IDN 5390: a new concept in taxane development

IDN 5390 is a seco-derivative cytostatic taxane. Originally selected for its ability to affect endothelial cell motility, the anti-angiogenic properties of IDN 5390 have been documented in experimental models, in vivo and in vitro. Preclinical studies indicate that, in vivo, oral IDN 5390 has a favorable bioavailability, is well tolerated and shows a significant anti-neoplastic activity on a panel of different tumor models, including paclitaxel-resistant tumors. According to its cytostatic rather than cytotoxic nature, frequent administrations of non-toxic doses have proven to be the optimal schedule for IDN 5390 treatment. Preliminary findings suggest the use of this compound in combination with conventional anti-neoplastic therapy. IDN 5390 can be considered the prototype of a new class of well-tolerated, orally available anti-angiogenic taxane derivatives with cytostatic properties.     

Incidence and characteristics of hospital-acquired pneumonia in a pulmonary rehabilitation setting.

BACKGROUND: The incidence of Hospital Acquired Pneumonia (HAP) varies according to the setting. It is estimated to be approximately 0.5% to 1% in hospitalized subjects but higher in mechanically ventilated patients in intensive care units. The incidence of HAP in a pulmonary rehabilitation unit has not been investigated. MATERIAL/METHODS: Patients with chronic obstructive pulmonary disease (COPD), admitted for pulmonary rehabilitation between January 1 and December 31, 2006, were included. HAP was defined by symptoms, signs, and radiograph imaging of pulmonary infiltrate. Chest radiography allowed us to distinguish HAP from COPD exacerbations. The disease course also was evaluated. RESULTS: In total, 143 subjects (85 men, 58 women; mean age, 74.2 years) were enrolled. Nine of them (6.3%; 6 men, 3 women; mean age, 72.8+/-3.2 years) developed HAP. Twenty-four (16.8%) had pneumonia signs and symptoms but no radiologic findings. In these patients, a diagnosis of COPD exacerbation was made. Seven of 9 patients with HAP were successfully treated with empiric antibiotic therapy, while the other 2 required a modification of the antibiotic regimen after resistant Klebsiella pneumoniae and Pseudomonas aeruginosa had been detected in sputum culture. CONCLUSIONS: The incidence of HAP in a pulmonary rehabilitation setting was approximately 6%, higher than that previously described in hospitalized subjects. The clinical course of HAP was favorable, no mortality occurred. This could be explained either by patient-related or by environment-related factors.     

Oxidative stress and kidney dysfunction due to ischemia/reperfusion in rat: attenuation by dehydroepiandrosterone

BACKGROUND: The pathogenesis of ischemia/reperfusion (I/R) involves generation of reactive oxygen and nitrogen species. This in vivo study investigates the effect of dehydroepiandrosterone (DHEA), a physiologic steroid with antioxidant properties, on oxidative balance and renal dysfunctions induced by monolateral I/R. METHODS: Normal and DHEA-treated rats (4 mg/day x 21 days, orally) were subjected to monolateral renal I/R (30 minutes/6 hours). The oxidative state was determined by measuring hydrogen peroxide level and activities of glutathione-peroxidase, catalase, and superoxide dismutase. Tumor necrosis factor-alpha (TNF-alpha) and nitric oxide production and inducible nitric oxide synthase (iNOS) levels were also measured. Hydroxynonenal content was used to probe lipid peroxidation. Functional parameters determined were creatinine levels and Na/K-ATPase activity. Immunohistochemical and morphologic studies were also performed. RESULTS: A markedly pro-oxidant state was evident in the kidney of rats subjected to I/R. Both hydrogen peroxide and reactive nitrogen species (nitric oxide and iNOS) increased, whereas antioxidants decreased. Oxidant species induce TNF-alpha increase, which, in turn, produces lipoperoxidative processes, as documented by the increased hydroxynonenal (HNE) level. As final result, impaired renal functionality, hydropic degeneration, and vacuolization of proximal convolute tubules were observed in kidneys of I/R rats. DHEA pretreatment improved the parameters considered. CONCLUSION: I/R induces oxidative stress and consequently damages the proximal convolute renal tubules. Rats supplemented with DHEA and subjected to I/R had reduced pro-oxidant state, oxidative damage, and improved renal functionality, indicating an attenuation of oxidative injury and dysfunctions mediated by I/R.     

Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation

BACKGROUND: Prolonged immunodeficiency after allogeneic bone marrow transplantation (allo BMT) results in significant morbidity and mortality from infection. Previous studies in murine syngeneic BMT models have demonstrated that posttransplantation insulin-like growth factor (IGF)-I administration could enhance immune reconstitution. METHODS: To analyze the effects of IGF-I on immune reconstitution and graft-versus-host disease (GVHD) after allo BMT, we used murine models for MHC-matched and -mismatched allo BMT. Young (3-month-old) recipient mice received 4 mg/kg per day of human IGF-I from days 14 to 28 by continuous subcutaneous administration. RESULTS: IGF-I administration resulted in increased thymic precursor populations (triple negative-2 and triple negative-3) as determined on day 28 but had no effect on overall thymic cellularity. In the periphery, the numbers of donor-derived splenic CD3+ T cells were increased and these cells had an improved proliferative response to mitogen stimulation. IGF-I treatment also significantly increased the numbers of pro-, pre-, and mature B cells and myeloid cell populations in the spleens of allo BMT recipients on day 28. The administration of IGF-I in combination with interleukin 7 had a remarkable additive effect on B-cell, but not on T-cell, lymphopoiesis. Finally, we tested the effects of IGF-I administration on the development of GVHD in three different MHC-matched and -mismatched models and found no changes in GVHD morbidity and mortality. CONCLUSION: IGF-I administration can enhance lymphoid and myeloid reconstitution after allo BMT without aggravating GVHD.     

Electric to acoustic pitch matching: a possible way to improve individual cochlear implant fitting

Poor pitch resolution has been shown to have negative implications for speech and music perception in implanted patients. Surprisingly, works on the subject have not focused much on the impact that the non-correspondence between frequencies allocated to electrodes and perceived frequencies could have on speech and music perception. The aim of the present study is to investigate the correlation between pitch mismatch and speech performance with the implant, and to ascertain the effects of mismatch correction through a mapping function making a personalized frequency reallocation possible. We studied ten postlingually deaf adult patients with detectable bilateral residual hearing, implanted in our Clinic with Cochlear^® Nucleus devices. In each test session, we asked the patients to find the best match between the pitch elicited by the residual ipsilateral and contralateral pure tones and the pitch elicited by stimulation of electrodes. We also assessed patients’ vowel and consonant recognition performance. Finally, in the only implanted patient in our clinic who had bilateral residual hearing and used a Digisonic DX10/C^® device, which makes manual electrode-by-electrode frequency reallocation possible, we modified electrode-assigned frequency ranges on the basis of the pitch matching test results. We found that in none of the studied patients, the electric-to-acoustic pitch matching corresponds to the theoretical assignment pattern. A very strong correlation was detected between the electric-to-acoustic pitch mismatch and patient’s speech performance. In the Digisonic^® patient, a remarkable improvement in all phoneme recognition scores was obtained 1 month after frequency reallocation. In the light of our results, we propose to assess, whenever possible, any frequency-to-electrode mismatch in all implanted patients, and correct it through mapping programs allowing manual frequency reallocation for the pitch-matched electrodes, and automated allocation of the non-tested electrodes. Cochlear implantation should therefore be proposed when residuals for all frequencies are still present, at least in one ear, so as to allow optimal alignment between allocated and subjectively perceived frequencies.     

Catecholaminergic polymorphic ventricular tachycardia: successful emergency treatment with intravenous propranolol

Catecholaminergic polymorphic ventricular tachycardia (VT) is a rare arrhythmogenic disorder, which may cause sudden death and whose relationships with mutations in cardiac ryanodine receptor gene have been recently established. The present article reports a catecholaminergic polymorphic VT case of a 9-year-old girl, without any previous history of syncope, who has been found unconscious while playing and referred comatose to pediatric intensive care unit. The electrocardiogram pattern showed runs of bidirectional and polymorphic VT degenerating into ventricular fibrillation, without QT interval abnormalities. Various attempts of cardioversion, lidocaine, and magnesium sulfate intravenous infusions were only partially effective. Owing to catecholaminergic polymorphic VT highly suggesting electrocardiogram pattern, intravenous propranolol was administered, achieving immediate VT interruption. Long-term nadolol therapy effectively prevented further arrhythmias, with no relapses up to 10 months later; a good neurologic recovery was also obtained. Genetic evaluation revealed in this patient-but not in relatives-a mutation in ryanodine receptor gene on chromosome 1.     

Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients

Islet survival in the early posttransplantation period is likely to be influenced by inflammatory events in and around islets. Twenty-seven human islet preparations were transplanted by 24 infusions into 14 patients with brittle type 1 diabetes under the Edmonton protocol. Patients were monitored for their coagulation [cross-linked fibrin degradation products (XDPs)] and liver function test [aspartate and alanine aminotransferase (AST and ALT)] as markers of early posttransplant complications, and these were correlated with in vitro islet number, purification, volume, monocyte-chemoattractant protein-1 (CCL2/MCP-1) and tissue factor (TF) islet release. Consistent with activation of coagulation pathways and hepatic damage, serum XDP values increased early after 11 infusions and transaminase after 13 of 24 infusions. TF and CCL2/MCP-1 were detected in supernatants of 21 and 22 islet preparations, respectively. Serum XDP peak values were correlated with TF/equivalent islets (EI) (r(2)=0.26, P = 0.001) and CCL2/MCP-1/EI (r(2) = 0.42; P < 0.001); serum transaminase areas under the curve in the first week posttransplantation were correlated with CCL2/MCP-1/EI (r(2) = 0.55; P < 0.001 for ALT and r(2) = 0.51; P = 0.001 for AST) and TF/EI (r(2) = 0.31; P = 0.002 for ALT, and r(2) = 0.36; P = 0.002 for AST). These data suggest that reducing the islet proinflammatory state may be a means to reduce the early posttransplant complications and perhaps improve islet engraftment.     

Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis

In this study, in an attempt to identify neuroblastoma-associated surface antigens, we generated mAbs against the ACN neuroblastoma cell line. A mAb was selected (5B14) that reacted with all neuroblastoma cell lines analyzed and allowed detection of tumor cell infiltrates in bone marrow aspirates from neuroblastoma patients. In cytofluorimetric analysis, unlike anti-disialoganglioside mAb, 5B14 mAb did not display reactivity with normal bone marrow hematopoietic cell precursors, thus representing a highly specific marker for identifying neuroblastoma cells. Molecular analysis revealed that the 5B14 mAb-reactive surface glycoprotein corresponded to the recently identified 4Ig-B7-H3 molecule. Remarkably, mAb-mediated masking of the 4Ig-B7-H3 molecule on cell transfectants or on freshly isolated neuroblastoma cells resulted in enhancement of natural killer-mediated lysis of these target cells. These data suggest that 4Ig-B7-H3 molecules expressed at the tumor cell surface can exert a protective role from natural killer-mediated lysis by interacting with a still undefined inhibitory receptor expressed on natural killer cells.     

Hypotension as an isolated factor may not be sufficient to provoke hearing impairment

OBJECTIVE: We investigated the possible role of hypotension and related autonomic phenomena in the pathogenic mechanism of sudden sensorineural hearing loss. METHODS: Forty-nine patients belonging to the ASA I-II classes of anaesthesiological risk and submitted to a non-otological surgical procedure were examined. Each operation was performed under general anaesthesia by controlled hypotension technique. Hearing function of the patients was evaluated before and after surgery by means of a pure tone audiometry recorded by the same clinician with the same instrument. RESULTS: No cases of bilateral hearing worsening were recorded after surgery. CONCLUSIONS: An induced and controlled steady hypotension under general anaesthesia did not affect the hearing function of any of the patients. It may be supposed, therefore, that an adverse effect on the cochlear oxygenation is more likely to be caused by the sympathetic changes induced by a consistent decrease of blood pressure rather than to hypotension itself.