Rearrangements of the RAR-α gene in acute promyelocytic leukaemia:

We have used genomic probes which specifically recognize DNA rearrangements of the RAR-alpha locus on chromosome 17q21 in patients with acute promyelocytic leukaemia (APL) and acute myeloid leukaemia (AML) subtypes. Molecular data were examined in comparison with morphological and immunophenotypic characterization at diagnosis in 20 hypergranular FAB M3 cases, five microgranular APL (M3v), 51 non-M3 AML and 12 myeloid CML blast crises. Rearrangements of the RAR-alpha locus were only detected in 23/25 APL cases and in none of the other FAB subtypes analysed. Surface marker characterization showed a consistent immunophenotypic profile--HLADR negative, CD9 and CD13/33 positive--in all M3 and M3v cases. Neither HLADR negativity nor CD9 positivity were associated with RAR-alpha rearrangements in non M3 AML. Our data indicate that RAR-alpha gene rearrangements are relevant diagnostic features of both M3 and M3v, and may prove useful molecular marker for follow-up analysis in APL patients.     

Lack of alpha-1 integrin alters lesion morphology during pulmonary Mycobacterium tuberculosis infection

The hallmark of Mycobacterium tuberculosis infection is the granuloma, a highly dynamic immune structure that contains the bacilli during chronic infection. Here, we examined if alpha1beta1 integrin is required in the development and maintenance of the granulomatous structure during pulmonary infection using the alpha1 integrin knockout (alpha1-null) mouse. The alpha1beta1 integrin is expressed on activated macrophages and T cells, and interacts with collagen molecules in the extracellular matrix (ECM), and thus may play a role in the granulomatous process. Following pulmonary infection with virulent M. tuberculosis, lungs of alpha1-null infected mice had striking differences in granuloma structure, as well as distinct and markedly thickened alveolar septae. By day 180, there were regions of cell death within granulomatous lesions, characterized by cellular debris in these mice. To determine if this molecule was necessary for T cell trafficking within the lungs, the expression of CD4, CD44 and CD62L was monitored. The number of activated and IFN-gamma-producing CD4(+) T cells increased in the lungs of alpha1-null mice during the chronic phase of infection, although they had decreased concentrations of TNF-alpha and MMP-9. These results suggest that while alpha1beta1 integrin is not required for trafficking or maintenance of T cells in M. tuberculosis infected lungs, it does play a role in granuloma structure and integrity during the chronic phase of infection.     

Prostate cancer cell proliferation is strongly reduced by the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in vitro on human cell lines and primary cultures

PURPOSE: To investigate the effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) ZD1839 ('Iressa') on the cellular proliferation of androgen-sensitive and androgen-independent human prostatic cancer cell lines and primary cultures in vitro. EXPERIMENTAL DESIGN: In this study, we investigated the effects of the quinazoline ZD1839, a potent, selective EGFR-TKI, on the EGFR autophosphorylation and cellular proliferation of androgen-sensitive (ND1, LNCaP, and ALVA-31) and androgen-independent (PC3, DU145, and TSU-Pr1) human prostatic cancer cell lines and 20 primary cultures derived from human prostatic cancer tissue. RESULTS: EGFR was present and phosphorylated in all cell lines tested. ZD1839 reduced EGFR autophosphorylation in intact cell lines with IC(50)s of 0.46-0.97 microM, and inhibited cellular proliferation with IC(50)s of 0.37-1.03 microM. Constitutive EGFR autophosphorylation was low in primary cell cultures, but addition of EGF (50 ng/ml) caused marked EGFR autophosphorylation; cellular proliferation in the presence of EGF was inhibited by ZD1839 with a mean IC(50) of 0.45 microM. At doses >1 microM, ZD1839 induced apoptosis in both androgen-dependent and androgen-independent PCa cell lines. CONCLUSION. Our experiments suggest that EGFR-TKIs such as ZD1839 may have potential in blocking the growth and progression of human prostatic cancers even in early phases of the disease.     

Ethnic variation in hypertension among premenopausal and perimenopausal women: Study of Women's Health Across the Nation

Data are sparse regarding hypertension prevalence, treatment, and control among some ethnic groups of American women. Furthermore, the effects of ethnicity on hypertension, independent of other factors that vary with ethnicity, are poorly understood. We examined the prevalence of hypertension (defined as systolic > or =140 or diastolic > or =90 mm Hg or receiving treatment), treatment, and control (to <140/<90 mm Hg) in a multiethnic study of premenopausal and perimenopausal women. Stepwise multivariable logistic regression was used to select covariates associated with hypertension. Among 3292 women, 46.9% were white, 28.3% were black, 8.7% were Hispanic, 7.6% were Chinese, and 8.5% were Japanese. Among these 5 ethnic groups, respectively, there was substantial variation in prevalence of normal blood pressure levels (<120/<80 mm Hg; 59.9%, 35.4%, 16.8%, 67.2%, and 63.7%) and hypertension (14.5%, 38.1%, 27.6%, 12.8%, and 11.0%). After multivariable adjustment, hypertension prevalence was 2 to 3x higher among black and Hispanic women but similar among Chinese and Japanese women compared with white women. Among hypertensive participants, prevalence of antihypertensive treatment was highest among blacks (58.9%) and whites (55.2%) and lowest among Chinese (34.4%). Prevalence of control to goal blood pressure levels was highest among whites (43.0%) and Japanese (38.7%) and markedly lower among Hispanic women (11.4%). Compared with whites, black and Hispanic women have significantly higher prevalence of hypertension independent of other factors, whereas Chinese and Japanese women have similar prevalence. Treatment and control rates vary considerably across ethnicities. Greater efforts must be made to improve hypertension awareness, treatment, and control in all middle-aged women, particularly those in ethnic minority groups.     

Risk factors for diagnostic delay in acute aortic dissection

In acute aortic dissection (AAD), timely diagnosis is challenging. However, dedicated studies of the entity and determinants of delay are currently lacking. We surveyed pre-/in-hospital time to diagnosis and explored risk factors for diagnostic delay. We analyzed the dedicated database of a metropolitan AAD network (161 patients diagnosed since 1996; 115 Stanford type A) in terms of hospital arrival times (from pain to presentation at any hospital) and in-hospital diagnostic times (presentation to final diagnosis). Median (interquartile range) in-hospital diagnostic times were approximately twofold greater than hospital arrival times (177 minutes, 644, vs 75 minutes, 124, p = 0.0001, Wilcoxon test). Median annual in-hospital diagnostic times were most often approximately 3 hours (spread was wide, but decreased after 2001; rho = -0.94, p = 0.005). Risk factors (univariate analysis) for in-hospital diagnostic time >75th percentile (12 hours) included pleural effusion (odds ratio 3.96, 95% confidence interval 1.80 to 8.69), dyspneic presentation (odds ratio 3.33, 95% confidence interval 1.93 to 8.59), and age <70 years (odds ratio 2.34, 95% confidence interval 1.03 to 5.36). Systolic arterial pressure < or =105 mm Hg decreased the likelihood of lengthy diagnosis (odds ratio 0.08, 95% confidence interval 0.01 to 0.59). In patients (n = 82) with routine values (since 2000), troponin positivity (odds ratio 3.63, 95% confidence interval 1.12 to 11.84) and an acute coronary syndrome-like electrocardiogram (odds ratio 2.88, 95% confidence interval 1.01 to 8.17) were also risk factors. In conclusion, in a metropolitan setting, most of the diagnostic delay may occur in hospital. At presentation, pleural effusion, troponin positivity, acute coronary syndrome-like electrocardiogram, and dyspnea are possible "clinical confounders" associated with particularly long in-hospital diagnostic times.     

Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequently, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM. METHODS: Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed. RESULTS: Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density. CONCLUSIONS: Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density.     

Results of a multi-level therapeutic approach for Alzheimer's disease subjects in the "real world" (CRONOS project): a 36-week follow-up study

BACKGROUND AND AIMS: Recently, the Italian Ministry of Health started a national project (CRONOS project), aiming at assessing how a multi-level therapeutic approach--including 2-year free-of-charge treatment with cholinesterase inhibitors (ChE-I), pharmacologic and non-pharmacologic management of behavioral disorders, periodic multi-dimensional assessment, and informal caregivers' counseling-performs in subjects with mild-to-moderate Alzheimer's disease (AD). Five hundred and three Alzheimer Evaluation Units (AEUs) were instituted for this purpose all over Italy. In this paper we present the results of this approach in a large population of AD subjects followed for 36 weeks by 14 AEUs in Eastern Lombardy, Italy. METHODS: The project lasted for two years (September 2000-September 2002). Subjects eligible for the CRONOS project had a diagnosis of probable AD, a Mini Mental State Examination (MMSE) score at baseline ranging from 10 to 26, and onset of cognitive disorders between 40 and 90 years of age. Periodic clinical and multi-dimensional assessments, including MMSE, Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) were made at 12 and 36 weeks; ChE-I doses, psychotropic and antidepressant drugs were also re-assessed at all clinical examinations. Caregivers were instructed about dementia and drug-related problems. RESULTS: Of the 808 subjects who completed the 36-week follow-up, 441 were na?ves (i.e., never previously treated with ChE-I drugs) and 367 non-na?ves. At 12 weeks, both na?ves (mean variation from baseline = 0.8 points) and non-na?ves (mean variation from baseline = 0.5 points) improved their MMSE scores, while at 36 weeks only na?ves improved (mean variation from baseline = 0.1) and non-na?ves decreased (mean variation from baseline = -1.2). The IADL and ADL scores progressively and mildly declined from baseline to the 36th week (ADL, mean variation from baseline = -0.5 for na?ves, -0.3 for non-na?ves; IADL = -0.7 for na?ves, mean variation from baseline = -0.4). However, when the MMSE, ADL and IADL variations were controlled for age, sex and education, no significant time effect was found (MMSE, Wilks' lambda p = 0.34; ADL, Wilks' lambda p = 0.25; IADL, Wilks' lambda p = 0.3, respectively). These patterns were apparently unrelated to ChE-I doses. Neuroleptic use doubled in na?ves and antidepressants increased in both groups. CONCLUSIONS: This multi-level therapeutic approach seems to slow down progression in cognitive and functional performance, in both na?ve and non-na?ve subjects. The possibility of recurrent examinations by specialized physicians, accurate, lose management of psychotropic drugs, and informal counseling to caregivers probably aid in achieving such results in a "real world" population of AD elderly subjects living at home. Future studies are needed to assess whether a multi-level therapeutic approach including higher ChE-I dose may perform better in these subjects.     

The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites.

BACKGROUND: The role of nitric oxide (NO) in the pathogenesis of splanchnic arterial vasodilation in cirrhosis has been recently debated by some experimental studies. AIMS: We investigated the role of NO in the pathogenesis of the splanchnic arterial vasodilation along the course of CCl(4)-induced experimental cirrhosis. METHODS: We analyzed the effect on mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), and resistance in the superior mesenteric artery (RSMA), before and after the administration of a unspecific NO synthase (NOS) inhibitor (Nomega-nitro-L-arginine-methyl-ester, L-NAME) and a specific NOS2 inhibitor (L-N-(1-iminoethyl)-lysine, L-NIL) to cirrhotic rats with and without ascites, and to control rats. NOS2 and NOS3 protein expression was also assessed in systemic and splanchnic arteries of these animals. RESULTS: L-NAME in cirrhotic rats markedly improved MAP, and TPR and decreased CO regardless of whether they had ascites or not. L-NIL did not produce any significant effect on systemic haemodynamics in control and cirrhotic rats. NOS3 overexpression in the aorta of cirrhotic animals paralleled the progression of the liver disease. L-NAME increased RSMA in cirrhotic rats, but this effect was much less intense in rats with ascites. L-NIL had an effect only on RSMA in rats with ascites, which was of a similar extent to that produced by L-NAME. Western blot experiment showed a faint overexpression of NOS3 in the mesenteric artery of cirrhotic rats with and without ascites and a clear induction of NOS2 only in the mesenteric artery of rats with ascites. Conclusions: These results indicate that NO contributes significantly to the pathogenesis of arterial splanchnic circulation in the early stages of experimental cirrhosis but has only a minor role in its maintenance after the development of ascites. Furthermore, the expression of the different NOS isoforms varies along the course of the liver disease.     

Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness

OBJECTIVES: We sought to evaluate whether the clustering of multiple components of the metabolic syndrome (MS) has a greater impact on these vascular parameters than individual components of MS. BACKGROUND: Intima-media thickness (IMT) and vascular stiffness have been shown to be independent predictors of adverse cardiovascular events. The MS is defined as the clustering of three or more of the cardiovascular risk factors of dysglycemia, hypertension, dyslipidemia, and obesity. METHODS: Carotid IMT and stiffness were derived via B-mode ultrasonography in 471 participants from the Baltimore Longitudinal Study on Aging, who were without clinical cardiovascular disease and not receiving antihypertensive therapy. RESULTS: The MS conferred a disproportionate increase in carotid IMT (+16%, p < 0.0001) and stiffness (+32%, p < 0.0001), compared with control subjects. Multiple regression models, which included age, gender, smoking, low-density lipoprotein, as well as each individual component of MS as continuous variables, showed that MS was an independent determinant of both IMT (p = 0.002) and stiffness (p = 0.012). The MS was associated with a greater prevalence of subjects whose values were in the highest quartiles of IMT, stiffness, or both. CONCLUSIONS: Even after taking into account each individual component of MS, the clustering of at least three of these components is independently associated with increased IMT and stiffness. This suggests that the components of MS interact to synergistically impact vascular thickness and stiffness. Future studies should examine whether the excess cardiovascular risk associated with MS is partly mediated through the amplified alterations in these vascular properties.