Proposal of model for personalized early adapted cancer screening in people living with HIV: experience of "Gaetano Martino" Hospital University of Messina.

Human immunodeficiency virus (HIV) infection has historically been related to the development of specific cancers, some of which are so closely linked to the infection, such as Kaposi's Sarcoma (KS), that they have earned the name Acquired Immuno-Deficiency Syndrome (AIDS)-defining cancers (ADCs). While the development of antiretroviral therapy (ART) has decreased the incidence of AIDS-defining cancers, the resulting aging of people living with HIV (PLWH) highlighted an increased occurrence of other forms of cancer. At the "Gaetano Martino" hospital in Messina, we developed a multidisciplinary approach by creating a bridge between the Oncology Unit and the Infectious Diseases Unit to carry out screening and a more rapid diagnostic and therapeutic journey for cancers in PLWH. The goal is to improve the diagnosis of various types of cancer by involving other professionals, such as gastroenterologists and gynecologists, to ensure faster access to treatment and, therefore, a greater chance of survival. In addition, our multidisciplinary approach has also included vaccine screening, offered by the "Gaetano Martino" hospital and useful for preventing the development of specific forms of cancer in the entire population and particularly in PLWH.

Measurement of intra-abdominal pressure in large incisional hernia repair to prevent abdominal compartmental syndrome.

INTRODUCTION: The repair of large incisional hernias may occasionally lead to a substantial increase in intra-abdominal pressure (IAP), and rarely to abdominal compartmental syndrome (ACS) with subsequent respiratory, vascular, and visceral complications. Measurement of the IAP has recently become a common practice in monitoring critical patients, even though such measurements were obtained in the early 1900s. PATIENTS AND METHODS: A prospective study involving 54 patients undergoing elective abdominal wall gap repair (mean length, 17.4 cm) with a tension-free technique after incisional hernia was conducted. The purpose of the study was to determine whether or not urinary pressure for indirect IAP measurement is a reliable method for the early identification of patients with a higher risk of developing ACS. IAP measurements were performed using a Foley catheter connected to a HOLTECH® medical manometer. IAP values were determined preoperatively, after anesthetic induction, upon patient awakening, upon patient arrival in the ward after surgery, and 24 h after surgery before removing the catheter. All patients were treated by the same surgical team using a prosthetic composite mesh (PARIETEX®). RESULTS: Incisional hernia repair caused an increase in the mean IAP score of 2.68 mmHg in 47 of 54 patients (87.04%); the IAP was decreased in two patients (3.7%) and remained equal in five patients before and 24 h after surgery (9.26%). FEV-1, measured 24 h after surgery, increased in 50 patients (92.6%), remained stable in two patients (3.7%), and decreased in two patients (3.7%). The mean increase in FEV-1 was 0.0676 L (maximum increase = 0.42 L and minimum increase = 0.01 L) in any patient who developed ACS. CONCLUSIONS: Measurement of urinary bladder pressure has been shown to be easy to perform and free of complications. Measurement of urinary bladder pressure can also be a useful tool to identify patients with a higher risk of developing ACS.

The interleukin-1ß/CXCL1/2/neutrophil axis mediates host protection against group B streptococcal infection.

Previous studies have indicated that group B streptococcus (GBS), a frequent human pathogen, potently induces the release of interleukin-1ß (IL-1ß), an important mediator of inflammatory responses. Since little is known about the role of this cytokine in GBS disease, we analyzed the outcome of infection in IL-1ß-deficient mice. These animals were markedly sensitive to GBS infection, with most of them dying under challenge conditions that caused no deaths in wild-type control mice. Lethality was due to the inability of the IL-1ß-deficient mice to control local GBS replication and dissemination to target organs, such as the brain and the kidneys. Moreover, in a model of inflammation induced by the intraperitoneal injection of killed GBS, a lack of IL-1ß was associated with selective impairment in the production of the neutrophil chemokines CXCL1 and CXCL2 and in neutrophil recruitment to the peritoneal cavity. Decreased blood neutrophil counts and impaired neutrophil recruitment to the brain and kidneys were also observed during GBS infection in IL-1ß-deficient mice concomitantly with a reduction in CXCL1 and CXCL2 tissue levels. Notably, the hypersusceptibility to GBS infection observed in the immune-deficient animals was recapitulated by neutrophil depletion with anti-Gr1 antibodies. Collectively, our data identify a cytokine circuit that involves IL-1ß-induced production of CXCL1 and CXCL2 and leads the recruitment of neutrophils to GBS infection sites. Moreover, our data point to an essential role of these cells in controlling the progression and outcome of GBS disease.

Efficacy and safety during formulation switch of a pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by the quantitative or qualitative deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived VWF/factor VIII (FVIII) concentrates is required in patients unresponsive to desmopressin. To assess the efficacy, safety and ease of use of a new, volume-reduced (VR) formulation of VWF/FVIII concentrate Haemate(®) P in patients requiring treatment for bleeding or prophylaxis for recurrent bleeding or for invasive procedures. Pharmacoeconomic variables were also recorded. Data were analysed using descriptive statistics. This was a multicentre, prospective, observational study. Consecutively enrolled patients received Haemate(®) P VR according to their needs, and were followed for 24 months. Of the 121 patients enrolled, 25.6% had type 3 VWD and more than 40% had severe disease. All patients were followed for 2 years, for a total of 521 visits. On-demand treatment was given to 61.9% of patients, secondary long-term prophylaxis to 25.6% and prophylaxis for surgery, dental or invasive procedures to 45.5%. The response to treatment was rated as good to excellent in >93-99% of interventions. The new formulation was well tolerated by all patients with no report of drug-related adverse events. The switch to volume-reduced Haemate(®) P was easy to perform and infusion duration was decreased twofold compared with the previous formulation. Volume-reduced Haemate(®) P was at least as effective and well-tolerated as the previous formulation.

Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that is often fatal despite treatment. It is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of histiocytes with uncontrolled hemophagocytosis and cytokines overproduction. The syndrome is characterized by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hyperferritinemia. HLH can be either primary, with a genetic aetiology, or secondary, associated with malignancies, autoimmune diseases, or infections. AIM: To focus on secondary HLH complicating zoonotic diseases. MATERIALS AND METHODS: PubMed search of human cases of HLH occurring during zoonotic diseases was performed combining the terms (haemophagocytic or haemophagocytosis or hemophagocytosis or hemophagocytic or erythrophagocytosis or macrophage activation syndrome) with each one of the etiological agents of zoonoses. RESULTS: Among bacterial diseases, most papers reported cases occurring during brucellosis, rickettsial diseases and Q fever. Regarding viral diseases, most of the cases were reported in patients with avian influenza A subtype H5N1. Among the protozoan zoonoses, most of the cases were reported in patients with visceral leishmaniasis. Regarding zoonotic fungi, most of the cases were reported in AIDS patient with histoplasmosis. No cases of secondary HLH were reported in patient with zoonotic helminthes. CONCLUSIONS: Zoonotic diseases are an important cause of HLH. Secondary HLH can delay the correct diagnosis of the zoonotic disease, and can contribute to an adverse outcome.

Diagnosis of congenital toxoplasmosis: pre- and post-natal evaluation in Sicilian (Italy) epidemiological area. Preliminary data.

To evaluate the usefulness of conventional serological methods with western blot assay (WB) in congenital toxoplasmosis diagnosis, we prospectively enrolled in a clinical and serological follow-up all pregnant women with Toxoplasma gondii infection and their offspring, referred to us from October 2004. Western blot and standard serological test were performed on sera collected from mother during pregnancy and from mother and child at birth, at postpartum month 1-3-6-9 and 12. At this point in time, 22 pregnant women and 14 infants have completed the follow-up. 4 newborns were infected and 2 had specific toxoplasmosis anomalies at the birth. In mothers without seroconversion, the WB performed during pregnancy demonstrates the highest accordance with postnatal follow-up whereas in 1 case the negative result of PCR analysis was not confirmed by postnatal observation. The detection of anti-T gondii IgG against 8 kDa accessory antigenic band and against the accessory band included between 35 and 40 kDa band in immunoblot assay was useful for diagnosis of acute phase but did not improve the evaluation of comparative postnatal profile. Althougth few infants have concluded the postnatal follow-up, the preliminary results showed a greater value of using a IgM and IgA WB test than other standard method for the early diagnosis of toxoplasmosis at birth also in child born to treated mothers. The comparative anti-T gondii IgG immunoblot profile of mother and child permitted us to reduce the time of ruling out infection in newborns born to mothers with probable or possible infection and/or when prenatal diagnosis is negative or not performed.

Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study.

The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP-unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.

Cigarette smoking and attention: processing speed or specific effects?

RATIONALE: It has been evidenced that nicotine acts on some dimensions of human attention. OBJECTIVE: This study was carried out to test whether the positive effects of nicotine usually observed on the posterior system are specific or should rather be explained in terms of an effect of nicotine on eye movement velocity. METHODS: Ten participants were submitted to four tasks assessing attention. The tasks were borrowed from Zimmermann and Fimm's Battery for the Assessment of Attention: alert, eye movements, visual search and incompatibility. The order of the different tasks was balanced among participants. A within-subjects repeated-measure design was used. Participants received a 0.9-mg or 0.1-mg nicotine cigarette. The 0.1-mg cigarette was used as control. The order of administration of doses over sessions was counterbalanced. During the testing day, volunteers smoked their own cigarette and then waited 3 h without smoking. At the end of this abstinence period, participants completed the baseline tests before smoking an experimental cigarette ad libitum. They were then tested again. RESULTS: Participants who received nicotine appeared to respond faster in an eye movement task--a task associated with a non-elaborated attentional process. Similarly, their alert state improved. On the contrary, no effect of nicotine was observed in the incompatibility task and in the visual search task depending on elaborated attentional process. CONCLUSIONS: Data support previous observations and suggest that, first, non-elaborated information processing appeared to be more sensitive to nicotine and, second, this effect is not due to a velocity factor.

Beta 2 integrins are involved in cytokine responses to whole Gram-positive bacteria.

Proinflammatory cytokines have an important pathophysiologic role in septic shock. CD14 is involved in cytokine responses to a number of purified bacterial products, including LPS. However, little is known of monocyte receptors involved in cytokine responses to whole bacteria. To identify these receptors, human monocytes were pretreated with different mAbs and TNF-alpha was measured in culture supernatants after stimulation with whole heat-killed bacteria. Human serum and anti-CD14 Abs significantly increased and decreased, respectively, TNF-alpha responses to the Gram-negative Escherichia coli. However, neither treatment influenced responses to any of the Gram-positive bacteria tested, including group A and B streptococci, Listeria monocytogenes, and Staphylococcus aureus. Complement receptor type III (CR3 or CD18/CD11b) Abs prevented TNF-alpha release induced by heat-killed group A or B streptococci. In contrast, the same Abs had no effects when monocytes were stimulated with L. monocytogenes or S. aureus. Using either of the latter bacteria, significant inhibition of TNF-alpha release was produced by Abs to CD11c, one of the subunits of CR4. To confirm these blocking Ab data, IL-6 release was measured in CR3-, CR4-, or CD14-transfected Chinese hamster ovary cells after bacterial stimulation. Accordingly, streptococci triggered moderate IL-6 production (p < 0.05) in CR3 but not CD14 or CR4 transfectants. In contrast, L. monocytogenes and S. aureus induced IL-6 release in CR4 but not CR3 or CD14 transfectants. Collectively our data indicate that beta 2 integrins, such as CR3 and CR4, may be involved in cytokine responses to Gram-positive bacteria. Moreover, CD14 may play a more important role in responses to whole Gram-negative bacteria relative to Gram-positive ones.

Human monocyte receptors involved in tumor necrosis factor responses to group B streptococcal products.

Several group B streptococcal products have been previously found to stimulate human monocytes to produce tumor necrosis factor alpha. In order to identify the receptors involved in these responses, monocytes were stimulated with purified group- or type-specific carbohydrates or lipoteichoic acid in the presence of anti-receptor monoclonal antibodies, soluble CD14, or lipopolysaccharide-binding protein. Results indicate that CD14 plays an important role in tumor necrosis factor alpha responses to all of the stimuli tested. Moreover, both CD14 and complement receptor type 3 may be involved in responses to the group-antigen.

Tumor necrosis factor-alpha and virus expression in the central nervous system of cats infected with feline immunodeficiency virus.

Cytokine disregulation has been implicated in the pathogenesis of lentivirus-induced diseases. In the present study, 18 specific pathogen free (SPF) cats were inoculated with feline immunodeficiency virus (FIV) Petaluma strain and sacrificed at different times post-infection. Five additional SPF cats were used as controls. The cell localization of the cytokine tumor necrosis factor alpha (TNF-alpha) in the central nervous system (CNS) was determined by immunohistochemical and morphometric analyses with a polyclonal rabbit anti-human TNF-alpha antibody. TNF-alpha and FIV RNA were measured using competitive reverse transcriptase polymerase chain reaction (PCR) assays and the number of proviral genomes was estimated by competitive PCR. Portions of frontal cortex were collected from each animal and both formalin-fixed and snap-frozen and stored at -80 degrees C until used. The results showed that TNF-alpha is present mainly in astrocytes and microglial cells. Morphometric analysis showed that areas of TNF-alpha production increased in the early phases of infection. Molecular analyses demonstrated that the kinetics of proviral loads in the CNS were comparable to what observed in lymph nodes and peripheral blood mononuclear cells, with the peaks in the early and late stages of infection. A positive correlation was found between viral parameters and TNF-alpha transcription, the strongest relationship was found between the transcription of the cytokine and viral RNA load. These results confirm that invasion of CNS by FIV occurs soon after virus exposure and that during this phase there is an increase of local viral loads with concomitant up-regulation of TNF-alpha expression. During the asymptomatic phase viral replication remains low in spite of the progression of CNS alterations. The dissociation between the viral load and the lesions observed suggests the importance of an indirect mechanism for the progression of these lesions, even if TNF-alpha seems to play a role particularly in the early phase of infection.

Selective effects of nicotine on attentional processes.

RATIONALE: It is now well established from electrophysiological and behavioural evidence that nicotine has effects on information processing. The results are usually explained either by a primary effect of nicotine or by a reversal effect of a nicotine-induced, abstinence deficit. In addition, there is dispute about the cognitive processes underlying the changes in performance. METHODS: This study has approached the first question by using the nicotine patch, in order to administer nicotine chronically. In addition, we examined the effects of nicotine on attention with a selection of tests which assessed the intensity and selectivity features of attention, using the Random Letter Generation test, the Flexibility of Attention test and the Stroop test. RESULTS: Nicotine enhanced the speed of number generation and the speed of processing in both the control and interference conditions of the Stroop test. There were no effects on attentional switching of the Flexibility of Attention test. CONCLUSION: The results are consistent with the hypothesis that nicotine mainly improves the intensity feature of attention, rather than the selectivity feature.

Role of IL-10 in a neonatal mouse listeriosis model.

This study was undertaken to test the hypothesis that altered IL-10 production plays a role in the increased susceptibility of neonates to listeriosis. Plasma IL-10 levels were measured in neonatal and adult mice at various times after infection with Listeria monocytogenes. Relative to adults, neonatal mice had markedly increased IL-10 levels early in the course of infection with Listeria using a 90% lethal dose. Higher neonatal IL-10 responses were also observed after injecting adults and pups with equal doses of killed organisms. Splenic macrophages from neonates produced higher IL-10 levels than those of adults after in vitro stimulation with killed bacteria, confirming in vivo observations. Moreover, IL-10 blockade had differential effects in neonates and adults infected with live Listeria. In adult mice, anti-IL-10 Abs decreased bacterial burden early in the course of infection, but were no longer effective at 6 days or later after challenge. In the pups, however, the same treatment had beneficial effects both early and late during infection and resulted in increased survival. Collectively, our data suggest that an overproduction of IL-10 by macrophages may at least partially explain the increased susceptibility of neonates to listeriosis, and provide further evidence that cytokine production is different in adults and neonates.

Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study.

Fifteen 18- to 25-year-old male smokers were tested in a within-subjects design to determine the influence of a transdermal patch of 21 mg nicotine on vigilance. Subjects were tested on the RVIP test (Rapid Visual Information Processing test) 1.30, 3.00 and 6.30 h after patch application, to verify the involvement of the dose of nicotine on the performance. This study confirms and extends the increasing effects of nicotine on vigilance previously found with orally and transdermally given nicotine. Moreover, it showed that such performance was independent of the time of nicotine absorption (1.30, 3.00 and 6.30 h after patch application), which suggests that a relatively low dose of nicotine suffices to activate vigilance processing. Regarding motor performance, no convincing effect of nicotine was observed on reaction time.

Evaluation of the information processing and mood effects of a transdermal nicotine patch.

The purpose of this study was to determine whether a transdermal nicotine patch will produce the same effects on performance and mood as cigarette smoking. The nicotine patch improved attentional processing and produced some improvements in memory. It produced the calming effects of smoking and induced feelings of happiness which were increased with smoking. These effects were obtained 6 h after application of the patch, showing that acute tolerance for these behavioural effects had not developed completely, if at all, after exposure to nicotine, although it is still possible that tolerance might occur with longer exposure.

Soluble antigens from group B streptococci induce cytokine production in human blood cultures.

Group B streptococcal antigens stimulated tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 production in human blood cultures in a concentration- and time-dependent fashion. The minimal concentrations of type-specific polysaccharides, lipoteichoic acid, and group-specific polysaccharide required to produce these effects were, respectively, 0.01, 1, and 10 microg/ml. Cell separation experiments indicated that monocytes were the cell type mainly responsible for cytokine production. Time course studies indicated that TNF-alpha was released before the other cytokines. TNF-alpha, however, did not appear to directly induce IL-1beta, as shown by blockade experiments with anti-TNF-alpha antibodies. IL-6 levels were moderately but significantly decreased by anti-TNF-alpha. These data indicate that several products from group B streptococci are able to directly stimulate human monocytes to release TNF-alpha, IL-1beta, and IL-6. These findings may be clinically relevant, since proinflammatory cytokines can mediate pathophysiologic changes during sepsis.

Endotoxin-induced lethality in neonatal mice is counteracted by interleukin-10 (IL-10) and exacerbated by anti-IL-10.

The lethal effects occurring in neonatal (<24-h-old) BALB/c mice after challenge with 25 mg of lipopolysaccharide (LPS) per kg of body weight were significantly counteracted by pretreatment with recombinant interleukin-10 (rIL-10; 25 or 50 ng/mouse). Concordantly, blockage of endogenous IL-10 with the SXC1 monoclonal antibody increased LPS-induced mortality. Both IL-10 and SXC1 modulated the release of tumor necrosis factor alpha (TNF-alpha) so that, relative to controls, peak TNF-alpha values after LPS challenge were decreased by rIL-10 and increased by anti-IL-10.