Protective effects of heme-oxygenase expression in cyclosporine A--induced injury

Cyclosporine A (CsA) is the immunosuppressant of first choice in allotransplantation. Its use is associated with side effects of nephrotoxicity and neurotoxicity, which are among the most prominent. This study was undertaken to explore whether expression and activity of heme oxygenase (HO), the rate-limiting enzyme in heme degradation, is altered in a rat model of CsA-induced injury. Male Sprague Dawley rats were divided into four groups and treated for 21 days. Group I (control) was injected with olive oil (vehicle), group II with CsA (15 mg/kg/day), group III with CsA and the HO inhibitor stannous mesoporphyrin (SnMP) (30 micromol/kg/day) and group IV with one dose of the HO inducer cobalt protoporphyrin (CoPP) 5 mg/100 or heme (10 mg/kg body weight), three days after onset of CsA treatment. Renal tissue was processed for light microscopy, and for HO-1 enzyme activity, assay and for Western blot analysis. In CsA-treated rats there was histological evidence of tubulointerstitial scarring. HO-1 was undetectable in CsA-treated rats compared to control while there was no change in HO-2. In animals treated with a combination of CsA and SnMP, HO-1 activity was further reduced. In animals treated with a combination of CsA and CoPP, HO-1 protein levels were partially restored. These observations indicate that downregulation of HO-1 expression by CsA could be one mechanism underlying CsA-induced toxicity. The CsA-induced decrease in HO-1 expression is partial and restorable, and attempts to preserve HO levels may attenuate CsA toxicity.     

Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature

We studied the genotype/phenotype correlation in a cohort of glycogen storage disease type (GSD) 1b patients. A total of 25 GSD1b patients, 13 females and 12 males, age range: 4.3–28.4 years, mean:14.6±6.8 years; median: 15 years, representing the entire case load of Italian GSD1b patients, were enrolled in the study. Molecular analysis of the glucose 6-phosphate translocase (G6PT1) gene was performed in all patients. We analysed the presence of a correlation among both the clinical features associated with GSD1b (neutropenia, frequency of admission to the hospital for severe infections) and the presence of systemic complications (liver adenomas, nephropathy, bone mineral density defect, polycystic ovaries, short stature, inflammatory bowel disease) and the mutations detected in each patient. Nine patients were homozygous or compound heterozygous for mutations causing stop codons. In particular, three patients were homozygous for the same mutation (400X); of these patients, one showed chronic neutropenia with severe and frequent infections and severe inflammatory bowel disease, another patient cyclic neutropenia associated with rare bacterial infections and mild bowel involvement and the last one normal neutrophil count. Two patients were homozygous for the mutation 128X; one of these patients did not show neutropenia, whereas the other one had severe neutropenia needing frequent hospital admission and was under granulocyte-colony stimulating factor treatment. In three patients no mutations were detected. Conclusion:no correlation was found between individual mutations and the presence of neutropenia, bacterial infections and systemic complications. These results suggest that different genes and proteins modulate neutrophil differentiation, maturation and apoptosis and thus the severity and frequency of infections. The absence of detectable mutations in three patients could suggest that a second protein plays a role in microsomal phosphate transport.     

Quality assessment of the mammographic screening programme in the Azienda Sanitaria locale Provincia Milano 1 -- analysis of interval cancers and discussion of possible causes of diagnostic error

PURPOSE: To evaluate the sensitivity of the mammographic screening programme and the causes of diagnostic fault in cases surfacing as interval cancers. MATERIALS AND METHODS: Interval cancers (CI) were identified by linkage of the screening database for the years 2000-2002 to the database of hospital discharge records (HDR) for breast cancer during 2000-2002. Linkage between screening attenders during 2000-2001 and HDR (biennial follow-up for year 2000, one year follow-up for year 2001) was used to calculate the proportional rate of observed/expected IC. The observed/ expected rate was compared with international standards and literature data. Screening mammograms followed by IC, randomly admixtured with negative controls, underwent blind review by an independent radiologist, using the recommended classification criteria to evaluate causes of error (occult, minimal signs, screening error). RESULTS: The analysis of HDR during 2000-2002 allowed us to identify 31 out of 89 expected IC. Proportional observed/expected IC rate in the first or second year of screening interval was 26 or 67%, respectively. Screening mammograms for radiological review were available in 38 of 61 total IC: 20 cases (52.6%) were classified as occult, whereas minimal signs or screening errors were 2 (5.2%) or 16 (42.1%), respectively. Diagnostic suspicion had been reported at screening in 7 of 16 cases classified as screening error, but were not diagnosed at the subsequent diagnostic assessment. CONCLUSIONS: Proportional IC rate was higher than reported in the literature or currently recommended (<30% in the 1st, <50% in the 2nd year). The analysis of error causes shows an excess of screening errors with respect to current recommendations (<20% of IC should be classified as screening error at review), but also an excess of IC suspected at screening but misdiagnosed at assessment (7/38=18.4 %). Overall the analysis revealed a reduced sensitivity of the screening programme, as often observed in service screening as compared to excellence centres, and suggests proper action to improve diagnostic accuracy. Analysis and critical review of IC is an early indicator of screening efficacy which is not currently used in Italian screening programmes. Using HDR for this purpose may have limited drawbacks, but gives the advantage of earlier identification of IC as compared to cancer registries and is the most reliable source of information in areas lacking a cancer registry. The present study methodology might be currently applied in screening programmes.     

Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation

BACKGROUND: Cardiopulmonary bypass induces a systemic inflammatory response that may contribute to clinical morbidity. Gaseous nitric oxide at relatively low concentrations may elicit peripheral anti-inflammatory effects in addition to a reduction of pulmonary resistances. We examined the effects of 20 ppm of inhaled nitric oxide administered for 8 hours during and after cardiopulmonary bypass. METHODS AND RESULTS: Twenty-nine consecutive patients undergoing aortic valve replacement combined with aortocoronary bypass were randomly allocated to either 20 ppm of inhaled nitric oxide (n = 14) or no additional inhalatory treatment (n = 15). Blood samples for total creatine kinase, creatine kinase MB fraction, and troponin I measurements were collected at 4, 12, 24, and 48 hours postsurgery. In addition, we collected perioperative blood samples for measurements of circulating nitric oxide by-products and brain natriuretic peptide. Soluble P-selectin was analyzed in blood samples withdrawn from the coronary sinus before and after aortic clamping. The area under the curve of creatine kinase MB fraction (P =.03), total creatine kinase (P =.04), and troponin I (P =.04) levels were significantly decreased in the nitric oxide-treated patients. Moreover, in the same group we observed blunted P-selectin and brain natriuretic peptide release (P =.01 and P =.02, respectively). Nitric oxide inhalation consistently enhanced nitric oxide metabolite levels (P =.01). CONCLUSIONS: Nitric oxide, when administered as a gas at low concentration, is able to blunt the release of markers of myocardial injury and to antagonize the left ventricular subclinical dysfunction during and immediately after cardiopulmonary bypass. The organ protection could be mediated, at least in part, by its anti-inflammatory properties.     

Short-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 microg of ethinyl estradiol: observational study in young postadolescent women

The clinical study of treated subjects and nontreated controls was made in healthy eumenorrheic young postadolescent women volunteers in the Department of Obstetrics and Gynaecology at Cagliari University, to investigate whether an oral contraceptive (OC) containing drospirenone (3 mg) plus ethinyl estradiol (30 microg) (DRSP+EE) can affect bone metabolism. Control group (n = 26) and OC group (n = 28) women did not differ in age, body mass index, waist-to-hip ratio and main outcome measures [urinary levels of deoxypyridinoline and pyridinoline, serum levels of osteocalcin, bone specific alkaline phosphatase (bSAP), total testosterone (total-T), sex hormone-binding globulin (SHBG), progesterone and bone mineral density (BMD) at the heel]. The control group was studied at the luteal phase (LP) during both the first and the sixth menstrual cycle; the OC group was studied during the first cycle at the LP, and on days 16-18 of the sixth cycle of DRSP+EE treatment. At the sixth cycle, in the control group, the main outcome measures did not change compared to baseline. In the OC group, deoxypyridinoline, pyridinoline, osteocalcin, bSAP, total-T and progesterone levels were reduced, whereas SHBG levels were increased. The BMD was unchanged compared to baseline. The results suggest that 6-month DRSP+EE treatment decreases bone turnover.     

Imatinib mesylate in chordoma

BACKGROUND: To the authors' knowledge, no effective medical therapy currently is available for advanced chordoma. Imatinib mesylate is a tyrosine kinase inhibitor targeting platelet-derived growth factor receptor-beta (PDGFRB), BCR-ABL, and KIT. METHODS: Six patients with advanced chordoma were treated with imatinib mesylate at a dose of 800 mg daily. In all patients, the tumor was found to be positive for PDGFRB, and in four patients PDGFRB was shown to be phosphorylated/expressed. RESULTS: After a treatment period of > or = 1 year, overt tumor liquefaction was evident on computed tomography (CT) scan in the first patient. In previous months, a decrease in contrast enhancement on magnetic resonance imaging (MRI) and a decrease in glucose uptake on positron emission tomography (PET) were detected. Similar signs on MRI and PET were observed in subsequent patients, who had a shorter treatment period. One of these patients initially was removed from therapy and then was readmitted to therapy because of difficulties with regard to tumor response assessment; 1 month after the reinitiation of therapy, an overt decrease in tumor density was visible on CT scan in this patient. In four of five symptomatic patients, a subjective improvement was observed early in the course of treatment. The first patient died after 17 months, with a sizeable, mostly liquefied mass. Another patient died early, apparently of unrelated causes. The remaining patients were on therapy at the time of last follow-up. CONCLUSIONS: Imatinib mesylate has been found to have antitumor activity in patients with chordoma. This activity might be mediated by inactivation of PDGFRB. Tumor response manifests through patterns that are similar to those observed in patients with gastrointestinal stromal tumors who respond to molecular-targeted therapy, but evolves more slowly. The benefit to the patient entailed by this pattern of tumor response in chordoma needs to be elucidated, but may be limited in the presence of significant local disease.     

Relationships of age at onset with clinical features and cognitive functions in a sample of schizophrenia patients

BACKGROUND: A number of studies investigated the relationships of age at onset with clinical presentation and cognitive performance of schizophrenic patients. The aim of the present study was to assess demographic and clinical characteristics; psychopathologic, social functioning, and quality-of-life ratings; and neuropsychological measures in a sample of patients with stabilized schizophrenia and to identify which factors independently contributed to a multiple regression model with age at onset as the dependent variable. METHOD: Ninety-six consecutive outpatients with schizophrenia (DSM-IV-TR criteria) were included in the study. Assessment instruments were as follows: a semistructured interview, the Clinical Global Impressions scale, the Comprehensive Psychopathological Rating Scale, and the Positive and Negative Syndrome Scale (PANSS) for psycho-pathology of schizophrenia; the Calgary Depression Scale for Schizophrenia (CDSS) for depression; the Social and Occupational Functioning Assessment Scale and the Sheehan Disability Scale for social functioning; the Quality of Life Scale; and a neuro-psychological battery including the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test. Two models of multiple regression were tested: the first included clinical features and psychopathologic, social functioning, and quality-of-life scales; the second also considered neuro-psychological variables. Data were collected from October 2001 to November 2002. RESULTS: The first multiple regression showed that age at onset was significantly related to scores on the PANSS subscale for negative symptoms (p =.042) and the CDSS (p =.041); the second regression found a relation of age at onset with PANSS score for negative symptoms (p =.002) and 2 neuropsychological measures, number of preservative errors on the WCST and Continuous Performance Test reaction time (p =.0005 for both). CONCLUSION: Our data indicate that, when results of neuropsychological tests are considered, early age at onset of schizophrenia is associated with severity of negative symptoms and compromised cognitive measures of executive functioning and sustained attention.