Multicenter prospective crossover study on new prosthetic opportunities in post-laryngectomy voice rehabilitation.

The aim of this study was to assess the clinical experience of three Italian centers using the third generation Provox Vega prosthesis, in terms of device life and voice outcome, comparing the results with the second generation Provox 2 prosthesis in the same sample. A prospective multicenter crossover study was performed in three phases. In the first phase we performed a reassessment, for enrollment purposes, of patients who were categorized into four different groups [normal ­ group A; radio-treated ­ group B; gastroesophageal reflux disease (GERD) ­ group C; and elderly subjects ­ group D]. In the second and third phases, all patients were monitored for prosthetic device life and assessed for objective and subjective voice characteristics after introducing Provox 2 and Provox Vega prostheses. In patients with Provox 2 prosthesis, the mean life was 165 days in group A, 148 days in group B, 91 days in group C and 188 days in group D. In Provox Vega patients, mean in situ prosthesis life was 213 days in group A, 182 days in group B, 118 days in group C and 227 days in group D. The perceptual voice data showed a better rating across all parameters for the Provox Vega samples compared to those of Provox 2. In this paper, we report the first multicenter crossover study comparing different prosthetic models in the same patients, categorized in relation to different typologies of tracheoesophageal rehabilitative status. Result analyses confirmed an optimal stability of the Provox Vega compared to the Provox 2, in terms of device life and perceptual voice parameters.

Efficacy and safety of omalizumab in paediatric age: an update of literature data.

Immunoglobulin E (IgE) was discovered in 1966 and was found responsible for immune defense against helminths, type I hypersensitivity and allergic diseases. IgE mediates allergic responses by binding to Fc receptors (the high affinity Fc-epsilon receptor I and the low affinity Fc-epsilon receptor II or CD23) expressed on tissue mast cells and blood basophils. This binding leads to degranulation and release of pro-inflammatory mediators. Considering the pivotal role of IgE in allergic diseases, antibodies against IgE potentiate an array of new therapeutic strategies and in this regard omalizumab (rhuMAb-E25, Xolair) has been developed as a monoclonal biologic drug to block serum IgEs. Although the use of omalizumab has been studied vigorously in many adult populations with allergic diseases, there are few heterogenous studies on children. There are very few ongoing clinical trials with omalizumab exclusively on children, although some adult studies have concluded pediatric patients as a part of their studies. Nevertheless, in pediatric clinical trials omalizumab has been demonstrated to be effective and safe also in this age group. Herein, the authors present a systematic review of extensive literature data on the use of omalizumab in children and adolescents.

Adaptive psychological structure in childhood hearing impairment: audiological correlations.

The present research deals with the clinical and social problems present during linguistic and cognitive development of deaf children. Currently, the development of Theory of Mind represents an important research field in deafness studies. These international studies highlighted a significant alteration in the development of Theory of Mind in deaf children compared to normal hearing children, especially in cases of congenital or preverbal hearing loss. In particular, the research focuses on the skills of deaf children in recognising emotions and desires, through both perceptive and cognitive methods, by evaluation of psycho-cognitive skills of children with severe hearing loss using a set of questions to be administered to hearing loss patients. The experiment was performed on a group composed of 10 children (5 males and 5 females) aged 4 to 9 years and 54 to 108 months, affected by bilateral congenital hearing loss (severe to total), or hearing loss that developed in preverbal children the year before entering elementary school, or during the fourth year of elementary school. The selection criteria were based on: audiologic evaluation, neuro-psychological tests administered to assess general, cognitive as well as praxis and perceptive abilities, and clinical observations performed to assess psychopathology using tests that assess development of both visual perceptive (Coloured Progressive Matrices) and graphic representational abilities (Test of Human Figure Drawings and the Family Drawing Test). The instrument "cognitive" was the "Deaf Children Series", arranged by us, that consists of a mental status examination (MSE) that evaluates: level of cognitive (knowledge-related) ability, emotional mood, and speech and thought patterns at the time of evaluation. Deaf children show a reduced responsiveness to the expressions of sadness on the perceptive side. Through the test, we observed a psychodynamic defense mechanism considering perceptive understanding performance. On the contrary, in normal hearing children, the emotion 'fear' is the most difficult to identify. Deaf children seem to be more susceptible to recognition of visual emotions. Furthermore, deaf children present significant problem-solving skills and emotional recognition skills, possibly as a result of their hearing impairment.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

Variable numbers of tandem repeat loci in genetically homogeneous Haemophilus influenzae strains alter during persistent colonisation of cystic fibrosis patients.

Serial sputum isolates of Haemophilus influenzae (n = 69) were obtained from eight patients suffering from cystic fibrosis. For two of these patients all strains were analysed for polymorphism in the major outer membrane protein profile. For all patients the strains were genetically characterised by random amplification of polymorphic DNA analysis. All strains were included in a survey for polymorphism in regions containing moieties of repetitive DNA as well. A single locus containing trinucleotide repeat units, three loci harbouring tetranucleotides, one region comprising pentanucleotide units and two hexanucleotide repeat unit-containing loci were analysed for repeat number variability. Most of the regions were previously shown to be directly adjacent to or even within virulence genes. All regions behaved as genuine variable number of tandem repeat loci in the sense that genetic polymorphism based on the presence of varying numbers of repeat units could be demonstrated among different strains. Interestingly, several of the repeats showed variation in the absence of the variability as assessed by major outer membrane protein or random amplification of polymorphic DNA analysis. These observations indicate that the repeat loci may vary independently from major chromosomal polymorphism. Consequently, H. influenzae appears to modify its virulence gene regions of the chromosome during persistent colonisation of the lung in cystic fibrosis patients.

Cloning and sequencing of a 16S/23S ribosomal spacer from Haemophilus parainfluenzae reveals an invariant, mosaic-like organisation of sequence blocks.

A 16S/23S ribosomal spacer from a Haemophilus parainfluenzae rrn locus was cloned and sequenced. Analysis of PCR-amplified genomic fragments showed that this region is strongly conserved among unrelated isolates; computer analysis of database homologies showed that the spacer consists of sequence blocks, arranged in a mosaic-like structure, with strong homologies with analogous blocks present in the spacer regions of Haemophilus influenzae, Haemophilus ducreyi and Actinobacillus spp. It also contains a tRNA(Glu) gene, which is highly homologous to tRNA(Glu) genes found in spacers of other species. These data strongly support the hypothesis that recombination events are involved in the organisation of the sequence of the spacer, as a result of horizontal gene transfer.

Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung.

Serum copper and ceruloplasmin levels were determined in patients with solid neoplasias in different sites (stomach, large intestine, lung). Statistical analysis showed that serum copper levels increased significantly in all the forms studied. The serum ceruloplasmin level, on the contrary, was high in gastric and pulmonary cancer, while in tumors localised in the large intestine the increase was not significant. In 58 cases, there was a correlation between copper and ceruloplasmin levels in the same subject; this correlation proved significant solely in gastric forms. Moreover, statistical analysis of the two parameters in question did not reveal any significant differences between localized and metastasized in forms.

Lithium carbonate in the treatment of drug-induced leukopenia in patients with solid tumors.

The authors report on the first part of an ongoing controlled trial (52 cases) on the evaluation of the effectiveness of Li2CO3 treatment of drug-induced leukopenia in patients with solid tumors. The results indicate that treatment with 750 mg/day per os of Li2CO3 for 7 days is capable of raising the leukocyte count to a highly significant extent, without serious side effects. The leukocytosis is due to an increase in neutrophil granulocytes.

Variations in serum copper and ceruloplasmin levels in advanced gastrointestinal cancer treated with polychemotherapy.

Serum copper and ceruloplasmin levels (SCL, SCeL) in 57 patients with advanced cancer of the stomach (35 cases) or large intestine (22 cases) treated with polychemotherapy were studies. In gastroenteric cancer, SCL, which are already high in untreated patients, have a tendency to increase further in cases of progression of the disease, while they seem to significantly decrease in cases of remission. SCeL during the trial appeared to be correlated to the clinical evolution of the disease only in the case of stomach cancer. In large intestine cancer, SCeL did not show any significant variation in relation to the normal range. These observations, in particular on the behavior of SCL in the neoplasms of the digestive tract, are in accordance with the results of other studies. The authors are inclined to attach a diagnostic and prognostic value to the variation in SCL and SCeL in gastrointestinal cancer.

Use of N-acetylcysteine in the management of coronary artery diseases.

Thrombolysis after acute myocardial infarction may lead to a number of adverse effects (reperfusion injury) such as myocardial stunning, arrhythmias and even myocardial damage and extension of the infarct size. Some recent clinical studies have demonstrated that the intravenous infusion of N-acetylcysteine during thrombolysis was associated with a decrease in infarct size and better preservation of left ventricular function, probably due to antioxidant and free radical scavenger properties of N-acetylcysteine. Short- and long-term studies indicated that also in patients with unstable angina pectoris and threat of infarct, the intravenous or oral administration of N-acetylcysteine in association with nitroglycerin is highly effective in decreasing the risk of worsening, mainly by preventing the occurrence of acute myocardial infarction.

Interleukin-6 gene expression and production induced in human monocytes by membrane proteoglycans from Klebsiella pneumoniae.

The present study was designed to investigate the effect of membrane proteoglycans (MPG) from Klebsiella pneumoniae on IL-6 production by human peripheral blood monocytes. Exposure in vitro to MPG induced release of IL-6 activity from human monocytes, as assessed by the 7TD1 hybridoma assay. MPG-induced hybridoma growth factor activity was blocked by anti-IL-6 antibodies. MPG induced expression in human monocytes of IL-6 mRNA transcripts as assessed by Northern blot analysis. Induction of IL-6 in mononuclear phagocytes may play a role in the immunomodulatory activity of MPG.

Chemotactic cytokine gene expression and production induced in human monocytes by membrane proteoglycans from Klebsiella pneumoniae.

The present study was designed to investigate the effect of membrane proteoglycans (MPG) from Klebsiella pneumoniae on production of the chemotactic cytokine, IL-8, and monocyte chemotactic protein (MCP) by human peripheral blood monocytes. Exposure of human peripheral blood monocytes to MPG in vitro induced high levels of mRNA transcripts for IL-8 and MCP, as assessed by Northern blot analysis. Cytokine gene expression was associated with the production of chemotactic activity in the supernatants. The levels of IL-8 and MCP expression induced by MPG were comparable with those elicited by LPS. Induction of chemotactic cytokines in mononuclear phagocytes may play a role in the immunomodulatory activity of MPG.

Immunomodulation of polymorphonuclear leukocytes by D53 Immucytal and its constitutive fractions.

D53 (Immucytal) is a compositive vaccine made of immunogenic ribosomes extracted from 4 bacterial species (Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pyogenes and Streptococcus pneumoniae) associated with a membrane proteoglycan from a non-encapsulated strain of Klebsiella pneumoniae (MPG-Kp). In this work we have studied the effect of the compound on human polymorphonuclear leukocyte (PMN) function "in vitro". We have demonstrated that D53 was able to significantly increase Fc- receptor dependent phagocytosis without modify the C3-receptor dependent activity. Furthermore D53 enhanced the oxidative metabolism (evaluated by chemiluminescence) both using cells in resting conditions or after stimulation with phagocytable or soluble stimuli. On the contrary D53 caused a dose-dependent inhibition of PMN migration toward different chemoattractants. Using the two constitutive fractions of the compound (ribosomes and proteoglycans) we have observed that the MPG-Kp component was mainly responsible for the modulating activity of the drug on human PMNs.

Absence of proarrhythmic effects of ibopamine in patients with congestive heart failure.

Ibopamine, the di-isobutyric ester of N-methyldopamine, is an orally effective dopamine-related drug. Ibopamine acts mainly through the stimulation of beta 1- and beta 2-adrenergic and dopaminic DA1 and DA2 receptors. Cardiac beta 1 activation may facilitate the occurrence of arrhythmias, by reducing the mean refractory period. The aim of this multicenter investigation was to ascertain whether the administration of ibopamine can induce any rhythm disorder or increase pre-existing arrhythmias. In the first part of the investigation, after a washout period 20 patients were treated randomly under double-blind conditions with ibopamine (100 mg t.i.d.) or placebo for 7 days. In the second part of the study, 25 patients were treated with placebo for 7 days, and then with ibopamine (100 mg t.i.d. and 200 mg t.i.d.) for another two 7-day periods. The results did not show any increase in arrhythmias during the two ibopamine periods, in comparison with the data collected under placebo treatment. Ibopamine did not affect heart rate and blood pressure. The number of SVPBs and VPBs decreased considerably in several patients and also the Lown classification improved after ibopamine treatment, even after the 200 mg t.i.d. dose. It can be concluded that ibopamine does not seem to elicit any significant proarrhythmic property.

Stimulation of cytotoxic and non-cytotoxic functions of natural killer cells by bacterial membrane proteoglycans and ribosomes.

The present study was designed to investigate the effect of membrane proteoglycans (MPG) from Klebsiella pneumoniae on the function of human natural killer (NK) cells. MPG combined with bacterial ribosomes from Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae, constitute a bacterial immunomodulator (MS D 53), currently in clinical use. Human peripheral blood lymphocytes (PBL) exposed in vitro to MPG or MS D 53 for 20 h showed enhanced NK cytotoxicity. Augmentation of NK cytotoxicity depended upon a direct effect on NK cells, inasmuch as these compounds were also effective on highly purified large granular lymphocytes (LGL). We also studied the effects of MPG on non-cytotoxic functions of NK cells, namely in vitro locomotion and production of IL-1. MPG (and MS D 53) induced IL-1 release in LGL. Moreover, MPG-treated LGL showed enhanced locomotory activity, as assessed by measuring the penetration into nitrocellulose filters. The capacity of MPG (and MS D 53) to activate cytotoxic and noncytotoxic functions of NK cells may contribute to enhancement of nonspecific resistance in vivo after treatment with this agent.

Safety of ibopamine therapy in congestive heart failure. Ibopamine cohort study: baseline and 1-year results.

The study was designed to evaluate the safety of ibopamine (3,4-diisobutyryl ester of N-methyldopamine. SB(-)-505. Inopamil; CAS 66195-31-1) for the chronic treatment of congestive heart failure. It was conducted as a comparative cohort survey, versus digitalis. A third cohort was made with patients who received both drugs in association. Any differences between cohorts at baseline were dealt with by identifying explanatory variables with linear discriminant analysis and by performing multivariate statistical analysis by Cox's proportional hazard model. During 16 months, 3.330 patients were enrolled and then followed-up for a median time of 1 year. Baseline characteristics are reported as well as follow-up results on mortality, disease progression, anginal episodes, arrhythmias, need for cointervention and other undesired on-therapy events. Results pointing to efficacy are consistent with the favourable results from controlled randomized double blind medium--long term clinical trials. In addition, data from the present study do indeed provide strong evidence on the safety of long-term treatment with ibopamine. At variance with inotropic agents ibopamine did not increase mortality. The results rather suggest that long-term treatment with ibopamine affords an increase in survival and a delay in the progression of the disease, without adverse effects on cardiac rhythm and myocardial oxygen balance, and with a general improvement in the patients' quality of life.

Molecular epidemiology and phylogenetic analysis of Haemophilus parainfluenzae from chronic obstructive pulmonary disease exacerbations.

This study was undertaken to characterize serial Haemophilus parainfluenzae strains from epidemiologically unrelated chronic obstructive pulmonary disease (COPD) patients and from healthy carriers. A comprehensive approach was used including different phenotypical and molecular typing methods: biotyping, antibiotyping, conventional ribotyping, pulsed field gel electrophoresis (PFGE) assay, and PCR-ribotyping. Conventional ribotyping and PFGE analysis were confirmed as excellent procedures to differentiate isolates of the same species and biotype. Conversely, in our study, PCR-ribotyping proved to be suitable for taxonomic purposes, unambiguously identifying H. parainfluenzae from H. influenzae but not discriminating strains at the intraspecific level for epidemiological typing. Phylogenetic analysis of restriction fragment length polymorphism (RFLP) data of sequences related to the rrn operon demonstrated that H. parainfluenzae strains associated to COPD are spread among many diverging lineages.

Long-term treatment of congestive heart failure with oral ibopamine. Effects of rhythm disorders and neurohormonal alterations.

A group of 30 patients with II-III NYHA class cardiac insufficiency was treated with ibopamine in association with other drugs for a 6-month period. The patients were submitted to a 24-h ambulatory ECG Holter monitoring, chest X-ray, Doppler echocardiography in order to calculate total peripheral vascular resistance. Blood levels of aldosterone and renin-angiotensin activity in plasma were also measured, together with norepinephrine excretion. The measurements and recordings were performed in basal conditions before the trial, and were repeated after the first, second, third and sixth month. Laboratory tests were performed at the baseline and after 6 months. The results showed a significant decline in the number of ventricular and supraventricular ectopic beats after treatment. Heart rate did not change. Cardio-thoracic ratio decreased significantly along with peripheral vascular resistance. A very noticeable decline in all three neurohormonal parameters, i.e. norepinephrine excretion, blood level of aldosterone and renin activity in plasma was observed after 1 month's treatment, and this reduction was still present without any attenuation after 6 months. No significant changes were observed in routine laboratory tests.

Polymerase chain reaction-mediated typing of microorganisms: tracking dissemination of genes and genomes.

The polymerase chain reaction (PCR) is a powerful molecular biology tool which can be used for the identification of species and strains of diverse microorganisms. By aimed amplification of characteristic genes (i.e., genes encoding ribosomal RNA molecules) and subsequent genetic analysis of amplified fragments, information on microbiological systematics and phylogeny can be obtained in a fast and efficient manner. Similar types of gene identification can be used to verify or detect genes responsible for phenotypic characteristics, whereas modified forms of the PCR enable whole genome searches for genetic polymorphisms among strains of a given species. In medical sciences, both strategies, gene and genome variability analysis by PCR, have an increasing impact on the study of the spread of especially those microbes that are multiply resistant to clinically used antibiotics. In this communication we will exemplify the usefulness of PCR-mediated typing of microorganisms from a clinical perspective while focusing on gene- versus genome-scanning. Special emphasis will be placed on analysis of the dissemination and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains and bacterial factors providing resistance to penicillin and other beta-lactam antibiotics. Technical limitations and possibilities for improvement will be discussed.

Lack of consistent short sequence repeat polymorphisms in genetically homologous colonizing and invasive Candida albicans strains.

Short sequence repeats (SSRs), potentially representing variable numbers of tandem repeat (VNTR) loci, were identified for the human-pathogenic yeast species Candida albicans by computerized DNA sequence scanning. The individual SSR regions were investigated in different clinical isolates of C. albicans. Most of the C. albicans SSRs were identified as genuine VNTRs. They appeared to be present in multiple allelic variants and were demonstrated to be diverse in length among nonrelated strains. As such, these loci provide adequate targets for the molecular typing of C. albicans strains. VNTRs encountered in other microbial species sometimes participate in regulation of gene expression and function as molecular switches at the transcriptional or translational level. Interestingly, the VNTRs identified here often encode polyglutamine stretches and are frequently located within genes potentially involved in the regulation of transcription. DNA sequencing of these VNTRs demonstrated that the length variability was restricted to the CAA/CAG repeats encoding the polyglutamine stretches. For these reasons, paired C. albicans isolates of similar genotype, either found as noninvasive colonizers or encountered in an invasive state in the same individual, were studied with respect to potentially invasion-related alterations in the VNTR profiles. However, none of the VNTRs analyzed thus far varied systematically with the transition from colonization to invasion. In contrast to the situation described for some prokaryotic species, this finding suggests that VNTRs of C. albicans may not simply function as contingency loci related to straightforward on/off regulation of invasion-related gene expression.