strength or increased dead space. Modalities of ventilation were pressure assisted/controlled or pressure support, delivered through nasal or facial masks. Fifteen out of 20 patients presented a marked improvement of oxygenation and ventilation. Mean times of treatment were 69 and 200 h in the hypoxic and hypercapnic groups, respectively. Five patients required intubation. Two patients presented reversible skin lesions over the nasal bridge. CONCLUSIONS: Noninvasive ventilation can be used in PICU. Major advantages regard immunocompromised children and patients with exacerbations from chronic respiratory diseases, whereas the exact role of noninvasive positive pressure ventilation in patients affected by acute respiratory distress syndrome is still controversial.

European multicenter survey on the laparoscopic treatment of gastroesophageal reflux in patients aged less than 12 months with supraesophageal symptoms.

BACKGROUND: This multicenter survey includes neonates and infants who underwent surgery for primary gastroesophageal reflux (GER) who presented with supraesophageal symptoms of unknown origin with a minimum of 12 months postoperative follow-up. METHODS: A total of 726 patients underwent GER surgery in 10 European Centers in the period 1998-2002. Respiratory symptoms were present in 204 patients (28%); 135 patients (17%) had surgery under 1 year of age, and 46 of them (6.3%) because of respiratory symptoms. Surgery was performed without any previous medical treatment in 10 cases (21%). The type of procedure included 37 complete 360 degrees wraps (80%) (Nissen, 12, and Rossetti, 25) and nine partial wraps (20%) (Thal five, Lortat Jacob one, Toupet one, others two). Gastrostomy was associated in 17 cases (37%) (6 PEG and 11 modified Stamm). No gastric emptying procedures were recorded. RESULTS: No major intraoperative complications were reported. Six patients developed complications (13%) and a redo operation was performed in three (6.5%). Respiratory outcome after antireflux surgery was good in 35 patients (76%) and fair with significantly improved respiratory symptoms in 11 (24%). CONCLUSIONS: This multicenter survey underlines that GER has to be suspected and aggressively treated in infants with difficult-to-treat supraesophageal symptoms, and also in high-risk cases, in order to prevent major complications.

[Compromise of work capacity and quality of life of epileptic subjects]. / Compromissione della capacità lavorativa e qualità della vita nei soggetti epilettici.

The authors test epileptic subjects as far as their professional ability is concerned. An enquiry into patients admitted to the Epilepsy Centre of San martino Hospital in Genova has been performed through a questionnaire about professional performance and quality of life. As far as work related problems are concerned 44.6 per cent of the subjects show the presence of difficulties, while the quality of life is primarily repressed in men relatively to work and in women relatively to social relationship.

Sludge bed development in denitrifying reactors using different inocula-performance and microbiological aspects.

Aerobic and methanogenic consortia were evaluated as inocula for laboratory scale denitrifying reactors, fed with a synthetic wastewater with acetate as the main electron donor. The denitrifying microflora of inocula and reactors was evaluated by specific denitrifying activity, enumeration and isolation of denitrifiers, which were screened by amplified ribosomal DNA restriction analysis. Reactor performance was monitored by COD and nitrate removal efficiencies and granule size. The aerobic sludge failed to form granules, probably due to the development of a filamentous, nitrate-reducing organism which was characterised by 16SrDNA sequencing as Bacillus cereus. The methanogenic sludge showed denitrifying activity and adapted very rapidly to denitrifying conditions in the two reactors seeded with granules of different sizes. Denitrifiers grew around the granules, increasing the specific denitrifying activity of the sludge over 10-fold. Exopolymer-forming organisms, belonging to the same species, were isolated from both reactors. Granule size increased during operation, but flotation of the aggregates, related to gas retention was observed.