Evaluation by dual energy X-ray absorptiometry of changed bone density in metastatic bone sites as a consequence of systemic treatment

Fourteen cancer patients with bone metastases from various primary malignancies were submitted to repeated dual X-ray absorptiometry (DEXA) scan before and after systemic antineoplastic treatments. In the nine patients with lytic lesions the Bone Mineral Density (BMD) increased after chemotherapy + pamidronate in four (by +11.2%, +7.5%, +5.0% and +6.6%, respectively), decreased in four (by -19.9%, -8.1%, -7.5%, and -7.0%, respectively) and remained unchanged in one. BMD changes paralleled variations in painful symptomatology and biochemical markers. In patients with blastic metastases the BMD on target metastatic lesions did not change after hormone therapy or chemotherapy in one case but showed a significant increase in four. BMD increase was associated to bone pain improvement and PSA decrease in two cases, and with a worsening in skeletal pain and/or serum PSA in the remaining two. Our data suggest that BMD evaluation by DEXA instrument may be a reliable tool in assessing the response of bone metastases to treatment.     

Excision repair of benzo[a]pyrene-deoxyguanosine adducts in baby hamster kidney 21/C13 cells and in secondary mouse embryo fibroblasts C57BL/6J.

The formation and excision of benzo[a]pyrene-deoxyguanosine adducts in metabolizing baby hamster kidney cells (21/C13) and secondary mouse embryo fibroblasts (C57BL/6J) was investigated. Both diastereomeric adducts, N2-(10-(7beta,8alpha,9alpha-trihydroxy-7, 8, 9, 10 tetrahydrobenzo[a]-7,8,9,10-tetrahydrobenzo[a]pyrene)yl)deoxyguanosine, were detected in both cell lines and both cell lines were capable of excising these lesions, albeit with low efficiency.     

Antiangiogenic properties of fibstatin, an extracellular FGF-2-binding polypeptide

By using the two-hybrid system with basic fibroblast growth factor (FGF-2) as bait, we isolated and characterized fibstatin, an endogenous M(r) 29,000 human basement membrane-derived inhibitor of angiogenesis and tumor growth. Fibstatin, a fragment containing the type III domains 12-14 of fibronectin, was produced as a recombinant protein and was shown to inhibit the proliferation, migration, and differentiation of endothelial cells in vitro. Antiangiogenic activity of fibstatin was confirmed in a Matrigel angiogenesis assay in vivo, and electrotransfer of the fibstatin gene into muscle tissue resulted in reduced B16F10 tumor growth. Taken together, these results suggest that fibstatin could act as a powerful molecule for antiangiogenic therapy.     

Instant centre frequency at anaesthetic induction--a new way to analyse sympathovagal balance

The instant centre frequency (ICF) of RR interval has been proposed as a global index to analyse the sympathovagal interaction in the heart. The aim of this study was to assess the ICF during anaesthesia to test if it can reliably capture the neural control of the cardiovascular system. Twenty-four ASA II or III patients scheduled for cardiac surgery were included in the study. They were allocated in two groups: control, no treatment (group 1, n = 12), and beta-adrenergic blockade by atenolol (group 2, n = 12). Spectra of pulse interval series were computed with a time-frequency method and they were divided into: very low frequency (VLF, 0.000-0.040 Hz), low frequency (LF, 0.050-0.150 Hz) and high frequency (HF, 0.160-0.500 Hz). Normalized power was obtained by dividing the cumulative power within each frequency band (LF or HF) by the sum of LF and HF; the ratio of LF/HF was also calculated. Instant centre frequency is a time-varying parameter that the evolution along time of the gravity centrum of a local spectrum. All spectral indexes were recorded at the following time points: before induction, after induction and before intubation, during intubation, and after intubation. The atenolol group had lower normalized LF and the LF/HF ratio (P < 0.05) higher HF before induction; and lower LF/HF ratio after induction and before intubation (P < 0.05). The ICF was higher in atenolol group at all times. The ICF shifted towards HF frequency after induction and before intubation and shifted towards LF during intubation in both groups. The autonomic nervous system control on the heart through the interaction of sympathetic and parasympathetic reflex mechanisms could be studied by the ICF. The ICF may assess the autonomic cardiac modulation and may provide useful information for anaesthetic management.     

Biomedical signal processing and modeling in cardiovascular systems

This article revisits the subject of short-term heart-rate and arterial-pressure variability from the perspective of model structures that can be useful in defining signal processing algorithms. We draw a general scheme of the oscillation sources and interactions that contribute to cardiovascular control mechanisms and highlight the elements that were considered in different modeling works.The origin, superposition, and interaction of respiratory high-frequency (HF) and vasomotor low-frequency (LF) rhythms is presented as the integration of supraspinal and spinal circuits, vasomotor activity, and pressure control loops. We analyze in detail the necessity of considering all relevant interactions for the algorithms designed to estimate the baroreflex sensitivity. We also pinpoint the components of cardiorespiratory coupling in relation to the analysis of data from the acoustic quantification of the left ventricular volume. Finally, we analyze the tendency to produce complex behaviors even in extremely simplified systems involving interactions between oscillatory mechanisms.     

Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.     

Advanced spectral methods for detecting dynamic behaviour

The traditional analysis in the frequency domain of cardiovascular variability signals requires stationarity along the considered temporal window, in order to obtain reliable indicators of the sympatho-vagal balance (low frequency (LF) and high frequency (HF) power and frequency, and LF/HF ratio). Through proper advanced algorithms of signal processing, it is possible to implement methods that allow the enhancement of important parameters about the behaviour of the system under investigation in the time and frequency domain. Both non-parametric and parametric time-frequency methods are generally employed at this purpose. Among them, Wigner-Ville Distribution and Time-Variant Autoregressive models are here described. Through such advanced methods of signal processing, it is possible to investigate the dynamic properties of the spectral parameters during transient physiological or pathological episodes, after a proper validation using simulated signals. The methods are used in various applicative areas of interest where the spectral parameters present a significant change in time and where the classical spectral analysis cannot be correctly applied. A few significant cases will be discussed such as tilting manoeuvre, vaso-vagal syncope onset and progression, and acute ischemic episodes. Further, multivariate analysis can be applied in which the focus is on squared coherence function and phase relationships, in order to estimate some possible causal effects in different experimental conditions. It is believed that such advanced methods of time-variant or time-frequency approaches are capable of overcoming the problem of stationarity in classical spectral analysis and to make applicable frequency domain techniques in the study of transient episodes which generally characterise various physiological and clinical conditions.     

Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis

While p53 is dispensable for development, an excess of p53 has dramatic consequences on the embryogenesis and on the cell differentiation. In an attempt to analyse in vivo the effects of p53 activity, we have generated transgenic mice expressing the wild-type p53 under the control of the metallothionein I promoter. In the three transgenic lines established, exogenous p53 is expressed constitutively in the postmeiotic cells of transgenic males and two lines are subfertile. Transgenic males expressing the upper level of p53 produce few spermatozoa since the majority of developing spermatids undergo apoptosis. In the subfertile males exhibiting an intermediate amount of p53, teratozoospermia is obvious suggesting an altered terminal differentiation of postmeiotic cells. In contrast lower level of p53 does not lead the third line to sterility. These results suggest that the activity of p53 is dependent in vivo on the amount of p53 present within cells, as it has been already demonstrated in vitro.