Cisplatin-associated anaemia in patients with solid tumours

We have reviewed the incidence of cisplatin-induced anaemia in patients affected with solid tumours treated with at least three courses of first-line cisplatincontaining regimens. In our experience, a low percentage (5%) of patients required transfusions of red blood cells. We think it is of the utmost importance to adopt uniform criteria in monitoring and treatment of patients at risk of developing cisplatin anaemia and to identify subsets of patients to eventually treat with erythropoietin.     

Update on ascites and hepatorenal syndrome

Ascites is the most common complication occurring during liver cirrhosis. Even if a significant decrease in renal clearance may be observed in the first step of chronic active liver disease, renal impairment, at times complicated by the typical signs of hepatorenal syndrome, occurs only in patients with ascites, especially when tense and refractory. Experimental and clinical data seem to suggest a primary sodium and water retention in the pathogenesis of ascites, in the presence of an intrahepatic increase of hydrostatic pressure, which, by itself, physiologically occurs during digestion. Abnormal sodium and water handling leads to plasma volume expansion, followed by decreased peripheral vascular resistance and increased cardiac output. This second step is in agreement with the peripheral arterial vasodilation hypothesis, depicted by an increase in total blood volume, but with a decreased effective arterial blood volume. This discrepancy leads to the activation of the sympathetic nervous and renin-angiotensin-aldosterone systems associated with the progressive activation of the renal autacoid systems, especially, that of the arachidonic acid. During advanced cirrhosis, renal impairment becomes more sustained and renal autacoid vasodilating substances are less available, possibly due to a progressive exhaustion of these systems. At the same time ascites becomes refractory inasmuch as it is no longer responsive to diuretic treatment. Various pathogenetic mechanisms leading to refractory ascites are mentioned. Finally, several treatment approaches to overcome the reduced effectiveness of diuretic therapy are cited. Paracentesis, together with simultaneous administration of human albumin or other plasma expanders is the main common approach to treat refractory ascites and to avoid a further decrease in renal failure. Other effective tools are: administration of terlipressin together with albumin, implantation of the Le Veen shunt, surgical porto-systemic shunting or transjugular intrahepatic portosystemic stent-shunt, or orthotopic liver transplantation, according to the conditions of the individual patient.     

Functional signatures of protective antiviral T-cell immunity in human virus infections

Summary: The most common human viruses have different abilities to establish persistent chronic infection. Virus‐specific T‐cell responses are critical in the control of virus replication and in the prevention of disease in chronic infection. A large number of phenotypic markers and a series of functions have been used to characterize virus‐specific CD4⁺ and CD8⁺ T‐cell responses, and these studies have shown great phenotypic and functional heterogeneity of the T‐cell responses against different viruses. The heterogeneity of the T‐cell response has been proposed to be specific to each virus. However, over the past 2 years, several studies have provided evidence that the phenotypic and functional heterogeneity of CD4⁺ and CD8⁺ T‐cell responses is predominantly regulated by the levels of antigen load. The levels of antigen load modulate the phenotypic and functional patterns of the T‐cell response within the same virus infection. Furthermore, the functional characterization of virus‐specific CD4⁺ and CD8⁺ T‐cell responses has identified signatures of protective antiviral immunity. Polyfunctional, i.e. interleukin‐2 and interferon‐γ (IFN‐γ) secretion and proliferation, and not monofunctional, i.e. IFN‐γ secretion, CD4⁺ and CD8⁺ T‐cell responses represent correlates of protective antiviral immunity in chronic virus infections.     

Increase in muscular pain threshold following low frequency-high intensity peripheral conditioning stimulation in humans

The effects of low frequency-high intensity transcutaneous and intramuscular electrical nerve stimulation (TENS and IENS, respectively) on ipsilateral muscular pain threshold were studied in healthy volunteers. The combined effects of TENS (or IENS) and vibration as well as the effects of TENS applied to contralateral regions were also investigated. Muscular pain threshold was evaluated by the subjects' verbal reports in response to electrical stimulation (wire electrodes) of the vastus medialis muscle and by the appearance of blink response (startle reaction) without habituation. TENS was generally applied to the skin overlying the same muscle, and in some instances to the skin overlying the contralateral vastus medialis or triceps muscle. IENS was performed through the same electrodes used for inducing muscular pain. Vibration was applied to the tendon of ipsilateral quadriceps femoris muscle. TENS consistently induced marked and long-lasting elevations of ipsilateral muscular pain threshold. Comparable results were obtained by IENS. TENS and vibration performed simultaneously induced increases in muscular pain threshold, which were greater than those obtained with each individual conditioning stimulation. TENS proved to be capable of enhancing muscular pain threshold even when applied to contralateral regions; however, these effects were smaller and of shorter duration. The results provide evidence that low frequency-high intensity TENS (or IENS) are effective in raising muscular pain threshold and support the hypothesis that this type of stimulation brings supraspinal control systems into action through the activation of group III afferent fibres.     

Chemical activation of caudal medullary expiratory neurones alters the pattern of breathing in the cat.

1. The purpose of this work was to ascertain whether the activation of caudal expiratory neurones located in the caudal part of the ventral respiratory group (VRG) may affect the pattern of breathing via medullary axon collaterals. 2. We used microinjections of DL-homocysteic acid (DLH) to activate this population of neurones in pentobarbitone-anaesthetized, vagotomized, paralysed and artificially ventilated cats. Both phrenic and abdominal nerve activities were monitored; extracellular recordings from medullary and upper cervical cord respiratory neurones were performed. 3. DLH (160 mM) microinjected (10-30 nl for a total of 1.6-4.8 nmol) into the caudal VRG, into sites where expiratory activity was encountered, provoked an intense and sustained activation of the expiratory motor output associated with a corresponding period of silence in phrenic nerve activity. During the progressive decline of the activation of abdominal motoneurones, rhythmic inspiratory activity resumed, displaying a decrease in frequency and a marked reduction or the complete suppression of postinspiratory activity as its most consistent features. 4. Medullary and upper cervical cord inspiratory neurones exhibited inhibitory responses consistent with those observed in phrenic nerve activity, while expiratory neurones in the caudal VRG on the side contralateral to the injection showed excitation patterns similar to those of abdominal motoneurones. On the other hand, in correspondence to expiratory motor output activation, expiratory neurones of the Bötzinger complex displayed tonic discharges whose intensity was markedly lower than the peak level of control breaths. 5. Bilateral lignocaine blockades of neural transmission at C2-C3 affecting the expiratory and, to a varying extent, the inspiratory bulbospinal pathways as well as spinal cord transections at C2-C3 or C1-C2, did not suppress the inhibitory effect on inspiratory neurones of either the ipsi- or contralateral VRG in response to DLH microinjections into the caudal VRG. 6. The results show that neurones within the column of caudal VRG expiratory neurones promote inhibitory effects on phrenic nerve activity and resetting of the respiratory rhythm. We suggest that these effects are mediated by medullary bulbospinal expiratory neurones, which may, therefore, have a function in the control of breathing through medullary axon collaterals.     

Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis.

Expression of platelet-derived growth factor (PDGF) and its receptor (R) subunits was evaluated in normal human liver and in cirrhotic liver tissue by in situ hybridization and immunohistochemistry. In normal liver, PDGF and PDGF-R subunit expression was limited to a few mesenchymal cells of the portal tract stroma and vessels. In cirrhotic liver, PDGF-A and -B chain mRNA expression was markedly increased and was co-distributed with immunoreactivity for PDGF-AA and -BB in infiltrating inflammatory cells and along vascular structures within fibrous septa. These aspects were paralleled by a marked overexpression of PDGF-R alpha- and beta-subunit mRNAs and of the relative immunoreactivities in a wide range of mesenchymal cells in fibrous septa and in perisinusoidal alpha-smooth-muscle-actin-positive cells. In general expression and distribution of PDGF-R subunits appeared to be related to the activation of different mesenchymal cell types involved in the fibroproliferative process. Therefore, we evaluated the expression of PDGF-R subunits in liver tissue specimens with increasing degrees of necroinflammatory activity. The results of this additional study confirmed that expression of PDGF-R subunits is highly correlated with the severity of histological lesions and collagen deposition. Our results, providing evidence for a functional involvement of PDGF/PDGF-R in liver fibrogenesis, greatly support the results of previous in vitro studies and direct attention toward pharmacological strategies able to affect the series of signaling events arising from the autophosphorylation of PDGF-R subunits.     

Stimulation and proliferation of CD4+ peripheral blood T lymphocytes induced by an anti-CD4 monoclonal antibody

There is experimental evidence that the CD4 molecule participates in the antigen-driven activation of T cells expressing this surface glycoprotein. Whether CD4, a member of the immunoglobulin supergene family, acts as a ligand-binding molecule and/or is directly involved in the activation pathway has yet to be established. In this study, we show that human CD4⁺ lymphocytes can be activated by exposure to the anti-CD4 monoclonal antibody (mAb) B66. Normal peripheral blood CD4⁺ cells were induced to proliferate and to synthesize interleukin 2 (IL2) by the antibody. The specificity of the antibody stimulatory activity was tested by using IL2-producing clones bearing either CD4 or CD8 on their surface. IL2 production was induced by mAb B66 in CD4+, but not CD8⁺, clones, whereas both types of clones responded to stimulation by the anti-CD3 mAb Leu-4. Despite its unique stimulatory activity, mAb B66 shared with other anti-CD4 antibodies the ability to inhibit the specific cytolytic activity of CD4⁺ effector cells. These results clearly indicate that cross-linking of surface CD4 molecules with appropriate antibodies can fully activate CD4⁺ lymphocytes. Whether the natural ligand for CD4 can trigger this activation pathway remains to be defined.     

Dissociation between syncytia formation and HIV spreading. Suppression of syncytia formation does not necessarily reflect inhibition of HIV infection

In this study, we have observed that a dissociation may occur in vitro between syncytia formation and HIV spreading. Efficient HIV spreading and virus replication occurred either in HIV-infected LFA-1+ lymphocytes treated with anti-LFA-1 mAb or in HIV-infected lymphocytes genetically deficient in LFA-1, despite the fact that syncytia formation was completely suppressed. Therefore, these results indicate that syncytia formation cannot be used as the sole parameter to evaluate the spread of HIV in vitro.