Indomethacin-Dipalmitoylphosphatidylcholine Interaction. A Calorimetric Study of Drug Release from Poly(Lactide-co-glycolide) Microspheres into Multilamellar Vesicles

A comparative study of indomethacin controlled release from poly(lactide-co-glycolide) (50:50, molecular weight 3000) (PLGA) microspheres loaded with two different amounts of drug (10.9 ± 1%, and 34.1 ± 1% w/w) and pure free indomethacin, considering the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine multilamellar vesicles, was carried out by differential scanning calorimetry (DSC). The release was monitored by comparing the effect exerted by the free indomethacin on lipid thermotropic behavior with that of the drug released by the microspheres and relating these effects to a lipid aqueous dispersion containing the molar ratio of drug able to cause it. By DSC measurements, the pure free indomethacin was found to be able to have a fluidifying effect on the model membrane, causing a shift toward lower values of the transitional temperature (T_m), characteristic of phospholipid liposomes, without variations in the enthalpic changes (ΔH). This shift was found to be modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Successively, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and indometha-cin-loaded microspheres as well as free powdered indomethacin, and the T_m shifts of the lipid bilayer caused by the drug released from the polymeric system, as well as by the free drug, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This drug release model could be employed to determine the different kinetics involved in the drug transfer from the microspheres to a membrane. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres. This calorimetric study shows that the PLGA microspheres are a good delivery system able to sustain drug release. Moreover, the DSC technique applied to the drug interaction with biomembranes constitutes a good tool for determining the drug release representing an innovative alternative in vitro model.     

Panoramic diagnostic microhysteroscopy and female sterility: analysis of results in 284 patients

The results of panoramic diagnostic microhysteroscopy are reported in 284 patients with sterility or infertility problems. In 33.5% of the patients, microhysteroscopy revealed uterine pathology; in the majority of cases they were pathologies which are unanimously recognized as being causes of sterility, while in others there were pathologies whose role infertilities is still unclear. There was a good correlation between microhysteroscopy and histology in cases of endometrial hyperplasia and of endometritis, whereas in cases of endometrial polyps and functional diagnosis of the endometrium, the correlation was less satisfactory. Although it is not possible at present to draw definite conclusions about the real value and advantages of microhysteroscopy in the diagnosis of female infertility, we are convinced that it is of great use and that it should be at the basis of any investigation involving the infertile woman.     

Computed tomography and tumor markers as diagnostic alternatives to second-look surgery in the treatment of malignant ovarian tumors]

Advanced malignant ovarian cancers are treated, after initial surgery, with first-choice mono/polychemotherapy, the response to which is evaluated by means of second-look laparotomy. The poor prognostic value of second-look results, the incidence of false negatives, the lack of valuable second-choice therapies, and the high incidence of complications after repeated interventions, lead to the testing of diagnostic imaging modalities--especially CT and tumor markers (Ca 125 and Ca 15-3). To define their actual clinical value, CT and serum assays of Ca 125 and Ca 15-3 have been performed on 32 treated patients affected with ovarian cancers (stages II-IV), who were clinically free of disease. The results have been compared with second-look pathology, but especially with patient follow-up (min. 24 months). Second-look laparotomy yielded a high number of false negatives (9/22 = 41%); moreover, many important/severe complications were observed. Thus, its value appears to be questionable. CT exhibited high positive predictive value (76.9% over the 24-month follow-up); high for both Ca 125 and Ca 15-3 (100% respectively, at 24-month follow-up) thus, few false positives were observed. Moreover CT, having higher sensitivity (55.5%) than Ca 125 (11.5%) and Ca 15-3 (27.7%), has greater diagnostic capabilities, especially when the lesion is in extraperitoneal location.     

Specific epstein-barr virus serological response in patients with nasopiiaryngeal carcinoma detected by immunoblotting

The specific humoral immune response against Epstein-Barr virus (EBV) antigens in patients with nasopharyngeal carcinoma (NPC) was compared to that of patients with infectious mononucleosis (IM) and other EBV-seropositive subjects using immunoblotting technique. Almost all sera from E,BV serologically associated NPC reacted reproducibly with a major group of polypeptides (four to six) of early antigen (EA) complex with molecular weights ranging from 50 kD to 58 kD, and with some additional polypeptides. Sera from IM-patients reproducibly recognized only one polypeptide of 50 kD belonging to the major group of polypeptides of EA-complex. Sera from patients with other types of head and neck cancer and relatively high levels of IgG antibody against viral capsid antigen (VCA) and EA did not react reproducibly with any of the EBV-associated proteins.     

Spatial and temporal pattern of purkinje cell degeneration in shaker mutant rats with hereditary cerebellar ataxia

Temporal-spatial patterns of surviving Purkinje cells were studied quantitatively in a rat mutant (shaker) with differential hereditary cerebellar ataxia and Purkinje cell degeneration. Shaker rat mutants are characterized behaviorally as mild if they are ataxic or as strong if they have ataxia and tremor. Purkinje cells degenerate in both mild and strong shaker mutants, but the temporal and spatial patterns of cell death are strikingly different. In mild shaker mutants, Purkinje cell death is temporally restricted, with 31-46% of the Purkinje cells in lobules I-IX dying by 3 months of age. Very few Purkinje cells degenerate after this age. Purkinje cell death is spatially random. In lobules I-IX, every second, third, or fourth Purkinje cell degenerates. Purkinje cells in lobule X do not degenerate. In strong shaker mutants, Purkinje cell degeneration is temporally protracted and spatially restricted. By 3 months of age, most Purkinje cells in lobules I-VIa, -b, and -d, and -d have degenerated. Numerous Purkinje cells in the paravermis of lobules VIIb-VIII have also degenerated. Surviving Purkinje cells in the vermis and lateral hemisphere of lobules VIIb-VIII are aligned in parasagittally oriented stripes or transversely oriented bands. Purkinje cells continue to degenerate in localized areas of the posterior lobe such that, by 18 months of age, surviving Purkinje cells are limited primarily to lobules VIc, VIIa, IXd, and X. Quantitative analysis indicates that none of the Purkinje cells in these lobules degenerate.     

Risk factors for endometrioid, mucinous and serous benign ovarian cysts

To evaluate the risk factors for serous, mucinous and endometrioid ovarian cysts, data were collected in a case-control study conducted in the greater Milan area based on 202 women with benign cysts (114 endometrioid and 88 serous or mucinous) of the ovary and 1127 controls. Questions were asked about menstrual and reproductive characteristics, marital status, education, history of various diseases, and lifetime use of oral contraceptives and other hormonal treatments. Higher social class, earlier menarche and longer interval between age at first marriage and first birth, a likely indicator of subfertility, were associated with an increased risk of serous, mucinous and endometrioid cysts. Women with endometrioid cyst were characterized by low parity, less frequent irregular or long menses, more frequent oral contraceptive use and low body mass index, while the most relevant risk factor associated with serous and mucinous cysts was greater age at first birth. The present data point out the epidemiological differences between endometrioid and serous or mucinous cysts. Further, they suggest that analyses of risk factors for epithelial ovarian cancer subdivided by various histotypes may be of interest in order to confirm possible heterogeneities in the aetiology of ovarian epithelial neoplasms.     

QSAR in a series of muscarinic agents. Note VI. Five-membered cyclic ligands

Proceeding in our study on the muscarinic receptor site, a refinement of its topology by means of Quantitative Structure-Activity Relationships has been carried out. Specific key structures have been selected considering not only muscarine and the corresponding desether derivative, but also a set of cyclopentenyltrimethylammoniummethyl salts. These derivatives, considered in a correlation equation extended to all of the five-membered cyclic structures previously examined, significantly improve understanding of contributions of critical ligand substructures to the overall interaction. The results obtained reinforce the reliability of correlation equations in structure-activity studies.     

Paternal and Maternal Smoking Habits before Conception and During the First Trimester: Relation to Spontaneous Abortion

PURPOSE: This study examined the association between maternal smoking before and during the first trimester of pregnancy and spontaneous abortion.

METHODS: We have been conducting a hospital-based case-control study on risk factors for spontaneous abortion in the greater Milan area. We collected information from 782 cases of spontaneous abortions and 1543 controls (women who delivered at term healthy infants).

RESULTS: With respect to never smokers, the odds ratio (OR) were 0.7 (95%, confidence interval (CI), 0.5–1.0) for women who quit smoking and 1.3 (95% CI, 1.0–1.6) for those who continued during pregnancy. Women who smoked more than 10 cigarettes/day in the first trimester were at increased risk of miscarriage, with an OR of 1.4 (95% CI, 1.0–2.1). No relationship was evident between the number of cigarettes smoked before conception and the risk of abortion. Likewise, no association emerged between paternal smoking and miscarriage. Moreover, no significant interaction or modification effect was obtained when strata of age and other major characteristics were investigated.

CONCLUSIONS: The risk of abortion associated with cigarette smoking during the first trimester of pregnancy was measurable and noticeable in this population, and accounted for 9% (95% CI, 6–13%) of all cases. The increased risk of spontaneous abortion in women smoking during pregnancy is a further reason to encourage pregnant women to quit.     

Association of serum IgA and C4 with severe atherosclerosis

To assess the possible involvement of humoral immunity in diffuse atherosclerosis, IgG, IgA, IgM, C3 and C4 were measured in the sera of 23 atherosclerotic subjects (at least 3 stenoses greater than 75% in the arteries of the limbs and neck, as assessed by panangiography) and of 20 controls (possible stenoses less than 40% documented by arteriography of the aortic arch and epi-aortic branches and "normal" response to exercise stress testing and Doppler ultrasonography of the arteries of the lower limbs). Age (59-69) and sex distribution did not differ significantly in the 2 groups. The following serum concentrations were higher in the atherosclerotic subjects than in the controls: C4 (28.7 +/- 6.5 (1 SD) vs. 23.4 +/- 3.8 mg/dl; P = 0.0013); IgA (323.3 +/- 155.0 vs. 210.3 +/- 87.9 mg/dl; P = 0.0020); and C3 (126.3 +/- 16.9 vs. 111.0 +/- 18.9 mg/dl; P = 0.0109). To assess whether these parameters were independently associated with atherosclerosis, a multiple logistic regression was performed, also including other variables which differed between the atherosclerotic group and the control group with P values less than 0.20 (cigarette smoking, arterial hypertension, body mass index, serum HDL-cholesterol, HDL-cholesterol/total cholesterol ratio, serum triglycerides, IgG and IgM). In multivariate analysis only IgA (P = 0.0012), C4 (P = 0.0072), cigarette smoking (P = 0.0141) and serum triglycerides (P = 0.0177) were independently associated with atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

The application of trend surface models to the analysis of time factors in Swiss cancer mortality

To study different temporal components on cancer mortality (age, period and cohort) methods of graphic representation were applied to Swiss mortality data from 1950 to 1984. Maps using continuous slopes ("contour maps") and based on eight tones of grey according to the absolute distribution of rates were used to represent the surfaces defined by the matrix of various age-specific rates. Further, progressively more complex regression surface equations were defined, on the basis of two independent variables (age/cohort) and a dependent one (each age-specific mortality rate). General patterns of trends in cancer mortality were thus identified, permitting definition of important cohort (e.g., upwards for lung and other tobacco-related neoplasms, or downwards for stomach) or period (e.g., downwards for intestines or thyroid cancers) effects, besides the major underlying age component. For most cancer sites, even the lower order (1st to 3rd) models utilised provided excellent fitting, allowing immediate identification of the residuals (e.g., high or low mortality points) as well as estimates of first-order interactions between the three factors, although the parameters of the main effects remained still undetermined. Thus, the method should be essentially used as summary guide to illustrate and understand the general patterns of age, period and cohort effects in (cancer) mortality, although they cannot conceptually solve the inherent problem of identifiability of the three components.