Metabolic and hormonal control of energy utilization and partitioning from early to mid lactation in Sarda ewes and Saanen goats.

In a recent study, we observed that starch-rich diets used in mid lactation induced lower milk production persistency and higher body fat accumulation in dairy ewes compared with dairy goats. Because these species differences could be linked to hormonal mechanisms that drive energy partitioning, in the same experiment, we explored the evolution of metabolic and hormonal status during lactation to test this hypothesis. Twenty mature Sarda dairy ewes and 20 mature Saanen goats [15-134 ± 11 d in milk (DIM), mean ± SD] were compared simultaneously. In early lactation, each species was allocated to one dietary treatment: high-starch diet [HS: 20.4% starch, on dry matter (DM) basis], whereas from 92 ± 11 DIM, each species was allocated to 1 of 2 dietary treatments: HS (20.0% starch, on DM basis) and low-starch (LS: 7.8% starch, on DM basis) diets. Blood samples were collected in the morning to analyze glucose, nonesterified fatty acids (NEFA), growth hormone (GH), insulin, and insulin-like growth factor I (IGF-I). Data were analyzed using the PROC MIXED procedure of SAS with repeated measurements (SAS Version 9.0). The HS and LS diets applied in mid lactation did not affect metabolic status of the animal within species; thus, only a comparison between species was carried out. From early to mid lactation, plasma glucose concentration was higher in ewes than in goats (54.57 vs. 48.35 ± 1.18 mg/dL), whereas plasma NEFA concentration was greater in goats than in ewes (0.31 vs. 0.25 ± 0.03 mmol/L). Goats had higher plasma GH concentration and lower plasma insulin content than ewes (4.78 vs. 1.31 ng/mL ± 0.47; 0.11 vs. 0.26 µg/L ± 0.02). Plasma IGF-I concentration did not vary between species. The comparison of metabolic and hormonal status of lactating Sarda dairy ewes and Saanen goats, carried out by studying simultaneously the 2 species in the same stage of lactation and experimental conditions, suggests that the higher insulin and glucose concentration observed in Sarda ewes explains why they partitioned more energy toward body reserves than to the mammary gland, especially in mid lactation. This can justify the negative effect of high-starch diets in mid-lactating Sarda ewes. Conversely, the highest GH and NEFA concentration observed in Saanen goats explain why they partitioned more energy of starch diets toward the mammary gland than to body reserves and justify the positive effect of high-starch diet in mid lactation. Together, these different responses contribute to explain why specialized dairy goats, such as the Saanen breed, have a higher milk production persistency than specialized dairy sheep breeds, such as the Sarda.

Dual ß-Lactam Combinations Highly Active against Mycobacterium abscessus Complex In Vitro.

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual ß-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain ß-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual ß-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual ß-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual ß-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of ß-lactam drugs.

A new platinum(II) compound anticancer drug candidate with selective cytotoxicity for breast cancer cells.

[Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcD) is able to induce apoptosis in various human cancer cells, including the cisplatin-resistant human breast carcinoma MCF-7 cells. Here, to confirm that PtAcD has the potentiality for therapeutic intervention, we studied its effects in primary cultured epithelial breast cells obtained from cancers and also from the corresponding histologically proven non-malignant tissue adjacent to the tumor. We demonstrated that PtAcD (1) is more cytotoxic in cancer than in normal breast cells; (2) activated NAD(P)H oxidase, leading to PKC-ζ and PKC-α translocations; (3) activated antiapoptotic pathways based on the PKC-α, ERK1/2 and Akt kinases; (4) activated PKC-ζ and, only in cancer cell PKC-δ, responsible for the sustained phosphorylation of p38 and JNK1/2, kinases both of which are involved in the mitochondrial apoptotic process. Moreover, crosstalk between ERK/Akt and JNK/p38 pathways affected cell death and survival in PtAcD-treated breast cell. In conclusion, this study adds and extends data that highlight the pharmacological potential of PtAcD as an anti breast cancer drug.

UV and IR photoisomerization of acetylacetone trapped in a nitrogen matrix.

UV- and IR-induced photoisomerization of acetylacetone trapped in a nitrogen matrix at 4.3 K have been carried out using a tunable optical parametric oscillator type laser, or a mercury vapor lamp, coupled with Fourier Transform IR and UV spectroscopies. After deposition, the main form present in the cryogenic matrix is that chelated (enol). Upon UV irradiation, the intramolecular H bond is broken leading to nonchelated isomers among seven possible open forms. These forms have then been irradiated by resonant pi* <-- pi UV irradiation, or by resonant nuOH irradiation. The selective UV irradiation allows us to suggest a first vibrational assignment while the nuOH irradiation leads us to observe interconversions between the nonchelated isomers. In order to support our vibrational assignment, we have carried out theoretical calculations at the B3LYP/6-311++G(2d,2p) level of theory. This study shows that only five isomers are observed among eight postulated.

Experimental and theoretical UV characterizations of acetylacetone and its isomers.

Cryogenic matrix isolation experiments have allowed the measurement of the UV absorption spectra of the high-energy non-chelated isomers of acetylacetone, these isomers being produced by UV irradiation of the stable chelated form. Their identification has been done by coupling selective UV-induced isomerization, infrared spectroscopy, and harmonic vibrational frequency calculations using density functional theory. The relative energies of the chelated and non-chelated forms of acetylacetone in the S0 state have been obtained using density functional theory and coupled-cluster methods. For each isomer of acetylacetone, we have calculated the UV transition energies and dipole oscillator strengths using the excited-state coupled-cluster methods, including EOMCCSD (equation-of-motion coupled-cluster method with singles and doubles) and CR-EOMCCSD(T) (the completely renormalized EOMCC approach with singles, doubles, and non-iterative triples). For dipole-allowed transition energies, there is a very good agreement between experiment and theory. In particular, the CR-EOMCCSD(T) approach explains the blue shift in the electronic spectrum due to the formation of the non-chelated species after the UV irradiation of the chelated form of acetylacetone. Both experiment and CR-EOMCCSD(T) theory identify two among the seven non-chelated forms to be characterized by red-shifted UV transitions relative to the remaining five non-chelated isomers.

[Current surgical management in ovarian cancer recurrences]. / Attuale management chirurgico delle recidive di carcinoma ovarico.

Ovarian cancer is a tumor with a high trend of recurrence and this occurrence consistently increases the difficulty of the patient cure and reduces the efficacy of current treatments. The role of surgery in persistent or recurrent ovarian cancer is controversial and the type of surgery can be different according to the different stages and invasion of tumor; it can be a debulking surgery followed by chemotherapy (to eradicate the most part of ovarian cancer, leaving a minimal tumoral residue), an interval surgery (for advanced ovarian cancer stage in previously operated patients, followed by 2 or 3 inductive chemotherapy cycles and subsequently a cytoreductive redo surgery) and a cytoreductive secondary surgery, after optimal primary surgical treatment and minimal tumoral recurrence. In some cases it is possible either to perform a debulking surgery during a primary (after the conclusion of primary treatment) or a salvage or palliative surgery (to improve, after an acceptable time period, clinical symptoms in patients with progressive cancer or resistant to treatments). The aims of surgical therapy, to be performed in a patient with ovarian cancer relapse, are to reduce, as much as possible, the tumour size, to increase the quality of life and to increase the survival time; in this review different surgical techniques to be carried out in each case, selected for disease staging, for tumour cells kinetic and for surgical goals, are discussed.

Early and subtle abnormalities of left ventricular function in clinically stable coronary artery disease patients with normal ejection fraction.

BACKGROUND: It has been reported that, in the initial phase of ischemic cardiomyopathy, the earliest alterations of left ventricular function are detected during the relaxation phase. The aim of this study was to look for precocious abnormalities in the early stage of ischemic cardiomyopathy in both left ventricular systolic and diastolic phases. METHODS AND RESULTS: Using simultaneous left ventricular catheterization and echo-Doppler techniques, we studied both systolic and diastolic function in 44 (37 males and 7 females, mean age 55.7+/-8) normotensive, clinically stable, coronary artery disease patients with normal left ventricular ejection fraction in comparison to 9 age- and sex-matched normal control subjects (7 males and 2 females, mean age 54.7+/-9). Mean values of E deceleration time, tau, left ventricular end-diastolic volume and pressure, and end-systolic volume and lowest diastolic pressure were significantly higher (from P<.05 to P<.01), whereas mean dP/dt/P values significantly lower (P<.05) in coronary artery disease patients than in controls. A strict relationship (P<.001) between dP/dt/P and tau, left ventricular lowest and end-diastolic pressure was found in all subjects studied. CONCLUSION: Early and subtle abnormalities in parameters of both systolic and diastolic function can be found in the majority of coronary artery disease patients with normal ejection fraction.

Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells.

Angiotensin II (Ang II) induces, through AT1, intracellular Ca(2+) increase in both normal and cancerous breast cells in primary culture (Greco et al., 2002 Cell Calcium 2:1-10). We here show that Ang II stimulated, in a dose-dependent manner, the 24 h-proliferation of breast cancer cells in primary culture, induced translocation of protein kinase C (PKC)-alpha, -beta1/2, and delta (but not -epsilon, -eta, -theta, -zeta, and -iota), and phosphorylated extracellular-regulated kinases 1 and 2 (ERK1/2). The proliferative effects of Ang II were blocked by the AT1 antagonist, losartan. Also epidermal growth factor (EGF) had mitogenic effects on serum-starved breast cancer cells since induced cell proliferation after 24 h and phosphorylation of ERK1/2. The Ang II-induced proliferation of breast cancer cells was reduced by (a) Gö6976, an inhibitor of conventional PKC-alpha and -beta1, (b) AG1478, an inhibitor of the tyrosine kinase of the EGF receptor (EGFR), and (c) downregulation of 1,2-diacylglycerol-sensitive PKCs achieved by phorbol 12-myristate 13-acetate (PMA). A complete inhibition of the Ang II-induced cell proliferation was achieved using the inhibitor of the mitogen activated protein kinase kinase (MAPKK or MEK), PD098059, or using Gö6976 together with AG1478. These results indicate that in human primary cultured breast cancer cells AT1 regulates mitogenic signaling pathways by two simultaneous mechanisms, one involving conventional PKCs and the other EGFR transactivation.

Detection of early abnormalities of left ventricular function by hemodynamic, echo-tissue Doppler imaging, and mitral Doppler flow techniques in patients with coronary artery disease and normal ejection fraction.

We have investigated the possibility of detecting early abnormalities of left ventricular function at the initial phase of ischemic cardiomyopathy. Sixteen normotensive patients with coronary artery disease and normal left ventricular ejection fraction and 6 control patients were studied by invasive hemodynamic techniques in combination with transmitral Doppler flow or with echo-tissue Doppler imaging. The extent of the percentage of left ventricular longitudinal shortening and the systolic peak velocity at echo-tissue Doppler were significantly higher in the control patients than in patients with ischemic cardiomyopathy (P <.01). Left ventricular end-diastolic pressure was higher (P <.05), whereas mean values of isovolumic contraction and relaxation indexes (dP/dt/P: P <.05; +dP/dt: P <.05; -dP/dt: P <.01) were lower in patients with ischemic cardiomyopathy. Tau was significantly longer in ischemic patients (42.7 +/- 8.8 versus 34.5 +/- 3.7 ms, P <.05). In the control patients, the aortic valve closure to peak E interval by transmitral Doppler flow was significantly longer than that measured by echo-tissue Doppler (P <.001), whereas in patients with ischemic cardiomyopathy, this interval difference was still present and significantly shorter (P <.05). In patients with coronary artery disease and normal ejection fraction, minor and early abnormalities of left ventricular function related to isovolumic contraction and relaxation as well as to longitudinal shortening could be detected. In addition, a suction-like effect, detected during early filling evaluation with echo-tissue Doppler, is significantly decreased but not abolished during the early stages of coronary artery disease.

Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha /beta.

To understand how virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with various human outbreak Mycobacterium tuberculosis clinical isolates. One clinical isolate, HN878, was found to be hypervirulent, as demonstrated by unusually early death of infected immune-competent mice, compared with infection with other clinical isolates. The differential effect on survival required lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tuberculosis-specific proliferation and IFN-gamma production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-12, and IFN-gamma mRNAs were observed in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contrast, IFN-alpha mRNA levels were significantly higher in lungs of these mice. To further investigate the role of Type 1 IFNs, mice infected with HN878 were treated intranasally with purified IFN-alpha/beta. The treatment resulted in increased lung bacillary loads and even further reduced survival. These results suggest that the hypervirulence of HN878 may be due to failure of this strain to stimulate Th1 type immunity. In addition, the lack of development of Th1 immunity in response to HN878 appears to be associated with increased induction of Type 1 IFNs.

Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits Mycobacterium smegmatis-induced cytokine production by human macrophages in vitro.

Vaccination of mice with Mycobacterium vaccae or M. smegmatis induces some protection against M. tuberculosis challenge. The 19-kDa lipoprotein of M. tuberculosis, expressed in M. vaccae or M. smegmatis (M. smeg19kDa), abrogates this protective immunity. To investigate the mechanism of this suppression of immunity, human monocyte-derived macrophages (MDM) were infected with M. smeg19kDa. Infection resulted in reduced production of tumor necrosis factor alpha (TNF-alpha) (P < 0.01), interleukin-12 (IL-12) (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05), compared to infection with M. smegmatis vector (M. smegV). Infection with M. smeg19kDa and with M. smegV had no differential effect on expression of costimulatory molecules on MDM, nor did it affect the proliferation of presensitized T cells cocultured with infected MDM. When MDM were infected with M. smegmatis expressing mutated forms of the 19-kDa lipoprotein, including non-O-glycosylated (M. smeg19NOG), nonsecreted (M. smeg19NS), and nonacylated (M. smeg19NA) variants, the reduced production of TNF-alpha or IL-12 was not observed. When the purified 19-kDa lipoprotein was added directly to cultures of infected monocytes, there was little effect on either induction of cytokine production or its inhibition. Thus, the immunosuppressive effect is dependent on glycosylated and acylated 19-kDa lipoprotein present in the phagosome containing the mycobacterium. These results suggest that the diminished protection against challenge with M. tuberculosis seen in mice vaccinated with M. smegmatis expressing the 19-kDa lipoprotein is the result of reduced TNF-alpha and IL-12 production, possibly leading to reduced induction of T-cell activation.

Estrogen derivative relaxes rabbit aorta via the endothelial receptor system.

BACKGROUND: It is well known that sexual hormones, in particular estrogens, may influence the cardiovascular system. Experimental and clinical studies have shown that estrogen directly or indirectly modulates the reactivity of vascular smooth muscle but at present the mechanism of action of this hormone has yet to be clarified. The aim of this study was to evaluate the vascular effects of a synthetic non-steroid estrogen, diethylstilbestrol, and the possible involvement of endothelial function. METHODS: We investigated, on aortic strips of a female rabbit, the inhibitory effects of diethylstilbestrol on the contractions induced by different spasmogenic agents, noradrenaline (10(-6) M), angiotensin II (10(-6) M), serotonin (10(-6) M), and KCl (10(-1) M). Some experiments were performed in high K+, Ca++-free solution. In some experiments endothelial function was abolished by mechanical ablation. Another series of experiments was incubated (30 min) with N(G)-monomethyl-L-arginine, which inhibits nitric oxide synthase or with tamoxifen, a specific antagonist of estrogen receptors. RESULTS: At doses from 10(-6) M to 10(-4) M, diethylstilbestrol showed an evident spasmolytic action on contractions induced by noradrenaline, angiotensin II and serotonin but no significant effect was observed on KCl spasm. The inhibitory response of diethylstilbestrol to increased vascular tone induced by noradrenaline disappeared when the endothelial function, validated by the acetylcholine test, was abolished by mechanical ablation. When tested in high K+, Ca++-free solution, diethylstilbestrol did not significantly shift the cumulative dose-response curve of calcium. In the experiments performed with N(G)-monomethyl-L-arginine, diethylstilbestrol failed to induce vasodilation suggesting that its action may be related to synthesis of nitric oxide. Moreover, in the presence of tamoxifen, diethylstilbestrol was unable to induce vasodilation. CONCLUSIONS: The early occurrence of vasodilation is in favor of a direct effect and seems to exclude a regulation of gene expression. These results suggest that estrogens may directly regulate vascular tone interacting with its specific endothelial cell receptors through the release of nitric oxide.

Doppler tissue echocardiography: myocardial wall motion velocities in essential hypertension.

AIMS: Doppler tissue echocardiography (DTE) was applied to extract the myocardial wall velocities along different planes and evaluate the left ventricular function in essential hypertension. METHODS AND RESULTS: Fifty-four hypertensives (HT) were compared to a control group of 31 normotensive (NT) subjects. The short-axis shortening and lengthening was assessed through the parasternal projections, sampling from interventricular septum and posterior wall. Through the apical projections the mitral annulus excursion was observed at four sites (anterior, posteroseptal, lateral, inferior walls) to assess the longitudinal dynamic of the heart. In each myocardial segment, peak velocity and time-velocity integral for systolic (S) and diastolic waves (E and A) were measured and their means for the long- and short-axis directions were calculated. Significant changes in hypertensives involved mainly the longitudinal motion. In diastole, the E-wave relaxation velocity was significantly decreased and the late A-wave velocity was unchanged. The E/A velocity ratio was significantly reduced. Relaxation velocity was negatively correlated to age, left ventricular mass and diastolic blood pressure. In systole, the peak S-wave shortening velocity was reduced and no association with age, left ventricular mass and blood pressure could be demonstrated. The range of segmental data produced by DTE proved useful to manufacture sensitive indices for recognition of hypertensive damage. Single DTE variables also proved slightly more sensitive than those extracted from the mitral flow pattern for the discrimination of HT patients. CONCLUSION: The presence of impaired relaxation was confirmed by DTE in a large portion of patients with hypertension and left ventricular hypertrophy. A peculiar systolic disturbance is evidenced by this technique. DTE-derived information can be used to detect early and quantify target-organ damage and its progression or regression during antihypertensive treatment.

The effects of transdermal estradiol on the response to mental stress in postmenopausal women: a randomized trial.

PURPOSE: Estrogens inhibit adrenomedullary catecholamine release and catecholamine-mediated responses to stress. We examined whether estrogen supplementation reduces the sympathoadrenal response to mental stress in postmenopausal women. MATERIALS AND METHODS: We compared the effects of 3-week treatment with transdermal 17-beta-estradiol and placebo in 10 postmenopausal women using a randomized, blinded, crossover design. We measured plasma catecholamine levels and the cardiovascular and metabolic responses to a 15-minute stress with mental arithmetic. Treatments were compared using repeated measures analysis of variance. RESULTS: During placebo treatment, mean (+/- SD) epinephrine levels reached a peak of 431 +/- 135 pmol/liter after 15 minutes of stress; the epinephrine response was blunted during estradiol treatment, with a peak of 357 +/- 77 pmol/liter (P <0.05). Estradiol also blunted the diastolic blood pressure response to stress (baseline levels of 78 +/- 15 mm Hg vs peak of 90 +/- 6 mm Hg during placebo; baseline of 80 +/- 8 mm Hg vs peak of 84 +/- 6 mm Hg during estradiol; P <0.05). Estradiol treatment also blunted the decrease in the standard deviation of the mean of the electrocardiographic RR intervals and the increase in the ratio between the low-frequency and high-frequency bandwidths. CONCLUSION: We observed a moderate, although significant, reduction in markers of the stress response to mental arithmetic in postmenopausal women treated with transdermal 17-beta-estradiol.

Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates.

Mycobacterium tuberculosis CDC1551, a clinical isolate reported to be hypervirulent and to grow faster than other isolates, was compared with two other clinical isolates (HN60 and HN878) and two laboratory strains (H37Rv and Erdman). The initial (1-14 days) growth of CDC1551, HN60, HN878, and H37Rv was similar in the lungs of aerosol-infected mice, but growth of Erdman was slower. Thereafter, the growth rate of CDC1551 decreased relative to the other strains which continued to grow at comparable rates up to day 21. In the lungs of CDC1551-infected mice, small well-organized granulomas with high levels of TNF-alpha, IL-6, IL-10, IL-12, and IFN-gamma mRNA were apparent sooner than in lungs of mice infected with the other strains. CDC1551-infected mice survived significantly longer. These findings were confirmed in vitro. The growth rates of H37Rv and CDC1551 in human monocytes were the same, but higher levels of TNF-alpha, IL-10, IL-6, and IL-12 were induced in monocytes after infection with CDC1551 or by exposure of monocytes to lipid fractions from CDC1551. CD14 expression on the surface of the monocytes was up-regulated to a greater extent by exposure to the lipids of CDC1551. Thus, CDC1551 is not more virulent than other M. tuberculosis isolates in terms of growth in vivo and in vitro, but it induces a more rapid and robust host response.

Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro.

Mycobacterium tuberculosis has a relatively high resistance to killing by hydrogen peroxide and organic peroxides. Resistance may be mediated by mycobacterial catalase-peroxidase (KatG) and possibly by alkyl hydroperoxide reductase (AhpC). To determine the interrelationship between sensitivity to H2O2, catalase and peroxidase activities, and bacillary growth rates measured both intracellularly in human monocytes and in culture medium, we examined one laboratory strain, two clinical isolates, and three recombinant strains of M. tuberculosis with differing levels of KatG and AhpC. Five of the mycobacterial strains had intracellular doubling times of 27 to 32 h, while one KatG-deficient clinical isolate (ATCC 35825) doubled in approximately 76 h. Killing of mycobacteria by exogenously added H2O2 was more pronounced for intracellular bacilli than for those bacilli derived from disrupted monocytes. Strains with no detectable KatG expression or catalase activity were relatively sensitive to killing (43 to 67% killing) by exogenous H2O2. However, once even minimal catalase activity was present, mycobacterial catalase activity over a 10-fold range (0.56 to 6.2 U/mg) was associated with survival of 85% of the bacilli. Peroxidase activity levels correlated significantly with resistance of the mycobacterial strains to H2O2-mediated killing. An endogenous oxidative burst induction by 4beta-phorbol 12beta-myristate 13alpha-acetate treatment of infected monocytes reduced the viability of the KatG null strain (H37Rv Inhr) but not the KatG-overexpressing strain [H37Rv(pMH59)]. These results suggest that mycobacterial resistance to oxidative metabolites (including H2O2 and other peroxides) may be an important mechanism of bacillary survival within the host phagocyte.

[The prognostic significance of 99mTc-MDP breast scintigraphy. A comparison with histological and molecular parameters]. / Significato prognostico della scintigrafia mammaria con 99mTc-MDP. Confronto con parametri istologici e molecolari.

INTRODUCTION: Breast scintigraphy (BS) with the bone-seeking agent 99mTc-medronate (MDP) can be usefully combined with mammography to diagnose and characterize questionable breast lumps. However this radiotracer does not seem to provide any further prognostic information about breast cancer. Therefore we investigated the prognostic yield of MDP-BS searching for correlations between scintigraphic findings and the major biological and histologic parameters. MATERIALS AND METHODS: We retrospectively analyzed a series of 44 primary breast cancers. All patients had undergone 99mTc-MDP bone scan for preoperative staging, as well as conventional breast imaging. We statistically compared the cancer/background ratio (c/b index) with lesion histotype, diameter, grading, and the tissue concentrations of steroid receptors, cathepsine D, type 1 timidine kinase, pS2 and p53 proteins. RESULTS: MDP-BS failed to depict 11 of 44 lesions (O 0.5-2 cm), detected 7 of 16 mammographically questionable lesions and correctly visualized the two multifocal cases. Also, MDP-BS depicted no metastatic axillary lymph nodes. We found no statistically significant correlation between the c/b index and the prognostic markers. DISCUSSION AND CONCLUSIONS: Differently from BS with 99mTc-MIBI, 201T1, 18F-FDG, 111In-OCT and radiolabeled estrogens and despite its good overall accuracy, MDP-BS appears to have no prognostic role. In fact, despite the well-known capability of soft tissue lesions to take up the tracer, MDP tumor trapping seems to depend mainly on the increased permeability of neovessels and on interstitial space enlargement. Few reports are available in the literature on the correlation between in vivo MDP uptake by the breast cancer and prognostic parameters. Thus, we tested possible correlations between the amount of MDP taken up by the breast cancer, histologic features and cell concentrations of some major biomarkers. The lack of any statistical significance is in agreement with the theory, and confirms the little prognostic value of MDP-BS. Nevertheless, further trials are warranted on larger series of cases to validate our personal findings.