Optical coherence tomography in bioabsorbable stents: mechanism of vascular response and guidance of stent implantation.

Fully biodegradable L-polylactic acid stents (biodegradable vascular scaffold, BVS), the latest breakthrough in the area of coronary implants, entered clinical trials in 2005 and became commercially available in 2011. Optical coherence tomography (OCT) was used from the first implants to study the vessel wall response and the timing of the resorption process in man. Analysis of BVS with OCT has several advantages over that of metallic stents. BVS polymeric struts are transparent to the light so that scaffold integrity, apposition to the underlying wall, presence of thrombus and hyperplasia, and changes in the strut characteristics over time can be easily studied. We present a comprehensive review of the findings OCT provided when used as a research tool in serial examination up to five years for investigation of the mechanism of resorption, neointimal coverage, shrinkage and late lumen enlargement. We also report our experience with OCT in 47 lesions of various complexity as a practical means of percutaneous coronary intervention guidance during BVS implantation.

Location of side branch access critically affects results in bifurcation stenting: Insights from bench modeling and computational flow simulation.

BACKGROUND: The aim of this study was to evaluate the impact of stent design and side branch access on final strut apposition during bifurcation stenting. METHODS AND RESULTS: A series of 6 different commercially available Drug Eluting Stents (DES) (n=42) were deployed in an identical model of a coronary bifurcation. Kissing Balloon (KB) optimization was performed after either proximal or distal recrossing of the guidewire and results were analyzed by micro-Computed-Tomography. Stent design only had a minor impact on side branch lumen area free of stent struts. Similar rate of strut malapposition was observed within the bifurcation when a consistent KB optimization protocol and an optimal distal recrossing of the wire to reaccess the side branch (SB) are followed. Conversely, proximal instead of distal cell recrossing toward the side branch produced a significant lower area of the side branch lumen free of struts than an optimal distal recrossing (60.3±7.1% versus 81.1±8.0%, p<0.0001), as well as a higher rate of strut malapposed toward the SB ostium (40.6±6.0% versus 26.0±5.7%, p=0.0005). CONCLUSIONS: Optimal cell recrossing of the guidewire may be critical to ensure successful stent optimization in bifurcation PCI.

Malaric placentas. A quantitative study and clinico-pathological correlations.

A histological and morphometric study was conducted on 372 placentae out of a total 440 delivered in Zanzibar. Fibrin (F), intervillous space (IVS) and Villi (V) relative volumes were determined by the point-counting system and the ratio of syncytium to blood capillaries by the linear intercept method. Parasitemia load and inflammatory reaction were graded semiquantitatively by the use of a 1 mm square grid. Parasitised red cells identified active malaria (AM), the presence of malarial pigment only identified past malaria (PM), and the absence of both characterized non-malarial placentae (NM). AM(17.87%), PM(21.61%) and NM(60.52%) placentae did not vary significantly in weight. Newborns from AM had a significantly lower weight than those from PM and NM. Peripheral and placental parasitemia were not coincident. Placental parasitemia load increased parallel with birthweight. The latter decreased with the increasing severity of the inflammation, particularly with the prevalence of lymphocytes in the IVS. Significantly increased volume of F was found in AM and PM placentae, while no significant variation was noticed in IVS and V volumes. The syncytium/capillaries ratio was significantly increased in AM. We conclude that low birthweight in malaria is linked to IVS inflammation but not to F deposits or parasitemia load. Non-leukotactic lymphokines might play some role. Morphologic aspects bespeak for a less mature placenta than expected and this might represent an adaptive change.

The heme moiety of malaria pigment (beta-hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages.

To investigate the effect of the heme moiety of malaria pigment, hemozoin, on phagocyte functions, mouse macrophages were fed with insoluble beta-hematin, the synthetic heme-polymer chemically identical to the native pigment, or the soluble monomer, hematin. Production of inflammatory cytokines, interleukin 1 (IL1), tumor necrosis factor alpha (TNF alpha), and nitric oxide (NO) was assayed in the supernatants after stimulation with lipopolysaccharide. The results indicate that both beta-hematin and hematin induce a dose-dependent inhibition of macrophage production of TNF alpha and NO, but not of IL1. One-hour pretreatment with soluble hematin inhibited production of cytotoxic mediators by more than 50% compared to controls, while 6-hr exposure was necessary for insoluble beta-hematin to induce the same level of inhibition. However, the same treatment did not modify the production of TNF alpha and NO by mouse microglia cell lines. The inhibition was partially counterbalanced by adding sulphydryl group donors such as 2-mercaptoethanol, glutathione, or N-acetyl-cysteine during the preincubation time. The results of the present study confirm the inhibitory role of malaria pigment and show that such effect is due to the heme moiety and may be selective for the production of cytotoxic mediators by specific phagocytes. The implications of these findings in the control of malaria infection and disease and in the pathogenesis of severe malaria are discussed.

[Histopathologic findings in CD1 albino mice infected with Plasmodium berghei in pregnancy. Experimental model for pathology of the feto- placental unit in malaria]. / Riscontri istopatologici in topi albini CD1 infettati in gravidanza con plasmodium berghei. Modello sperimentale per la patologia della unità fetoplacentare nella malaria.

Three study groups of pregnant CD1 albino mice were inoculated intraperitoneally with Plasmodium berghei on the 6th (Group I), 13th (Group II) and 18th (Group III) day of gestation. Two control Groups were included, one of non pregnant mice (Group IV) and the other of pregnant non inoculated mice. Group IV was inoculated in the same day of group I. All mice of these two Groups died. Of the 20 mice in Group II 8 died, 7 delivered prematurely and 5 gave birth of low birth weight offspring. The 15 mice in Group III delivered normally with only 4 low birth weight offspring and no deaths. Histological examination revealed total placental necrosis, resorption of the products of conception and widespread foci of hepatic necrosis, malarial pigment accumulation in Group I. Such changes were also present in 8 mice of Group II, but the remainder of the Group retained the product of conception, had marked morphological changes in the placenta and moderate focal hepatic necrosis and malarial pigment accumulation. Group III had mild placental changes and moderate pigment accumulation. The products of conception displayed marked hepatic hematopoiesis in Group II while it was moderate in Group III. No parasitized red cells were observed in the fetal circulation. The stage of gestation at which the malarial infection was contracted was decisive. Malarial infection does not cross the placental barrier so its pathogenetic effects are felt in the maternal circulation with variable effects on the products of conception.

Activity of bilobalide, a sesquiterpene from Ginkgo biloba, on Pneumocystis carinii.

The sesquiterpene bilobalide, extracted from Ginkgo biloba leaves, was tested in vitro and in vivo for the ability to inhibit Pneumocystis carinii growth. Bilobalide was inhibitory to trophozoites cultured on human embryonic lung fibroblasts (HEL 299) at approximately the same concentration as trimethoprim plus sulfamethoxazole (lowest effective concentration, 50 micrograms of bilobalide per ml versus 9/45 microgram of trimethoprim-sulfamethoxazole per ml), inducing microscopically detectable morphological changes in the cytoplasm of the parasite. In pharmacologically immunosuppressed Sprague-Dawley rats transtracheally infected with a suspension of about 5 x 10(6) P. carinii trophozoites per ml, the daily intraperitoneal administration of bilobalide (10 mg/kg of body weight for 8 days) lowered the number of organisms by approximately 2 logs (that is, about 99%). There was no apparent toxicity either in uninfected HEL 299 feeder cells or in infected and uninfected animals. These studies suggest that the sesquiterpene bilobalide might be useful for therapy of and prophylaxis against P. carinii infections in humans.

Ocular pharmacokinetics of rufloxacin a new fluoroquinolone antibiotic.

Ocular pharmacokinetics of rufloxacin (MF 934), a new monofluorinated quinolone derivative, has been investigated in rabbits. A long half-life, good g.i. absorption and a higher tissue/plasma concentration than that of other quinolones, are its interesting pharmacokinetic properties. However, there is reason to believe that drug accumulation may occur in deep body compartments. We determined plasma, aqueous, and vitreous concentrations of the drug at 1, 4, 8, and 24h after a single 50 mg/kg i.v. administration of rufloxacin. Our data show that rufloxacin, administered by the i.v. route, rapidly reaches chemotherapeutically useful levels in aqueous and vitreous fluids. Although still present in plasma 8 hours after administration, it proved to be undetectable in ocular fluids, signifying that the depletion of the deep compartments occurs well in advance of the next invasion. Due to its antibacterial effectiveness and pharmacokinetic properties rufloxacin may take a relevant place among the quinolone derivatives in the treatment of ocular infections.

An anti-doxorubicin monoclonal antibody modulates kinetic and dynamic characteristics of the drug.

A monoclonal antibody (MAb) directed against doxorubicin (DXR), denominated MAD II, was found to exert an antidotal action by modulating the kinetic and dynamic characteristics of the drug. In vitro, MAD II has been found to reduce the cytotoxicity of DXR and the drug uptake on spleen lymphocytes more efficiently than on tumor cells (P388 leukemia cells). In vivo, the anti-DXR MAb modified the drug distribution; the drug uptake was found to be reduced in the intestine and myocardial tissues and increased in the tumor, liver and spleen. In mice treated with DXR, the administration of anti-DXR MAb exerted an antidotal activity which was proved by the reduction in body-weight loss and mortality. In contrast, the therapeutic efficacy of the drug in P388-tumor-bearing mice was not influenced by the anti-DXR MAb.

Anti-drug monoclonal antibodies antagonize toxic effect more than anti-tumor activity of doxorubicin.

Monoclonal antibodies (MAbs) able to bind epitope(s) of drug molecule can interfere with the biologic action of the drug. This is known and already exploited in some instances of practical relevance, as in the reversal of the digoxin effect. Similar antidotal action is exhibited by MAbs reacting with a cytotoxic antibiotic, doxorubicin (DXR), and in such a way as to induce differential neutralization of drug action. Indeed, within certain limits, the cytotoxic action of DXR in vitro as well as in vivo is more effectively neutralized on normal than on tumor cells, with consequent increase in therapeutic index.

Antigen-specific immunodepression induced by doxorubicin-BSA conjugate in mice.

Injection into mice of the anthracycline cytotoxic derivative Doxorubicin (DXR) covalently bound to bovine serum albumin (BSA) was associated with antigen-specific depression of the primary (but not of the secondary) antibody reaction to the carrier, whereas DXR and BSA injected in the form of a mixture caused no such effect. Tetanus toxoid completely prevented the carrier-specific inhibiting effect when administered at the same time as, but not three days before or after, injection of the DXR-BSA conjugate. Possible mechanisms of the antigen-specific immunodepression and its prevention by unrelated antigen are discussed.

A new monoclonal antibody recognizing anthracyclinic molecule.

The immunosuppressive effect of Doxorubicin (DXR) has been circumvented so that monoclonal antibodies (MAbs) reacting with DXR and other anthracycline derivatives have been obtained. The MAb described here (MAD11) belongs to the IgG2 class and selectively recognizes epitopes located at or near the aromatic ring D of the anthracycline molecule. MAD11 differs from another MAb (MAD2) obtained from the same somatic hybridization and previously described which preferentially reacts with aliphatic ring A of anthracycline.

Skin and perivascular toxicity induced experimentally by doxorubicin.

Extravasation of antitumor drugs and particularly doxorubicin (DXR) can be followed by skin ulceration and slowly evolving perivascular necrosis. DXR lesions have some characteristics in common with those induced by ionizing radiation and, with respect to gross morphology, are reminiscent of skin lesions induced by necrotizing agents. Time course and histopathology of toxic phenomena induced by intradermal or perivascular injection of various doses of either DXR or caustic chemicals have been studied in hairy outbred and hairless inbred (MF1 hr/hr) mice. The latter strain has been found to be intrinsically more sensitive to DXR induced toxic effects, particularly as far as perivascular administration is concerned. Long lasting lesions and, in a few cases, systemic involvement have been observed. On the contrary, necrotic foci induced by caustic chemicals rapidly regressed in both strains. The perivascular administration model, which has not been previously investigated, appears to be representative of what happens in clinical conditions and can be of use for assessing either skin toxicity of antitumor compound or the protective effect of candidate antidotes.

Humoral circulatory immune response to Gardnerella vaginalis.

Strain-specific circulating immunoglobulin G and/or M was detected by enzyme-linked immunosorbent assay and immunofluorescence test by using Formol-treated suspensions of Gardnerella vaginalis from 28 women with overt vaginitis but only three symptom-free subjects among 43 otherwise healthy women found to be colonized by G. vaginalis. Analogous but less stringent strain specificity patterns were elicited by immunization of BALB/c mice.

Monoclonal antibodies against doxorubicin.

Hybridomas which secrete monoclonal antibodies (MAbs) reacting with doxorubicin (DXR), a widely used anthracycline cytotoxic antibiotic, have been obtained by fusing NSO/P3 mouse myeloma cells with spleen cells from BALB/c mice immunized with DXR-BSA conjugate. The best producer among the several clones obtained was expanded and the secreted MAb (MAD2) purified and characterized. MAD2 cross-reacts to varying degrees with anthracycline compounds such as some DXR analogues and derivatives, but does not recognize anthracene and anthraquinone structures, with the exception of weakly reacting Mitoxantrone. MAD2 and the panel of MAbs which are at present being purified may become a tool for studying the relevance of different domains of the anthracyclin molecule in terms of biologic activity.

Usnic acid revisited, its activity on oral flora.

The antibacterial activity of usnic acid, the most widely distributed antibiotic among the numerous ones produced by many lichen species has been re-examined and particular attention has been devoted to the activity of optically active forms of usnic acid against Streptococcus mutans. The D(+) enantiomer was found to be more active than the L(+) form and was observed to exert a rather selective activity against S. mutans. Trials carried out in volunteers showed that mouth-rinse with D(+) usnic acid preparations exerted a selective and long lasting action against S. mutans, without substantially altering the equilibrium of normal oral bacterial flora. The adherence of S. mutans to smooth surfaces is not increased by the presence of subinhibiting concentrations of D(+) usnic acid. This is at variance with what has been observed with other antibiotics. These characteristics make D(+) usnic acid a suitable candidate for topical use in oral medicine.

[Indirect immunofluorescence in the serodiagnosis of Trichomonas vaginalis infections]. / L'immunofluorescenza indiretta nella sierodiagnosi di infezioni da T. vaginalis.

By using immunofluorescent technique the Authors have observed that high titer circulating antibodies reacting with membrane or cytoplasmic structures of T. vaginalis occur in the majority (42/45) of women presenting because of trichomonas vaginitis. Only exceptionally high titer antibodies have been detected in serum of male subjects affected by urethral trichomoniasis. Low titer antibodies are found in serum of noninfected subjects and are supposed to be induced by cross reacting flagellate group antigens. The contribution of these findings to a better understanding of the natural history of trichomoniasis is briefly discussed.

Human fibroblast interferon in cervical and vulvar intraepithelial neoplasia associated with viral cytopathic effects. A pilot study.

Sixteen patients with cervical intraepithelial neoplasia (CIN), grades 2 and 3, and vulvar intraepithelial neoplasia (VIN), grade 3, associated with human papillomavirus (HPV) infection were treated with human fibroblast interferon (HFI). Treatment consisted of 2-3 X 10(6) IU/day injected intra- and perilesionally for five days per week for two to three weeks with or without topically applied cream (1.2 X 10(6) IU/day for five days). Eight complete and two partial regressions occurred. The duration of the response ranged from 4 to 20 months. Fever, chills and fatigue with or without headache were the side effects. Our preliminary results indicate that HFI was active against CIN and VIN associated with HPV infection.