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SUMMARYThe zoonotic risk ofBrucella canishas been considered fairly high for persons who handle breeding dogs in kennels or are exposed to infected animals. Transmission to humans in other circumstances has been thought to be rare. We describe an uncommon outbreak of brucellosis caused byB. caniswhich, to the best of our knowledge, is the first reported in the literature. This outbreak involved six persons (three children and three adults), a bitch and three puppies which had close daily contact with the family. The clinical symptoms of the index case led to an erroneous diagnosis and the infection would have gone undiagnosed if culture had not been positive. This report aims to increase awareness of medical personnel of the need to order screening tests for children, immunodeficient persons or pregnant women presenting with fever of unknown origin, unexplained spleen or liver enlargement or other systemic signs. The emerging zoonotic potential of this disease in urban areas and the need to coordinate canine brucellosis surveillance systems should be evaluated.

Summary 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.

Major questions are whether mothers infected with the Human Immunodeficiency Virus type 1 (HIV-1) transmit the virus through breast milk and the magnitude of the additional transmission risk. The demonstration of a dose-response effect is an epidemiological method to demonstrate causality. Thus, a study was carried out by the Italian Register for HIV Infection in Children on 961 children of known infection status. Duration of breast-feeding was considered as the level of exposure in 168 ever breast-fed children. Results showed that duration of practice significantly increased the risk of transmission. The adjusted infection odds ratio for one day of breast- versus exclusive formula-feeding was 1.19 with narrow confidence limits (1.10-1.28). In a second study by the Register on 556 children of known infection status and derived prospectively, an infection odds ratio of 2.55 (confidence interval: 1.03-6.37) was calculated in breast- versus exclusively formula-fed children. Several lines of evidence, including the above-mentioned data from the Italian Register for HIV Infection in Children, showed a contribution of breast-feeding to mother-to-child HIV-1 transmission. Thus, this practice is now discouraged in HIV-1 infected mothers living in industrialized societies where formula feeding is practical and attainable. Mode of feeding was known in 2183 children enrolled in the Register and born to HIV-1 infected mothers since 1981. It could be observed that feeding habits of at-risk infants changed in Italy in the middle 1980s, when a large majority of subjects was identified at birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Integrin signalling co-ordinates with signalling originating from growth factor receptors in the co-operative control of cell proliferation, survival and migration. Increasing evidence suggests that integrins form physical complexes at the cell membrane with growth factor receptors, giving rise to signalling platforms at the adhesive sites. It is probable that at these sites integrins regulate adhesion and at the same time physically constrain and direct the response to soluble growth factors towards proliferation or survival stimuli. These co-operative effects might depend on integrin ability to activate growth factor receptors. In the present paper, we summarize our recent study showing that integrin-dependent adhesion triggers ligand-independent EGFR (epidermal growth factor receptor) activation to transduce downstream signalling. In addition, we also show that integrin-induced signalling pathways are necessary for EGF-dependent transcriptional response, demonstrating the requirement of the co-operation between cell–matrix adhesion and EGFR to achieve full biological responses.

The localization of HIV-1 proviruses in compositional DNA fractions from 27 AIDS patients during the chronic phase of the disease with depletion of CD4+ and different levels of viremia showed the following. (1) At low viremia, proviruses are predominantly localized in the GC-richest isochores, which are characterized by an open chromatin structure; this result mimics findings on HIV-1 integration in early infected cells in culture. (2) At higher viremia, an increased distribution of proviruses in GC-poor isochores (which match the GC poorness of HIV-1) was found; this suggests a selection of cells in which the ‘isopycnic’ localization leads to a higher expression of proviruses and, in turn, to higher viremia. (3) At the highest viremia, integrations in GC-rich isochores are often predominant again, but generally not at the same level as in (1); this may be the consequence of new integrations from the extremely abundant RNA copies.

Many patterns of mutations selected by HIV-1 protease inhibitors have been described, but in most cases isolates with these patterns have been obtained from pre-clinical studies or after failures of monotherapies. We compared genotype and phenotype in HIV-1 infected patients who have failed more than one PI-including regimen. Phenotypic resistance could arise also in the absence of specific primary mutations and in the presence of different substitutions among those known to confer resistance to ritonavir, indinavir or nelfinavir. The number of secondary mutations was significantly associated with phenotypic resistance for each protease inhibitor. Thus, more study of mutational patterns in heavily pretreated patients is warranted; in the mean time treatment choices might be optimized if phenotyping could integrate genotyping within this setting.

We examined samples from 98 naïve HIV-1 positive patients with the seroconversion period between 1984 and 1997, 64 of whom with a diagnosed primary infection. We observed a progressive increase in the percentage of patients harboring mutations associated with zidovudine resistance, starting from 8% during the period 1987-1994 to 20% and 36% in patients with HIV infection diagnosed during 1996 and 1997 respectively. The small number of patients analyzed in groups 3 and 4 is an important limitation to establish the real increase in the prevalence of mutations we observed during the past two years. However, it is important to underline the trend and, in our opinion, further studies to better define the relevance of such phenomenon in the clinical practice must be performed.

In spite of repeated exposures to HIV, some individuals remain seronegative and apparently uninfected. A variety of mechanisms potentially able to confer resistance to HIV infection, including cell-mediated and (unconventional) humoral immune responses, as well as mutations affecting receptors for virus entry have been considered and analysed. In this article, we want to discuss recent reports on specific immune responses and genetic factors potentially involved in mechanisms of protection, and to present some of our data relative to a cohort of people sexually exposed to HIV-1, but persistently seronegative. These EU (exposed uninfected) individuals can be distinguished from "normal" unexposed controls on the basis of significantly increased frequencies of a number of immunological parameters that might be considered "unconventional" correlates of HIV infection/protection. However, EU individuals are highly heterogeneous since the various unconventional immune responses considered can be present in all possible combinations. Aim of future research will be to ascertain the role of such immune responses in the maintenance of the protection state, or their secondary nature as signals of a particular kind of infection.

The location of HTLV-I (human T-cell leukemia virus type 1) pro viral sequences in the genome of infected human cells was explored by hybridization of a viral probe with compositional fractions of host-cell DNAs. In the twelve cases examined, HTLV-I sequences were absent from the GC-poorest 40% of the host genome (namely, from isochores that are below 39% GC). Transcriptionally inactive proviral sequences were localized in GC-poor isochores (comprised between 39% and 42–44% GC) of the human genome, which are characterized by a constant and low gene concentration. In contrast, transcriptionally active proviral sequences were found in the GC-rich and very GC-rich isochores, which are gene rich, transcriptionally and recombinationally active, and endowed with an open chromatin structure. Since GC-rich isochores are present in R'-bands and very GC-rich isochores form T-bands, these results also provide information on the location of HTLV-I proviral sequences in human chromosomes. The results obtained with HTLV-I are in agreement with the non-random, compartmentalized integration of animal retroviral sequences that had been previously observed in other viral-host systems. They provide, however, much more detailed information on the regional location of proviral sequences in the host genome and on the correlation between their transcription and their location.

It was recently demonstrated that vascular endothelium produces many substances which modulate the vascular tone by acting locally (endothelium derived relaxing factor, angiotensin II, endothelin, prostacyclin). The authors review the physiological regulatory role of these substances and their involvement in cardiovascular diseases. They also consider the interaction between the endothelium derived factors and some cardiovascular drugs (such as calcium antagonists and ACE-inhibitors) and also the mechanisms of the possible protective action of these drugs on the vascular wall.

Essential thrombocythemia (ET) is a chronic myeloproliferative disease, rarely observed in pediatric age, characterized by a persistently increased platelet count. Abnormalities of platelet function observed in ET patients may be, at least in part, responsible for the thrombohemorrhagic complications. The authors report about a pediatric patient affected by ET, showing an abnormal platelet response following stimulation by anti-platelet monoclonal antibody. Such finding may be attributable to a structural abnormality of the platelet fibrinogen receptor or to post-receptor alterations.

The oncoretrovirus HTLV-I is the etiological agent of adult T cell leukemia (ATL) and tropical spastic paraparesis/HLTV-I associated myelopathy (TSP/HAM). In contrast to the human lentiretroviruses, HIV-I and HIV-2, the causative agents of AIDS, HTLV-I is genetically very stable. We report here the molecular characterization of the envelope gene of an HTLV-I variant present in a TSP/HAM patient from Zaïre, raising the question of its relevance to disease or the ethnic and/or geographical origin of the patient.

It has been known since 1911 (Henze) that the blood of Phallusia mamillata Cuv. contains vanadium, which is found in special cells, called vanadocytes by Webb (1939). Webb estimated that the vanadocytes constitute about 60% of the blood cells and the blood cell volume amounts to between 1 and 2% of the total blood volume. It was found by Henze that the inner medium of the vanadocytes is very acid, due to free sulphuric acid which is present in a concentration of about 3%. According to Webb, the vanadium content of the animal amounts to about 0-15% of the dry weight of the body, and three-quarters of the total amount of vanadium is present in the blood, 15 % in the gut and associated viscera and 10% in the mantle and branchial sac.

The aim of this study is the behavior of Normotest (NT) values in newborns in the first 4 days of life. The study has been carried out between January, 1982, and December, 1984, at the Department of Child Health and Neonatal Medicine - School of Medicine - University of Genoa. The number of infants tested was 1320. 694 were males and 626 females, 529 preterm (G.A. less than 37 weeks) and 791 full term babies. Infants have been tested from one to five times in the first four days of life, with the first evaluation within 12 hours of life. 1215 newborns (92%) presented NT values greater than 20%, 105 babies (8%) had NT below 20% in at least one evaluation, and received Vitamin K1 (0.5 mg/kg i.m.) as prophylaxis, being thereafter excluded from this study. Among the neonate with NT greater than 20%, 426 babies have been considered, who had, at least, three evaluations in the first four days of life. 288 (68%) of the 426 newborns, had not important disease, while 138 (32%) were sick neonates; of these babies 88 (64%) had respiratory distress syndrome and 50 (36%) had an infectious condition. The mean of NT values of the 426 newborns decreased from the first (33.84%) to the 2nd day (32.72%), with a following increment in 3rd (35.29%) and 4th day of life (39.01%). Newborns with gestational age (G.A.) less than 34 weeks showed significantly lower values than newborns with G.A. between 34-37 weeks and those with G.A. greater than 37 weeks. No newborn with NT values greater than 20% either received vitamin K or showed symptoms of haemorrhagic disease in early or later neonatal period.

To investigate the effective usefulness of penicillin prophylaxis in splenectomized patients, we retrospectively focused on a group of sixty-two splenectomized patients affected by thalassemia major. Thirty-six out of 62 has been receiving monthly 1.200.000 Us. of benzathine-penicillin as prophylaxis. The remaining 26 did not receive prophylaxis, but was treated with antibacterial drugs as soon as symptoms of upper respiratory tract infection occurred. During a total period of eleven years of observation we did not observe any pneumococcal sepsis; the incidence of bacterial infections within the two groups is not different. We conclude for the uselessness of penicillin prophylaxis in splenectomized beta-thalassemic patients.

A new autosomally inherited dysfibrinogenaemia was recognized in 3 members of an Italian family. No bleeding tendency or thrombotic disease in any of the affected members were demonstrated. Coagulation tests revealed prolonged prothrombin, thrombin and Reptilase times. Plasma fibrinogen levels were normal with immunologic method and slightly reduced with chrono-metric assay: the other blood coagulation factors were normal. In addition, cross-immuno-electrophoresis performed on patients' plasma was indistinguishable from the normal. Dysfibrinogenaemia was confirmed by studying the purified fibrinogen. The fibrin polymerization curve, measured spectrophotometrically, showed a lower slope than the normal. A delay in fibrin monomer aggregation was revealed when compared to the normal at an equal concentration. The release of fibrinopeptides was normal. SDS polyacrylamide gel electrophoresis, isoelectric focusing and cross-immunoelectrophoresis of purified fibrinogen were not able to demonstrate any structural abnormality. The fibrinogen was named fibrinogen Genova.

The laboratory tests of 38 patients in pediatric age with Disseminated Intravascular Coagulation (DIC) were retrospectively evaluated. In all patients were performed PT, aPTT, platelets count, FDP dosage and biological assay of Fibrinogen. In most of them the activity of FII, FV, FVII, FX and FVIII was assaied. According to the diagnostic criteria of FSP greater than 8 micrograms/ml, Platelets less than 150 10(9)/1 and Fibrinogen less than 150 ml/dl, in 16 patients the diagnosis of DIC was possible since first examination, while in 9 patients it became possible within 2-4 days; in 13 patients we never could diagnose DIC, although it was reasonably present, since the criteria above mentioned were never simultaneously satisfied. Looking back in our experience, we confirm that the platelets count and the quantitation of plasmatic Fibrin Degradation Products (FDP) are the most useful tests for the diagnosis of full blown DIC, and that the biological assay of plasmatic fibrinogen helps to follow the disorder. A low level of FVIII:C seems to be a forecast of failure. None of the other test performed give any useful information for diagnosis when it is not possible with the above mentioned tests.

We describe 3 patients affected by Pearson's syndrome, presenting anemia, exocrine pancreas failure, and skeletal abnormalities; insulin-dependent diabetes mellitus arose in two cases during the course of the disease. Bone marrow dysplasia and exocrine pancreas failure are also reported in Shwachman's syndrome; the two forms differ in bone marrow morphology. The clinical pattern of Pearson's syndrome can be so polymorphic as to increase the difficulties of differential diagnosis with Shwachman's syndrome.

In this study, we used DNA polymorphisms for carrier detection and prenatal diagnosis of hemophilia A in a large group of Italian families. The restriction fragment length polymorphisms (RFLPs) investigated were the intragenic polymorphic Bc/I site within the factor VIII gene; the extragenic multiallelic Taq I system at the St14 locus; and the extragenic Bg/II site at the DX13 locus. The factor VIII probe was informative in 30%, St14 in 82%, and DX13 in 60% of obligate carriers. The combination of factor VIII-Bc/I and St14-Taq I showed that 91% of obligate carriers were heterozygotes for one or both; with all three probes, only 4% of obligate carriers were noninformative. In families clearly segregating for hemophilia A, RFLP analysis allowed us to define the carrier status for the hemophilia A gene in all 27 women tested. RFLP analysis allowed us to exclude the carrier status in 39 of 45 female relatives of sporadic patients. The combination of RFLP analysis and biological assay of factor VIII allowed us to identify a de novo mutation in the maternal grandfather in 7 of 12 of the families with sporadic cases, for which members of three generations were available for study. Nine of 10 couples requesting prenatal diagnosis provided informative RFLP DNA pattern. Carrier status was excluded in two women, two fetuses were shown to be female, and prenatal diagnosis was carried out in five pregnancies by DNA analysis. Prenatal testing was successful in three instances and failed in two because a sufficient amount of chorionic villous DNA was not obtained for the analysis.

An outbreak of malignant lymphoma has been observed in one of the baboon (Papio hamadryas) stocks of Sukhumi Primate Center. More than 300 cases in this "high-lymphoma stock" have been registered since 1967. Human T-cell lymphotropic virus type 1 (HTLV-1)-related virus was implicated as the etiologic agent of Sukhumi baboon lymphoma. The origin of this virus remained unclear. Two possibilities were originally considered: the origin could be baboon simian T-cell leukemia/lymphoma virus type 1 (STLV-1) or HTLV-1 (before the outbreak started, some Sukhumi baboons were inoculated with human leukemic material). The third possibility entered recently: interspecies transmission of rhesus macaque STLV-1 to baboons. It was prompted by the finding of very close similarity between STLV-1 991-1cc (the strain isolated from a non-Sukhumi baboon inoculated with material from a Sukhumi lymphomatous baboon) and rhesus STLV-1. To test this hypothesis, we investigated 37 Sukhumi STLV-1 isolates from baboons of high-lymphoma stock by PCR discriminating rhesus type and baboon type STLV-1 isolates. All of them were proved to be rhesus type STLV-1. In contrast, all six STLV-1 isolates from baboons belonging to other stocks or populations were of baboon type. The PCR results were fully confirmed by DNA sequence data. The partial env gene gene sequences of all four STLV-1 isolates from Sukhumi lymphomatous baboons were 97 to 100% similar to the sequence of known rhesus STLV-1 and only 85% homologous with the sequence of conventional baboon STLV-1. Thus, interspecies transmission of STLV-1 from rhesus macaques (or closely related species) to baboons occurred at Sukhumi Primate Center. Most probably this event initiated the outbreak of lymphoma in Sukhumi baboons.

The principal neutralizing epitope of the human immunodeficiency virus type 1 (HIV-1) lies between two invariant cysteines in the third variable region (V3) of the viral envelope (gp120), and its amino acid sequence varies among different HIV-1 isolates. HIV-2 carries an analogous amino acid sequence between two cysteines of the V3 regions, but its functional similarity with the HIV-1 principal neutralizing epitope is uncertain. We studied the degree of genetic variation of the HIV-2 V3 region in fresh blood samples from 12 HIV-2-seropositive individuals from Guinea-Bissau. Polymerase chain reaction was used to amplify viral fragments of 465 bp containing the V3 region from cellular DNA. Nucleotide sequence analysis of the entire envelope fragment from each patient revealed that the degree of variation among field isolates of HIV-2 is comparable to that observed in the analogous region of HIV-1. Most of the HIV-2 isolates studied were highly related, suggesting the existence of a limited number of different viral strains in the cohort studied. Thus, the HIV-2 and HIV-1 V3 regions vary to a similar degree and may also have analogous functions.