Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression.

MicroRNAs (miRNAs) from the gene cluster miR-143-145 are diminished in cells of colorectal tumor origin when compared with normal colon epithelia. Until now, no report has addressed the coordinate action of these miRNAs in colorectal cancer (CRC). In this study, we performed a comprehensive molecular and functional analysis of the miRNA cluster regulatory network. First, we evaluated proliferation, migration, anchorage-independent growth and chemoresistance in the colon tumor cell lines after miR-143 and miR-145 restoration. Then, we assessed the contribution of single genes targeted by miR-143 and miR-145 by reinforcing their expression and checking functional recovery. Restoring miR-143 and miR-145 in colon cancer cells decreases proliferation, migration and chemoresistance. We identified cluster of differentiation 44 (CD44), Kruppel-like factor 5 (KLF5), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as proteins targeted by miR-143 and miR-145. Their re-expression can partially revert a decrease in transformation properties caused by the overexpression of miR-143 and miR-145. In addition, we determined a set of mRNAs that are diminished after reinforcing miR-143 and miR-145 expression. The whole transcriptome analysis ascertained that downregulated transcripts are enriched in predicted target genes in a statistically significant manner. A number of additional genes, whose expression decreases as a direct or indirect consequence of miR-143 and miR-145, reveals a complex regulatory network that affects cell signaling pathways involved in transformation. In conclusion, we identified a coordinated program of gene repression by miR-143 and miR-145, in CRC, where either of the two miRNAs share a target transcript, or where the target transcripts share a common signaling pathway. Major mediators of the oncosuppression by miR-143 and miR-145 are genes belonging to the growth factor receptor-mitogen-activated protein kinase network and to the p53 signaling pathway.

The impact of the Catholic Jubilee in 2000 on infectious diseases. A case-control study of giardiasis, Rome, Italy 2000-2001.

Mass gatherings are believed to increase the transmission of infectious diseases although surveillance systems have shown a low impact. The Catholic Jubilee was held in Rome, Italy in 2000. We conducted a case-control study to analyse the risk factors of giardiasis among residents. All diseases reported to the laboratory surveillance system from January 2000 to May 2001 were compared with hospital controls concurrently selected in the same season as cases and frequency-matched for age and birth country. Fifty-two cases (44.1%) and 72 controls were enrolled. In the multivariable analysis factors associated with giardiasis among adults were: travelling abroad (OR 24.2, P>0.01), exposure to surface water (OR 4.80, P=0.05), high educational level (OR 3.8, P=0.03). Having a maid from a high-prevalence country was independently associated (OR 2.3) although not statistically significant. This is the only exposure that changed during the Jubilee.

Assessing effectiveness of home care for persons with AIDS: analysis of methodological problems.

The aim of this paper is to assess the methodological problems of an unsuccessful randomized controlled trial (RCT) conducted to evaluate the effectiveness, in terms of survival and quality of life, of the early offer of home care (HC) to persons with AIDS (PWA). The study carried out was an intention-to-treat RCT. Persons in the treatment group (TG) received the offer of HC at the moment of AIDS diagnosis; those in the control group (CG) received it six months from diagnosis. Many problems have hindered the progress of the study: particularly, the low compliance to the offer and the failure to enroll the required sample size have made the results unreliable. Analogous problems have been reported within other trials evaluating HC in different fields. The present study thoroughly evaluates the specific ethical and methodological problems encountered in designing and conducting a RCT on HC for PWA. We conclude that, before designing and conducting a RCT in this field, it is advisable to examine some main issues carefully, such as the acceptability of the offer of treatment, the expected compliance and the required size of the study population. If one or more of these elements prove to be problematic, the results of the trial risk being seriously compromised, and alternative approaches should be considered.

Zinc distribution in various tissues, (brain, eye, skin, muscle and blood) of rat during hindlimb suspension.

Postural changes in 1-G environment induce well documented haemodynamic changes. On going from Earth's 1-G environment to the microgravity of space a marked cephalic blood volume shift occurs in humans with a subsequent loss of 2-3 L of fluid determined by diuresis and decreased fluid intake. Moreover, a number of transient changes in serum concentrations of sodium, potassium and calium have been observed in astronauts during spaceflight. It is conceivable that changes in the fluid status, and reduced muscle activities, which are changed by the microgravity environment, would also result in redistribution of some trace elements, such as zinc, copper and manganese. In particular, zinc metabolism, directly involved in many physiological processes, can be altered by a wide variety of factors including stress, rest, exercise, hormones and diet. Some of the microgravity-induced responses in space can be simulated in humans by using the posture of head-down tilt, and in rat by using the posture of hindlimb suspension. The aim of the present study was to investigate the effects of hindlimb suspension for 3-14 days on sodium, potassium and zinc content in various rat tissues including blood, muscle, brain, eye and nose's skin.

Heterogeneity of home care assistance needs of people with AIDS.

A multidisciplinary home care service for people with AIDS (PWAs) was started in Rome in September 1990. This paper describes the features of the home care service offered by the Associated Health Care Workers' Co-operative (OSA), an example of the integration of private and state systems. We detail the types and numbers of visits that PWAs have needed, and we explore the possible correlation between demographic and clinical variables and the care required. As of September 1994 service had been provided to 372 PWAs. During the 4-year period, 62,927 home care visits were made (an average of 4.3 visits/patient/week): 66% were made by psychologists, social workers and home helps, and 34% by health professionals. PWAs who, at the outset of their home care, suffered from AIDS-dementia complex (ADC), toxoplasmosis, wasting syndrome or cytomegalovirus retinitis required the highest number of visits. Psychologists, social workers and home care helps made more frequent visits than health professionals for all AIDS-defining conditions except retinitis (for which 63% of visits were for health care). Our study shows that careful assessment of patients receiving home care helps in planning visits and in organizing available resources. A controlled randomized multicentre study is under way with the aim of determining the effectiveness of home care in terms of survival, quality of life and care workload and related costs.

9-(2-Phosphonylmethoxyethyl) adenine increases the survival of influenza virus-infected mice by an enhancement of the immune system.

PMEA (9-(2-phosphonylmethoxyethyl)adenine) is a potent inhibitor of DNA viruses and retroviruses able to enhance natural immune functions such as natural killer cell activity and interferon production. The results reported in this paper show that the treatment with PMEA significatively decreased the mortality of mice challenged with influenza A/PR8 virus (an RNA virus, non sensitive to the antiviral effect of PMEA) compared to untreated, infected controls (median survival 8.64 days and 7.61 days, respectively), and reduced lung weight and consolidation (two surrogate markers of virus infection). Furthermore, virus titer obtained from lung homogenates was substantially decreased in PMEA-treated mice compared to controls. Finally, enhancement of natural killer cell activity was achieved in PMEA-treated A/PR8-infected mice compared to A/PR8-infected controls. Overall, results suggest that PMEA decreases the influenza virus-related mortality and morbidity through the enhancement of some immune functions, and that this effect might be additive or even synergystic with the direct inhibitory effect of DNA viruses or retroviruses induced by PMEA itself. This supports the importance of evaluating this drug in patients with diseases related to herpesviruses or to human immunodeficiency virus.

Assessment of left ventricular hypertrophy in patients with essential hypertension. A rational basis for the electrocardiogram.

There is a large body of evidence that the electrocardiogram (ECG) is insensitive in the recognition of left ventricular hypertrophy (LVH), in comparison with the echocardiogram; however, its specificity is high. In this study we further analyzed the performance of the ECG in detecting LVH in 200 consecutive patients (124 men and 76 women, mean age 50.9 years) with mild to moderate essential hypertension, using echocardiographically determined left ventricular mass (LVM) as the standard for comparison. To test the hypothesis that, owing to the high number of true positive findings, the ECG may still be useful for clinical purposes by selecting subsets of hypertensives with higher degrees of LVH, we compared the mean values of LVM index corresponding to either positive (true positive) or negative (false negative) electrocardiographic signs of LVH. In this study 69 patients (34.5%) had echocardiographic LVH, as defined by a LVM index exceeding 125 g/m2 for men and 112 g/m2 for women. Almost all criteria demonstrated high levels of specificity (> or = 89%). In the whole group the Lewis index ((RI - RIII)+(SIII - SI) > or = 17 mm) showed a slight superiority in diagnosing LVH (sensitivity = 43%) in comparison to the remaining criteria; the confidence intervals estimate of sensitivities confirmed such diagnostic superiority only with respect to those criteria with a sensitivity < or = 17%. However, the use of McNemar's test to compare sensitivities of all electrocardiographic criteria at matched specificities (> or = 95%) did not show significant differences (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Efficacy of flecainide in the treatment of ventricular tachycardia in the elderly. Dynamic electrocardiographic study]. / Efficacia della flecainide nel trattamento della tachicardia ventricolare dell'anziano. Studio elettrocardiografico dinamico.

The antiarrhythmic activity of flecainide has been tested in seven old patients (mean age 71 years) suffering from recurrent episodes of ventricular tachycardia. A basal 24-hour dynamic electrocardiogram was recorded for each patient and was repeated on day 5 of oral flecainide treatment (200 mg). A significant reduction (p less than 0.0001) of premature ventricular beats, of bigeminism (p = 0.0025) and of the episodes of ventricular tachycardia (p = 0.017) was obtained with plasma flecainide levels between 322 and 614 ng/ml. In addition, sinus rhythm was restored in two patients with stable atrial fibrillation and in the others ectopic atrial beats were markedly reduced. Among the ECG parameters examined, only QRS was significantly increased (p = 0.034). No significant change of blood pressure and laboratory parameters was observed. Untoward side effects were not observed.

Ultrastructural localization of sulphate glycoconjugates in the human glomerular capillary wall using the high iron diamine method.

The distribution of fixed anionic sites within glomerular capillary walls has been studied in man by applying two ultrastructural histochemical methods--the high iron diamine and dialysed colloidal iron methods--to tissue chopper sections and to isolated glomeruli obtained from surgical fragments of renal tissue. By using the high iron diamine method we have been able to demonstrate that in man, too, there are sulphate (possibly heparan sulphate proteoglycan) sites preferentially located in the lamina rara esterna of the basement membrane and in the cell coat of the urinary surface of podocytes. Non-sulphate (high iron diamine-negative, dialysed colloidal iron-positive) anionic sites have been identified not only in the glycocalyx of the epithelial and endothelial cells but also in the laminae rarae of the basement membranes, where they show a more extensive distribution pattern than sulphate sites. The proposed methods seem particularly suitable for the study of human renal tissue; they could, in fact, provide useful information about the behaviour of the various anionic components of the glomerular capillary wall in pathological conditions.