Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.

Betulinic acid is a triterpene with selective cytotoxicity against melanoma, neuroectodermal and malignant brain tumor cell lines. In this study the betulinic acid activity was evaluated, in comparison with doxorubicin, on different human neoplastic and non-neoplastic cell lines and on proliferating normal lymphocytes. Growth inhibition was evident in all the neoplastic cell lines independently on p53 status and histotype. Antiproliferative activity of betulinic acid was related to a cytotoxic effect on two p53 wild-type and on one p53 mutant cell lines and to a cytostatic effect on one p53 mutant melanoma clone. At the same concentrations, normal cells were unaffected indicating a selective effect of this agent. A cytotoxic activity of doxorubicin was evident on all the tested systems. In vivo experiments, performed on one of these cell lines, confirmed the antineoplastic activity of this drug. These data support further preclinical studies of betulinic acid not confined to melanoma and neuroectodermal tumors independently of p53 status.     

Intrahepatic Lithiasis: A Western Experience

(Received for publication on Dec. 2, 1998; accepted on Nov. 11, 1999)     

Clinically relevant cognitive impairment after cardiac surgery: a 6-month follow-up study

BACKGROUND AND PURPOSE: The majority of studies on neuropsychological complications after cardiac surgery used the raw variation of selective tests scores to define the occurrence of cognitive decline. We prospectively estimated the frequency of cognitive impairment after cardiac surgery, with a particular emphasis on persistent and clinically relevant cognitive decline. Possible baseline and operative predictors were also evaluated. METHODS: An extensive neuropsychological battery was administered to 110 patients (mean age 64.1+/-9.4 years; 70.9% males) undergoing cardiac surgery before and 6 months after the operation. After evaluating the variations in the cognitive performances, two independent neuropsychologists ranked the patients as unchanged-improved, mildly-moderately deteriorated, or severely deteriorated, using a global and functionally oriented judgement. The degree of the impairment was determined in relation to its impact on everyday life activities. RESULTS: Ten patients (9.1%) were ranked as severely deteriorated, 22 (20%) as mildly-moderately deteriorated, and 78 (70.9%) as unchanged-improved. Cognitively impaired patients were older (p=0.031), more often females (p=0.005), with a low education level (p=0.013). At multivariate analysis, female gender (odds ratio (OR) 6.14, 95% confidence interval (95% CI) 2.16-17.50), baseline use of beta-blockers (OR 4.55, 95% CI 1.30-15.92), and PaO2 at arrival in intensive care unit (OR for 1 mm Hg increment 1.012, 95% CI 1.004-1.020) were significant predictors of cognitive impairment of any degree. Positive predictors of severe cognitive impairment were history of hypertension (OR 5.33, 95% CI 1.03-27.64) and PaO2 at arrival intensive care unit (OR for 1 mm Hg increment 1.020, 95% CI 1.006-1.035), while education was protective (OR per year of increment 0.53, 95% CI 0.31-0.90). CONCLUSIONS: A considerable proportion of cardiac surgery patients may undergo clinically relevant cognitive impairment. The knowledge of variables influencing cognitive outcome is essential for the adoption of preventive measures.     

Chronic liver herniation through a right Bochdalek hernia with acute onset in adulthood

Congenital right diaphragmatic hernia of Bochdalek rarely occurs in adults and usually is asymptomatic. We report a right Bochdalek hernia with chronic liver herniation and intestinal malrotation in a 55-year old woman who presented with acute intestinal occlusion. The diagnosis required definitive confirmation by CT scan. With impending strangulation, emergency surgery through a thoracoabdominal approach resulted in an easy hernia repair and reduced the technical difficulties due to the intestinal malrotation.     

Zona Thinning with Noncontact Diode Laser in Patients Aged ≤37 Years with No Previous Failure of Implantation: A Prospective Randomized Study

Purpose: Zona thinning (ZT) is a technique used to improve pregnancy rates among patients 38 years old and/or patients presenting previous implantation failure. The objective of the study was to determine whether ZT has a beneficial effect on patients younger than 37 years who are undergoing the first ICSI attempt. Methods: A total of 103 patients submitted to ICSI for the first time and those aged 37 years were divided in a prospective and randomized manner into two groups: group I, patients submitted to ZT (n = 51) (a laser diode with 1.48-m wavelength (Fertilaser) was used for the procedure); group II, patients with no ZT (n = 52). In both groups, embryo transfer was performed on the second day. Results: The age of group I patients (31.8 ± 3.6) did not differ (P = 0.53) from that of group II patients (31.4 ± 3.6). The number of metaphase II oocytes was similar(P = 0.76) for the two groups (group I = 9.12 ± 5.27; group II = 8.67 ± 5.02). The average number of embryos available per transfer of group I (6.14 ± 4.02) did not differ (P = 0.69) from that of group II (5.75 ± 3.83). The number of embryos transferred was similar (P = 0.61) for the two groups (group I = 2.76 ± 0.9; group II = 2.87 ± 0.79). The thickness of the zona pellucida of group I embryos (16.6 ± 2.2 m) did not differ (P = 0.08) from that of group II embryos (17.1 ± 1.7 m). The rate of embryo implantation (20.8%) and the rate of clinical pregnancy per embryo transfer (40.3%) were higher for group II than for group I (17.7% and 33.3%, respectively), but the difference was not significant (P = 0.55 and P = 0.54). Conclusions: These results suggest that ZT in the population aged 37 years and with no previous failure of implantation may have no impact on intracytoplasmic sperm injection success rates.     

Parotid localized Castleman’s disease and HHV-8 infection: a case report

Castleman’s disease (CD) is an unusual massive proliferation of lymphoid tissue distinct in two clinical forms, localized and multicentric. The multicentric form has been related to human herpesvirus 8 (HHV-8), especially in HIV-infected patients, whereas the localized form of CD is still unrelated to viral pathogens. We report a case of a HIV-negative 16-year-old male referred to our hospital with a 12-month history of a painless swelling in his right parotid region. A parotidectomy was performed, and histological analysis evidenced a localized CD. The search for HHV-8 revealed an active virus infection. The patient was commenced on corticosteroid therapy and a follow-up was performed every 6 months. The patient was commenced on corticosteroid therapy and there has been no recurrence after 24 months. The authors report a case of localized parotid CD in a patient with evidence of an active HHV-8 infection. The results of this study does for the first time suggest an association between HHV-8 and localized CD in HIV-negative subjects.     

Alcohol reduces MMP-2 in humans and isolated smooth muscle cells

Alcoholic beverages are known to exert a protective effect on atherosclerotic disease. This study aimed to assess the in vivo and in vitro effects of alcohol on matrix metalloproteinase (MMP) -2 and -9, known to determine atherosclerosis progression. Eighteen healthy volunteers, regular drinkers (two standard alcohol servings/day, on average) at first examination (baseline) were asked to abstain from any alcoholic beverage for one week (abstention), and then to assume two standard alcohol servings of beer daily for 1 week (re-exposure). Activity of MMP-2 and -9, total antioxidant activity (AOA), glutathione (GSH) plasma levels were carried out at baseline, at the end of abstention, and after 1 week of re-exposure. To validate the in vivo results, MMP-2 activity and expression, AOA, and GSH, were determined in human smooth muscle cells treated for 96 h with increasing concentrations (12.5-100 mM) of ethanol. MMP-2, but not MMP-9 plasma activity was higher at abstention than at baseline or re-exposure (P<.001 and P< or =.005, respectively). Changes in AOA and GSH throughout the study were not significant. No correlation was found between MMPs and antioxidant activity. In vitro, ethanol at 25 mM reduced by around 10% MMP-2 activity (P=.003) in smooth muscle cells, whereas MMP-2 expression, AOA, and GSH were unaffected. Alcohol reduces MMP-2 plasma activity in healthy humans and in isolated vascular smooth muscle cells. This in vitro reduction is unrelated to MMP-2 expression in vascular cells or to antioxidant levels changes.     

Long-term impact of reproductive factors on cancer risk

The relationship between reproductive variables (parity, age at first birth, number of induced and spontaneous abortions) and cancer risk has been analysed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1992. The overall data-set included women below age 75 with histologically confirmed cancers of the following sites: oesophagus, 58; stomach, 280; colon, 405; rectum, 210; liver, 82; gall-bladder, 29; pancreas, 129; breast, 3,415; cervix, 742; endometrium, 725; ovary, 953; bladder, 68; kidney, 56; thyroid, 180; lymphomas, 80; myelomas, 57; and a total of 5,619 controls admitted to hospital for acute non-neoplastic, non-gynaecological, non-hormone-related conditions. Multivariate odds ratios, as estimators of relative risks (RR), were obtained after allowance for age, education, use of oral contraceptives and oestrogen replacement treatments, plus various reproductive factors. Direct significant trends with parity were observed for cancer of the liver (RR for women with ≥4 births vs. nulliparae = 3.3) and cervix uteri (RR = 4.1). The risk of gall-bladder cancer was also elevated for multiparae (RR = 1.9). No significant inverse trend in risk emerged. However, the RRs in multiparae were significantly below unity for breast (RR = 0.8), endometrium (RR = 0.7), and ovary (RR = 0.8). With reference to age at first birth, a significant trend in risk was observed for breast cancer (RR = 1.4 for 25 to 29 and 1.5 for ≥30 vs. ≤ 25 years). In contrast, the risk of cervical cancer was inversely related to age at first birth. For spontaneous abortions, the only significant inverse trend was for ovarian cancer (RR = 0.7 for ≥2 vs. 0 abortions), but also the point estimate for endometrial cancer in women with ≥2 abortions was below unity. For induced abortions, there was a strong inverse trend in risk for endometrial cancer (RR = 0.5), and the RRs were below unity also for colon and breast cancer. In contrast, cervical cancer was directly associated with the number of spontaneous abortions. Although the underlying aetiological interpretations are different for various cancer sites, this study provides, in a large and uniform data-set, quantitative information on the long-term impact of reproductive factors on cancer risk.     

Incidence of colorectal cancer following adenomatous polyps of the large intestine

An association between adenomatous polyps of the large bowel and colorectal cancer has been reported, in the absence, however, of population-based estimates of risk. Subjects with histologically confirmed first diagnosis of large-bowel polyps notified to the population-based Cancer Registry of the Swiss Canton of Vaud (about 600,000 inhabitants) during the calendar period 1979-1990 were actively followed up to the end of 1990 for the subsequent occurrence of malignant neoplasms. Among 2,496 individuals with intestinal polyps, followed for a total of 10,310 person-years at risk (6,201 among males and 4,109 among females), 150 malignant neoplasms were registered versus 152 expected. Thus, the standardized incidence ratio (SIR) for all cancers combined was 0.99. A significant excess was observed for colorectal cancer, with 35 cases observed (19 males, 16 females) versus 17.0 expected (SIR = 2.1; 95% CI: 1.5–3.0). There was also an excess, although not significant, for small-bowel cancer (2 cases observed vs. 0.4 expected; SIR = 5.4). In none of the other cancer sites was SIR significantly or appreciably elevated: in subjects with colorectal polyps the SIR was 1.6 for stomach, 1.0 for lung, 0.9 for breast and 1.2 for prostate. The SIR of colorectal cancer was 3.1 in the first year since polyp registration, and declined thereafter to 1.8, in the absence, however, of any further trend with time since diagnosis. The cumulative risk of colorectal cancer in subjects with colorectal polyps was 2% at 5 years and 3% at 10 years. The quantitative estimates of this study are of interest for their population-based nature, and are potentially useful for defining and targeting screening colonoscopy programmes.