Infective endocarditis in patients with hepatic diseases.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD- patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD- patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD- and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

Tubercular liver abscess: an uncommon presentation of disseminated tuberculosis.

We present a case of tubercular liver abscess with disseminated tuberculosis, associated with underlying HIV infection. The patient responded well to percutaneous drainage of the abscess and first-line quadruple antitubercular therapy. We report this case to highlight a rare manifestation of a common disease and to create greater awareness which may ensure timely diagnosis and avoid unnecessary surgical intervention.

Acute transient inflammatory leukoencephalopathy in HIV.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) is characterized by abrupt onset of symptoms generally associated with focal brain lesions and inflammatory CSF findings. A previously asymptomatic 31-year-old HIV+ woman presented with acute cognitive difficulties, right hemiparesis and dysphasia. Brain MRI showed a large contrast-enhancing lesion in the left frontal lobe; brain biopsy revealed an inflammatory process. No etiological agent was found in blood, CSF or brain tissue. The patient was given systemic steroids and gammaglobulins and put on HAART. Clinical conditions progressively and completely recovered. Further brain MRI showed the shrinkage of the lesion with no contrast enhancement. Our case could be classified as AIL in HIV resembling ADEM pattern and highlights the importance of taking into consideration. ADEM in the diagnostic process of HIV-related leukoencephalopathy even if the typical features are lacking, as immunodeficiency could modify both presentation and disease course.

Neuropsychological evaluation and follow up in jcv- and non-jcv-related leukoencephalopathies in HIV infection.

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis.

A Novel In Silico Benchmarked Pipeline Capable of Complete Protein Analysis: A Possible Tool for Potential Drug Discovery.

Current in silico proteomics require the trifecta analysis, namely, prediction, validation, and functional assessment of a modeled protein. The main drawback of this endeavor is the lack of a single protocol that utilizes a proper set of benchmarked open-source tools to predict a protein's structure and function accurately. The present study rectifies this drawback through the design and development of such a protocol. The protocol begins with the characterization of a novel coding sequence to identify the expressed protein. It then recognizes and isolates evolutionarily conserved sequence motifs through phylogenetics. The next step is to predict the protein's secondary structure, followed by the prediction, refinement, and validation of its three-dimensional tertiary structure. These steps enable the functional analysis of the macromolecule through protein docking, which facilitates the identification of the protein's active site. Each of these steps is crucial for the complete characterization of the protein under study. We have dubbed this process the trifecta analysis. In this study, we have proven the effectiveness of our protocol using the cystatin C and AChE proteins. Beginning with just their sequences, we have characterized both proteins' structures and functions, including identifying the cystatin C protein's seven-residue active site and the AChE protein's active-site gorge via protein-protein and protein-ligand docking, respectively. This process will greatly benefit new and experienced scientists alike in obtaining a strong understanding of the trifecta analysis, resulting in a domino effect that could expand drug development.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin: review of the literature.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) has been anecdotally described in literature as being responsible for cognitive and motor deficits. We carried out a review of all the cases of AIL published in literature. Articles were selected according to 2 criteria: acute onset of symptoms; undetermined aetiology and non-fulfilment of multiple sclerosis diagnostic criteria. They were then analyzed in terms of clinical, biological and instrumental features, therapy, diagnostic classification and prognosis. Although rare (21 patients out of about 4,000 publications), AIL is of particular interest, as the comprehension of its mechanisms could give some insight into the direct and immune-mediated actions of HIV within the brain. All the reported patients share several clinical, histopathological, radiological and CSF features, leading to hypothesize a similar aetiopathogenetic mechanism. Conversely, we observed a high heterogeneity of treatment and diagnostic classification, which could have conditioned the broad prognostic variability. The absence of a defined aetiology leads to consider these forms as a particular subgroup of not determined leucoencephalopathies (NDLE), with both MRI and histological pattern dominated by inflammation as distinctive feature.

Cognitive abnormalities and disease progression in a selected population of asymptomatic HIV-positive subjects.

A selected population of 41 homosexual/bisexual asymptomatic HIV-positive subjects were administered neurophysiological tests to assess language, memory, attention, logic faculties and visuo-motor functions. HIV-positive subjects differed from individually matched control subjects only in certain measures of verbal memory. Longitudinal evaluation performed after 1.5 years, however, did not indicate any further development of this mild amnesic deficit. Despite the small number studied in our sample, there seems to be a trend for older subjects to be at greater risk of developing AIDS and cognitive abnormalities than younger subjects, while differences in immunological status play a significant role in disease progression.

Usefulness of computerized electroencephalography in diagnosing, staging and monitoring AIDS-dementia complex.

One hundred and one subjects, with various degrees of HIV infection, were enrolled in a longitudinal study aimed at evaluating the correlation between clinical and instrumental findings in the development of HIV-related subacute encephalitis. The method used was electroencephalography coupled with computerized spectral analysis (EEG-CSA) and mapping. The findings recorded by this method were compared with those obtained by computed tomography (CT) scan and neurological examination. The EEG-CSA findings were divided into four categories according to their severity. EEG-CSA was shown to be very sensitive in detecting the first signs of a forthcoming neurological disease. Following 11 months of observation, 22 out of 40 (55%) neurologically asymptomatic individuals who, at the beginning of the study showed some EEG-CSA abnormalities, had clinical evidence of a subacute encephalitis whereas only two out of 37 (5.4%) subjects who were previously free of EEG-CSA abnormalities had some signs of neurological disease (P less than 0.001) after the same period. Of those remaining who were already symptomatic when the study started, the neurological progression of HIV infection was also monitored by EEG-CSA.

Involvement of hormonal circadian secretion in the growth of HIV-infected children.

OBJECTIVE: To evaluate the circadian secretion of hormones involved in the regulation of growth in childhood, namely growth hormone, insulin-like growth factor (IGF)-I, cortisol, adrenocorticotropin hormone (ACTH), and thyroid-stimulating hormone (TSH) in HIV-infected children. DESIGN: The circadian secretory pattern of growth hormone, IGF-I, cortisol, ACTH and TSH was evaluated in 14 HIV-infected children; 13 healthy age- and sex-matched children were chosen as controls. METHODS: Sampling was performed every 4 h from 0400 h to 2000 h and every 2 h from 2000 h to 0400 h. Rhythmometric data were analysed by single and population mean cosinor methods and by analysis of variance. RESULTS: A statistically significant circadian rhythm for growth hormone, IGF-I and cortisol was detectable in HIV-seropositive children, but the mean basal IGF-I levels were below the normal range for age in 12 patients. A statistically significant circadian rhythm was not detectable for ACTH or TSH. CONCLUSION: These results show that there is a loss of the physiological regulation of growth hormone-IGF-I axis and a modification of 24 h TSH profile in our HIV-infected children. These abnormalities might be involved in the altered growth mechanism leading to the failure to thrive that is a peculiar feature of HIV-infected children.

Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine.

The in vitro and in vivo antiviral activity of hydroxyurea in combination with either zidovudine or didanosine was evaluated in primary human peripheral mononuclear cells and in a cohort of 29 asymptomatic patients infected with HIV. In vitro, hydroxyurea alone did not significantly affect HIV replication, whereas the combination of hydroxyurea with didanosine was more effective than the combination of hydroxyurea with zidovudine. Our clinical results confirmed these studies. Patients were randomly assigned to five arms (zidovudine, hydroxyurea or didanosine monotherapy, or hydroxyurea in combination with either zidovudine or didanosine) to evaluate preliminary safety and efficacy. Bone-marrow toxicity occurred in two patients treated with zidovudine plus hydroxyurea, alopecia was reported in one patient treated with hydroxyurea monotherapy, and there were no toxic effects recorded in the remaining three groups. Plasma viraemia was not influenced by hydroxyurea monotherapy, and the hydroxyurea-zidovudine combination did not give any advantage over either zidovudine or didanosine monotherapy (0.3-0.5 log decrease in plasma viraemia). In contrast, a 1.1 log drop in plasma viraemia was observed in patients treated with hydroxyurea plus didanosine, this reduction was sustained throughout the 24-week course of the treatment. Combination therapy with hydroxyurea and didanosine exhibited statistically significant improvements compared with the other therapeutic approaches. Although further clinical trials are required, these results suggest that hydroxyurea in combination with didanosine might be an effective and well-tolerated, simple and affordable, treatment for HIV infection.

Detection of HTLV-III-specific IgG bands in the CSF from a patient with AIDS and encephalitis.

Recent evidence would suggest that HTLV-III may be neurotropic. We have found oligoclonal IgG bands by isoelectric focusing in the CSF of a homosexual man with AIDS and encephalitis. Subsequent analysis revealed that such bands contained anti-HTLV-III activity, suggesting that neurologic symptoms in AIDS patients may be caused by replication of HTLV-III inside the CNS.

Assessment of atherosclerosis using carotid ultrasonography in a cohort of HIV-positive patients treated with protease inhibitors.

OBJECTIVE: Lipid disorders associated with the use of protease inhibitors (PI) may be a risk factor for premature atherosclerosis development. The aim of this study is to evaluate the extent of carotid intima media thickness (IMT) among HIV-positive patients treated with PI containing regimens compared to PI-naïve and HIV-negative subjects. METHODS: We analysed plasma lipid levels and carotid IMT in 28 HIV-positive patients treated with protease inhibitors (PIs) for a mean of 28.7 months (range 18-43) and in two control groups constituted, respectively, by 15 HIV-positive naïve patients and 16 HIV-negative subjects, that were matched for age, risk factors for HIV infection, cigarette smoke use and CD4+ cell count. RESULTS: PI-treated patients had higher triglyceride, HDL and apo B levels than controls. Carotid IMT was significantly increased in PI-treated patients compared to naïve or HIV-negative subjects. A correlation between cholesterol HDL, triglyceride and ApoB levels and IMT was observed among the entire cohort. CONCLUSIONS: Plasma lipid alterations were associated with an increased IMT and intima media thickening was more pronounced in PI-treated patients than in the two control groups. Periodical evaluation of blood lipid profile and, if required, the use of lipid-lowering agents is advisable. Moreover, physicians should address concurrent risk factor for atherosclerosis that can be modified, including smoking, hypertension, obesity and sedentary life-style.

Clinical and virological monitoring of human cytomegalovirus infection in 294 heart transplant recipients.

Two hundred and ninety-four heart transplant recipients (HTR) were followed prospectively for a mean of 44.9 +/- 28.4 (range 1.0-100.8 months) after transplantation (tx). Immunosuppression was based on cyclosporine, azathioprine, and steroids, supplemented by a 7-day course of antithymocyte globulins. All patients were virologically monitored by inoculating aliquots of 2 x 10(5) peripheral blood polymorphonuclear leukocytes (PMNs) onto human embryonic lung fibroblasts monolayers grown in shell vials for early cytomegalovirus (CMV) identification and quantification (viremia). The same number of PMNs was cytocentrifuged onto glass slides for direct CMV pp65 antigen detection and quantification (antigenemia). Heparinized blood samples were collected weekly during the first 3 months following tx and at least twice a week if antigenemia and viremia levels were increasing. After 3 months, samples were collected if antigenemia and viremia persisted or when clinically indicated. The overall incidence of CMV infection was 53.4% (157/294). Only 32.4% (51/157) of the viremic patients required antiviral treatment because of symptomatic infection. Of the remaining 106 untreated CMV viremic HTR, 104 were asymptomatic while 2 had only mild clinical symptoms. The overall incidence of CMV infection in pre-tx CMV seropositive (CMV+) HTR was 50.9% (136/267); 75.7% (103/136) were asymptomatic and 24.3% (33/267); 75.7% (103/136) were asymptomatic and 24.3% (33/136) were symptomatic. The overall incidence of CMV infection in pre-tx CMV-seronegative (CMV-) HTR was 77.8% (21/27; P = 0.007 vs. seropositive HTR). Among 22 CMV- HTR with CMV+ donor, 20 (90.9%) had a CMV infection and all of them were symptomatic (versus 1 of 5 (20%) CMV- HTR with CMV- donor; P = 0.002, Fisher's exact test). The median numbers of circulating CMV-infected PMNs detected at the onset of clinical symptoms by the antigenemia and viremia assays were 385/2 x 10(5) and 100/2 x 10(5), respectively.

Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection.

The circadian rhythms of plasma growth hormone (GH), insulin-like growth factor type I (IGF-I), cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin (PRL) were evaluated in 13 HIV-seropositive patients (8 males and 5 females; mean age [+/-SD], 30 +/- 5 years), classified as CDC C2. Sixteen clinically healthy subjects (9 males and 7 females; mean age [+/-SD], 32 +/- 8 years) were chosen as control group. Samples were taken every 4 hr from 04:00 to 20:00 and every 2 hr from 20:00 to 04:00. Plasma GH was evaluated by IRMA procedure, plasma IGF-I by RIA (after separation of soluble IGF-I from IGF-I-binding proteins, using acid-ethanol extraction), plasma cortisol by a solid-phase RIA, plasma ACTH by double-antibody RIA, and serum TSH and serum PRL by a solid-phase two-site fluoroimmunometric assay. Rhythmometric data were analyzed by single and population mean cosinor analysis; the comparison of the parameters of the rhythm between patients and controls was carried out by the mesor test and the amplitude-acrophase Hotelling test. Alterations of the circadian pattern of GH, IGF-I, cortisol, ACTH, TSH, and PRL were demonstrated in HIV-seropositive patients. In fact, the circadian profiles of these hormones were clearly flattened and no statistically significant 24-hr rhythm was detectable (with the exception of cortisol). These results are consistent with the hypothesis that alterations of the circadian temporal structure may already be present in HIV-seropositive patients without wasting and infectious complications.

Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency virus type 1 resistance.

Combinations of drugs targeting viral proteins have been used to limit or control drug resistance, which is the most important cause of treatment failure in HIV-1-infected individuals. We suggest an alternative approach, namely to target cellular proteins, which are less prone to mutations than viral proteins. Here we show that simultaneous inhibition of a cellular protein (by hydroxyurea) and a viral protein (by ddI) produces a consistent and sustained suppression of HIV-1 for as long as 40 weeks in the absence of virus rebound. We identified the mechanism to explain this lack of rebound: although the combination of the two drugs did not prevent the emergence of mutant viral strains resistant to didanosine (ddI) in these patients, the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. These in vivo results were consistent with our in vitro observations: HIV-1 molecular clones resistant to ddI were rendered sensitive to this drug (at concentrations routinely achievable in vivo) after addition of hydroxyurea. This phenomenon can be explained by the observation that hydroxyurea decreases the level of dATP, the cellular competitor of ddI. A low level of dATP favors the incorporation of ddI, even if the viral reverse transcriptase is resistant to this nucleoside analog. This is a novel mechanism of control of resistance and it explains the efficacy of a treatment that is well tolerated, simple, and inexpensive.

Sternal osteomyelitis due to Aspergillus fumigatus after cardiac surgery.

Sternal osteomyelitis due to Aspergillus fumigatus after cardiac surgery occurred in two nonimmunosuppressed patients. The clinical features of the infection were markedly different in the two cases. In the first patient, sepsis showed a late and insidious onset followed by slow progression. In the second case, fungi were isolated from wound swabs within a few days of surgery and the clinical picture showed acute onset and rapid progression. Only a few cases of sternal osteomyelitis due to Aspergillus have been described previously after cardiac surgery. Aspergillus infection should be considered in the differential diagnosis of mediastinitis after cardiac surgery, especially in a clinical setting of otherwise unexplained sepsis or nonhealing wound despite apparently adequate treatment.

Infections in heart transplant recipients: the experience of the Italian heart transplantation program. Italian Study Group on Infections in Heart Transplantation.

Infectious complications are an important cause of morbidity and mortality in heart transplantation. In this report we describe their incidence in the Italian Heart Transplantation Program and their relationship to induction immunosuppressive protocols used. A total of 662 heart transplantations in 651 patients had been performed by March 1, 1990, in 10 Italian centers, with a follow-up of 12,022 patient-months. Actuarial survival at 54 months was 80%. There were 115 deaths, 28 as a result of infection (24%); 30 were perioperative. Mortality from infection was 15% in the first 30 postoperative days and 35% thereafter. During follow-up, 256 life-threatening infectious episodes occurred in 180 patients, for a mean of 1.42 infections/patient. Of these episodes, 28 (10.9%) were lethal. The rate at 54 months, excluding perioperative deaths, was 0.021 episodes/patient-month, with a mean of 0.39 infections/patient in the 651-patient series. At 6 months, 72% of patients were free from infection. This value did not change significantly during subsequent follow-up. Bacterial infections were most frequent (49.2%); fungal (10.5%) and protozoan (5.9%) infections had the worst outcome (lethality 26% and 20%, respectively). A primary cytomegalovirus infection was observed in 23 cases (12 mismatches). Lung involvement (99 episodes) and bacterial sepsis (47 episodes) were most common. Eighty episodes of infection (31.2%) were preceded by a supplementary treatment for rejection with steroid pulses (69%), prednisone boost (20%), or cytolytic therapy (11%). Treatment had preceded the infection by less than 15 days in 55% of cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic determinants of six-month morbidity and mortality in heart transplant recipients. The Italian Study Group on Infection in Heart Transplantation.

BACKGROUND: Knowledge of time course and risk factors for morbidity and mortality may allow better cardiac graft allocation, surveillance timing, and planning of immunosuppressive strategies. METHODS: Six-month morbidity and mortality were retrospectively analyzed in a multiinstitutional series of 645 heart transplant recipients. RESULTS: During a 3432 patient-months follow-up, 87 patients died of infection (n = 11), rejection (n = 11), multiorgan failure (n = 9) and other transplant-related causes (n = 56); six-month survival rate was 86%. Three hundred thirty-seven recipients had 967 treated rejection episodes (2.87 episodes/patient with rejection, lethality 3.2%); 223 major infectious episodes occurred in 162 patients (1.38 episodes/infected patient, lethality 7%). Six-month rejection and infection-free survival rates were 44% and 73%. Total mortality and cause-specific morbidity sharply declined after the first month; 160 patients (25%) had no events during follow-up. At multivariable analysis, significant risk factors for mortality were postoperative acute kidney failure, prolonged cardiopulmonary bypass time, and previous cardiac surgery. Rejection was associated with steroid-free and globulin-free immunosuppression and infection was associated with steroid immunosuppression, cytolytic treatment, venous lines placement greater than 7 days, and mechanical ventilation time. No single or combination of variables was able to discriminate patients with an event-free course. CONCLUSIONS: Morbidity and mortality have the highest incidence during the early posttransplantation phase. Preoperative variables are of limited value with respect to immunosuppressive treatment in predicting outcome. Infection is far less frequent than rejection but, in view of the higher lethality rate, deserves a vigorous effort for prevention, which is best addressed by appropriate modulation of immunosuppressive strategies.

Longitudinal neuropsychological evaluation of HIV-infected intravenous drug users.

The present study aimed to describe the cognitive status of a group of HIV-positive asymptomatic intravenous drug users (IVDU) and changes which occurred over a 12-month follow-up period. Forty-two HIV positive IVDU were selected and matched for age, sex, educational level and pattern of drug abuse with 39 seronegative IVDU controls. Baseline and follow-up evaluation included neuropsychological tests exploring attention, language, memory, logic and visuomotor abilities, biological markers and clinical parameters. About one-third of both seropositive and seronegative subjects showed at baseline slight cognitive deficits, which did not change during the follow-up period.

[Clinical aspects of immunoneuroendocrine alterations in HIV infection]. / Aspetti clinici delle alterazioni immunoneuroendocrinologiche nell'infezione da HIV.

A number of studies confirm that any human tissue can be targeted by HIV, and also the endocrine system is involved during HIV infection. No endocrine adenus is saved by the assault of the opportunistic pathogens that overrun the organism unprotected due to the severe and progressive immune deficits induced by the HIV. As a consequence clinical, but often subclinical alterations can be detected that underline the close relationship among the systems of body adaptation to the environment (immune, endocrine, and nervous). Indeed these alterations can be viewed as an immunoneuroendocrine pathology. AIDS is a paradigmatic syndrome for the variety of immune dysfunctions, and also presents endocrine and neurological dysfunctions, which allow to better understand the connections among these systems, and the interactions of HIV with the immunoneuroendocrine dynamics.