Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells.

Thiazolidinediones (TZD) are widely prescribed for the treatment of Type 2 diabetes. Increased loss of bone mass and a higher incidence of fractures have been associated with the use of this class of drugs in post-menopausal women. In vitro studies performed in rodent cell models indicated that rosiglitazone (RGZ), one of the TZD, inhibited osteoblastogenesis and induced adipogenesis in bone marrow progenitor cells. The objective of the present study was to determine for the first time the RGZ-dependent shift from osteoblastogenesis toward adipogenesis using a human cell model. To this purpose, bone marrow-derived mesenchymal stem cells were characterized and induced to differentiate along osteogenic and adipogenic lineages. We found that the exposure to RGZ potentiated adipogenic differentiation and shifted the differentiation toward an osteogenic phenotype into an adipogenic phenotype, as assessed by the appearance of lipid droplets. Accordingly, RGZ markedly increased the expression of the typical marker of adipogenesis fatty-acid binding protein 4, whereas it reduced the expression of Runx2, a marker of osteoblastogenesis. This is the first demonstration that RGZ counteracts osteoblastogenesis and induces a preferential differentiation into adipocytes in human mesenchymal stem cells.

What Is the Best Treatment before Bariatric Surgery? Exercise, Exercise and Group Therapy, or Conventional Waiting: a Randomized Controlled Trial.

OBJECTIVE: This trial's objective was to investigate the effect of an exercise program with and without cognitive-behavioral therapy (CBT), compared by a control group, on weight, functional capacity, and cardiometabolic profile of morbidly obese individuals while waiting for bariatric surgery. MATERIALS AND METHODS: This randomized controlled trial investigated the effect of a 4-month low-intensity exercise program (two weekly sessions of 25 min each) on 66 morbidly obese individuals awaiting bariatric surgery. Participants were randomly divided into three groups: EXER, exercise program; EXER + CBT, exercise program plus support group sessions for lifestyle modification, with a CBT; and CONTROL, routine treatment. They were compared on weight, functional capacity, and cardiometabolic profile. RESULTS: The weight change (Kg) was -7.4 (-9.6 to 5,1); -4,2 (-6,8 to -1.6) and 2.9 (0.4 to 5.3) and the BMI change (kg/m2) was -2.7 (-3.6 to -1.8); -1.4 (-2.4 to -0.4) and 1.1 (0.1 to 2.1) for groups EXER, EXER + CBT, and CONTROL, respectively. Changes were significant when compared to the control group (p < 0.001), but there were no differences between the two intervention arms (p = 0.2). Functional capacity and cardiometabolic parameters significantly improved in the intervention arms and worsened in the control group. The adherence to the exercise program in both groups was above 78 %. CONCLUSION: A 4-month, twice-weekly supervised program of low-intensity physical activity that encourages individuals to adopt a more active lifestyle can positively interfere with weight loss and improvement in functional capacity and cardiometabolic parameters of morbidly obese individuals with and without the aid of support group sessions.

Effects of omalizumab in severe asthmatics across ages: A real life Italian experience.

BACKGROUND: This retrospective study aimed at evaluating long-term effects of Omalizumab in elderly asthmatics in a real-life setting. METHODS: 105 consecutive severe asthmatics (GINA step 4-5; mean FEV1% predicted:66 ± 15.7) treated with Omalizumab for at least 1 year (treatment mean duration 35.1 ± 21.7 months) were divided into 3 groups according to their age at Omalizumab treatment onset: 18-39, 40-64 and ≥ 65 years. RESULTS: Comorbidities, number of overweight/obese subjects and patients with late-onset asthma were more frequent among older people. A similar reduction of inhaled corticosteroids dosage and SABA on-demand therapy was observed in all groups during Omalizumab treatment; a similar FEV1 increased was also observed. Asthma Control Test (ACT) improved significantly (p < 0.001) in the three groups, increasing from 15 [IQR:12-18] to 24 [IQR:22-25] in younger subjects, from 14 [IQR:10-16] to 21 [IQR:20-23] in the 40-64-year-group and from 15 [IQR:12-16] to 20 [IQR:18-22] in elderly patients where improvement was lower (p = 0.039) compared to younger people. Asthma exacerbations decreased significantly after Omalizumab but the percentage of exacerbation-free patients was higher in younger people (76.9%) compared to middle aged patients (49.2%) and the elderly (29%) (p = 0.049). After Omalizumab treatment, the risk for exacerbations was lower in subjects aged 40-64 (OR = 0.284 [CI95% = 0.098-0.826], p = 0.021) and 18-39 (OR = 0.133 [CI95% = 0.026-0.678], p = 0.015), compared to elderly asthmatics. Also, a significantly reduced ACT improvement (ß = -1.070; p = 0.046) passing from each age class was observed. CONCLUSION: Omalizumab improves all asthma outcomes independently of age, although the magnitude of the effects observed in the elderly seems to be lower than in the other age groups.

Prognostic significance of microsatellite instability in sporadic mucinous colorectal cancers.

We investigated the prognostic significance of microsatellite instability (MI) in 50 consecutive patients with sporadic mucinous colorectal cancer who had undergone only surgery. We evaluated MI and the pathological features with a possible prognostic value for each tumor, and the effect of the examined parameters on patients' outcome was statistically analyzed (univariate and multivariate analysis). All patients were followed-up for a minimum of 72 months or until death; in evaluating survival, only deaths of colorectal cancer were considered. DNA extracted from tumor sections and the corresponding normal tissue was analyzed by polymerase chain reaction at six microsatellite loci: D2S123, D3S1611, D3S49, D5S107, BAT26, BAT40. Alterations at two or more loci were detected in 36% of cases (MI+ tumors). MI+ and MI- cancers differed significantly in the pattern of growth, and most MI+ tumors showed an expanding type of growth (72.2%, P = .005). At univariate analysis, improved survival rate was significantly associated with MI, as well as with the following parameters: expanding cancer growth, Dukes stage, and absence of venous invasion. Nevertheless, at multivariate analysis, only the pattern of cancer growth and Dukes stage were independent prognostic factors, whereas the effect on survival of MI and venous invasion was found to be negligible. In our study, MI+ and MI- cancers differ only on the pattern of growth; therefore, our data suggest that the better survival rate in mucinous cancers with genomic instability is strictly related to their less aggressive type of growth.

Nasal-continuous positive airway pressure in the treatment of near-drowning in freshwater.

In patients who have experienced near-drowning, hypoxemia is the major clinical consequence. We report two cases of patients who have experienced near-drowning in freshwater who were successfully treated with nasal-continuous positive airway pressure (N-CPAP) plus oxygen therapy. Both patients presented a radiographic appearance of bilateral pulmonary edema. We suggest the use of N-CPAP as an easier and less costly alternative to tracheal intubation for treating near-drowning in patients who are breathing spontaneously and who have not experienced loss of consciousness.

Morphological response to positive end expiratory pressure in acute respiratory failure. Computerized tomography study.

Ten patients with acute respiratory failure (ARF), (4 pneumonia, 4 sepsis, 2 polytrauma), underwent computerized tomography (CT) of the lungs, (apex, hilum, base), at 5, 10, 15 cm H2O positive end expiratory pressure (PEEP). The ARF lungs, on CT scan, appeared as a patchwork of normal and dense areas with generally well defined boundaries. Most of the densities were found in the dependent regions. The areas of density were correlated with PaO2 (r = 0.51). The PEEP increase resulted in a significant expansion of total cross-sectional lung surface area. The dense areas decreased significantly at the hilum and base when increasing PEEP while the changes at the apex were not significant. The changes of density with PEEP were highly correlated with the changes in oxygenation (r = 0.91). In the individual patient, however, the modifications of gas exchange can not be entirely predicted from morphological changes, possibly due to a diversion of pulmonary blood flow.

An open, comparative pilot study of thiamphenicol glycinate hydrochloride vs clarithromycin in the treatment of acute lower respiratory tract infections due to Chlamydia pneumoniae.

The aim of this study was to evaluate the efficacy and tolerability of thiamphenicol glycinate hydrochloride (TGH) i.m. versus clarithromycin in acute lower respiratory infections due to Chlamydia pneumonia. 113 patients with suspected pneumonia were screened. 40 patients with IgM and/or IgA titers > or = 1:16 and/or IgG titers > or = 1:512 were assigned to 10 days of treatment with TGH 1500 mg daily or clarithromycin 1000 mg daily. 34 patients were considered a clinical success. 33 patients were a radiological success. 22 patients showed a decrease in IgG values. 3 patients had an increase in IgG values. Blood/urine values presented no clinically significant variations. Clinical efficacy was similar in both treatment groups. These are the first results confirming in vivo the recent in vitro evidence that TGH is effective against acute lower respiratory tract infections due to C. pneumoniae, thus representing an alternative therapy to clarithromycin.

Inflammatory pulmonary edema and positive end-expiratory pressure: correlations between imaging and physiologic studies.

The anatomic and physiologic response to positive end-expiratory pressure (PEEP) was investigated using computed tomography (CT) in patients with adult respiratory distress syndrome (ARDS). The lesions (densities) in ARDS are distributed inhomogeneously but tend to concentrate in the dependent regions. The estimated lung weight (by CT scan, quantitative analysis, and lung gas volume measured with helium dilution) is, on the average, 200% higher than expected. Changing the body position from supine to prone causes a change in the density distribution in response to gravitational forces. The main effect of PEEP is to clear the densities through alveolar anatomic recruitment. Anatomic recruitment changes the mechanical characteristics of the lung and parallels the improvement in gas exchange. The effects of PEEP on pulmonary arterial pressure appear to be related to anatomic recruitment.

Adult respiratory distress syndrome profiles by computed tomography.

Ten patients with full-blown ARDS, on mechanical ventilation with PEEP underwent lung CT. Seven normal subjects were also studied. Three tomographic levels (apex, hilum, and base) were selected. The most consistent morphologic finding in ARDS was the presence of densities in the dependent regions of the lung. Assuming that the three levels were a representative sample of the whole lung, the lung weight was computed from the mean CT number and lung gas volume. Analysis of the CT number frequency distribution revealed three definite patterns of distribution: type 1, bimodal, with one mode in the normal CT number range; type 2, unimodal narrow distribution, with the mode in the CT range of water; and type 3, unimodal broad distribution in the abnormal CT number range.

Basis for nebulized antibiotics: droplet characterization and in vitro antimicrobial activity versus Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

The aims of this study were to (1) quantify the particle size characteristics of several antibiotics considered suitable for aerosol therapy after aerosolization with the PARI IS/2 nebulizer (Pari GmbH, Sarnberg, Germany) and (2) determine the degree to which in vitro antimicrobial activity of these antibiotics is maintained after nebulization. The aerosolized drugs were tobramycin sulfate, streptomycin, and imipenem, with saline solution as the control. Mean mass aerodynamic diameter of the nebulized drugs was 3.25 microns for tobramycin, 2.26 microns for imipenem, and 2.38 microns for streptomycin. In vitro tests showed that tobramycin and imipenem were unaltered in their bacteriostatic activity against strains of Escherichia coli (American Type Culture Collection [ATCC] 25922) and Staphylococcus aureus (ATCC 29213) as well as against Pseudomonas aeruginosa (ATCC 27853) with minimal inhibitory concentration (MIC) values less than 0.3 microgram/mL. Nebulized streptomycin showed significantly higher MIC values against P. aeruginosa (ATCC 27853). These results suggest that tobramycin and imipenem may be prescribed as an aerosol generated by jet nebulization (PARI IS/2) to treat S. aureus, E. coli, and P. aeruginosa infections without any risk of altering the drugs minimum bacteriostatic activity by the nebulization process. Aerosolization of streptomycin with this nebulizer may not be as effective against P. aeruginosa because it seems to alter the bacteriostatic activity.

99mTc-DTPA-surfactant inhalation in adult respiratory distress syndrome (ARDS): a new diagnostic-therapeutic tool.

ARDS is a life-threatening pulmonary disease with a rapidly progressive decline due mainly to multi-organ failure. Death occurs in 50-75% of ARDS cases. The diagnosis and therapy should start in the first six days of this fatal disease when mortality is at its lowest level. The 99mTc-DTPA-measured pulmonary alveolar epithelial permeability (PAEP) is strikingly increased in ARDS even in comparison to heavy smokers. Furthermore, surfactant inhalation has been shown to be of therapeutic value. In five ARDS patients with increased PAEP (T0.5 = 12% pred.) 20 mg/kg of aerosolized surfactant determined a dramatic improvement in blood gases and PAEP (51.8% pred.) No patient remained dependent on ventilatory treatment.

Iron lung versus mask ventilation in acute exacerbation of COPD: a randomised crossover study.

OBJECTIVE: To compare iron lung (ILV) versus mask ventilation (NPPV) in the treatment of COPD patients with acute on chronic respiratory failure (ACRF). DESIGN: Randomised multicentre study. SETTING: Respiratory intermediate intensive care units very skilled in ILV. PATIENTS AND METHODS: A total of 141 patients met the inclusion criteria and were assigned: 70 to ILV and 71 to NPPV. To establish the failure of the technique employed as first line major and minor criteria for endotracheal intubation (EI) were used. With major criteria EI was promptly established. With at least two minor criteria patients were shifted from one technique to the other. RESULTS: On admission, PaO(2)/FiO(2), 198 (70) and 187 (64), PaCO(2), 90.5 (14.1) and 88.7 (13.5) mmHg, and pH 7.25 (0.04) and 7.25 (0.05), were similar for ILV and NPPV groups. When used as first line, the success of ILV (87%) was significantly greater (P = 0.01) than NPPV (68%), due to the number of patients that met minor criteria for EI; after the shift of the techniques; however, the need of EI and hospital mortality was similar in both groups. The total rate of success using both techniques increased from 77.3 to 87.9% (P = 0.028). CONCLUSIONS: The sequential use of NPPV and ILV avoided EI in a large percentage of COPD patients with ACRF; ILV was more effective than NPPV on the basis of minor criteria for EI but after the crossover the need of EI on the basis of major criteria and mortality was similar in both groups of patients.

Thyroid hormones promote cell differentiation and up-regulate the expression of the seladin-1 gene in in vitro models of human neuronal precursors.

Thyroid hormones (TH) play an important role in the development of human brain, by regulating the expression of specific genes. Selective Alzheimer's disease indicator-1 (seladin-1) is a recently discovered gene with neuroprotective properties, which has been found to be down-regulated in brain regions affected by Alzheimer's disease. Seladin-1 has anti-apoptotic properties mainly due to the inhibition of the activation of caspase 3. The aim of this study was to determine whether seladin-1 may be regarded as a new mediator of the effects of TH in the developing brain. In order to demonstrate this hypothesis, the effects of TH both on cell differentiation and on the expression of seladin-1 were assessed in two different cell models, i.e. fetal human neuroepithelial cells (FNC) and human mesenchymal stem cells (hMSC), which can be differentiated into neurons. 3,3',5-Triiodothyronine (T3) determined different biological responses (inhibition of cell adhesion, induction of migration, and increase in the expression of the neuronal marker neurofilament-M and Na+ and Ca2+ channel functionality) in both FNC and hMSC, which express TH receptors. Then, we showed that TH significantly increase the expression levels of seladin-1, and that T3 effectively prevents camptothecin-induced apoptosis. However, in hMSC-derived neurons the expression of seladin-1 was not affected by TH. Our results demonstrated for the first time that seladin-1 is a novel TH-regulated gene in neuronal precursors. In view of its anti-apoptotic activity, it might be hypothesized that one of the functions of the increased seladin-1 levels in the developing brain may be to protect neuronal precursor cells from death.

Antineoplastic effects of rosiglitazone and PPARgamma transactivation in neuroblastoma cells.

Neuroblastoma (NB) is the most common extracranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. In the present study, we evaluated the role of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone (RGZ) in two NB cell lines (SK-N-AS and SH-SY5Y), which express PPARgamma. Rosiglitazone decreased cell proliferation and viability to a greater extent in SK-N-AS than in SH-SY5Y. Furthermore, 20 microM RGZ significantly inhibited cell adhesion, invasiveness and apoptosis in SK-N-AS, but not in SH-SY5Y. Because of the different response of SK-N-AS and SH-SY5Y cells to RGZ, the function of PPARgamma as a transcriptional activator was assessed. Noticeably, transient transcription experiments with a PPARgamma responsive element showed that RGZ induced a three-fold increase of the reporter activity in SK-N-AS, whereas no effect was observed in SH-SY5Y. The different PPARgamma activity may be likely due to the markedly lower amount of phopshorylated (i.e. inactive) protein observed in SK-N-AS. To our knowledge, this is the first demonstration that the differential response of NB cells to RGZ may be related to differences in PPARgamma transactivation. This finding indicates that PPARgamma activity may be useful to select those patients, for whom PPARgamma agonists may have a beneficial therapeutic effect.

A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer.

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.